Title of Invention	COMPOUNDS FOR THE TREATMENT OF MULTI-DRUG RESISTANT BACTERIAL INFECTIONS
Abstract	The present invention relates to compounds that demonstrate antibacterial activity, processes for their preparation, pharmaceutical compositions containing them as the active ingredient, to their use as medicaments and to their use in the manufacture of medicaments for use in the treatment of bacterial infections in warm-blooded animals such as humans. In particular this invention relates to compounds useful for the treatment of bacterial infections in warmblooded animal such as humans, more particularly to the use of these compounds in the manufacture of medicaments for use in the treatment of bacterial infections in warm-blooded animals such as humans.

Title of Invention

COMPOUNDS FOR THE TREATMENT OF MULTI-DRUG RESISTANT BACTERIAL INFECTIONS

Abstract

The present invention relates to compounds that demonstrate antibacterial activity, processes for their preparation, pharmaceutical compositions containing them as the active ingredient, to their use as medicaments and to their use in the manufacture of medicaments for use in the treatment of bacterial infections in warm-blooded animals such as humans. In particular this invention relates to compounds useful for the treatment of bacterial infections in warmblooded animal such as humans, more particularly to the use of these compounds in the manufacture of medicaments for use in the treatment of bacterial infections in warm-blooded animals such as humans.

Full Text	COMPOUNDS FOR THE TREATMENT OF MULTI-DRUG RESISTANT BACTERIAL INFECTIONS BACKGROUND OF THE INVENTION The international health community continues to express serious concern that the evolution of antibacterial resistance will result in strains against which currently available antibacterial agents will be ineffective. For example, resistant strains of Gram-positive pathogens such as methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant coagulase-negative staphylococci (MRCNS), penicillin-resistant Streptococcus pneumoniae and multiple resistant Enterococcus faecium are both difficult to treat and difficult to eradicate. Consequently, in order to overcome the threat of widespread multi-drug resistant organisms, there is an on-going need to develop new antibiotics, particularly those with either a novel mechanism of action and/or containing new pharmacophoric groups, SUMMARY OF THE INVENTION These and other needs are met by the invention disclosed herein which is directed to a compound of formula I: L— Uj— M— U2— R I or a pharmaceuticaUy acceptable salt thereof, or N-oxides thereof, wherein: L is a group of formula LI -LI 5: R2a f R2a R2a f R r^ 6'7 >T R 6 R r> 6'7^ W R P R ,1 r\2 ^ Ii 2 "^2 I 2 2r '^'T97' R2d R2e R2d 0 R2d R.,d R2e ) J t LI L2 L3 L4 R2a j» R2a f R2a ^ R2a f IN ,2 Rr\ 2Cc - 6^' Z NIN' Rn 2cc^ R2d j9 R2d R2gR29 R2d R2d » > J L5 L6 L7 L8 R2a f R2a { R2a f R2a f R cxZ6'Z;YN>R g R c^'ZfNC.0 R c^'Z^^\ ^ R-jc'^'Z^^A^ ' R2d O R2d R2g z9 R2d Rse R2d R2e J ) ) 3 L9 L10 Lll L12 R2a * R2a > R2a , •7 ^L x/ -7 ^L /=: R2C^6'ZPN R2c"Z6'zf^N R,d R2B R,d R,d 22 ,or Rz9 L13 L14 L15 wherein " "* " indicates the point of attachment; Zs, Zfi, and Z? are C or N provided that when Zs, Ze, or Z? is N, then R2a, R2C, or are absent; Rza, Rab, R2C, R2d, R2e, and R2f, are each independently H, halo, cyano, carboxy, nitro, carbamoyl, -CO-(Ci-C6)alkyl, CO2-(CrC6)alkyl, (CrC6)alkyI, hydroxy, halo(Ci-C6)alkyl, halo(Ci-C6)alkoxy, (d-C6)alkoxy, NHCO-(Ci-C6)alkyl, SO2(C\|-C6)a1kyl, S02NH(Ci-C6)alkyl, or S02N((Ci-C6)alkyl)2; Rag) Rag', and R2g" are each independently II, (Ci-C6)alkyl, or halo(Ci-C6)allcyl; Ui is CRaRb— CRcRd or CRaRb— CRcRd— CReRf, wherein Ra, Rb, Re, Rd, Re, and Rf are each independently hydrogen or (Ci-Cfi)alkyl; M is a group of formula M1-M5: M3 1 ,and M4 M5 wherein R2 is H or carboxy, and wherein " "** " indicate points of attachment; Ry and Ry1 are each independently H, halo, hydroxy, (Ci-C6)alkyl, (Ci-C6)alkoxy, CO2R", wherein R" is H, (Ci-C6)alkyl, or halo(C]-C6)alkyl, or Ry and Ry1 together with the carbon to which they are attached form C=0; or Ry and Ry' together form a bridge; X and Y are each independently CH2, O, or NR'; " — " is a bond or is absent; nis 1, or 2, or 3; when M is a group of fonnula Ml or M4, U2 is NR'—W, wherein W is CH2, CO, SO2, A /-ITT TIT-' OTJ 2 , CH2CH2, CH2CH=CH, or CttiCsC, wherein each hydrogen may be optionally replaced by halo or (Ci-C6)alkyl; when M is a group of formula M2, M3, or M5, U2 is W wherein W is as defined herein above; R1 at each occurrence is independently H, (Ci-C6)alkyl, -(Cj-C^alkylcarboxy, -CO-(Ci-C6)alkyl, -C02(C,-C6)alkyl, -CO-NH(Ci-C6)alkyl, -CO-N((Ci-C6)alkyl)2, or SO2(Ci-C6)alkyl, any of which may be optionally substituted on carbon with halo, hydroxy, (Ci-C6)alkyl, (CrC6)alkoxy, SO2(Ci-C6)alkyl, NH2, NH(Ci-Q)alkyl, or N((CrC6)alkyl)2; when W is CH2, CO or SOi, R is aryl, heteroaryl, hetcrocyclyl or ortho-iused bicyclic A heteroaryl, or when W is CH2HC-CH t CH2CH2j CH2CH=CH, or CH2CsC, R is aryl, heteroaryl, heteroaryloxy, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylamino; wherein any R may be optionally substituted on carbon; and wherein any ring nitrogen in R may be optionally substituted by (Ci-C6)alkyl; and any of L, Ui, M, U2, or R may be optionally substituted on carbon by one, two or three substituents selected from halo, nitro, cyano, hydroxy, oxo, trifluoromethoxy, trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulphamoyl, methyl, ethyl, ethenyl, ethynyl, methoxy, ethoxy, methoxycarbonyl, ethoxycarbonyl, heteroaryl, heterocyclyl, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, //-methyl-jV-ethylamino, or acetylamino; with the proviso that when L is a group of formula L8 or L15, W is not CO. What is also provided is a compound of formula I which is a compound of formula II: R0a U—M-U-R R2b> II or a pharmaceutically acceptable salt thereof, wherein R23, R2b, Rac, and Rjd are each independently H, fluoro, chloro, cyano, (Cihalo( Ci-C6)alkyl, halo(CrC6)alkoxy, (Ci-C6)alkoxy; " " is a bond or is absent; Z is CH or N when "— " is a bond, or Z is 0 or NH when "— "isabsent; Ui is CRaRb—CRcRd or CRaRb—CRcRd—CReRf, wherein Ra, Rb, Re, Rd, Re and Rf are each independently hydrogen or (Ci-C M is a group of formula Mia or M2-M5: M3 M4 Ryx /Ry' ~.hRv' [UJ^N , or Mia M5 in the trans configuration relative to "", wherein R2 is H or carboxy; Ry and Ry1 are each independently H, hydroxy, fluoro, chloro, methoxy, carboxy, CO2(Ci-Q)alkyl, or (Ci-C6)alkyl, or together with the carbon to which they are attached form C^O; or Ry and Ry' together form a bridge; X is CH2, NH, N[CO-(Ci-C6)alkyl], N[SO2(C1-C6)alkyl], N(C,-C6)alkyl, or O; Y is CH2, NH, N[CO-(Ci-G0alkyl], N[SO2(C1-C(i)alkyl], N(CrC6)alkyl, or 0; " " is a bond or is absent; nis 1, 2, or 3; when M is a group of formula Mia or M4, U2 is NR'-W, wherein R' is H, (C]-C6)aIkyl, -(Ci-C6)alkylcarboxy, -CO-(Ci-C6)alkyl, -C02(Ci-Cfi)alkyl, -CO-NH(Ci-C6)alkyl, -CO-N((Ci-C6)alkyl)2) any of which may be optionally substituted on carbon with halo, hydroxy, (Ci-C6)alkyl, (C]-C6)alkoxy, SO2(Ci-C6)alkyl, NH2, NH(C,-C6)alkyl, orN((C,-C6)alkyl)2; W is CH2, CO, SO2) CH2CH2, CHaCH^CH, or CH2CsC, wherein each hydrogen may be optionally replaced by halo or (Ci-Cs)alkyl; when M is a group of formula M2, M3, or M5, U2 is W; and when W is CH2, CO or SO2, R is aryl, heteroaryl, heterocyclyl or ortho-fused bicyclic heteroaryl, or when W is CH2CH2) CH2CH=CH, or CH2CsC, R is aryl, heteroaryl, heteroaryl(Ci -C6)alkyloxy, heteroaryl(Ci -C6)alkylthio, heteroaryl(C i -C^alkylsulfiny 1, heteroaryl(Ci-C6)alkylsulfonyl, heteroaryl(Ci-C6)alkylamino; wherein any R may be optionally substituted on carbon; and wherein any ring nitrogen in R may be optionally substituted by (Ci-C6)alkyl. What is also provided is a compound of formula I which is a compound of formula III: Ry, III or a pharmaceutically acceptable salt thereof, wherein R2a, R2b, R2c, and R2d are each independently H, fluoro, chloro, cyano, (C]-C6)alkyl, halo(C]-C6)alkyl, halo(Ci-C6)alkoxy, (C,-C6)alkoxy; Z is CH or N when " — - " is a bond, or, when " " " "is absent, Z is O or NH; V is N or CR2, wherein R2 is H, hydroxy, or carboxy; U2 is NR'-W, wherein W is CH2, CO, SO2, CII2CH2, CH2CH=CH, or CH2CsC, wherein each hydrogen may be optionally replaced by halo or (Ci-Cfi)alkyl; and H .0 H .0 0 Ris ,or What is also provided is a compound of formula I which is a compound of formula IV: RV \ ,R N-W IV or a pharmaceutically acceptable salt thereof, wherein Rja, Rjb, R2c, and R2d are each independently H, fluoro, chloro, cyano, nitro, (Ci-Qj)alkanoyl, (Ci-Cfi)alkoxycarbonyl, (C,-C6)alkyl, halo(Ci-C6)alkyl, halo(Ci-C6)alkoxy, (Ci-C6)alkoxy,NHCO-(Ci-C6)alkyl, S02(C,-C6)alkyl, S02NH(C,-C6)a]kyl, or S02N((C1-C6)alkyl)2; Z is CH orN when " "" " is a bond, or, when " --" " is absent, Z is O or NH; R'isHor(C,-C6)alkyl; W is CO, SO2, or CH2, wherein each hydrogen may be optionally replaced by halo or (CVC6)alkyl; and H .0 H .0 N- \\ /-o Ris N , — ,or What is also provided is a compound of formula I which is a compound of formula V: R'R2b V or a pharmaceutically acceptable salt thereof, wherein Rja, Rab, Rac, and R2d are each independently H, fluoro, chloro, cyano, nitro, (Ci-Cfi)alkanoyl, (Ci-C6)alkoxycarbonyl, (Ci-C6)alkyl, halo(Ci-C6)alkyl, halo(C,-C6)alkoxy, (Ci-C6)alkoxy,NHCO-(Ci-C6)alkyl, S02(C]-C6)alkyl, S02NH(Ci~C6)alkyl, or S02N((C,-C6)alkyl)2; Z is CH or N when " ' ' " " is a bond, or, when " • " " "is absent, Z is 0 or NH; and H O H 0 M N= _ Ris N , — , or What is also provided by the invention is a compound which is: 1 -(2- {4-[(2,3-Dihydro[ 1 ,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin- 1 - yl}ethyl)-7-methoxyquinolin-2(l/f)-one; l-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-lyl} ethyl)-7-methoxyquinolin-4(l//)-one; Methyl l-(2-{4-[(2,3-dthydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin- 1 -yl} etbyl)-6-methoxy- l//-indole-2-carboxylate; 6-[({l-[2-(7-Methoxy-2-oxoquinolin-l(2//)-yl)ethyl]piperidin-4-yl}amino)methyl]- 2/f-pyrido[3,2-6][l,4]oxazin-3(4/:0-one; l-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-lyl} ethyl)-2-oxo-l,2-dihydroquinoline-7-carbonitrile; 2-Oxo-l-[2-(4-{[(3-oxo-3,4-dihydro-2//-pyrido[3)2-6][l,4]oxazin-6- yl)methyl]amino}piperidin-l-yl)ethyl]-l,2-dihydroquinoline-7-carbonitrile; 6-[({ 1 -[2-(7,8-Difluoro-2-oxoquinolin- 1 (2#)-yl)ethyl]piperidin-4-yl} amino)methyl] - 2//-pyrido[3,2-6][l,4]oxazin-3(4^-one; 6-[({l-[2-(5,7-Difluoro-2-oxoquinolin-l(2//)-yl)ethyl]piperidin-4-yl}amino)rnethyl]- 2#-pyrido[3,2-&][l,4]oxazin-3(4#)-one; 6-[( { 1 -[2-(7-Fluoro-2-oxoquinolin- 1 (2#)-yl)ethyl]piperidin-4-yl } amino)methyl]-2//- pyrido[3,2-6][l,4]oxazin-3(4//)-one; l-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)arnino]piperidin-lyl} ethyl)-7-fluoroquinolin-2(!Ar)-one; 6-[({ l-[2-(7-Methoxy-2-oxo-3,4-dihydroquinolin- 1 (2//)-yl)ethyl]piperidin-4- yl}amino)methyl]-2//-pyrido[3,2-6][l,4]oxazin-3(4//)-one; (36',4^)-l-[2-(5)7-Difluoro-2-oxoquinoUn-l(2JW)-yl)ethyl]-4-[(2,3- dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidine-3-carboxylic acid; (3.S',4^)-l-[2-(5,7-Difluoro-2-oxoquinolin-l(2W)-yl)etbyl]-4-{[(2J?)-3-(2,5- difluorophenyl)prop-2-en- 1 -yl]amino}piperidine-3-carboxylic acid; Methyl (35r,4^)-l-[2-(5)7-difluoro-2-oxoquinolin-l(2H)-yl)ethyl]-4-[(2)3- dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidine-3-carboxylate; Methyl (3S,4R)-1 -[2-(5,7-difluoro-2-oxoquinolin-l (2J¥)-yl)ethyl]-4- {[(2£)-3-(2,5- difluorophenyl)prop-2-en-l-yl]amino}piperidine-3-carboxylate; (3^,4^)-l-[2-(5,7-Difluoro-2-oxoquinolin-l(2//)-yl)ethyl]-4-[(2s3- dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)ainino]piperidine-3-carboxylicacid; (3/?)4^)-l-[2-(5,7-Difluoro-2-oxoquinolin-l(2W)-yl)ethyl]-4-{[(2E)-3-(2J5- difluorophenyl)prop-2-en-l-yl]amino}piperidine-3-carboxylic acid; Methyl (3/?,4^)-l-[2-(5,7-difluoro-2-oxoquinolin-l(2^)-yl)ethyl]-4-[(2,3- dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidine-3-carboxylate; Methyl (3^,4^)-l-[2-(5,7-difluoro-2-oxoquinolin-l(2/i)-yl)ethyl]-4-{[(2£)-3-(2J5- difluorophenyl)prop-2-en-l-yl]amino}piperidme-3-carboxylate; Cis(±)6-[({l-[2-(5,7-Difluoro-2-oxoquinolin-l(2//)-yl)ethyl]-3-hydroxypiperidin-4- yl} amino)methyl]-2#-pyrido[3,2-b] [ 1,4]oxazin-3 (4/f)-one; 4-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-lyl} ethyl)-6-methoxy-2/f-l,4-benzoxazin-3(4//)-one; 6-[({l-[2-(6-Methoxy-3-oxo-2,3-dihydro-4flr-l,4-benzoxazin-4-yl)ethyl]piperidin-4- yl} amino)methyl]-2//-pyrido[3,2-b] [ 1,4]oxazin-3(4/7)-one; 6-[( {1 -[2-(6-Methoxy-3 -oxo-2,3-dihydro-4//-1,4-benzothia/dn-4-yl)cthyl ]pipcridin-4- yl} amino)methyl]-2/f-pyrido[3,2-b] [ 1,4]oxazin-3(4/:/)-one; 4-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin"lyl} ethyl)-6-methoxy-2#-l,4-benzothiazin-3(4#)-one; 6-[( {1 -[2-(6-Fluoro-3-oxo-2,3-dihydro-4/7-1,4-benzoxazin-4-yl)ethyl]piperidin-4- yl} amino)methyl]-2H-pyrido[3,2-b] [ 1,4]oxazin-3(4#)-one; 4-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-lyl} ethyl)-6-fluoro-2/f-1,4-benzoxazin-3(4//)-one; 6-[({l-[2-(6-Chloro-3-oxo-2,3-dihydro-4//-l)4-benzoxazin-4-yl)cthyl]pipcridin-4- yl}amino)methyl]-2flr-pyrido[3,2-i][l,4]oxazin-3(4//)-one; 6-[({l-[2-(6-Methoxy-3-oxo-2,3-dihydro-4//-l,4-benzoxazin-4-yi)ethyl]piperidm-4- yl} amino)methyl]-2H-pyrido[3,2-b][ 1,4]thiazin-3(4//)-one; 3-Oxo-4-[2-(4-{[(3-oxo-3,4-dihydro-2//-pyrido[3,2-6][l,4]oxazin-6- yl)methyl]amino}piperidin-1 -yl)ethyl]-3,4-dihydro-2//-1,4-benzoxazine-6-carbonitrile; 6-{[(l-{2-[3-Oxo-6-(trifluoromethoxy)-2I3-dihydro-4//-l,4-benzoxazin-4- yl]ethyl}piperidin-4-yl)amino]methyl}-2/7-pyrido[3,2-6][l,4]oxazin-3(4/i)-one; 6-[({l-[2-(6-Fluoro-3-oxo-2,3-dihydro-4/f-l,4-benzoxazin-4-yl)ethyl]piperidin-4- yl}amino)methyl]-2//-pyrido[3J2-6][l,4]thiazin-3(4//)-one; 4-(2-{4-[(2,3-Dihydro[l,4]dioxinot2,3-c]pyridin-7-ylmethyl)amino]piperidin-lyl} ethyl)-3-oxo-3,4-dihydro-2//-l,4-benzoxazine-6-carbonitrile; 6-[( {1 -[2-(6-Bromo-3 -oxo-2,3 -dihydro-4#-1,4-benzoxazin-4-yl)ethyl]piperidin-4- yl}amino)methyl]-2/:/'-pyrido[3,2-6][l)4]oxazin-3(4J:0-one; 6-[({l-[2-(6-Hydroxy-3-oxo-2,3-dihydro-4/f-l,4-benzoxazin-4-yl)ethyl]piperidin-4- yl} amino)methyl]-2#-pyrido[3,2-b][l ,4]oxazin-3(4fl)-one; 4- {2-[4-({[2-(2,5-Difluorophenyl)cyclopropyl]methyl} amino)piperidin-l -yl]ethyl} -3- oxo-3,4-dihydro-2//-1,4-benzoxazine-6-carbonitrile; 6-[({l-[2-(6,8-Difluoro-3-oxo-2,3-dihydro-4//-l,4-benzoxazin-4-yl)ethyl]piperidin-4- yl} amino)methyl]-2//-pyrido[3,2-6] [ 1,4]oxazin-3(4//)-one; 4-[2-(4-{[(2£)-3-(2,5-Difluorophenyl)prop-2-en-l-yl]amino}piperidin-l-yl)ethyl]-3- oxo-3,4-dibydro-2/f-1,4-benzoxazine-6-carbonitrile; 6-[( { yl)ethyl]cyclohexyl} amino)methyl]-2//-pyrido[3,2-b][ 1,4]oxazin-3(4//)-one; 3-Oxo-4-[2-(fra«5-4-{[(3-oxo-3,4-dihydro-2/;f-pyrido[3,2-i][l,4]oxazin-6- yl)methyl]amino}cyclohexyl)ethyl]-3,4-dihydro-2H-l,4-benzoxazine-6-carbonitrile; 6-Bromo-4-[2-(4-{[(3-oxo-3,4-dihydro-2//-pyrido[3,2-&][l,4]oxazin-6- yl)methyl]amino}piperidm-l-yl)ethyl]-2W-pyrido[3,2-6][l,4]oxazin-3(4/3r)-one; 6-[({l-[2-(6-Nitro-3-oxo-2,3-dihydro-4//'-l,4-benzoxazin-4-yl)ethyl]piperidin-4- yl} amino)methyl]-2H-pyrido[3,2-b][ 1,4]oxazin-3(4J:/)-one; 3-Oxo-4-[2-(4-{[(3-oxo-3)4-dihydro-2//-pyrido[3)2-6][l)4]oxaziu-6- yl)methyl]amino} piperidin-1 -yl)ethyl]-3,4-dihydro-2//-pyrido [3,2-b] [ 1,4] oxazine-6- carbonitrile; 3-Oxo-4-[2-(4-{[(3-oxo-3,4-dihydro-2//-pyrido[3,2-i][l>4]oxazin-6- yl)metbyl]amino}piperidin-l-yl)ethyl]-3,4-dihydro-2//-pyridot3,2-&][l,4]oxazine-6- carboxamide; Methyl 3-oxo-4-[2-(4-{[(3-oxo-3,4-dihydro-2//-pyrido[3,2-6][l ,4]oxazin-6- yl)methyl]amino}piperidin-l-yl)ethyl]-3,4-dihydro-2//-l,4-benzoxa/,ine-6-carboxylate; 6-[({l-[2-(6-Acelyl-3-oxo-2,3-dihydro-4/7-l,4-benzoxazin-4-yl)e%l]piperidin-4- yl} amino)methyl]-2flr-pyrido[3,2-Z>] [ 1 ,4]oxazin-3 (4/f)-one; 6-Acetyl-4-(2-{4-[(2,3-dihydro[l)4]dioxiao[2,3-c]pyridin-7- ylraethyl)amino]piperidin-l-yl}ethyl)-2^-l,4-benzoxazin-3(4fl')-one; 4.(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-lyl} ethyl)-6-methyl-2W- 1 ,4-benzoxazin-3(4/:/)-one; 3-Oxo-4-[2-(6-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-6][l,4]oxazui-6- carbonitrile; 4-(2-{4-[(2,3-Dihydro[l,4]dioxino[2>3-c]pyridin-7-ylmethyl)amino]piperidin-lyl} ethyl)-2/f-l,4-benzoxazin-3(4#)-one; 6- {[(1- {2-[6-(l -Hydroxyetbyl)-3-oxo-2,3-dihydro-4/f- 1 ,4-benzoxazin-4- yl]ethyl}piperidin-4-yl)amino]methyl}-2//-pyrido[3,2-fo][l,4]oxazin-3(4//)-onc; Ethyl 7/-{l-[2-(6-cyano-3-oxo-2,3-dihydro-4//-l,4-benzoxazin-4-yl)ethyl]pipcridin-4- yl}-A^-[(2£)-3-(2,5-difluorophenyl)prop-2-en-l-yl]glycinate; 6-{[(l-{2-[6-(Methylsulfony])-3-oxo-2,3-dihydro-4/:/-l,4-benxoxazin-4- yl]ethyl}piperidin-4-yl)amino]methyl} -2//-pyrido[3 ,2-b] [ 1 ,4]oxazin-3 (4/f)-one; 6-{[(l-{2-[6-(Ethylsulfonyl)-3-oxo-2,3-dihydro-4/7-l,4-bcnzoxazin-4- yl]ethyl}piperidin-4-yl)amino]methyl}-2//-pyrido[3,2-i]tl,4]oxazin-3(4f/)-onc; 6-[( { 1 -[2-(7-Methoxy-2-oxo-2//-3 , 1 -benzoxazin- 1 (4ff) -yl)etbyl]piperidin-4- yl} amino)methyl]-2//-pyrido[3 ,2-b] [ 1 ,4]oxazm-3(4ff)-one; 7-Methoxy-3-methyl-l-[2-(4-{[(3-oxo-3,4-dihydro-2F-pyrido[3,2-^][l,4]oxazin-6- yl)methyl]amino}piperidin- 1 -yl)ethyl]quinazoline-2,4( \H,3H)-diaw, 4-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-2-oxopii5eridin-lyl} ethyl)-6-methoxy-2//- 1 ,4-benzoxazin-3 (4/f)-one; 6-[({l-[2-(6-Methoxy-3-oxo-2)3-dihydro-47f-l,4-benzoxazin-4-yl)ethyl]-2- oxopiperidin-4-yl}amino)methyl]-2//-pyrido[3,2-fo][l,4]oxazin-3(4//)-one; 3-Oxo-4-[2-(2-oxo-4-{[(3-oxo-3J4-dihydro-2//-pyrido[3,2-i][l,4]oxazin-6- yl)methyl]amino}piperidin- l-yl)ethyl]-3,4-dihydro-2//- 1 ,4-benzoxazine-6-carbonitrile; 6-( {4-[3-(7-Methoxy-2-oxo-2//-3, 1 -benzoxazin- 1 (4/^)-yl)propy l]piperazin- 1 - yl}methyl)-2//-pyrido[3,2-][l,4]oxazin-3(4//)-one; 4-{3-[4-(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)piperazin-l-yl]propyl}-6- methoxy-2H- 1 ,4-benzoxazin-3 (4//)-one; 1 -[(2£)-3-(2,5-Difluorophenyl)prop-2-en-1 -yl]piperidin-4-yl} amino)ethyl]-6- methoxy-2//-1,4-benzoxazin-3 (4H)-on&; 4-(3.{4.[(2£)-3-(2,5-Difluorophenyl)prop-2-en-l-yl]piperazin-l-yl}propyl)-6- methoxy-2#-l,4-benzoxazin-3(4W)-one; 6-[({ 1 -[2-(6-Methoxy-2-oxo-1,7-naphthyridin-1 (2#)-yl)ethyl]piperidin-4- yl}ammo)methyl]-2#-pyrido[3,2-6][l,4]oxazm-3(4#)-one; Methyl l-[(2£)-3-(2,5-difluorophenyl)prop-2-en-l-yl]-4-[3-(6-cyano-3-oxo-2,3- dihydro-4#-1,4-benzoxazin-4-yl)propyl]piperidine-3 -carboxylate; 4-[3-(6-Cyano-3-oxo-2,3-dihydro-4H-l,4-benzoxazin-4-yl)propyl]-l-[(2E)-3-(2,5- difluorophenyl)prop-2-en-1 -yl]piperidine-3-carboxylic acid; 7-Fluoro-3-methyl-l-[2-(4-{[(3-oxo-3,4-dihydro-27/-pyrido[3,2-6][lJ4]oxazin-6- yl)metbyl]amino}piperidin-1 -yl)ethyl]quinazoline-2,4( lH,3H)-dians; 7-Chloro-l-(2-{4-[(2,3-dihydro[l,4]dioxino[2,3-c]pyridin-7- ylmethyl)araino]piperidin-1 -yl} ethyl)-1,8-naphthyridin-2(l H)-one; l-(2-{4-[(2,3-Dihydro[l)4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-lyl} ethyl)-7-methoxy-1,8-naphthyridin-2( 1 H)-one; l-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)araino]piperidm-lyl} ethyl)-7-fluoroquinoxalin-2( l//)-one; 6-[({ 1 -[2-(7-Fluoro-2-oxoquinoxalin-1 (2//)-yl)ethyl]piperidin-4-yl) amino)methyl]- 2//-pyrido[3,2-6][l,4]oxazin-3(4/^)-one; l-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-lyl} ethyl)-6-fluoroquinoxalin-2(l/f)-one; 1 -(2- {4-[(2,3-Dihydro[ 1 ^dioxinop^-cJpyridin^-ylmetiiyOaminoJpiperidin-1 - yl}ethyl)-7-methoxyquinoxalin-2(l/:/)-one; 6-[({l-[2-(7-Methoxy-2-oxoquinoxalin-l(27:r)-yl)ethyl]piperidin-4-yl}amino)methyl]- 2#-pyrido[3,2-6][l,4]oxazin-3(4#)-one; 6-[({l-[2-(7-Methoxy-2-oxoquinoxalin-l(2//)-yl)ethyl]piperidin-4-yl}amino)mothyl]- 2/f-pyrido[3J2-6][l>4]thiazin-3(4^)-one; l-(2-{4-[(2,3-Dihydrotl,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-lyl} ethyl)-6,7-difluoroquinoxalin-2( llf)-one; 6-[({l-[2-(6,7-Difluoro-2-oxoquinoxalin-l(2F)-yl)ethyl]piperidin-4- yl)amino)methyl]-2Jcf-pyrido[3,2-fc][l,4]oxazin-3(4//)-one; l-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-lyl} ethyl)-7,8-difluoroquinoxalin-2(l.fr)-one; 6-[( {1 -[2-(7,8-Difluoro-2-oxoquinoxalin-1 (2^f)-yl)ethyl]piperidin-4- yl}amino)methyl]-2Jy-pyrido[3,2-fc][l,4]oxazin-3(4/f)-one; 6-[({l-[2-(6,7-Dimethoxy-2-oxoquinoxalin-l(2/:/)-yl)ethyl]piperidin-4- yl}amino)methyl]-2#-pyrido[3,2-6][l,4]oxazin-3(4Jy)-one; 6-[({l-[2-(7-Methoxy-3-methyl-2-oxoquinoxalin-l(2^)-yl)ethyl]piperidin-4- yl} amino)methyl]-2/f-pyrido[3,2-b] [ 1,4]oxazin-3(4#)-one; 1 -(2- {4-[(2,3-Dihydro[ 1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1 - yl}ethyl)quinolin-2(l//)-one; l-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-lyl} ethyl)quinolin-4(l/0-one; Cis(±)6-[({l-[2-(5,7-difluoro-2-oxoqumolin-l(27J)-yl)ethyl]-3-mcthoxypiperidin-4- yl} amino)methyl]-2//'-pyrido[3,2-b][ 1,4]oxazin-3(4//)-one; 7-FIuoro-2-oxo-l-[2-(4-{[(3-oxo-3,4-dihydro-27/-pyrido[3,2-6][l,4]oxazin-6- yl)methyl]amino}piperidin-1 -yl)ethyl]-l ,2-dihydroquinoline-5-carbonitrile; 5-Fluoro-2-oxo-l-[2-(4-{[(3-oxo-3,4-dihydro-2//-pyrido[3,2-/?][l,4]oxa/in-6- yl)methyl]amino}piperidin-l-yl)ethyl]-l,2-dihydroquinoline-7-carbonitrile; 7-Fluoro-1 -[2-(4- {[(2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino} piperidin-1 - yI)ethyl]quinoxalin-2(l//)-one; l-[2-(4-{[(2,2-Dimethyl-3)4-dihydro-2//-chromen-6-yl)raethyl]araino}piperidin-lyl) ethyl]-5,7-difluoroquinolin-2(l/f)-one; l-[2-(4-{[(l,3-Dimethyl-2-oxo-2,3-dihydro-l//'-benziinidazol-5- yl)methyl]amino}piperidin-l-yl)ethyl]-57-difluoroquinolin-2(l/:0-one; 5,7-Difluoro-l-(2-{4-[(5,6,7,8-tetrahydronaphthalen-2-ylmethyl)amino]piperidin-lyl} ethyl)quinolin-2(l^T)-one; 5,7-Difluoro-l-[2-(4-{[(6-fluoro-4flr-l,3-benzodioxin-8-yl)methyl]amino}piperidin-lyl) ethyl]quino!in-2(l//)-one; 5,7-Difluoro-l-(2-{4-[(l//P-indol-6-ylmethyl)amino]piperidin-l-yl}ethyl)quinolin- 2(lH)-one; l-(2-{4-[(2,3-Dihydro-l//-inden-5-ylmethyl)amino]piperidin-l-yl}ethyl)-517- di£luoroquinolin-2(lJ:0-onc; 5,7-Difluoro-l-[2-(4-{[(l-methyl-l//-l,2,3-benzotriazol-5-yl)methyl]amino}piperidinl- yl)ethyl]quinolin-2(l#)-one; 5,7-Difluoro-1 -(2- {4-[( l//-indol-5-ylmethyl)amino]piperidin-1 -yl} ethyl)quinolin- 2(l#)-one; 5,7-Difluoro-l-[2-(4-{[(4-methyl-3>4-dihydro-2//-l)4-benzoxazin-7- yl)methyl]amino}piperidin-l-yl)ethyl]quinolin-2(l/f)-one; 1 -(2- {4-[(2,1,3-Benzoxadiazol-5-ylmethyl)amino]piperidin-1 -yl} ethyl)-7- fluoroquinoxalin-2( l//)-one; AT-{l-[2-(7-Fluoro-2-oxoquinoxalin-l(2//)-yl)ethyl]piperidin-4-yl}-2,3-dihydro-l,4- benzodioxine-6-sulfonamide; N- {1 -[2-(7-Fluoro-2-oxoquinoxalin-1 (2#)-yl)ethyl]piperidin-4-yl} -3 -oxo-3,4- dihydro-2/f-l,4-benzoxazine-6-sulfonamide; 5-Fluoro-^-{l-[2-(7-fluoro-2-oxoquinoxalin-l(2Jy)-yl)ethyl]piperidin-4-yl}-l/:/- indole-2-carboxamide; A^{l-[2-(5,7-Difluoro-2-oxoquinolin-l(2//)-yl)ethyl]piperidin-4-yl}-6-morpholin-4- ylnicotinamide; N- {1 -[2-(5,7-Difluoro-2-oxoquinolin-1 (2#)-yl)etkyl]piperidin-4-yl} -2,3-dihydi'O-1,4- benzodioxine-2-carboxamide; N- {l-[2-(5,7-Difluoro-2-oxoquinolin-1 (2ff)-yl)ethyl]piperidin-4-yl} -1 -methyl-1/7- 1,2,3-benzotriazole-5-carboxamide; N- {l-[2-(5,7-Difluoro-2-oxoquinolin-l (2//)-yl)ethyl]pipcridin-4-yl} -3-(2-methyl-1,3- thiazol-4-yl)benzamide; A^{l-[2-(557-Difluoro-2-oxoquinoHn-](2/f)-yl)ethyl]piperidin-4-yl}-4-(5-methyl- 1,2,4-oxadiazol-3-yl)benzamide; 3-Oxo-4-[2-((2/?,55)-5-{[(3-oxo-3,4-dihydro-2//-pyrido[352-6][l,4]oxazin-6- yl)methyl]amino}piperidin-2-yl)ethyl]-3,4-dihydro-2//-l,4-benzoxazine-6-carbonitrile; 3-Oxo-4-[2-((25,5/?)-5-{[(3-oxo-3,4-dihydro-2//-pyrido[3,2-6][l,4]oxazin-6- yl)methyl]amino}piperidin-2-yl)ethyl]-3,4-dihydro-2//-l,4-benzoxazine-6-carbonitrile; 6-[({l-[2-(5J7-Difluoro-2-oxoquinoxalin-l(2/0-yl)ethy1]PiPeridin-4- yl}amino)methyl]-2//-pyrido[3,2-6][l,4]oxazin-3(4//)-one; 6-[({ 1 -[2-(6,8-Difluoro-2-oxoquinoxalin-l (2//)-yl)ethyl]piperidin-4- yl} amino)methyl]-2//-pyrido[3,2-6] [ 1,4]oxazin-3 (4#)-one; 2-Oxo-1 -[2-(4- {[(3 -oxo-3,4-dihydro-2#-pyrido[3,2-b] [ 1,4]oxazin-6- yl)methyl]amino}piperidin-l-yl)ethyl]-l,2-dihydroquinoxaline-6-carbonitrile; 3-Oxo-4-[2-(4-{[(3-oxo-3,4-dihydro-2//-pyrido[3,2-i][l,4]oxazin-6- yl)rnethyl]amino}piperidin-l-yl)ethyl]-3,4-dihydroquinoxaline-6-carbonitrile; 6-[({l-[2-(6-Methoxy-3-oxopyrido[2,3-6]pyrazin-4(3//)-yl)ethyl]piperidin-4- yl}amino)methyl]-2//-pyrido[3)2-i][lJ4]oxazin-3(4^)-one; 4-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-lyl} ethyl)-6-methoxypyrido[2,3-i]pyrazin-3(4/f)-one; 6-[( {1 -[2-(6-Chloro-1 -oxido-3-oxo-1 )2,4-benzotriazin-4(3J:/)-yl)ethyl]piperidin-4- yi} amino)methyl]-2J7-pyrido[3,2-b] [ 1,4]oxazin-3(4//)-one; 6-Chloro-4-(2-{4-[(2,3-dihydro[l,4]dioxino[2,3-c]pyridin-7- ylmethyl)amino]piperidin-1 -yi} ethyl)-1,2,4-benzotriazin-3 (4//)-one 1 -oxide; 6-[( {1 -[2-(6-Chloro-3-oxo-1,2,4-benzotriazin-4(3//)-yl)ethyl]piperidin-4- yl}amino)methyl]-2//-pyrido[3,2-i][l,4]oxazin-3(47/)-one; 4-(2-{(2iS',5J?)-5-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin- 2-yl} ethyl)-3-oxo-3,4-dihydro-2/f-1,4-benzoxazine-6-carbonitrile; 6-[({l-[2-(7-Bronio-2-oxo-2,3-dihydro-l//-pyrido[2,3-6][l,4]oxazin-lyl) ethyl]piperidin-4-yl} amino)methyl]-2//-pyrido[3,2-b] [ 1,4]oxay;in-3 (4H)-one; 2-Oxo-1 -[2-(4- {[(3-oxo-3,4-dihydro-2tf-pyrido[3,2-b] [ 1,4]oxazin-6- yl)methyl]amino}piperidin-1 -yl)ethyl]-2,3-dihydro- l^T-pyrido[2,3-b] [ 1,4]oxazine-7- carbonitrile; 2-Oxo-l-[2-(4-{[(3-oxo-3>4-dihydro-2flr-pyrido[3,2-i][l)4]oxazin-6- yl)methyl]amino}piperidin-l-yl)ethyl]-2,3-dihydro-l//-pyrido[2,3-3][l,4]oxazine-7- carboxamide; l-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-2- methylpiperidin-l-yl}ethyl)-5,7-difluoroquinolin-2(l//)-°ne; l-(2-{4-[(2,3-Dihydro[l ,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino jpiperidin-1- yl} ethyl)-2-oxo-1,2-dihydrbquinoline-7-carbonitrile; Cis±4(l-[(2JS)-3-(2,5-difluorophenyl)prop-2-en-l-yl]-4-[3-(6-methoxy-3-oxo-2,3- dihydro-4fl'-l,4-benzoxazin-4-yl)propyl]piperidine-3-carboxylic acid; Methyl (Cis±4)-l-[(2£)-3-(2,5-difluorophenyl)prop-2-en-l-yl]-4-[3-(6-methoxy-3- oxo-2,3-dihydro-47/-l,4-benzoxazin-4-yl)propyl]piperidine-3-carboxylate; Cis±l-(2-{4-[(2,3-dihydro[l54]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3- hydroxypiperidin-l-yl}ethyl)-2-oxo-l,2-dihydroquinoline-7-carbonitrile; Q8±l-\|>xo-3,4-dihydro-2fl'-pyrido[3>2-6][l,4]oxazin-6- yl)methyl]amino}piperidin- 1 -yl)ethyl]-2-oxo- 1 ,2-dihydroquinoline-7-carbonitrile; 5,7-Difluoro-l -(2- {4-[(5,6,7,8-tetrahydro- 1 ,8-naphthyridin-2- ylmethyl)amino]piperidin-l-yl}ethyl)quinolin-2(l#)-one; Cis±l-(2-{4-[(2>3-dihydro\|;i)4]dioxino[2J3-c]pyridin-7-ylmethyl)amino]-3- methoxypiperidin-l-yl}ethyl)-2-oxo-l,2-dihydroquinoline-7-carbonitrile; yl)methyl]amino}piperidin- 1 -yl)ethyl]-2-oxo- 1 ,2-dihydroquinoline-7-carbonitrile; Cis±l-(2-{4-[(2,3-dihydro[lJ4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3- fluoropiperidin- 1 -yl} ethyl)-2-oxo- 1 ,2-dihydroquinoline-7-carbonitrile; yl)metbyl]araino}piperidin- 1 -yl)ethyl]-2-oxo- 1 ,2-dihydroquinoline-7-carbonitrile; Cis±l-(2-{4-[(2,3-dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3- hydroxypiperidin-l-yl}ethyl)-7-fluoroquinoxalin-2(l//)-one; Cis±6-[({l-[2-(7-fluoro-2-oxoquinoxalin-l(2//)-yl)ethyl]-3-hydroxypiperidin-4- yl} araino)methyl]-2/:/-pyrido[3J2-i][l ,4]oxazin-3(4/0-one; Cis±l-(2-{4-[(2,3-dihydro[l,4Jdioxino[2,3-c]pyridin-7-ylmethyl)amino]-3- methoxypiperidin- 1 -y 1} ethyl)-7-fluoroquinoxalin-2( 1 H)-one; Cis±6-[({l-[2-(7-fluoro-2-oxoquinoxalin-l(2//)-yl)ethyl]-3-methoxypiperidin-4- yl} amino)methyl]-2#-pyrido[3 ,2-6] [ 1 ,4]oxazin-3 (4J7)-one; Cis±l-(2-{4-[(2,3-dihydro[l,4]dioxino[2)3-c]pyridin-7-ylmethyl)amino]-3- fluoropiperidin-l-yl}ethyl)-7-fluoroquinoxalin-2(l^)-one; Cis±6-[( { 1 -[2-(7-fluoro-2-oxoquinoxalin- 1 (2//)-yl)ethyl]-3-fluoropiperidin-4- yl} amino)methyl]-2^r-pyrido[3 ,2-b] [ 1 ,4]oxazin-3 (4//) -one; Cis±l-(2-{4-[(2,3-dihydro[l,4]dioxmo[2,3-c]pyridin-7-yln]ethyl)amino]-3- hydroxypiperidin- 1 -yl} ethyl)-7-methoxyquinoxalin-2( l//)-one; Cis±6-[({l-[2-(7-methoxy-2-oxoquinoxalin-l(2fl)-yl)ethyl]-3-hydroxypiperidinyl} amino)methyl]-2//-pyrido[3)2-i][l,4]oxazin-3(4//)-one; Cis±l-(2-{4-[(2,3-dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3- methoxypiperidin-]-yl}ethyl)-7-methoxyquinoxalin-2(l//)-one; Cis±6-[({l-[2-(7-methoxy-2-oxoquinoxalin-l(2/f)-yl)ethyl]-3-methoxypiperidin-4- yI}ammo)memyl]-2//-pyrido[3,2-6][l,4]oxazin-3(4#)-one; Cis±l-(2-{4-[(2,3-dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3- fluoropiperidin- 1-yl} ethyl)-7-methoxyquinoxalin-2(l.#)-one; Cis±6-[({l-[2-(7-methoxy-2-oxoquinoxalin-l(2H)-yl)ethyl]-3-fluoropiperidin-4- yl}amino)methyl]-2/^pyrido[3,2-&][l,4]oxazin-3(4#)-one; Cis±4-[2-(3-hydroxy-4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-6][l,4]oxazin-6- yl)methyl]amino}piperidin-l-yl)ethyl]-3-oxo-3,4-dihydro-2//-l,4-benzoxazine-6-carbonitrilc; Cis±4-[2-(3-methoxy-4-{[(3-oxo-3,4-dihydro-2/7-pyrido[3,2-6][I,4]oxazm-6- yl)methyl]amino}piperidin-l-yl)ethyl]-3-oxo-3,4-dihydro-27/-l,4-benzoxazme-6-carbonitrile; Cis±4-[2-(3-fluoro-4-{[(3-oxo-3,4-dihydro-2//-pyrido[3,2-6][l,4]oxazin-6- yl)methyl]amino}piperidin- l-yl)ethyl]-3-oxo-3,4-dihydro-27/-1,4-benzoxazine-6-carbonitrilc; l-(2-{4-t(2,3-Dihydro[l ,4]dioxino[2,3-c]pyridin~7-ylmethyl)amino]piperidin-1 - yl} ethyl)-7-methoxy-3,4-dihydroquinoxalin-2( 1 //)-one; 5,7-Difluoro-1 -[2-(4- {[(1 -oxo-1,3-dihydro-2-benzofuran-5- yl)methyl]amino}piperidin-l-yl)ethyl]quinolin-2(l/:f)-one; 6-[({l-[2-(7-Methoxy-2-oxoquinoxalin-l(2//)-yl)propyl]piperidin-4- yl}amino)methyl]-2//-pyrido[3,2-/)][l,4]oxazin-3(4//)-one; or 5,7-Difluoro-l-(2- {4-[(5,6,7,8-tetrahydro-l ,8-naphthyridin-2- ylmethyl)amino]piperidin-l-yI}ethyI)quinolin-2(l//)-one. The invention also provides a pharmaceutical composition comprising a compound of formulas I-V admixed with a pharmaceutically acceptable adjuvant, carrier, or excipient. The invention also provides a method of treating a bacterial infection comprising administering a therapeutically effective amount of a compound of formulas I-V to a mammal in need thereof. The invention also provides a method of treating a bacterial infection in a warm-blooded animal, such as a human being, in need of such treatment, which comprises administering to said animal an effective amount of a compound of formulas I-V or a pharmaceutically-acceptable salt thereof. The invention also provides a method for inhibiting bacterial DNA gyrase in a warm-blooded animal, such as a human being, in need of such treatment which comprises administering to said animal an effective amount of a compound of formulas I-V or a pharmaceutically acceptable salt. The invention also provides a compound of formulas I-V and pharmaceutically acceptable salts thereof for use as a medicament. The invention also provides the use of a compound of formulas I-V or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the production of an anti-bacterial effect in a warm-blooded animal such as a human being. The invention also provides the use of a compound of formulas I-V or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of a bacterial infection in a warm-blooded animal such as a human being. The invention also provides a process for making a compound of formulas I-V, comprising one of the following: (a) N-alkylation of L with X-UjM, wherein X is a leaving group in the presence of a base to form LUiM, wherein Uj is CHaCHa, followed by attachment of Uj and R via functional group manipulation, alkylation, or reductive animation; X-UrM U2 —»- L-UrM • Base R L-UrM-U2 L-UrM-U2-R (b) N-alkylation of L with HO-U]M, under Mitsunobu conditions to form LU]M, followed by attachment of Ua and R via functional group manipulation, alkylatioa, or reductive amination; HO-UrM U2 L — • L-UrM - Mitsunobu R L-UrM-U2 • L-UrM-U2-R (c) N-alkylation of L with bromo- or chloroacetic acid or a derivative thereof to form L-CH2C02H ... ,. * * followed by • ,• .. -A • „ • L-CH2C02i) activation of the acid moiety in * H; ii) amide coupling to form LUiM, wherein Ui is CHzCO, iii) attachment of Ua and R via functional group manipulation, alkylation, or reductive amination; and iv) optional reduction of the carbonyl moiety in Ui to form a compound wherein Ui is CH2CH2. XCH2C02H X= Cl, Br M L ». L-CH2CO2H " Base L-CH2COM - • L-CHZCO-M-U2 U2 L-CH2COM-U2-R - • L-CH2CH2M-U2-R (d) N-alkylation of L with X-(CH2)nCH=CH2 wherein X is a leaving group and n is 1 or 2 to form L-(CH2)nCH=CH2, followed by: i) oxidativc cleavage using an oxidant such as ozone or sodium periodatc (with reductive workup) to form L-(CH2)nCH2OH; ii) conversion of the alcohol moiety in L-(CHi)nCH2OH to a leaving group; iii) reaction of L--(CH2)nCH2-Y with M, in the presence of a base to form LUjM; and iv) attachment of U2 and R via functional group manipulation, alkylation, or reductive animation; X-(CH2)n-CH=CH2 L— (-Op [O] L— ( L _ Base — V~OH L— (-\)n U2 R •- L-UrM-U2 - L-UrM-U2-R X,Y = leaving group n= 1 or 2 (e) N-alkylation of L with X-(CH2)nCH=CH2 wherein X is a leaving group and n is 0 or 1 to form L-(CH2)nCH=CH2, provided that when n is 0, a metal catalyst is optionally used, followed by: i) hydroboration followed by an oxidative workup to form to form L-(CH2)nCH2CH2OH; ii) conversion of the alcohol moiety in L-(CH2)nCH2CH20H to a leaving group; iii) reaction of L-(CH2)nCH2CH2-"LG" with M, in the presence of a base to form LUiM; and iv) followed by attachment of U2 and R via functional group manipulation, alkylation, or reductive amination; X-(CH2)n-CH=CH2 L—(-Jn Hydroboration L—(-\)n Base ^= Oxidative Workup OH L—(-v)n M L-UrM Y U2 R - L-UrM-U2 ^ L-UrM-U2-R X,Y = leaving group n= 1 or 2 L—v (f) Oxidation of the alcohol intermediate in d) and e) supra to the aldehyde L—vy=o H .followed by i) reductive amination with MUz; to form LU]MU2, wherein Ul is ' ii) reductive amination with R; or L^ [O] L ^-OH H R L-UrM-U2 - L-UrM-U2-R (g) N-alkylation of L with X-(CH2)nCH2CH20H, wherein X is a leaving group and n is 0 or 1 to form the intermediate L-(CH2)nCH2CH20H as depicted in (e), supra, followed by i) conversion of the alcohol moiety in L-(CH2)nCH2CH2OH to a leaving group; ii) reaction of L-(CH2)nCH2CH2-"LG" with M, in the presence of a base to form LUiM; and iii) followed by attachment of Ua and R via functional group manipulation, alkylation, or reductive amination. L—(-y)n M Y U2 R L-U,-M - »- L-UrM-U2 - „ L-UrM-U2-R X,Y = leaving group n= 1 or 2 DETAILED DESCRIPTION OF THE INVENTION Unless otherwise stated, the following terms used in the specification and claims have the following meanings. Definitions "Alky!" means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl, pentyl, and the like, that may be optionally substituted. "Alkenyl" means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms, containing at least one double bond, e.g., ethenyl (-CH=CH2), propenyl, and the like that may be optionally substituted. "Alkylene" means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms, e.g., methylene (-CHa-), ethylene (-CKfoCHa-), propylene, 2-methylpropylene, pentylene, and the like that may be optionally substituted. "Acyl" means a radical ~C(O)R where R is hydrogen, alkyl, alkenyl, cycloalkyl, heteroalkyl, haloalkyl, aryl, aralkyl, heteroaralkyl or heteroaryl, e.g., acetyl, benzoyl, thienoyl, and the like that may be optionally substituted. "Acyloxy" means a radical — OC(O)R where R is hydrogen, alkyl, alkenyl, cycloalkyl, heteroalkyl, haloalkyl or optionally substituted phenyl, e.g, , acetoxy, benzoyloxy, and the like that may be optionally substituted. "Halo" means fluoro, chloro, bromo or iodo. "Haloalkyl" means alkyl substituted with one or more same or different halo atoms, e.g., —CH2C1, —CF3> —CH2CF3) ~-CH2CCl3, and the like. "Cycloalkyl" means a saturated monovalent cyclic hydrocarbon radical of three to six ring carbons, e.g., cyclopropyl, cyclohexyl, and the like that may be optionally substituted. "Amine" or "amino" refers to radicals of the general formula —NRR', wherein R and R' are independently selected from hydrogen or a hydrocarbyl radical, or wherein R and R' combined form a heterocycle, Examples of amino groups include: —Ntfe, methyl amino, diethyl amino, anilino, benzyl amino, piperidinyl, piperazinyl and indolinyl. "Monosubstituted amino" means a radical —NHR where R is alkyl, heteroalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl or optionally substituted phenyl, e.g., methylamino, (l-methylethyl)amino, phenylamino, and the like. "Disubstituted amino" means a radical -NRR' where R and R' are independently alkyl, alkenyl, heteroalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl or optionally substituted phenyl. Representative examples include, but are not limited to, dimethylamino, methylethylamino, di(l-methylethyl)amino, methylbenzylamino, and the like. "Aryl" means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical of 6 to 10 ring atoms, and optionally substituted independently with one or more substituents, preferably one, two or three substituents selected from alkyl, haloalkyl, heteroalkyl, cycloalkyl, cycloalkylalkyl, halo, cyano, nitro, acyloxy, alkoxy, optionally substituted phenyl, heteroaryl, heteroaralkyl, amino, monosubstituted amino, disubstituted amino, acylamino, hydroxyamino, amidino, guanidino, cyanoguanidinyl, hydrazino, hydrazido, —OR [where R is hydrogen, alkyl, haloalkyl, alkenyl, cycloalkyl, cycloalkylalkyl, optionally substituted phenyl, heteroaryl or heteroaralkyl], —S(O)nR [where n is an integer from 0 to 2 and R is hydrogen, alkyl, haloalkyl, alkenyl, cycloalkyl, cycloalkylalkyl, optionally substituted phcnyl, heteroaryl, heteroaralkyl, amino, mono or disubstituted amino], —NRSC^R' (where R is hydrogen or alkyl and R' is alkyl, amino, monosubstituted or disubstituted amino) —C(O)R (where R is hydrogen, alkyl, alkenyl, cycloalkyl, heteroalkyl, haloalkyl or optionally substituted phenyl), —COOR (where R is hydrogen, alkyl, optionally substituted phenyl, heteroaryl or heteroaralkyl), — (alkylene)-COOR (where R is hydrogen, alkyl, optionally substituted phenyl, heteroaryl or heteroaralkyl), methylenedioxy, 1,2-ethylenedioxy, — CONR'R" or—(alkylene)CONR'R" (where R' and R" are independently selected from hydrogen, alkyl, cycloalkyl, haloalkyl, cycloalkylalkyl, optionally substituted phenyl, heteroaryl and heteroaralkyl). More specifically the term aryl includes, but is not limited to, phenyl, 1-naphthyl, 2-naphthyl, and derivatives thereof. The term "ortho-fused" as used in the phrase "ortho-fused bicyclic subunit" means a bicyclic saturated, partially aromatic or fully aromatic, fully unsaturated or partially saturated, carbocyclic or heterocyclic ring system wherein the two rings have only two atoms and one bond in common. Both rings may be aromatic; for example, such as in naphthalene, pteridine, cinnoline, quinazoline, quinoxaline, naphthyridine, phthalazine, quinoline, isoquinoline, quinolizine, purine, indazole, indole, isoindole, indolizine, or pyrrolizine and the like. "Heteroaryl" means a monovalent monocyclic or bicyclic aromatic radical of 5 to 10 ring atoms containing one, two, or three ring heteroatoms selected from N, 0, or S, the remaining ring atoms being C. For the avoidance of doubt, "heteroaryl" includes "ortho-fused bicyclic heteroaryl". The aromatic radical is optionally substituted independently with one or more substituents, preferably one or two substituents selected from oxo, alkyl, haloalkyl, heteroalkyl, cycloalkyl, cycloalkylalkyl, halo, cyano, nitro, acyloxy, optionally substituted phenyl, amino, monosubstituted amino, disubstituted amino, acylamino, hydroxyamino, amidino, guanidino, cyanoguanidinyl, hydrazino, hydrazido, —OR [where R is hydrogen, alkyl, haloalkyl, alkenyl, cycloalkyl, cycloallcylalkyl or optionally substituted phenyl], — S(O)nR [where n is an integer from 0 to 2 and R is hydrogen, alkyl, haloalkyl, alkenyl, cycloalkyl, cycloalkylalkyl, optionally substituted phenyl, amino, mono or disubstituted amino], —C(O)R (where R is hydrogen, alkyl, alkenyl, cycloalkyl, heteroalkyl, haloalkyl or optionally substituted phenyl), —COOR (where R is hydrogen, alkyl, or optionally substituted phenyl), —(alkylene)-COOR (where R is hydrogen, alkyl or optionally substituted phenyl), methylenedioxy, 1,2-ethylenedioxy,—CONR'R" or —(alkylene)-CONR'R" (where R' and R" are independently selected from hydrogen, alkyl, cycloalkyl, haloalkyl, cycloalkylalkyl or optionally substituted phenyl). The term heteroaryl includes, but is not limited to pyridyl, pyrrolyl, thiopbene, pyrazolyl, thiazolyl, imidazolyl, pyrimidinyl, thiadiazolyl, indolyl, carbazolyl, azaindolyl, benzofuranyl, benzotriazolyl, benzisoxazolyl, purinyl, quinolinyl, benzopyranyl, and derivatives thereof. "Heterocycle" or "Heterocyclyl" means a saturated, partially unsaturated or fully unsaturated cyclic radical of 3 to 8 ring atoms in which one or two ring atoms are heteroatoms selected from N, O, or S(O)n (where n is an integer from 0 to 2). The heterocyclo ring may be optionally substituted independently with one, two or three substituents selected from alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, halo, cyano, acyl, acylamino, amino, monosubstituted amino, disubstituted amino, —COOR (where R is hydrogen or alkyl), —XR (where X is 0 or S(0),, where n is an integer from 0 to 2 and R is hydrogen, alkyl, haloalkyl, cyoloalkyl, aralkyl, aryl, heteroaryl or heteroarallcyl) or — CONRH" (where R' and R" are independently selected from hydrogen or alkyl). Representative examples include, but are not limited to tetrahydropyranyl, piperidino, l-(4-chlorophenyl)piperidino, and the like. In one aspect of the invention "Ry and Ry1 together form a bridge". A bridge is a bond, a carbon atom or two carbon atoms connecting two different ring atoms of M which are meta or para to each other. Particularly the bridge is a bond. Particularly the bridge is one carbon atom. Alternatively the bridge is two carbon atoms. Examples of M where"Ry and Ry' together form a bridge" are: (Ml, bridge is a bond, atoms of M are meta to each other), (M2, bridge is one carbon atom, atoms of M are meta to each other), (M4, bridge is two carbon atoms, atoms of M are para to each other), (M5, bridge is a bond, atoms of M are meta to each and other). •\ ~"Aralkyl" means a radical —Ra—Rb where Ra is bound to Rb and Ra is an alkylcne group and Rb is an aryl group as defined above e.g., benzyl, phenylethyl, 3-(3-chlorophenyl)-2-methylpentyl, and the like. "Heteroaralkyl" means a radical —Ra—Rb where Ra is bound to Rb and R alkylene group and Rb is a heteroaryl group as defined above e.g., pyridin-3-ylmethyl, 3-(benzofuran-2-yl)propyl, and the like. "Alkoxy", "aryloxy" or "heteroaryloxy" means a radical —OR where R is an alkyl, aryl or heteroaryl, respectively as defined above e.g., methoxy, phenoxy, pyridin-2-yloxy and the like. "Alkylthio" and "heteroarylthio" respectively mean an alkyl group or heteroaryl group attached via a thioether linkage. "Alkylsulfinyl" and "heteroarylsulfmyl" respectively mean an alkyl group or heteroaryl group attached via a sulfinyl linkage. "Alkylcarbonyloxy" refers to an alkyl group attached to a COa group, as in alkyl-COj—, alkenyl-CO2—, aryl-CCV, respectively, where alkyl is as defined herein. For example, alkylcarbonyloxy includes but is not limited to, acetoxy, ethylcarbonyloxy, n- or iso-propylcarbonyloxy, n-, iso-, sec- or tert-butylcarbonyloxy, n-pentylcarbonyloxy, n-hexylcarbonyloxy. "Optionally substituted" means that the group at issue is optionally substituted independently with one, two or three substituents selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulphamoyl, methyl, ethyl, ethenyl, ethynyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, JV-methyl-A^-ethylamino, acetylamino, or as otherwise provided, "Amino-protecting group" refers to those organic groups intended to protect nitrogen atoms against undesirable reactions during synthetic procedures e.g., benzyl, benzyloxycarbonyl (CBZ), t-butoxycarbonyl (BOC), trifluoroacetyl, and the like. Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed "isomers". Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers". Stereoisomers that are not mirror images of one another are termed "diastereomers" and those that are non-superimposable mirror images of each other are termed "enantiomers". When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a "racemic mixture". The compounds of this invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof. For example, if the Y and Y' substituents in a compound of formula I are attached to the same carbon are different, then the carbon to which they are attached is an asymmetric center and the compound of formula I can exist as an (R)- or (S)-stereoisomer relative to that carbon. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of "Advanced Organic Chemistry", 4th edition J. March, John Wiley and Sons, New York, 2001). A "pharmaceutically acceptable excipient" means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes an excipient that is acceptable for veterinary use as well as human pharmaceutical use. A "pharmaceutically acceptable excipient" as used in the specification and claims includes both one and more than one such excipient. A "pharmaceutically acceptable counterion" means an ion having a charge opposite to that of the substance with which it is associated and that is pharmaceutically acceptable. Representative examples include, but are not limited to, chloride, bromide, iodide, methanesulfonate, p-tolylsulfonate, trifluoroacetate, acetate, and the like. A "pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Such salts include: 1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxyben?,oyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-napthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2,2,2]oct-2-ene-l-carboxylic acid, glucoheptonic acid, 4,4'-metbylenebis-(3-hydroxy-2-ene-l-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynapthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or 2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. 3) "Leaving group" has the meaning conventionally associated with it in synthetic organic chemistry i.e., an atom or group capable of being displaced by a nucleophile and includes halogen(such as chloro, bromo, iodo), alkanesulfonyloxy (such as mesyloxy or trifluorosulfonyloxy) or arenesulfonyloxy (such as tosyloxy), ester, or amino, and the like. "Pro-drugs" means any compound which releases an active parent drug according to formula I in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of formula I are prepared by modifying functional groups present in the compound of formula I in such a way that the modifications may be cleaved in vivo to release the parent compound. Prodrugs include compounds of formula I wherein a hydroxy, thio or amino group in compound I is bonded to any group that may be cleaved in vivo to regenerate the free hydroxy, amino, or thio group, respectively. Examples of prodrugs include, but are not limited to esters (e.g., acetate, formate, and benzoate derivatives), carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxy functional groups in compounds of formula I, and the like. "Treating" or "treatment" of a disease includes: 1) preventing the disease, i.e. causing the clinical symptoms of the disease not to develop in a mammal that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease; 2) inhibiting the disease, i.e., arresting or reducing the development of the disease or its clinical symptoms; or 3) relieving the disease, i.e., causing regression of the disease or its clinical symptoms. A "therapeutically effective amount" means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated. Invention Compounds Referring again to a compound of the invention, the following specific values are disclosed. In a compound of formula I, a specific value for L is ' »indicates the point of attachment and Z is CH or N. Other specific values for L include the following structures, wherein " ~f " has the same meaning. R2d O R,a R2b f Yo \|N2" f R2a £ ,-N^^.O R2bv.x4^,N R 2 b^ \|\| \| /^"R2^ R -.' -s^ \x\ 'R2f R p'^v^^f R2c y ^\ R2c y N RR r' 2c , R2d Kze R2d Kze R2d R2e R2d ,or R2d A specific value for R2b is H. Other specific values for Rab include halo, (d-CsJalkanoyl, cyano, carboxy, (Ci-C6)alkoxycarbonyl, (Ci-C6)alkyl, hydroxy, halo(Ci-C6)alkyl, halo(CrC6)alkoxy, (Ci-C6)alkoxy, NHCO-(CrC6)alkyl, SO2(Ci-C6)alkyl, S02NH(Ci-C6)alkyl, or SO2N((Ci-C6)alkyl)2. To that end, specific values for R2b include H, methoxy, cyano, fluoro, chloro, trifluoromethoxy, bromo, hydroxy, CONH2, C02Me, MeCO, methyl, 1-hydroxyethyl, 2-hydroxyethyl, SO2Me, and SO2Et. A specific value for R2a, is H. Other specific values for R2a include halo, (Ci-C6)alkanoyl, cyano, carboxy, (Cj-CeJalkoxycarbonyl, (Ci-C$)alkyl, hydroxy, halo(Ci-C6)alkyl, halo(C,-C6)alkoxy, (C)-C6)alkoxy, NHCO-(CrC6)alkyl, SO2(CI-C6)alkyl) SO2NH(Ci-C6)alkyl, or S02N((Ci-C6)alkyl)2. To that end, specific values for R2a include H, methoxy, cyano, fluoro, chloro, trifluoromethoxy, bromo, hydroxy, CONH2, CO2Me, MeCO, methyl, 1-hydroxyethyl, 2-hydroxyethyl, SO2Me, and SO2Et. A specific value for R2c is H. Other specific values for R2c include halo, (C]-C6)alkanoyl, cyano, carboxy, (Ci-CgJalkoxycarbonyl, (Ci-C6)alkyl, hydroxy, halo(CrC6)alkyl, halo(Ci-C6)alkoxy, (Ci-C6)alkoxy,NHCO-(Ci-C6)alkyl, SO2(CrC6)alkyl, SO2NH(C,-C6)alkyl, or SO2N((CrC6)alkyl)2. To that end, specific values for R2c include H, methoxy, cyano, fluoro, chloro, trifluoromethoxy, bromo, hydroxy, CONH2, C02Me, MeCO, methyl, 1-hydroxyethyl, 2-hydroxyethyl, SO2Me, and SO^t. A specific value for R2d is H. Other specific values for R2d include halo, (Ci-Cfi)alkanoyl, cyano, carboxy, (Ci-C6)alkoxycarbonyl, (Ci-C6)alkyl, hydroxy, halo(CrC6)alkyl, halo(Ci-C6)alkoxy, (Ci-C6)alkoxy, NHCO-(Ci-C6)alkyl, SO2(d-C6)alkyl, S02NH(C,-C6)alkyl, or SO2N((d-C6)alkyl)2. To that end, specific values for R2d include H, methoxy, cyano, fluoro, chloro, trifluoromethoxy, bromo, hydroxy, CONH2, C02Me, MeCO, methyl, 1-hydroxyethyl, 2-hydroxyethyl, SO2Me, and SO^t. A specific value for R2e is H. Other specific values for R2e include halo, (Cj-CeJalkanoyl, cyano, carboxy, (Ci-C6)alkoxycarbonyl, (CpCeJalkyl, hydroxy, halo(CrC6)alkyl, halo(CrC6)alkoxy, (Ci-C6)alkoxy, NHCO-(Ci-C6)alkyl, SO2(Ci-C6)alkyl, S02NH(Ci-C6)alkyl, or S02N((Ci-C6)alkyl)2. To that end, specific values for R2e include H, methoxy, cyano, fluoro, chloro, trifluoromethoxy, bromo, hydroxy, CONH2> CO2Me, MeCO, methyl, 1-hydroxyethyl, 2-hydroxyethyl, SO2Me, and SO2Et. A specific value for R2f is H. Other specific values for R2f include halo, (C\|-C6)alkanoyl, cyano, carboxy, (Ci-C6)alkoxycarbonyl, (Ci-CeXlkyl, hydroxy, halo(CrC6)alkyl, halo(CrC6)alkoxy5 (Ci-C6)alkoxy, NHCO-(C,-C6)allcyl) SO2(C,-C SO2NH(Ci-C6)alkyl, or S02N((C,-C6)alkyl)2. To that end, specific values for R2f include H, methoxy, cyano, fluoro, chloro, trifluoromethoxy, bromo, hydroxy, CONH2, C02Me, MeCO, methyl, 1-hydroxyethyl, 2-hydroxyethyl, SO2Me, and SO2Et. A specific value for R2g and R2g' is H. Other specific values for R2g and R2g' include (Ci-C6)alkyl, andhalo(CrC6)alkyl. A specific value for Uj is CH2CH2. Other specific values for Ui include CH2CH2CH2 and CH2CH(Me). A further specific value for U] is CH(Me)CH2. RyN Y" C( » A specific value for M is 1 , wherein Y is 0, NH or CH2 and is absent or is a bond. Other specific values for M include a group of formula MS DO V-^'-^ which is , M3 , a group of formula M4 which is XA g^N V^v [U , or a group of formula M2 which is , wherein " uidicates the point of attachment and [Ui] and 112 is H or carboxy, n is 1, 2, or 3, and Ry is H, F, hydroxy, (Ci-C6)alkyl, (Ci-C6)alkoxy, or carboxy. A specific value for M is a group of formula M4 which is ^^N V^vv >0 HO Other specific values for M include groups of formula M.4 which are / v y v [UJ^-N VM- [Ujjv-N V"* V.^ OH OMe , wherein " "^ " indicates the point of attachment. When M is a group of formula Ml or M4, a specific value for [M]-Ua is [MJ-NHCEfe. When M is a group of formula Ml or M4, other specific values for [M]-U2 include OA [M]— r f^ [M]-NHCH2CH=CH, [M]-NHS02> n , when M is a group of formula M2, M3, or M5, a specific value for [M]-U2 is [M]-CH2CH=CH- or [M]-CH2CH2-. A specific value for R is 2,l,3-oenzothiadiazol-5-yl; 3-oxo-3 ,4-dihydro-2/f- 1 ,4-benzothiazin-6-yl; 2,3-dihydro-benzo[l,4]dioxin-6-yl; 1 ,2,3 -benzothiadiazol-5 -yl; 3-oxo-3,4-dihydro-2//'-l,4-benzoxazin-6-yl; 7-fluoro-3-oxo-3,4-dihydro-2//-l,4-benzoxazin-6-yl; 2-oxo-2,3-dihydro-lH-pyrido[2,3-b][l,4]thiazm-7-yl; 2,3-dihydro-[l,4]dioxmo[2,3-c]pyridin-7-yl; 3-oxo-3 ,4-dihydro-2H-pyrido[3 ,2-b] [ 1 ,4]oxazin-6-yl; [l,2,3]thiadiazolo[5,4-b]pyridin-6-yl; 3-oxo-3 ,4-dihydro-2H-pyrido[3,2-b] [ 1 4] thiazin-6-yl; 7-chloro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][l,4]thiazin-6-yl; 7-fluoro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][l,4]thiazin-6-yl; 2-thienylthio; or 2,5-difluorophenyl. H O H O _ More specifically R is IN , , or wherein " indicates the point of attachment. A specific group of compounds of the invention are compounds wherein L is , wherein " "^ " indicates the point of attachment; " ' is a bond or is absent; Z is CH or N when " " is a bond, or, when " — "is absent, Z is 0 or NH; R2a, Rzb, Rzc, and R2d are each independently H, halo, cyano, (Ci-C(i)alkanoyl, carboxy, (Cj-C6)alkoxycarbonyl, (Ci-C6)alkyl, halo(C\|-C6)alkyl, halo(Cj-C6)alkoxy, (C1-C6)alkoxy,NHCO-(C1-C6)alkyl1 S02(Ci-C SO2N((C1-C6)alkyl)2. A specific group of compounds of the invention are compounds wherein Ui—M—U2 RyN Y* [L] is N[SO2(Ci-C6)alkyl] or CH2 and " "is absent or is a bond. Other specific groups of compounds of the invention are compounds wherein Ui-M-U: is Ry Rev Rf Pa " l x/ -N N-W-v ">1-N >—NR1 «-„/-»- ^ lLlr7 Re Rd Ra „ en- Re Rf X-^xCH . \^W^v ^ Rd ) wherein "[L] ^^ " indicates the point of attachment to L and " "~M' indicates the point of attachment to R, and wherein R2 is H or carboxy and n is 1, 2, or 3; Ra, Rb, Re, Rd, Re, and Rf are each independently H or (Ci-C( Ry is H, F, hydroxy, (Ci-C6)alkyl, (d-CeJalkoxy, or carboxy; R1 is H, (Ci-C6)alkyl, or -(C1-C6)alkylcarboxy; and W is CH2, CO, SO2) CH2CH2, CH2CH=CH, or CH2CsC, wherein each hydrogen may be optionally replaced by halo or (C)-C6)alkyl; X is CH2, NH, N(C,-C6)alkyl, N[CO-(C,-C6)alkyl], N[SO2(Ci-C6)alkyl] or 0. A specific group of compounds of the invention are compounds of formula I which are compounds of formula II: R2a U—M-U2-R II or a pharmaceutically acceptable salt thereof, wherein R2a, R2b, R2c, and R2d are each independently H, fluoro, chloro, cyano, (Ci-Cf,)alkyl, halo(CrC6)alkyl, halo(C]-C6)alkoxy, (Ci-C6)alkoxy; " " is a bond or is absent; Z is CH or N when " " is a bond, or Z is 0 or NH when " — "is absent; Uj is CRaRb—CRcRd or CRaRb—CRcRd—CReRf, wherein Ra, Rb, Re, Rd, Re and Rf are each independently hydrogen or (Ci-Cs M is a group of formula Mia or M2-M5: [U,]' Mia M5 in the trans configuration relative to "", wherein R2 is H or carboxy; Ry and Ry' are each independently H, halo, (Ci-C6)alkyl, or together with the carbon to which they are attached form C=0; or Ry and Ry' together form a bridge; X is CH2, or provided n is 2 or 3, X is NH, N(C}-C6)alkyl, or O; Y is CH2, NH, N(C,-C6)alkyl, or O; « .» jg a b0n£j OJ. jg absgjjtnisi, 2, or 3; when M is a group of formula Mia or M4, Ife is NR1—W, wherein R' is H, , or _ md w., CH2CH2, CEfeCKNCH, or CHaCsC, wherein each hydrogen may be optionally replaced by halo or (Ci-CeJalkyl, provided that when M is a group of formula M2, M3, or M5, U2 is W; and when W is CHa, CO or SOz, R is aryl, heteroaryl, heterocyclyl or ortho-fused bicyclic A C^M T-fO f1T-f heteroaryl, or when W is 2 " , CH2CH2, CH2CH=CH, or CHjOC, R is aryl, heteroaryl, heteroaryl(CrC6)alkyloxy, heteroaryl(Ci-C6)alkylthio, heteroaryl(Ci-C6)alkylsulfinyl, heteroaryl(Ci-C6)alkylsulfonyl, heteroaryl(Ci-C6)alkylamino wherein any R may be optionally substituted on carbon; and wherein any ring nitrogen in R may be optionally substituted by (Ci-C6)alkyl. A specific group of compounds of the invention are compounds of formula I which are compounds of formula III: III or a pharmaceutically acceptable salt thereof, wherein Rja, Rib, R2C, and Rjd are each independently H, fluoro, chloro, cyano, (Ci-C6)alkyl, halo(Ci-C6)alkyl, halo(d-C6)alkoxy, (Ci-C6)alkoxy; Z is CH or N when " ' is a bond, or, when " — "is absent, Z is 0 or NH; V is N or CRa, wherein R2 is H or carboxy; Ry is H, fluoro, hydroxy, methoxy, carbomethoxy, or carboxy; U2 is NR'—W, wherein R' is H, (Ci-C6)alkyl, (C.-C^alkyl , or -0(C,-C6)alkyl ^ ^ ^ and w .g ^ CQ> ^ CH2CH2j CH2cH=CHj or CH2OC, wherein each hydrogen may be optionally replaced by halo or (Ci-CeJalkyl; and R is 2,l,3-benzothiadiazol-5-yl; 3-oxo-3,4-dihydro-27/-l,4-benzothiazin-6-yl; 2,3-dihydro-benzo[l,4]dioxin-6-yl; 1,2,3-benzothiadiazol-5-yl; 3-OXO-3,4-dihydro-2/f-1,4-benzoxazin-6-yl; 7-fluoro-3 -oxo-3,4-dihydro-277-1,4-benzoxazin-6-yl; 2-oxo-2,3-dihydro-lH-pyrido[2,3-b][l,4]thiazin-7-yl; 2,3-dihydro-[l,4]dioxino[2,3-c]pyridin- 7-yl; 3-oxo-3,4-dihydro-2H-pyrido[3,2-b] [ 1,4]oxazin-6-yl; [l,2,3]thiadiazolo[5,4-b]pyridin-6-yl; 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][ 1,4] thiazin-6-yl; 7-chloro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][l,4]thiazin-6-yl; 7-fluoro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][l,4]thiazin-6-yl; 2-thienylthio; or 2,5-difluorophenyl. A specific group of compounds of the invention are compounds of formula I which are compounds of formula IV: R'sN-W IV or a pharmaceutically acceptable salt thereof, wherein is H, halo, cyano, nitro, (Ci-C6)alkanoyl, carboxy, (C\|-C6)alkoxycarbonyl, (Ci-C6)alkyl, hydroxy, halo(CrC6)alkyi, halo(CrC6)alkoxy, (Ci-C6)alkoxy, NHCO-(C,-C6)alkyl, SO2(C,-C6)alkyl, S02NH(Ci-C6)alkyl, or SO2N((C,-C6)alkyl)2; Z is CH or N when " " " " is a bond, or, when " -'" • "is absent, Z is 0 or NH; Ry is H, fluoro, hydroxy, methoxy, carbomethoxy, or carboxy; R1 is H or (Ci-C6)alkyl; W is CO, SO2, or CEfe, wherein each hydrogen may be optionally replaced by halo or (Ci-C6)alkyl; and H O H O Ris N , ^ ,or A specific group of compounds of the invention are compounds of formula V: RV ,R V or a pharmaceutically acceptable salt thereof, wherein R2b is H, halo, cyano, nitro, (Ci-C6)alkanoyl, carboxy, (C]-C6)alkoxycarbonyl, (Ci-C6)alkyl, hydroxy, halo(Ci-C6)alkyl, halo(C]-C6)alkoxy, (d-C6)alkoxy, NHCO-(Ci-C6)alkyl, SO2(C,-C6)alkyl, S02NH(C,-C6)alkyl, or SOzNCCC^alkyFh; Z is CH or N when " " is a bond, or, when " "is absent, Z is 0 or Nil; Ry is H, fluoro, hydroxy, methoxy, carbomethoxy, or carboxy; R1 is H or (Ci-C6)alkyl; and H O H.O ,or A specific group of compounds of the invention are compounds wherein L is a group of formula LI. A specific group of compounds of the invention are compounds wherein L is a group of formula L2. A specific group of compounds of the invention are compounds wherein L is a group of formula L3. A specific group of compounds of the invention are compounds wherein L is a group of formula L4. A specific group of compounds of the invention are compounds wherein L is a group of formula L5. A specific group of compounds of the invention are compounds wherein L is a group of formula L6. A specific group of compounds of the invention are compounds wherein L is a group of formula L7. A specific group of compounds of the invention are compounds wherein L is a group of formula L8. A specific group of compounds of the invention are compounds wherein L is a group of formula L9. A specific group of compounds of the invention are compounds wherein L is a group of formula LI 0. A specific group of compounds of the invention are compounds wherein L is a group of formula LI 1. A specific group of compounds of the invention are compounds wherein L is a group of formula LI 2. A specific group of compounds of the invention are compounds wherein L is a group of formula LI 3. A specific group of compounds of the invention are compounds wherein L is a group of formula L14. A specific group of compounds of the invention are compounds wherein L is a group of formula LI 5. A specific group of compounds of the invention are compounds wherein M is a group of formula Ml. A specific group of compounds of the invention are compounds wherein M is a group of formula Ml a. A specific group of compounds of the invention are compounds wherein M is a group of formula M2. A specific group of compounds of the invention are compounds wherein M is a group of formula M3. A specific group of compounds of the invention are compounds wherein M is a group of formula M4. A specific group of compounds of the invention are compounds wherein M is a group of formula M5. A specific group of compounds of the invention are compounds wherein when M is a group of formula Ml or M2, W is CH2l CO or SO2. Preparation of Invention Compounds In a further aspect, the present invention provides a process for preparing a compound of the invention or a pharmaceutically-acceptable salt or an in-vivo hydroly sable ester thereof. It will be appreciated that during certain of the following processes, certain substituents may require protection to prevent their undesired reaction. The skilled chemist will appreciate when such protection is required, and how such protecting groups may be put in place and later removed. Examples of protecting groups are disclosed in, for example, 'Protective Groups in Organic Synthesis' by Theodora Green (John Wiley & Sons, 1999). Protecting groups may be removed by any convenient method described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with minimum disturbance of groups elsewhere in the molecule. Thus, if reactants include, for example, groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein. A suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or /-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a f-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulfuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group that may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine. A suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon. A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a f-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon. Resins may also be used as a protecting group. The protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art. A compound of the invention, or a pharmaceutically-acceptable salt or an in vivo hydrolysable ester thereof, may be prepared by any process known to be applicable to the preparation of chemically-related compounds. Such processes, when used to prepare a compound of the invention, or a pharmaceutically-acceptable salt or an in vivo hydrolysable ester thereof, are provided as a former feature of the invention and are illustrated by the following representative examples. Necessary starting materials may be obtained by standard procedures of organic chemistry (see, for example, Advanced Organic Chemistry (Wiley-Interscience, 2001), Jerry March or Houben-Weyl, Methoden der Organischen Chemie), The preparation of such starting materials is described within the accompanying non-limiting Examples. Alternatively, necessary starting materials are obtainable by analogous procedures to those illustrated that are within the ordinary skill of an organic chemist. Information on the preparation of necessary starting materials or related compounds (which may be adapted to form necessary starting materials) may also be found in the certain Patent Application Publications, the contents of the relevant process sections of which are incorporated herein by reference; for example W02004/058144; US2004/0224946; WO2004/002992. The skilled organic chemist will be able to use and adapt the information contained and referenced within the above references, and accompanying Examples therein and also the Examples herein, to obtain necessary starting materials, and products. Thus, the present invention also provides that the compounds of the invention and pharmaceutically-acceptable salts and in vivo hydrolysable esters thereof, can be prepared by a process (a) to (h); and thereafter if necessary: i) removing any protecting groups; ii) forming a pro-drug (for example an in-vivo hydrolysable ester); and/or iii) forming a pharmaceutically-acceptable salt; wherein said processes (a) to (h) are as follows (wherein the variables are as defined above unless otherwise stated): Thus, the present invention also provides that the compounds of the invention and pharmaceutically-acceptable salts and in vivo hydrolysable esters thereof, can be prepared by a process (a) to (h); and thereafter if necessary: i) removing any protecting groups; ii) forming a pro-drug (for example an in-vivo hydrolysable ester); and/or iii) forming a pharmaceutically-acceptable salt; wherein said processes (a) to (g) are as follows (wherein the variables are as defined above unless otherwise stated): a) By modifying a substituent in, or introducing a substituent into another compound of the invention by using standard chemistry (see for example, Comprehensive Organic Functional Group Transformations (Pergamon), Katritzky, Meth-Cohn & Rees). For example: • a hydroxy group may be converted into a fluoro group, an acyloxy group (for instance an acetoxy group), an amino group, a heterocycly] group linked through nitrogen (optionally substituted on a carbon other than a carbon atom adjacent to the linking nitrogen ring atom—for instance an optionally substituted amino group). The skilled artisan understands that such reactions of the hydroxy group take place directly (for instance by acylation or Mitsunobu reaction) or through the intermediacy of one or more derivatives (for instance a mesylate or an azide); • an acyloxy group may be converted into a hydroxy group or into the groups that may be obtained from a hydroxy group (either directly or through the intermediacy of a hydroxy group); an alkyl halide group may be converted to a hydroxy group, an amino group, a tliioalkyl group or a heterocyclyl group linked through nitrogen; a keto group may be reduced to a hydroxy group or an saturated alkyl group. b) as depicted in Scheme 1, by alkylation of a suitable bicyclic ring system containing a NH group in the ring with a suitable alkylating reagent containing a leaving group (such as an O-mesylate, chloro, bromo or iodo) in the presence of a base. Alkylation may be followed by functional group manipulations and/or further alkylations or reductive aminations, Scheme 1 I.NaH N V-NH 1.HCI 2.3A Mol Sieves, ( P— O 3. NaBH(OAc)3 c) As depicted in Scheme 2, by reaction of a suitable bicyclic ring system containing a NH group in the ring with a suitable alcohol under Mitsunobu conditions, followed by deprotection and reductive amination with an aldehyde. This sequence may be followed by functional group manipulations and/or further alkylations or reductive aminations. NH Mi le Me Scheme 2 dlisopropylazodicarboxylate, (Ph)3P P [Pb 1.HCI 2. 3A Mol Sieves, °' [I 3. NaBH(OAc)3 d) As depicted in Scheme 3, by alkylation of a suitable bicyclic ring system containing a NH group in the ring with bromo- or chloroacetic acid or with a derivative thereof, followed by activation of the acid and amide coupling. The amide coupling reaction may be followed by functional group manipulations and/or further alkylations or reductive animations and optional reduction of the amide moiety. Scheme 3 H 1)BrCH2COOH 2) Peptide coupling with amine Me 1.HCI 2. 3A Mol Sieves, 3. NaBH(OAc)3 DIBAL e) As depicted in Scheme 4, by alkylation of a suitable bicyclic ring system containing a NH group in the ring with allylbromide, followed by oxidative cleavage of the double bond with a suitable oxidizing agent, such as ozone or periodate and subsequent manipulation of the resulting alcohol, e.g., by conversion to a mesylate, followed by alkylation. The alkylation reaction may be followed by functional group manipulations and/or further alkylations or reductive animations. Scheme 4 1)Allylbromide/NaH 2) Nal04 OH R 1) Mesylchloride/ NEt3 2) Me Me 1. HCI 2. 3A Mol Sieves, cr H O' 3. Na(BOAc)3H f) As depicted in Scheme 5, by alkylation of a suitable bicyclic ring system containing a NH group in the ring with allylbromide, followed hydroboration and subsequent manipulation of the resulting alcohol, e.g. by conversion to a mesylate, followed by alkylation. The alkylation reaction may be followed by functional group manipulations and/or further alkylations or reductive animations. Scheme 5 H 1)Allylbromide/NaH 2) borane, 1)Mesylchloride/NEt3 Me Me Me 2. 3A Mol Sieves, 3. NaBH(OAc)3 ^^—•* -og) Alternatively, as depicted in Scheme 6,the alcohol intermediate in Scheme 5 may be oxidized to the aldehyde, followed by reductive amination to arrive at the same intermediate. Scheme 6 H -OH -N I JL/ NaBH(OAc)3 O v / Me Me Me 1.HCI 2. 3A Mol Sieves, C r ] \| 3. NaBH(OAc)3 ^sr~~~y -Qh) using essentially the procedure described under c), by reaction of a suitable bicyclic ring system containing a NH group in the ring with an alcohol HO ^\J~ // ~Ny— 0 /-Me Me X= 0 or NR (ii) under Mitsunobu conditions; or by alkylation of a suitable bicyclic ring system containing a NH group with a derivative of (II), where the alcohol moiety is converted to a leaving group, such as 0-mesylate, followed by deprotection and reductive ammination with an aldehyde. This sequence may be followed by functional group manipulations and/or further alleviations or reductive aminations, also using essentially the procedure described under c). For example, as depicted in Scheme 7, an 0-mesylate alkylating reagent may be prepared from the alcohol, by reaction with mesyl chloride, in the presence of a base, such as a trialkyl amine or an immobilized version thereof on a resin. It is understood, that such an alkylating reagent is potentially unstable and needs to be prepared fresh under careful, controlled conditions. Scheme 7 Me O Me 9 Me MsCI NEt3 I I — triethylamine 50°C pressure tube With respect to (a)-(g) and Schemes 1-5 above, the removal of any protecting groups, formation of pharmaceutically-acceptable salts and/or formation of in-vivo hydrolysablc esters or amides are within the skill of an ordinary organic chemist using standard techniques. Furthermore, details regarding these transformations; for example, the preparation of iri-vivo hydrolysable ester prodrugs has been described in the section above on such esters. When an optically active form of a compound of the invention is required, it may be obtained by carrying out one of the above procedures using an optically active starting material (formed, for example, by asymmetric induction of a suitable reaction step), or by resolution of a racemic form of the compound or intermediate using a standard procedure, or by chromatographic separation of diastereoisomcrs (when produced). Enzymatic techniques may also be useful for the preparation of optically active compounds and/or intermediates. Similarly, when a pure regioisomer of a compound of the invention is required, it may be obtained by carrying out one of the above procedures using a pure regioisomer as a starting material, or by resolution of a mixture of the regioisomers or intermediates using a standard procedure. Biological Activity According to a further feature of the invention there is provided a compound of the invention, or a pharmaceutically-acceptable salt, or in-vivo hydrolysable ester thereof for use in a method of treatment of the human or animal body by therapy. According to a further feature of the present invention there is provided a method for producing an antibacterial effect in a warm blooded animal, such as man, in need of such treatment, which comprises administering to said animal an effective amount of a compound of the present invention, or a pharmaceutically-acceptable salt, or in-vivo hydrolysable ester thereof. The ability of the invention compounds disclosed herein to achieve an antibacterial effect is demonstrated by the following tests. Enzyme Potency Testing Methods Supercoiling assay description: Compounds were tested for inhibition of Escherichia coli DNA supercoiling activity as follows. Assays were performed in polypropylene multiwell plates in 50 ul reactions containing 35 mM Tris-HCl (pH 7.5), 24 mM KC1,4 mM MgCl2, 2 mM dithiothreitol, 1.8 mM spermidine, 5% (v/v) glycerol, 200 nM bovine serum albumin, 1.25% (v/v) DMSO, 3 mM ATP, 10 ng/ml relaxed pBR322 plasmid, 0.6 nM DNA gyrase, and test compound. Reactions were quenched after 1 hour by the addition of 10 (j,l of 30% (w/v) Ficoll-400,10 mM EDTA, and 5% sodium dodecyl sulfate. Twenty-five ul of each sample was loaded onto a 0.8% (w/v) agarose gel and electrophoresed. The gel and gel buffer contained IX THE buffer (89 mM Tris base, 89 mM boric acid, and 2 mM EDTA at pH 8.3). After electrophoresis for 3 hours at 70V, the gel was stained with ethidium bromide and visualized by excitation with ultraviolet light. The fluorescence intensity of the most supercoiled plasmid band was used to measure gyrase activity. Compound potency was based ICso measurements determined from reactions performed with eight 2-fold serial dilutions of each compound and a control without compound. Compounds of the Examples generally have an ICso of ATPase assay description: Compounds were tested for inhibition of GyrB ATPase activity using an ammonium molybdate/malachite green-based phosphate detection assay (Lanzetta, P. A., L. J. Alvarez, P. S. Reinach, and O. A. Candia, 1979,100: 95-97). Assays were performed in multiwell plates in 100 \|il reactions containing: 50 mM TRIS buffer pH 7.5, 75 rnM ammonium acetate, 5.5 mM magnesium chloride, 0.5 mM ethylenediaminetetraacetic acid, 5% glycerol, 1 mM 1,4- dithio-DL-threitol, 200 nM bovine serum albumin, 16 ug/ml sheared salmon sperm DNA, 4 nM E. coli GyrA, 4 nM E. coll GyrB, 250 /M ATP, and compound in dimethylsulfoxide. Reactions were quenched with 150 //L of ammonium molybdate/malachite green detection reagent containing 1.2 mM malachite green hydrochloride, 8.5 mM ammonium rnolybdate tetrahydrate, and 1 M hydrochloric acid. Plates were read in an absorbance plate reader at 625 run and percent inhibition values were calculated using dimethylsulfoxide (2%)-containing reactions as 0% inhibition and novobiocin-containing (2 /M) reactions as 100% inhibition controls. Compound potency was based on ICso measurements determined from reactions performed in the presence of 10 different compound concentrations. Compounds of the invention generally have an ICso of Bacterial Susceptibility Testing Methods Compounds were tested for antimicrobial activity by susceptibility testing in liquid media in a 96 well format. Compounds were dissolved in dimethylsulfoxide and tested in 10 doubling dilutions in the susceptibility assays. The organisms used in the assay were grown overnight on suitable agar media and then suspended in a liquid medium appropriate for the growth of the organism. The suspension was a 0.5 McFarland and a further 1 in 10 dilution was made into the same liquid medium to prepare the final organism suspension in 100 jjL. Plates were incubated under appropriate conditions at 37 °C for 24 hours prior to reading. The Minimum Inhibitory Concentration (MIC) was determined as the lowest drug concentration able to reduce growth by 80% or more. Compounds were evaluated against a panel of Gram-positive species, including Staphylococcus aureus, Streptococcuspneumoniae, Streptococcus pyogenes, and Enterococcus faecium. In addition, compounds were evaluated against a panel of Gramnegative species including Haemophilus influenzas, Escherichia coli and Moraxella catarrhalis. Compounds of the present invention have MIC's less than or equal to 8 ug/ml versus one or more of the organisms named above. Data for several compounds of the invention are depicted below: Example 5 66 37 26 49 gyrase ATPase [microgram/ml] 0.07 0.3 0.008 ND ND gyrase supercoiling [microgram/ ml] 0.051 ND ND 0.42 3 E. coli MIC [microgram/ ml] 0.5 4 0.25 1 8 S. pneumo [microgram/ ml] 0.12 8 0.06 0.25 4 Pharmaceutical Formulations In another embodiment the present invention provides a pharmaceutical composition which comprises a compound of formula (I) admixed with a pharmaceutically-acceptable carrier, diluent, or excipient. The invention compositions may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration as eye-drops, for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, sub-lingual, intramuscular or intramuscular dosing or as a suppository for rectal dosing). In addition to the compounds of the present invention, the pharmaceutical composition of this invention may also contain (i.e. through co-formulation) or be co-administered (simultaneously, sequentially or separately) with one or more known drugs selected from other clinically useful antibacterial agents (for example, B-lactams, macrolides, quinolones or aminoglycosides) and/or other anti-infective agents (for example, an antifungal triazole or amphotericin). These may include carbapenems, for example meropenem or imipenem, to broaden the therapeutic effectiveness. Compounds of this invention may also be coformulated or co-administered with bactericidal/permeability-increasing protein (BPI) products or efflux pump inhibitors to improve activity against gram negative bacteria and bacteria resistant to antimicrobial agents. The compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical diluents, carriers, or excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more coloring, sweetening, flavoring and/or preservative agents. A pharmaceutical composition to be dosed intravenously may contain advantageously (for example to enhance stability) a suitable bactericide, antioxidant or reducing agent, or a suitable sequestering agent. Suitable pharmaceutically acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl p_~hydroxybenzoate, and anti-oxidants, such as ascorbic acid. Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absorption of the active ingredient within the gastrointestinal tract, or to improve their stability and/or appearance, in either case, using conventional coating agents and procedures well known in the art. Compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil. Aqueous suspensions generally contain the active ingredient in finely powdered form together with one or more suspending agents, such as sodium carboxymethylcellulosc, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl p_-hydroxybenzoate, antioxidants (such as ascorbic acid), coloring agents, flavoring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame). Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil (such as arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin). The oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set out above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid. Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water generally contain the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as sweetening, flavoring and coloring agents, may also be present. The pharmaceutical compositions of the invention may also be in the form of oil in water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as for example liquid paraffin or a mixture of any of these. Suitable emulsifying agents may be, for example, naturally-occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soya bean, lecithin, an esters or partial esters derived from fatty acids and hexitol anhydrides (for example sorbitan monooleate) and condensation products of the said partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening, flavoring and preservative agents. Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, preservative, flavoring and/or coloring agent. The pharmaceutical compositions may also be in the form of a sterile injectable aqueous or oily suspension, which may be formulated according to known procedures using one or more of the appropriate dispersing or wetting agents and suspending agents, which have been mentioned above. A sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example a solution in 1,3-butanediol. Solubility enhancing agents, for example cyclodcxtrins may be used. Compositions for administration by inhalation may be in the form of a conventional pressurised aerosol arranged to dispense the active ingredient either as an aerosol containing finely divided solid or liquid droplets. Conventional aerosol propellants such as volatile fluorinated hydrocarbons or hydrocarbons may be used and the aerosol device is conveniently arranged to dispense a metered quantity of active ingredient. For further information on formulation the reader is referred to Chapter 25.2 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990. The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. A suitable pharmaceutical composition of this invention is one suitable for oral administration in unit dosage form. For example, a formulation intended for oral administration to humans will generally contain, for example, a therapeutically effective amount of active agent compounded with an appropriate and convenient amount of excipients which may vary from about I to about 98 percent by weight of the total composition. For further information on Routes of Administration and Dosage Regimes the reader is referred to Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990. In another aspect a pharmaceutical composition of the invention is one suitable for intravenous, subcutaneous or intramuscular injection. Each patient may receive, for example, a daily intravenous, subcutaneous or intramuscular dose of a compound of this invention, the composition being administered 1 to 4 times per day. The intravenous, subcutaneous and intramuscular dose may be given by means of a bolus injection. Alternatively, the intravenous dose may be given by continuous infusion over a period of time. Alternatively, each patient may receive a daily oral dose which may be approximately equivalent to the daily parenteral dose, the composition being administered 1 to 4 times per day. A composition of the present invention is synergistic and exhibits surprising and unexpected effects. Therefore, the said composition is synergistic in nature. Examples The invention will now be illustrated by the following non-limiting examples. Example 1 l-(2-{4-[(2,3-Dihydro[l,4]dioxino[2^-c]pyridln-7-ylmethyl)amino]piperidin-lyl} ethyl)-7-methoxyquinolm-2(lJ3)-one A solution of l-[2-(4-aminopiperidin-l-yl)ethyl]-7-methoxyquinolin-2(l//)-one (Intermediate 1, crude, 60 mg, 0.20 mmol) and 2,3-dihydro[l,4]dioxino[2,3-c]pyridine-7- carbaldehyde (WO 2004/058144) (33 mg, 0.20 mmol) in dry chloroform/methanol (5 raL, 1:1) was heated over 3 A molecular sieves at 70°C for 3 hours. The reaction mixture was cooled to 0°C, and sodium triacetoxy borohydride (127 mg, 0.6 mmol) was added. The resulting reaction mixture was stirred at room temperature for 30 minutes and then was filtered through a 0.45 um membrane and concentrated to dryness under reduced pressure. The residue was taken up in dichloromethane (50 mL) and saturated aqueous sodium hydrogen carbonate solution (5 mL). The pH of the aqueous phase was adjusted to a pH of 10 with 1M aqueous sodium hydroxide solution. The aqueous phase was back extracted twice with dichloromethane (2x 20 mL) and the combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. Chromatography on silica gel with dichloromethane/ methanol (8:1 to 4:1) gave the free base of the title compound as a colorless oil. The free base was taken up in dichloromethane (2 mL), ethanol (7 mL) was added, followed by addition of 1M HC1 in ether (0.3 mL). The colorless precipitate was collected by filtration and gave 50 mg (48%) of the bis-hydrochloride salt of the product, mp 243°C. MS (ESV 451.14 (MH) for QjHsoN-A fDMSO-d^ 8 (ppm): 2.00-3.80 (m, 1 1H); 3.96 (s, 3H); 4.20-4.45 (m, 6H); 4.68 (m, 2H); 6.45 (d, 1H); 6.93 (d, 1H); 7.18 (s, 1H); 7.30 (s, 1H); 7.68 (d, 1H); 7.88 (d, 1H); 8.25 (s, 1H); 9.74 (brs, 2H); 11.18 (brs, 1H). Intermediate 1: l-[2-(4-Aminopiperidin-l-vl')ethvn-7-methoxvquinolin-2('lffl-one A solution of tert-butyl {l-[2-(7-methoxy-2-oxoquinolin-l(2//)-yl)ethyl]piperidin-4- yl}carbamate (Intermediate 2, 150 mg, 0.37 mmol) in dioxane (4 mL) was treated at room temperature under vigorous stirring with a solution of HC1 in dioxane (4M, 2 mL). After 18 hours, the reaction mixture was concentrated under reduced pressure. The residue was taken up in dichloromethane (60 mL) and saturated aqueous sodium hydrogen carbonate solution (10 mL). The aqueous phase was extracted three times with dichloromethane (3x 50 mL) and the combined organic phases were dried over sodium sulfate and concentrated under reduced pressure to give 1 13 mg (100% yield) of the crude product as an oil. MS (ESV. 302.24 (MH) for Ci7H23N302 'H-NMR (DMSO-d^ 8: 1.21 (m, 2H); 1.65 (m, 2H); 2.04 (t, 2H); 2.40-2.52 (m, 2H); 2.89 (m, 2H); 3.69 (m, 1H); 3.88 (s, 3H); 4.31 (t, 2H); 6.40 (m, 1H); 6.88 (m, 1H); 6.94 (m, 1H); 7.63 (m, 1H); 7.80 (m, 1H). (The NH2 protons were not observed) Intermediate 2: te/V-ButvI n-[2z(7-methoxv-2-oxoquinolin-l(2ffl-yI)e(hyl]piperidin- 4-yl} carbamate A solution of 7-methoxyquinolin-2(l#)-one (Intermediate 3, 340 mg, 2.2 mmol) in dry dimethylformarnide (DMF) (10 mL) was treated at 0°C with a cooling bath under stirring with sodium hydride (88 nig, 60% in oil, 2,2 mmol). The cooling bath was removed and the mixture was stirred for 30 minutes at room temperature. A solution of 2-{4-[(tertbutoxycarbonyl) amino]piperidin-l-yl} ethyl methanesulfonate in N,N-dimethylformamide (DMF) (Intermediate 6, 0.58 mmol/ mL, 3.5 mL, 2.03 mmol) was then added and the resulting mixture was stirred over night at room temperature. Thin Layer Chromatography (TLC): Rf = 0.1 (hexanes/ acetone, 1:1) (the 0-alkylated product was observed as a minor product and has a rf value of 0.3). The DMF was removed under reduced pressure, and the residue was taken up in ethyl acetate (100 mL) and saturated aqueous sodium hydrogencarbonate solution (30 mL). The aqueous phase was back extracted once with ethyl acetate (50 mL). The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. Chromatography on silica gel with hexanes/acetonc (1:1) gave!53 mg (20% yield) of the product as a colorless hard foam. MS (ES): 402.25 (MH+) for CaHajNsCU 'H-NMR (DMSO-d^ 5: 1.30-1.42 (m, 2H); 1.36 (s, 9H); 1.66 (m, 2H); 2.04 (m, 211); 2.45-2.53 (m, 2H); 2.92 (m, 2H); 3.15 (m, 1H); 3.88 (s, 3H); 4.31 (t, 211); 6.39 (m, 1H); 6.76 (m, 1H); 6.88 (m, 1H); 6.93 (m, 1H); 7.62 (d, 1H); 7.80 (d, 1H). (The structure was confirmed by an HMBC-NMR experiment) Intermediate 3: 7-Methoxyquinolin-2(lffl-one A solution of methyl (2£)-3-(2-amino-4-methoxyphenyl)acrylate (Intermediate 4, 500 mg, 2.4 mmol) in acetonitrile (600 mL) was deoxygenated under vacuum, purged with nitrogen and irradiated at 365 nm with a long wave UV lamp (B-100AP, Blak Ray) for 28 hours. The solvent was removed under reduced pressure and the product was precipitated from dichloromethane (20 mL) by the addition of hexanes (100 mL) to give 357 mg (76% yield) of the crude product as a colorless solid, 90 % pure by 'H-NMR (together with 10% dimer), mp 190°C. MS (ESV. 176.21 (MH) for Ci0H9N02 'H-NMR fDMSO-dfil 8: 3.79 (s, 3H); 6.28 (d, 1H); 6.75-6.81 (m, 2H); 7.55 (d, 1H); 7.79 (d, 1H); 11.59 (s, 1H). Intermediate 4: Methyl f2Jg)-3-f2-amino-4-methoxvphenvl)acrvlate To a solution of methyl (2JS)-3-(4-methoxy-2-nitrophenyl)acrylate (Intermediate 5, 4.9 g, 20.66 mmol) in acetic acid (150 mL) at room temperature under nitrogen was added zinc powder (7.7 g, 118 mmol) in portions. After 4 hours, another 5 g of zinc was added and the resulting reaction mixture was heated at 50°C for two hours. The reaction mixture was then cooled to room temperature, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was chromatographed on silica gel with hexanes/ethyl acetate (3:1) to give 1.0 g (23% yield) of product as a yellow solid, mp 149°C. MS (Eg): 208.17 (MH4" for CnHi3N03 'H-NMR (DMSO-dQ 5: 3.67 (s, 3H); 3.68 (s, 3H); 5.68 (brs, 2H); 6.14 (dd, 1H); 6.21 (d, 1H); 6.23 (s, 1H); 7.40 (d, 1H); 7.82 (d, 1H). Intermediate 5: (2E)-3 -(4-Methoxv-2-nitrophenvl)acrylate A solution of 4-iodo-3-nitroanisole (10 g, 36 mmol), methylacrylate (3.87 mL, 43 mmol), tris(4-methylphenyl)phosphine (1.1 g, 3.6 mmol) and triethylamine (6.05 mL, 43 mmol) was degassed and flushed with nitrogen. Palladium(II) acetate (1.2 g, 1.8 mmol) was added and the mixture was heated at 70°C overnight. It was filtered through a 0.45 urn membrane and the solvent was removed under reduced pressure. The residue was taken up in ethyl acetate (300 mL), it was washed with potassium phosphate buffer (1M, pH 7, 2x 300 mL) and dried over sodium sulfate. Chromatography on silica gel with dichloromethane, followed by precipitation from dichloromethane (50 mL) with hexanes (500 mL) gave 4,96 g (58% yield) of product as a yellow solid. MSnBS): 260.20 (MNa) for CnH,iN05 'H-NMR CDMSO-d^l 5: 3.73 (s, 3H); 3.88 (s, 3H); 6.59 (d, 1H); 7.33 (dd, 1H); 7.57 (d, 1H); 7.78 (d, 1H); 7.94 (d, 1H). Intermediate 6: 2-(44(ter/-Butoxvcarbonyl)arnino]piperidin-1 -yl)ethyl methanesulfonate A mixture of tert-butyl [l-(2-hydroxyethyl)piperidin-4-yl]carbamate (Intermediate 7, 1.7 g, 7 mmol) in dry dichloromethane (20 mL) and triethyl amine (1.4 mL, 9.8 mmol) was treated at 0°C with methanesulfonyl chloride (0.65 mL, 8.4 mmol). After 45 minutes the reaction was complete by TLC (chloroform/methanol 6:1, rf 0.54). Potassium phosphate buffer (pH 7, 1M, 50 mL) was added, dichloromethane was removed under reduced pressure and it was extracted with ice-cold ethyl acetate (2 x 100 mL) and dried over sodium sulfate. The solvent was removed under reduced pressure and the crude preparation of the mesylate was used without delay for the next step, MS HSS>: 323.18 (MH) for Intermediate 7: tert-Butvl [l-('2-hydroxvethyl')piperidin-4-vl1carbamate A mixture of tert-butyl piperidin-4-ylcarbamate (5 g, 25 mmol), 2-bromoethanol (1.77 mL, 25 mmol) and triethylamine (3.86 mL, 27.5 mmol) in acetonitrile (20 mL) was heated in a sealed tube at 50°C for 16 hours. The solvent was removed under reduced pressure, and the residue was taken up in ethyl acetate (300 mL) and washed with saturated aqueous sodium hydrogen carbonate solution (100 mL). The aqueous phase was back-extracted once with ethyl acetate (100 mL) and the combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. Chromatography on silica gel with dichloromethane/ methanol (4:1) gave 4.04 g (66% yield) of product as a colorless solid, mp 66°C. MS (BS): 245.28 (Mtf) for CuR^Os 'H-NMR fPMSO-dft 5: 1.33 (m, 2H); 1.36 (s, 9H); 1.62 (m, 2H); 1.92 (t, 2H); 2.32 (t, 2H); 2.77 (m, 2H); 3.17 (m, 1H); 3.43 (m, 2H); 4.34 (t, 1H); 6.73 (d, 1H). Example 2 l-(2-{4-[(23-I>ihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)aminolpiperidin-lyl} ethyl)-7-methoxyquinolin-4(lfl)-one A solution of l-[2-(4-aminopiperidin-l-yl)ethyl]-7-methoxyquinolin-4(l//)-onc (Intermediate 8, 60 mg, 0.20 mmol) and2J3-dihydro[l,4]dioxino[2,3-c]pyridine-7- carbaldehyde (WO 2004/058144) (33 mg, 0.20 mmol) in dry chloroform/ methanol (5 mL, 1:1) was heated over 3 A molecular sieves at 70°C for 3 hours. The reaction mixture was cooled to 0°C, and sodium triacetoxyborohydride (127 mg, 0.6 mmol) was added and the resulting mixture was stirred at room temperature for 30 minutes. The mixture was then filtered through a 0.45 urn membrane, acidified with cone. HC1 to pll 1 and concentrated to dryness under reduced pressure. The residue was taken up in dichloromethane (50 mL) and saturated aqueous sodium hydrogen carbonate solution (5 mL). The pH of the aqueous phase was adjusted to pHIO with 1M aqueous sodium hydroxide solution. The aqueous phase was back extracted twice with dichloromethane (2x 20 mL) and the combined organic phases were dried over sodium sulfate. Chromatography on silica gel with dichloromethane/methanol (4:1), containing 0.125% ammonium hydroxide, gave the free base of the title compound as a colorless oil. The free base was taken up in dichloromethane (2 mL), ethanol (7 mL) was added, followed by addition of 1M HC1 in ether (0.45 mL). The colorless precipitate was collected by filtration and gave 84 mg (81% yield) of the bis-hydrochloride salt of the product, mp 260°C. MS (ESV 451.21 (MH+) for C25H3oN404 'H-NMR fDMSO-d^ 5: 2.00-3.80 (m, 11H); 4.07 (s, 3H); 4.30-4.46 (m, 6H); 5.06 (m, 2H); 6.83 (d, 1H); 7.28 (d, 1H); 7.45-7.58 (m, 2H); 8.22 (d, 1H); 8.37 (s, 1H); 8.61 (d, 1H); 9.94 (brs, 2H); 11.90 (brs, 1H). Intermediates: l-r2-(4-Arninopiperidin-l-yDethvl]-7-methoxvquinolin-4d/f)-Qne A mixture of tert-butyl {l-[2-(7-methoxy-4-oxoquinolin-l(4/f)-yl)ethyl]piperidin-4- yl}carbamate (Intermediate 9, 370 mg, 0.92 mmol) in dioxane (10 mL) was treated at room temperature under vigorous stirring with a solution of HC1 in dioxane (4M, 4 mL). After 18 hours, the reaction mixture was diluted with isopropanol (10 mL) and with water (4 ml.) and more HC1 in dioxane (4M, 5 mL) was added. After Ihour, the reaction mixture was concentrated under reduced pressure to give the hydrochloride of the product as a colorless solid. The hydrochloride salt was taken up in aqueous sodium hydroxide solution (1M, 10 mL) and extracted with dichloromethane (60 mL). The aqueous phase was extracted three times with dichloromethane (3x 60 mL) and the combined organic phases were dried over sodium sulfate to give 278 mg (100% yield) of the crude product as an oil. MS (ES): 302.24 (MH+) for CnH^NaC^ 'H-NMR (DMSO-d^ (data for the hydrochloride salt) 6: 1.80-2.30 (m, 4H); 3.14 (m, 2H); 3.36 (m, 1H); 3.48 (m, 2H); 3.68 (m, 2H); 4.06 (s, 3H); 5.03 (m, 2H); 6.74 (d, 1H); 7.24 (d, 1H); 7.45 (s, 1H); 8.21 (d, 1H); 8.46 (brs, 2H); 8.55 (d, 1H); 8.60 (brs, 1H); 11.95 (brs, 1H). Intermediate 9: te/V-Butyl ll-[2-C7-methoxy-4-oxoquinolin-ir4//)-vl')ethvl1piperidin- 4-yUcarbamate A solution of 7-methoxyquinolin-4-ol (Intermediate 10, 500 mg, 2.85 mmol) in dry DMF (10 mL) was treated at 0°C with a cooling bath under stirring with sodium hydride (114 mg, 60% in oil, 2.85 mmol). The cooling bath was removed and the mixture was stirred for 30 minutes at room temperature. A solution of 2-{4-[(te/-/-butoxycarbonyl)amino]piperidin-] - yl}ethyl methanesulfonate in DMF (Intermediate 6, 0.58 mmol/ mL, 5 raL, 2.9 mmol) was added and the resulting solution was stirred over night at room temperature. DMF was removed under reduced pressure, the residue was taken up in ethyl acetate (100 mL) and saturated aqueous sodium hydrogen carbonate solution (30 mL) and the aqueous phase was back extracted three times with ethyl acetate (3x 70 mL). The combined organic phases were dried over sodium sulfate. Some starting 7-methoxyquinolin-4-ol was precipitated from dichloromethane (30 mL) with hexanes (20 mL) and removed by filtration. The filtrate was concentrated to dryness under reduced pressure. Chromatography of the residue on silica gel with acetonitrile/water (15:1 to 10:1) gave 373 mg (33% yield) of the product as a colorless solid, mp 207°C. MS (ES): 402.36(MH+) for C22H3iN304 'H-NMR(DMSO-dg) 5: 1.25-1.37 (m, 2H); 1.35 (s, 9H); 1.63 (m, 2H); 2.02 (m, 2H); 2.60 (t, 2H); 2.82 (m, 2H); 3.16 (m, 1H); 3.89 (s, 3H); 4.28 (t, 2H); 5.92 (d, 1H); 6.75 (d, 1H); 6.96 (dd, 1H); 7.00 (d, 1H); 7.82 (d, 1H); 8.06 (d, 1H). Intermediate 10; 7-Methoxvquinolin-4-ol 5-{[(3-Methoxyphenyl)amrno]methylene}-2,2-dimethyl-l,3-dioxane-4,6-dione (Intermediate 11, 43.5 g, 157 mmol) was added in small portions to phenylether (200 mL) at 225-260°C under stirring. The reaction mixture was stirred for an additional 5 minutes, until the evolution of gas had stopped. The reaction mixture was cooled to room temperature and the precipitate was collected by filtration and washed with hexanes. Purification by recrystallization from methanol gave 12.4 g (45% yield) of product as a green solid, mp 210°C. MS (ES): 176.21 (MM"1) forCi0H9N02 te-NMR rDMSO-d^ 5: 3.83 (s, 3H); 5.93 (d, 1H); 6.85-6.95 (m, 2H); 7.80 (m, 1H); 7.97 (d,!H);l 1.55 (brs, 1H). Intermediate 11; S-lfG-MethoxyphenvDaminolmethylenel^^-dimethyl-l^- dioxane-4.6-dione A mixture of m-anisidine (22 g, 178 mmol), 2,2-dimethyl-l,3-dioxane-4,6-dione (30.75 g, 214 mmol) and triethylorthoformate (30 mL, 178 mmol) in ethanol (200 mL) was heated at 85°C for two hours. The mixture was allowed to cool to room temperature and the precipitate was collected by filtration and washed with ethanol to give 43,7 g (89% yield) of product as a pale yellow solid, mp 108°C. MS fESV 276.12 (M-H-) for CwHijNOs ^ 5: 1.66 (s, 6H); 3.78 (s, 3H); 6.81 (d, 1H); 7.09 (d, 1H); 7.19 (ra, 1H); 7.32 (dd, 1H); 8.59 (d, 1H); 11.19 (d, 1H). Example 3 Methyl l-(2-{4-[(2,3-dihydro[l,4]dioxino[2,3-c]pyridin-7- ylmethyl)amino]piperidin-l-yl}ethyl)-6-niethoxy-l//-indole-2-carboxylate A solution of methyl l-[2-(4-aminopiperidin-l-yl)ethyl]-6-methoxy-l//-indole-2- carboxylate (Intermediate 12, 200 mg, 0.60 mmol) and 2,3-dihydro[l,4]dioxino[2,3- c]pyridine-7-carbaldehyde (WO 2004/058144) (100 rag, 0.60 mmol) in dry chloroform/ methanol (10 mL, 1:1) was heated over 3 A molecular sieves at 70°C for 3 hours. The reaction mixture was cooled to 0°C, sodium triacetoxy borohydride (384 mg, 1.8 mmol) was added and the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was filtered through a 0.45 u,m membrane and concentrated to dryness under reduced pressure. The residue was taken up in dichloromethane (150 mL) and saturated aqueous sodium hydrogen carbonate solution (30 mL), the aqueous phase back extracted once with dichloromethane (70 mL) and the combined organic phases were dried over sodium sulfate. Chromatography on silica gel with dichloromethane/ methanol (5:1), containing 0.125% ammonium hydroxide, gave the free base of the title compound, 239 mg (82% yield), as a colorless solid, mp 130°C. MS (ESV 481 .15 (MH4) for C^Hb^Os 'H-NMR rDMSO-d^ 5: 1.10-1.25 (m, 2H); 1.70 (m, 2H); 1.96 (t, 2H); 2.12 (m, 1H); 2.30 (m, 2H); 2.79 (m, 2H); 3.62 (s, 2H); 3.80 (s, 3H); 3.82 (s, 3H); 4.22-4.35 (m, 4H); 4.58 (t, 2H); 6.75 (m, 1H); 6.91 (s, 1H); 7.01 (s, 1H); 7.17 (s, 1H); 7.52 (d, 1H); 7.98 (s, 1H). Intermediate 12: Methyl l-r2-(4-aminopiperidin-l-yl)etlw!]-6-methoxy-l//-indole-2- carboxylate A solution of methyl l-(2-{4-[(te/"/-butoxycarbonyl)amino]piperidin-l-yl}ethyl)-6- methoxy-l/f-indole-2-carboxylate (Intermediate 13, 520 mg, 1.2 mmol) in dioxane (4 mL) was treated at room temperature under vigorous stirring with a solution of HC1 in dioxane (4M, 2 mL). After 3 days, the reaction mixture was concentrated under reduced pressure. The residue was taken up in dichloromethane (60 mL) and saturated aqueous sodium hydrogen carbonate solution (10 mL), the aqueous phase was extracted three times with dichloromethane (3x 50 mL) and the combined organic phases were dried over sodium sulfatc to give 407 mg (100% yield) of the crude product as colorless solid, mp 101°C, MS (ES\. 332.23 (MH4) for CiglfeNsOa 'H-NMR fDMSO-d^ 5: 1.15 (m, 2H); 1.61 (m, 2H); 1.99 (t, 2H); 2.51 (m, 2H); 2.79 (m, 2H); 3.49 (m, 1H); 3.81 (s, 3H); 3.83 (s, 3H); 4.59 (t, 2H); 6.76 (m, 1H); 7.02 (brs, 1H); 7.18 (s, 1H); 7.53 (d, 1H). (The NH2 protons were not observed) Intermediate 13: Methyl l-(2-H-[( 6-methoxy-l/jr-indole-2-carboxylate A solution of methyl 6-methoxy-2-indole-carboxylate (574 mg, 2.8 mmol) in dry DMF (10 mL) was treated at 0°C with a cooling bath under stirring with sodium hydride (123 mg, 60% in oil, 3.08 mmol). The cooling bath was removed and the mixture was stirred for 30 minutes at room temperature. A solution of 2-{4-[(ter ethyl methanesulfonate in DMF (Intermediate 6, 0.58 mmol/ mL, 3.4 mL, 2.0 mmol) was added and the resulting mixture was stirred over night at room temperature. The DMF was removed under reduced pressure, the residue was taken up in ethyl acetate (100 tnL) and saturated aqueous sodium hydrogencarbonate solution (30 mL) and the aqueous phase was back extracted once with ethyl acetate (70 mL). The combined organic phases were dried over sodium sulfate. Chromatography on silica gel with hexanes/ethyl acetate (1:1 to pure ethyl acetate) gave 523 mg (43% yield) of the product as a colorless solid, mp 158°C. MS fESV 432.25 (MH+) for CaHtoNaOs 'H-NMR (DMSO-d^ S: 1.23-1.37 (m, 2H); 1.35 (s, 9H); 1.63 (m, 2H); 1.99 (t, 2H); 2.51 (m, 2H); 2.81 (m, 2H); 3.15 (m, 1H); 3.81 (s, 3H); 3.83 (s, 3H); 4.58 (t, 2H); 6.72-6.78 (m, 2H); 7.01 (brs, 1H); 7.17 (s, 1H); 7.53 (d, 1H). Example 4 6-[({l-[2-(7-Methoxy-2-oxoquinolin-l(2J?)-yl)ethyl]piperidin-4-yl}amino)methyl]- 2#-pyrldo[3,2-A] [1,4] oxazin-3(4#)-one l-[2-(4-Aim'nopiperidm-l-yl)emyl]-7-methoxyquinolin-2(l//)-one (Intermediate 1, crude, 60 mg, 0.20 mmol), 3-oxo-3,4-dihydro-2/f-pyrido[3,2-i][l,4]oxazine-6-carbaldehyde (WO 2004/058144) (43 mg, 0.24 mmol) in dry dichloroethane/methanol (10 mL, 1:1) were heated over 3 A molecular sieves at reflux for 4 hours. The reaction mixture was cooled to 0°C, and sodium cyanoborohydride (19 mg, 0.30 mmol) was added and it was stirred at room temperature for 2 hours. The mixture was filtered through a fritted runnel and concentrated to dryness under reduced pressure. The residue was taken up in ethyl acetate and washed with saturated sodium bicarbonate followed by saturated sodium chloride. The saturated sodium bicarbonate was extracted with chloroform, and the chloroform was washed with saturated sodium chloride. The ethyl acetate and chloroform extracts were combined, dried over sodium sulfate and concentrated to dryness under reduced pressure. Silica gel chromatography with dichloromethane/methanol/ammonia ammonia (8:2:0.01) gave title compound as a colorless oil, 27 mg (30%). MS fESV 464.34 (MET") for Cis^NsCU 'H-NMRrCDCK-d) 6: 1.93 (m, 4H); 2.94 (m, 3H); 3.38 (m, 2H); 3.48 (s, 2H); 4.02 (m, 6H); 4.64 (s, 2H); 4.66 (m, 1H); 6.51 (d, J = 9.4 Hz, 1H); 6.83 (dd, J = 6.5,2.1 Hz, 1H); 7.22 (d, J - 8.1 Hz, 1H); 7.46 (m, 2H); 7.62 (m, 211). Example 5 l-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]pipcridin-lyl} ethyl)-2-oxo-l,2-dihydroquinoline-7-carbonitrile 1 -[2-(4-Aminopiperidin-1 -yl)ethyl]-2-oxo-1,2-dihydroquinoline-7-carbonitrile (Intermediate 14, 70 mg, 0.24 mmol), 2,3-dihydro[l,4]dioxino[2,3-c]pyridine-7- carbaldehyde (WO 2004/058144) (40 mg, 0.24 mmol) and sodium triacetoxy borohydride (150 mg, 0.75 mmol) were reacted as described for Example 1, but the aqueous workup was omitted. Chromatography on silica gel with dichloromethane/ methanol (6:1) and crystallization from dichloromethane/ ether/ hexanes gave the monoacetate salt of the product as a colorless solid, 69 mg (58%), mp 130-135°C. MS (ES\. 446.24 (MH+) for Cjs^NsOs 'H-NMR (PMSO-d^ 8: 1.19 (m, 2H); 1.73 (m, 2H); 1.89 (s, 3H); 2.00 (t, 2H); 2.34 (m, 1H); 2.51 (m, 2H, under solvent peak); 2.88 (m, 2H); 3.65 (s, 2H); 4.24-4.37 (m, 6H); 6.76 (d, 1H); 6.92 (s, 1H); 7.63 (dd, 1H); 7.90 (d, 1H); 7.97-8.00 (m, 2H); 8.07 (brs, 1H). Intermediate 14: H2-(4-Ammopiperidin-l-ynethyl1-2-oxo-1.2-dihydroquinoline-7- carbonitrile A solution of ter/-butyl {l-[2-(7-cyano-2-oxoquinolin-l(2//)-yl)ethyl]piperidin-4- yl}carbamate (Intermediate 15) (6.57 g, 16.57 mmol) in dichloromethane (100 :nL) was treated with trifluoroacetic acid (40 mL) at 0°C for 30 minutes. The solvent was removed under reduced pressure and the residue codistilled once with dichloromethane, then taken up in dichloromethane (200 mL) and washed with saturated sodium hydrogencarbonate solution (50 mL, pH adjusted to 10 with sodium hydroxide). The aqueous phase was back-extracted three times with dichloromethane (3x 100 mL) and dried over sodium sulfate. The solvent was removed under reduced pressure to give the product as off-white solid, 5g, mp 138°C. MS (ES): 296.91 (MH+) for Ci7H2oN40 'H-NMRfDMSO-dO 5: 1.13 (m, 2H); 1.48 (m, 1H); 1.62 (m, 2H); 2.01 (t, 2H); 2.50 (m, 2H, under solvent peak); 2.86 (m, 2H); 4.35 (t, 2H); 6.76 (d, 1H); 7.63 (d, 1H); 7.90 (d, 1H); 7.98 (d, 1H); 8.07 (s, 1H). Intermediate 15: ter/-Butvl (l-[2-r7-cvano-2-oxoquinolin-U2flr)-vl)ethvnpiperidin- 4-vl}carbamate A mixture of ter/-butyl {l-[2-(7-bromo-2-oxoquinolin-l(2//)-yl)ethyl]piperidin-4- yl}carbamate (Intermediate 16) (9.85 g, 21.9 mmol) and potassium cyanide (2.14 g, 32.8 mmol) in dry acetonitrile (60 mL) was degassed and flushed with nitrogen three times. Tributyltinchloride (0.059 mmol, 1.13 mL of a 51.6 mM solution in heptane) was added, followed by 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (63 mg, 0.11 mmol) and tris(dibenzylideneacetone)dipalladium (0) (100 mg, 0.11 mmol) and it was degassed and flushed with nitrogen like above, The mixture was stirred for 30 minutes at room temperature and then degassed and flushed with nitrogen again. It was heated at 85°C for 20 hours. The solvent was removed under reduced pressure and the residue taken up in dichloromethane (500 mL) and washed with water (200 mL). The aqueous phase was back-extracted once with dichloromethane (200 mL) and combined organic phases were dried over sodium sulfate. Solvent was removed under reduced pressure and the residue was crystallized from acetonitrile ( 60 mL) to give the product as a colorless solid, 6.57g (76%), mp 202°C. MS (ESI: 397.21 (MH) for 'H-NMRfDMSO-d.) 5: 1.30 (m, 2H); 1.36 (s, 9H); 1.64 (m, 2H); 2.02 (m, 2H); 2.50 (m, 2H, under solvent peak); 2.90 (m, 2H); 3.15 (m, Hi); 4.34 (t, 2H); 6.74-6.78 (m, 2H); 7.63 (m, 1H); 7.89 (d, 1H); 7.99 (d, 1H); 8.05 (s, 1H). Intermediate 16: tert-Butvl n-r2-f7-bromo-2-oxoquinolin-l(2fln)-vl')ethvnpiperidin- 4-yl} carbamate 7-Bromoquinolin-2(l//)-°ne (Intermediate 17) (7.4 g, 33 mmol) was deprotonated with sodium hydride (1.45 g, 60% in oil, 36 mmol) and alkylated with 2-{4-[(tertbutoxycarbonyl) amino]piperidin-l-yl} ethyl methanesulfonate (Intermediate 6) (40 mmol) as described for Intermediate 2; Chromatography on silica gel with hexanes/ acetone (5:2) gave 9.87 g (66%) of the product as a colorless solid, mp 155°C. MS (ES\. 450\452 (MIT1) for CjiEbBrNsOa 'H-NMR (DMSO-d^ 5: 1.32 (m, 2H); 1.36 (s, 9H); 1.65 (m, 2H); 2.01 (t, 2H); 2.46 (m, 2H); 2.90 (m, 2H); 3.19 (m, 1H); 4.29 (t, 2H); 6.61 (d, 1H); 6.75 (d, 1H); 7.41 (d, III); 7.65 (d, 1H); 7.73 (brs, 1H); 7.89 (d, 1H). Intermediate 17: 7-Bromoquinolin-2(l//)-one (2£)-W-(3-bromophenyl)-3-phenylacrylamide (Intermediate 18) (16 g, 53 mmol) and aluminium trichloride (31.8 g, 238 mmol) were heated in chlorobenzene (100 mL) at 90°C bath temperature for one hour. The reaction mixture was cooled to room temperature and poured onto ice. It was stirred until the ice was completely melted, the mixture was filtered and washed with water and ethyl acetate to give the crude product as slightly brown solid in a mixture with the minor product 5-bromoquinolin-2(l/3f)-one (3:2), 8.8 g (70%). This mixture could not be separated. The mixture was heated in phosphoroxychloride (50 mL) at 65°C for one hour. The reaction mixture was cooled to room temperature and poured onto ice. Tt was carefully neutralized at 0°C with sodium carbonate, extracted into ethyl acetate (300 mL), washed with brine, dried over sodium sulfate and concentrated to give the crude mixture of 7- bromo-2-chloroquinoline and 5-bromo-2-chloroquinoline. The mixture was taken up in dichloromethane (100 mL), treated with silica gel (20 g), filtered and the filter cake was washed with dichloromethane. Filtrate and wash were combined and concentrated. The residue was crystallized from toluene/ hexanes (70 mL, 1:1) to provide pure 7-bromo-2- chloroquinoline, 3.74 g as a colorless solid mp 113 °C. MS (ES): 242/244/246 (Mtf) for C9H5BrClN 'H-NMRfDMSO-dfi') 5:1.63 (d, J 8.4 Hz, 1H); 7.81 (dd, J 8.4,1.6 Hz, 1H); 8.03 (d, J 8.4 Hz, 1H); 8.18 (d, J 1.6 Hz, 1H); 8.48 (d, J 8.4 Hz, 1H). 7-Bromo-2-chloroquinoline was heated in 5M HC1 (100 mL) and dioxanc (10 mL) for 1 hour at reflux. The Reaction mixture was cooled, filtered and washed with water to give the title compound, 2.89 g, as a colorless solid, mp 295°C. MS (ES): 224.13/226.13 (MH) for C9H6BrNO 'H-NMR(DMSO-dg) 5: 6.51 (d, J 9.6 Hz, 1H); 7.32 (dd, J 8.6,1.6 Hz, 1H); 7.46 (d, J 1.6 Hz, 1H); 7.61 (d, J 8.6 Hz, 1H); 7.88 (d, J 9.6 Hz, 1H); 11.80 (brs, 1H). Intermediate 18: (2Jg)-JV-(3-BromophenylV3-phcnvlacrylamide To a solution of 3-broraoaniline (13.1 mL, 120 mmol) in dichloromethane (100 mL) and 2,6-lutidine (21 mL, 180 mmol) at 0°C was added a solution of cinnamoylchloride (20 g, 120 mmol) in dichloromethane (50 mL) dropwise. The reaction mixture was allowed to reach room temperature and was stirred for 2 hours. It was quenched with potassium phosphate buffer (100 mL, 1M, pH 7) and stirred for 15 minutes. Dichloromethane was removed under reduced pressure. The residue was extracted with ethyl acetate. The organic phase was washed with phosphate buffer (200 mL), dried over sodium sulfate and concentrated to dryness. The residue was crystallized from toluene/ hexanes to give the product as colorless solid (33.4 g, 92%). MS (BS); 302/304 (MH) for CisHnBrNO 'H-NMRfDMSQ-dfilS: 6.79 (d, 1H); 7.23-7.70 (m, 9H); 8.07 (s, 1H); 10.38 (s, 1H). Example 6 2-Oxo-l-[2-(4-{[(3-oxo-3,4-dihydro-2ff-pyrido[3,2-6][l,4]oxazin-6- yl)methyl]amino}piperidin-l-yl)ethyl]-l,2-dihydroquinoline-7-carbonitrile l-[2-(4-Aminopiperidin-l-yl)ethyl]-2-oxo-l,2-dihydroquinoline-7-carbonitrile (Intermediate 14, 70 mg, 0.24 mmol), 3-oxo-3,4-dihydro-2#-pyrido[3,2-Z>][l,4]oxazine-6- carbaldehyde (WO 2004/058144) (42 mg, 0.24 mmol)and sodium triacetoxy borohydride (150 mg, 0.75 mmol) were reacted as described for Example 5. Chromatography on silica gel with dichloromethane/ methanol (6:1) and crystallization from ethyl acetate/ hexanes gave the product as a colorless solid, 73 mg (67%), mp 212°C. MS (ES): 459.37 (MH) for C2sHa6N«03 'H-NMRfDMSO-dgtS: 1.19 (m, 2H); 1.74 (m, 2H); 2.01 (t, 2H); 2.35 (m, 1H); 2.51 (m, 2H, under solvent peak); 2.88 (m, 2H); 3.65 (s, 2H); 4.35 (t, 2H); 4.59 (s, 2H); 6.76 (d, 1H); 7.00 (d, 1H); 7.28 (d, 1H); 7.63 (dd, 1H); 7.89 (d, 1H); 7.99 (d, 1H); 8.06 (bis, 1H); 11.08(brs, Example 7 6-[({l-[2-(7,8-Difluoro-2-oxoquinolin-l(2fl)-yl)ethylJpiperidin-4- yl}amino)methyl]-2#-pyrido[3,2-&][l,4]oxazin-3(4#)-one 1 -[2-(4-Aminopiperidin- 1 -yl)ethyl] -7, 8-difluoroquinolin-2( 1 /f)-one (Intermediate 19) (100 mg, 0.325 mmol), 3-oxo-3)4-dihydro-2#-pyrido[3,2-&][l,4]oxazine-6-carbaldehyde (WO 2004/058144) (58 mg, 0.325 mmol) and sodium triacetoxy borohydride (207 mg, 0.98 mmol) were reacted as described for Example 1, but the aqueous workup was omitted, to give 107 mg of the mono acetate salt of the product after chromatography, as a colorless solid, mp 158-170°C. MS (ESV. 470.13 (MH4) for CwHasFjNjOs 'H-NMRfDMSO-d^ 5: 1.20 (m, 2H); 1.75 (m, 2H); 1.89 (s, 3H); 2.03 (t, 2H); 2.36 (m, 1H); 2.55 (m, 2H); 2.82 (m, 2H); 3.66 (s, 2H); 4.40 (m, 2H); 4.59 (s, 2H); 6.60 (d, 1H); 7.00 (d, 1H); 7.28 (d, 1H); 7.34 (m, 1H); 7.60 (m, 1H); 7.91 (d, 1H); 11.17 (brs, 1H). Intermediate 19; l-\|'2-(4-Aminopiperidin-l-vl)ethvl1-7,8-difluoroquinolm-2(lflr)-one The title compound was obtained from tert-buty\ {l-[2-(7,8-difluoro-2-oxoquinolinl( 2//)-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 20) (412 mg, 1.01 mmol) by the procedure described for Intermediate 1, 316 mg (quantitative yield), as a colorless gum. MS (ESV 308.29 (MH+) for Ci6H,9F2N3O 'H-NMR rDMSO-d^ 5: US (m, 2H); 1.46 (m, 1H); 1.62 (m, 2H); 2.03 (t, 2H); 2.53 (m, 2H, under solvent peak); 2.79 (m, 2H); 4.39 (m, 2H); 6.60 (d, 1H); 7.34 (m, 1H); 7.59 (m, 1H); 7.91 (d, 1H). Intermediate 20: tert-Butyl U-r2-(7.8-difluoro-2-oxpquinolin-l(2//)- yDethyl]piperidin-4-vl } carbamate 7,8-Difluoroquinolin-2(l/f)-one (Intermediate 21) (500 mg, 2.8 mmol) was deprotonated with sodium hydride (121 mg, 60% in oil, 3.04 mmol) and alkylated with 2-{4- [(tert-butoxycarbonyl)amino]piperidin-l-yl} ethyl methanesulfonate (Intermediate 6) (3.3 mmol) as described for Intermediate 2. Chromatography on silica gel with hexanes/ acetone 2:1 gave the product as a colorless solid, 414 mg (37%). MS (ES): 408.30 (MH+) for CaiEfoFzNaOa 'H-NMRfDMSQ-d^ 5: 1.32 (m, 2H); 1.36 (s, 9H); 1.65 (m, 2H); 2.04 (t, 2H); 2.53 (m, 2H); 2.83 (m, 2H); 3.16 (m, 1H); 4.38 (m, 2H); 6.61 (d, 1H); 6.75 (d, 1H); 7.34 (m, 1H); 7.60 (m, 1H); 7.91 (m, 1H). Intermediate 21: 7.8-Difluoroquinolin-2(l/f)-one The compound was prepared from {2£)-A'-(2,3-difluorophenyl)-3-phenylacrylaniide (Intermediate 22) (7.4 g, 28.5 mmol) and aluminium trichloride (19 g, 142 mmol) as described for Intermediate 17. The crude cyclization product was obtained as a single regioisomer, which was used without further purification, 2 g light brown solid (37%). MS fESI: 182.04 (MH+) for C9H5F2NO 'H-NMR(DMSO-d6) 8: 6.51 (d, 1H); 7.22 (m, 1H); 7.52 (m, 1H); 7.91 (m, 1H). Intermediate 22: (2ff)-N-(2.3-DifluorophenylV3-phenylacrylamide The compound was prepared from 2,3-difluoroaniline (5 g, 38.7 mmol) and cinnamoylchloride (6.45 g, 38.7 mmol) in the presence of 2,6-lutidine (6.8 mL, 58 mmol) as described for Intermediate 18 to give a colorless solid, 7.4 g (74%). MS (ES1: 260.08 (MH) for Ci5HnF2NO 'H-NMR (DMSO-d^ 6: 7.05 (d, 1H); 7.14-7.22 (m, 2H); 7.40-7.50 (m, 3H); 7.59-7.64 (m, 3H); 7.89 (m, 1H); 10.16 (brs, 1H). Example 8 6-[({l-[2-(5,7-Difluoro-2-oxoquinolin-l(2/^-yl)ethyl]piperidin-4- yl}ammo)methyl]-2#-pyrido[3,2-&][l,41oxazin-3(4#)-one l-[2-(4-Aminopiperidin-l-yl)ethyl]-5,7-difluoroquinolin-2(l//)-one (Intermediate 23) (100 mg, 0.325 mmol), 3-oxo-3,4-dihydro-2#-pyrido[3,2-Z>][l,4]oxazine-6-carbaldehyde (WO 2004/058144) (58 mg, 0.325 mmol) and sodium triacetoxy borohydride (207 mg, 0.98 mmol) were reacted as described for Example 6, to give 114 mg of the mono acetate salt of the product as a colorless solid, mp 170-180°C. MS (ES): 470.32 (MH) for Ca^sFzNsOa 'H-NMRflDMSQ-dj) 5: 1.20 (m, 2H); 1.74 (m, 2H); 1.89 (s, 3H); 2.00 (t, 2H); 2.36 (m, 1H); 2.48 (m, 2H); 2.88 (m, 2H); 3.66 (s, 2H);.4.29 (t, 2H); 4.59 (s, 2H); 6.61 (d, 1H); 7.00 (d, 1H); 7.18-7.33 (m, 3H); 7.96 (d, 1H); 11.16 (brs, 1H). Intermediate 23; l-[2-(4-Aminopiperidin-l-vl')ethvl1-5.7-difluoroquinolin-2(lJ:D-one The title compound was obtained from tert-butyl {l-[2-(5,7-difluoro-2-oxoquinolinl( 2#)-yl)ethyl]piperidin~4-yl}carbamate (Intermediate 24) (637 mg, 1.01 mmol) by the procedure described for Intermediate 1, 483 mg (quantitative), as a colorless solid. MS (ES): 308.27 (MM") for Ci6Hi9F2N30 y 'H-NMRfDMSQ-dg") 5: 1.15 (m, 2H); 1.46-1.64 (m, 3H); 2.00 (t, 2H); 2.46 (m, 2H, under solvent peak); 2.85 (m, 2H); 4.28 (t, 2H); 6.61 (d, 1H); 7.21 (m, 1H); 7.30 (d, 1H); 7.95 (d, 1H). Intermediate 24: fe/7-Butyr(l-[2-(5.7-difluoro-2-oxoquinolin-l(2/jr)- vr)ethyl]piperidin-4-yl) carbamate 5,7-Difiuoroquinolin-2(l.H)-one (Intermediate 25) (500 mg, 2.8 mmol) was deprotonated with sodium hydride (121 mg, 60% in oil, 3.04 mmol) and alkylated with 2-{4- [(ter/-butoxycarbonyl)amino]piperidin-l-yl}ethyl methanesulfonate (Intermediate 6) (3.3 mmol) as described for Intermediate 20. Colorless solid, 637 mg (57%). MS (ES): 408.30 (MH+) for C2iH27F2N3O3 :H-NMR fDMSO-d^ 5: 1.32 (m, 2H); 1.36 (s, 9H); 1.64 (m, 2H); 2.01 (t, 2H); 2.48 (m, 2H); 2.88 (m, 2H); 3.18 (m, 1H); 4.28 (m, 2H); 6.61 (d, 1H); 6.75 (d, 1H); 7.21 (m, 1H); 7.30 (d, 1H); 7.95 (m, 1H). Intermediate 25: 5.7-Difluoroquinolin-2(l/f)-one The compound was prepared from (2£)-A^-(3,5-difluorophenyl)-3-phenylacrylamide (Intermediate 26) (8.1 g, 31.2 mmol) and aluminium trichloride (21 g, 156 mmol) in a similar way as described for Intermediate 21. 3.47 g light brown solid (61%), mp 292-318°C. MS (ES): 181.98 (Ml-f) for C9H5F2NO 'H-MMR (PMSO-d^ S: 6.51 (d, 1H); 6.90 (m, 1H); 7.10 (ddd, 1H); 7.93 (d, Hi); 12.05 (brs, 1H). Intermediate 26: (2Jg)-Ar-f3.S-Difluoronhenvl)-3-phenvlacrylamide The compound was prepared from 3,5-difluoroaniline (5 g, 38.7 mmol) and cinnamoylchloride (6.45 g, 38.7 mmol) in the presence of 2,6-lutidine (6.8 mL, 58 ramol) as described for Intermediate 18 to give a colorless solid, 8.1 g (81%). MS HBSV 260.10 (MH4) for CijHiiF2NO 'H-NMR fDMSO-da 8: 6.76 (d, 1H); 6.92 (m, 1H); 7.35-7.49 (m, 5H); 7.60-7.65 (m, 3H); 10.59 (s, 1H). Example 9 6-[({l-[2-(7-Fluoro-2-oxoquinolin-l(2fif)-yl)ethyl]piperidin-4-yl}amino)metliyl]- 2J7-pyrido [3,2-6] [1,4] oxazin-3(4fl)-one l-[2-(4-Aminopiperidin-l-yl)ethyl]-7-fluoroquinolin-2(l//)-one (Intermediate 27) (100 mg, 0.346 mmol), 3-oxo-3,4-dihydro-2#-pyrido[3,2-6][l,4]oxazine-6-carbaldehyde (WO 2004/058144) (62 mg, 0.346 mmol) and sodium triacetoxy borohydride (220 mg, 1.04 mmol) were reacted as described for Example 7 to give 115 mg (74%) of the monoacetatc salt of the product as a colorless solid, mp 150-155°C, MS fES): 452.22 (MH4) for C24H26FN503 'H-NMR CDMSO-d^ 6: 1.22 (m, 2H); 1.75 (m, 2H); 1.89 (s, 3H); 2.01 (t, 2H); 2.37 (m, 1H); 2.48 (m, 2H); 2.89 (m, 2H); 3.67 (s, 2H); 4.29 (t, 2H); 4.59 (s, 2H); 6.55 (d, 1H); 7.00 (d, 1H); 7.12 (ddd, 1H); 7.28 (d, 1H); 7.38 (dd, 1H); 7.78 (dd, 1H); 7.90 (d, 1H); 11.16 (brs, 1H). Intermediate 27; 1 -f 2-f 4-Aminopiperidin-1 -vl)ethvl1-7-fluoroquinolin-2f Iffl-one The title compound was obtained from tert-butyl {l-[2-(7-fluoro-2-oxoquinolinl( 2H)-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 28) (565 mg, 1.45 mmol) by the procedure described for Intermediate 1,425 mg (quantitative), as a colorless solid. MS (ESY. 290.19 (MH+) for Ci6H2oFN30 'H-NMR (DMSQ-d^ S: 1.16 (m, 2H); 1.62 (m, 2H); 2.00 (t, 2H); 2.46 (m, 2H, under solvent peak); 2.85 (m, 2H); 3.46 (m, 1H); 4.28 (t, 2H); 6.54 (d, 1H); 7.12 (ddd, 1H); 7.36 (dd, 1H); 7.76 (dd, 1H); 7.89 (d, 1H). Intermediate 28: tert-Butvl n-[2-r7-fluoro-2-oxoquinolin4(2/f)-vlWhvl1piperidin- 4-yl} carbamate 7-Fluoroquinolin-2(l//)-one (Intermediate 29) (500 mg, 3.06 mmol) was deprotonated with sodium hydride (135 mg, 60% in oil, 3.37 mmol) and alkylated with 2-{4- [(tert-butoxycarbonyl)amino]piperidin-l-yl} ethyl methauesulfonate (Intermediate 6) (3.7 mmol) as described for Intermediate 20. Colorless solid, 570 mg (48%). MS (ESY. 390.21 (MH+) for C2iH28FN3O3 'H-NMR (DMSO-(V)S: 1.32 (m, 2H); 1.36 (s, 9H); 1.64 (m, 2H); 2.02 (t, 2H); 2.48 (m, 2H); 2.90 (m, 2H); 3.19 (m, 1H); 4.28 (m, 2H); 6.54 (d, 1H); 6.75 (d, 1H); 7.12 (m, 1H); 7.38 (m, 1H); 7.78 (dd, 1H); 7.90 (d, 1H). Intermediate 29: 7-Fluoroquinolin-2('l//Vone The compound was prepared from {2/^-Af-(3-fluorophenyl)-3-phenylacrylamide (Intermediate 30) (13.8 g, 57.2 mmol) and aluminium trichloride (30.5 g, 229 mmol) in a similar way as described for Intermediate 21 to give a mixture of the title compound together with the corresponding 5-fluoro regioisomer in a ratio of 3:1. This mixture was vigorously stirred in dichloromethane (100 mL) for 3 hours at room temperature and then filtered. The solid obtained was resuspended in diethyl ether (200 mL) and stirred like above and filtered to give 3.63 g (34%) of the crude product containing 12% of the 5-fluoro regioisomer. This was used without further purification for the next step. MS (ESV 164.02 (MH+) for C9H6FNO 'H-NMR (CPCy MeOD) S: 6.31 (d, IH); 6.73 (ddd); 6.79 (dd, 1H); 7.35 (dd, III); 7.60 (d, 1H). Intermediate 30: (2ffi-W3-Fluorophenvn-3-phenylacrvlamide The compound was prepared from 3-fluoroaniline (5.8 mL, 60 mmol) and cinnamoylchloride (10 g, 60 mmol) in the presence of 2,6-lutidine (10.5 mL, 90 mmol) as described for Intermediate 18 to give a colorless solid, 13.9 g (96%), mp 110°C. MS (ES\. 242.20 (MH4) for C,5Hi2FNO 'H-NMR (DMSO-d^ 5: 6.80 (d, 1H); 6.89 (m, 1H); 7.31-7.48 (m, 5H); 7.58-7.65 (m, 3H); 7.73 (m, 1H); 10.43 (s, 1H). Example 10 l-(2.{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-lyI} ethyl)~7-fluoroquinolin-2(lH)-one l-[2-(4-Aminopiperidin-l-yl)ethyl]-7-fluoroquinolin-2(l//)-one (Intermediate 27) (100 mg, 0.346 mmol), 2)3-dihydro[l,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO 2004/058144) (57 mg, 0.346 mmol) and sodium triacetoxy borohydride (220 mg, 1.04 mmol) were reacted as described for Example 7. The free base obtained after chromatography was dissolved in dichloromethane/ ether (10 mL, 1:1) and HC1 in ether (1M, 1 mL) was added under vigorous stirring. It was evaporated to dryness under reduced pressure and the residue was taken up as a suspension in dichloromethane/ hexanes ( 10 mL, 1:1). It was filtered and dried to give 1 18 mg (78%) of the bis HC1 salt of the product as a colorless solid, mp >275°C (decomposed). MS (ESV. 439.23 (MH+) for CM^R^OS 'H-NMR (PMSO-d,;) 5: 2.10 (m, 2H); 2.37 (m, 2H); 3.10 (m, 2H); 3.20-3.38 (m, 311); 3.78 (m, 2H); 4.27 (m, 2H); 4.37 (m, 2H); 4.43 (m, 2H); 4.62 (t, 2H); 6.60 (d, 1H); 7.19 (ddd, 1H); 7.41 (s, 1H); 7.78 (dd, 1H); 7.84 (dd, 1H); 7.98 (d, 1H); 8.31 (s, 1H); 9.91 (brs, 2H); 11.04(brs, Example 11 6-[({l-[2-(7-Methoxy-2-oxo-3,4-dihydroquinolin-l(2jH)-yl)ethyl]piperidin-4- yl}amino)methyl]-2/f-pyrido[3,2-£][l,4]oxazin-3(4/f)-one l-[2-(4-Aminopiperidin-l-yl)ethyl]-7-methoxy-3,4-dihydroquinolin-2(l/f)-one (Intermediate 31) (110 mg, 0.36 mmol), 3-oxo-3,4-dihydro-2//-pyrido[3,2- 6][l,4]oxazine-6-carbaldehyde (WO 2004/058144) (65 mg, 0.325 mmol) and sodium triacetoxy borohydride (220 mg, 1.04 mmol) were reacted as described for Example 1, but the aqueous workup was omitted. Chromatography on a Phenomenex Synergy Polar-RP4um column, eluent: 30-60% acetonitrile, 10 mM ammonium acetate pH8, followed by chromatography on silica gel with dichloromethane/ methanol (7:1). The bis HC1 salt of the product was prepared as described for Example 10 to give 46 mg (24%) as a colorless solid, mp >285°C (dec). MS (BS): 466.21 (MH) for C25H3iN504 'H-NMR fDMSO-d^ 8: 2.10 (m, 2H); 2.36 (m, 2H); 2.53 (t, 211); 2.86 (t, 2H); 3.10 (m, 2H); 3.16 (m, 2H); 3.36 (m, 1H); 3.70 (m, 2H); 3.73 (s, 3H); 4.16 (m, 2H); 4.28 (m, 2H); 4.70 (s, 2H); 6.80 (m, 1H); 6.86 (s, 1H); 7.23-7.28 (m, 2H); 7.45 (d, 1H); 9.70 (brs, 211); 11.07 (brs, 1H); 11.37 (s, 1H). Intermediate 31; l-f2-f4-Aminopiperidin-l-ynethvri-7-methoxv-3,4- dihydroquinolin-2(l/:f)-one The title compound was obtained from ter/-butyl {l-[2-(7-methoxy-2-oxo-3,4- dihydroquinolin-l(2//)-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 32) (550 mg, 1.36 mmol) by the procedure described for Intermediate 1, 338 mg (82%), as a colorless oil. MS (ESV 304.23 (MH+) for CnlfoNaCU 'H-NMR (DMSO-d^ 8: 1.19 (m, 2H); 1.62 (m, 2H); 1.96 (t, 2H); 2.36 (t, 2H); 2.46 (m, 2H); 2.73-2.80 (m, 5H); 3.71 (s, 3H); 3.91 (m, 2H); 6.77-6.84 (m, 2H); 7.04 (m, 1H). Intermediate 32: tert-Butvl U-f2-f7-memoxy-2-oxo-3.4-dihydroquinolin-l(2//)- yl)ethyl]piperidin-4-yllcarbamate 7-Methoxy-3,4-dihydroquinolin-2(l//)-one (Intermediate 33) (300 mg, 1.78 mmol) was deprotonated with sodium hydride (75 mg, 60% in oil, 1.86 mmol) and alkylated with 2- {4-[(/er/-butoxycarbonyl)amino]piperidin-l-yl} ethyl methanesulfonate (Intermediate 6) (2.03 mmol) as described for Intermediate 2. Chromatography on silica gel eluting with ethyl acetate and then acetone/ dichloromethane (4:1) gave the product as a colorless oil, 559 mg (82%). MS (ES): 404.21 (MH4^ for C22H33N304 'H-NMR fDMSO-df,1 8: 1.32 (m, 2H); 1.36 (s, 9H); 1.64 (m, 2H); 1.93-2.00 (m, 411); 2.37 (m, 2H); 2.47 (m, 2H); 2.78 (m, 2H); 3.16 (m, 1H); 3.71 (s, 3H); 3.91 (t, 2H); 6.72-6.82 (m, 3H); 7.05 (d, 1H). Intermediate 33: 7-Methoxy-3.4-dihydroquinolin-2(l//)-one A mixture of 7-hydroxy-3,4-dihydroquinolin-2(l/7)-one (3.0 g, 17 mmol) and triethyl amine (3.14 mL, 22 mmol) in dichloromethane/ methanol/ acetonitrile (10:1:10, 168 mL) was treated with (trimethylsilyl)diazomethane (2M solution in hexanes, 10.25 mL, 20.5 mmol). It was stirred over night at room temperature, the.solvcnt was removed under reduced pressure and chromatography on silica gel with hexanes/ acetone (1:1) gave 2.2 g (67%) of the product as a colorless solid. MS (ES\. 178.16 (MH) for Ci0HuN02 'H-NMRfDMSQ-d^ 8: 2.38 (t, 2H); 2.81 (t, 2H); 3.68 (s, 3H); 6.68-6.78 (m, 311); 9.90 (brs, 1H). Example 12 (35,4fi)-l-[2-(S,7-Difluoro-2-oxoquinolin-l(2JH)-yl)ethyl]-4-[(2,3- dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidine-3-carboxylic acid A solution of methyl (35l,4/?)-l-[2-(5,7-difluoro-2-oxoquinolin-l(2H)-yl)ethyl]-4- [(2,3-dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidine-3-carboxylate (Example 13) (120 mg, 0.233 mmol) in tetrahydrofuran/ water (1:1,10 mL) was treated with sodium hydroxide (15% aqueous, 0.2 mL) at room temperature for 3 hours. It was quenched with glacial acetic acid (1 mL) and concentrated to dryness under reduced pressure. Chromatography on a CIS cartridge (RediSep, ISCO) with 0-25 % acetonitrile in water, containing 0.1% acetic acid and treatment with HC1 as described for Example 10 gave 113 mg (90%) of the mono hydrochloride salt of the product as a colorless solid, mp 100-180°C. MSfESV 501.03 (MH") for CzsHafiFjN^s 1H-NMR nPMSQ-d^ 8: 2.02 (m, 2H); 2.60 (m, 2H); 3.15-3.51 (m, 8H); 4.18 (m, 2H); 4.33 (m, 2H); 4.37 (m, 2H); 4.50 (m, 1H); 6.62 (d, 1H); 7.12 (s, 1H); 7.24 (m, 1H); 7.41 (m, 1H); 7.98 (d, 1H); 8.15 (s, 1H). Example 13 (35,4/?)-l-[2-(5,7-Difluoro-2-oxoquinoHn-l(2flf)-yl)ethyl]-4-{[(2£)-3-(2,Sdifluorophenyl) prop-2-en-l-yl]amino}piperidine-3-carboxylic acid Methyl (3S,4^)-l-[2-(5,7-difluoro-2-oxoquinolin-l(2J:0-yl)ethyl]-4-{[(27?)-3-(2,5- difluorophenyl)prop-2-en-l-yl]amino}piperidine-3-carboxylate (Example 15) (80 mg, 0.155 mmol) was treated with sodium hydroxide as described for Example 12 to give 51 mg (61 %) of the mono hydrochloride salt of the product as a colorless solid, mp 150-180°C. MS (ESV. 504.19 (MH+) for 026^4^03 'H-NMRfDMSO-d/Q 5: 2.10 (m, 2H); 2.75-3.75 (m, 8H); 3.86 (m, 2H); 4.33 (m, 1H); 4.54 (m, 1H); 6.50 (m, 1H); 6.64 (d, 1H); 6.91 (d, 1H); 7.19-7.34 (m, 3H); 7.48 (m, 2H); 8.00 (s, 1H); 9.19 (brs, 1H). Example 14 •Methyl (3J,4J?)-l-[2-(5,7-dinuoro-2-oxoquinolin-l(2//)-yl)ethyl]-4-[(2,3- dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)ainino]piperidine-3-carboxylate Methyl (35,4/Z)-4-amino-1 -[2-(5,7-difluoro-2-oxoquinolin-1 (2#)-yl)ethyl]piperidine- 3-carboxylate (Intermediate 34) (120 mg, 0.328 ramol), 2,3-dihydro[l,4]dioxino[2,3- c]pyridine-7-carbaldehyde (WO 2004/058144) (54 mg, 0.328 mmol) and sodium triacetoxy borohydride (209 mg, 0.98 mmol) were reacted as described for Example 6. Chromatography on silica gel with dichloromethane/ methanol (20:1) gave 130 mg (77%) of product as a colorless hard foam. MS (ESV. 515.03 (MH+) for QwHaiFzN^s 'H-NMR (PMSO-d^ 5: 1.52 (m, 1H); 1.75 (m, 1H); 2.43 (m, 1H); 2.50 (m, 1H); 2.54 (m, 2H); 2.60-2.73 (m, 3H); 2.87 (m, 1H); 3.51 (s, 3H); 3.53 (d, 1H); 3.69 (d, 1H); 4.22-4.34 (m, 6H); 6.61 (d, 1H); 6.86 (s, 1H); 7.21 (m, 1H); 7.30 (m, 1H); 7.95 (d, 1H); 7.97 (s, 1H). Example IS Methyl (35J4^)-l-[2-(5,7-difluoro-2-oxoquinolin-l(2fl)-yl)cthyI]-4-{[(2£)-3-(2,5- difluorophenyl)prop-2-en-l-yl]amino}piperidine-3-carboxylate Methyl (35,4/?)-4-amino-l-[2-(5,7-difluoro-2-oxoquinolin-l(2/f)-yl)ethyl]piperidinc- 3-carboxylate (Intermediate 34) (120 mg, 0.328 mmol), (2£)-3-(2,5- difluorophenyl)acrylaldehyde (FR 2872164) (54 mg, 0.328 mmol) and sodium triacetoxy borohydride (209 mg, 0.98 mmol) were reacted as described for Example 6. Chromatography on silica gel with dichloromethane/ N,N-dimethylformamide (30:1) gave 83 mg (49%) of product as a colorless hard foam. MS (ESV 518.10 (MH4) for CwHWWA 'H-NMRfDMSO-d^S: 1.56 (m, 1H); 1.75 (m, 1H); 1.90 (m, 1H); 2.41 (m, 1H); 2.51- 2.72 (m, 5H); 2.90 (m, 1H); 3.25 (dd, III); 3.39 (dd, 1H); 3.51 (s, 3H); 4.29 (m, 211); 6.42 (m, 1H); 6.57 (d, 1H); 6.61 (d, 1H); 7.09 (m, 1H); 7.17-7.24 (m, 2H); 7.30 (m, 1H); 7.43 (m, III); 7.95 (d, 1H). Intermediate 34: Methyl f3^.4J?)-4-amino-1-[2-(5.7-difluoro-2-oxoquin.olin-l('2//)- ynethyl]piperidine-3-carboxylate A solution of methyl (35,4/?)-4-{[(benzyloxy)carbonyl]amino}-1 -[2-(5,7-difluoro-2- oxoquinolin-l(2#)-yl)ethyl]piperidine-3-carboxylate (Intermediate 35) (595 mg, 1.19 mmol) in methanol (10 mL) was hydrogenated over palladium on carbon (10%, wet) at normal pressure and room temperature for 30 minutes. It was filtered through a 0.45 um membrane, washed with methanol and the wash and filtrate were concentrated under reduced pressure to give 395 rag (91%) of the product as a colorless hard foam. MS (ESV. 365.98 (MH+) for QsIfciF^Os 'H-NMR fDMSO-dg') 8: 1.58 (m, 2H); 2.37-2.69 (m, 7H); 3.14 (m, 1H); 3.53 (s, 3H); 4.28 (m, 2H); 6.60 (d, 1H); 7.21 (m, 1H); 7.30 (m, 1H); 7.95 (d, 1H). Intermediate 35: Methvl difluoro-2-oxoquinolin- 1 (2/A-yl)ethyl]piperidine-3-carboxylate 5,7-Difluoroquinolin-2(l/f)-one (Intermediate 25) (350 mg, 1.93 mmol) was deprotonated with sodium hydride (85 rng, 60% in oil, 2.13 mmol) and alkylated with methyl (3S',47?)-4-{[(benzyloxy)carbonyl]amino}-l-(2-chloroethyl)piperidine-3-carboxylate (Intermediate 36) ( 1.93 mmol) as described for Intermediate 20. Colorless hard foam, 604 mg (63%). MS fBS); 500.05 (MH+) for C26H27F2N305 'H-NMR(60°a rDMSO-dfi) 5: 1.64 (m, 1H); 1.72 (m, 1H); 2.44 (m, 1H); 2.59 (t, 2H); 2.61-2.76 (m, 3H); 2.85 (dd, 1H); 3.49 (s, 3H); 3.93 (m, 1H); 4.28 (m, 2H); 4.99 (d, 1H); 5.03 (d, 1H); 6.60 (d, 1H); 6.90 (m, 1H); 7.13 (m, 1H); 7.24-7.37 (m, 6H); 7.93 (d, 1H). Intermediate 36: Methyl (3tSl.4J?)-4-ir(benzvloxv)carbonvl]amino)-l-(2- chloroethyl)piperidine-3-carboxylate Methyl (35',4/?)-4-{[(benzyloxy)carbonyl]amino}-l-(2-hydroxyethyl)piperidine-3- carboxylate (Intermediate 37) (650 mg, 1 .93 mmol) was reacted with methanesulfonyl chloride (0.18 mL, 2.32 mmol) in the presence of triethylamine (0.38 mL, 2.7 mrnol) as described for Intermediate 6. The crude chloride was used without delay for the next step. MS (ES^ 355/357 (MIT1) for Intermediate 37: Methyl f3£4#V4-(rO?enzyloxv')carbonvl1amino}-l-(2- hydroxyethvl)piperidine-3-carboxylate A mixture of methyl (3S,4^)-4-{[(benzyloxy)carbonyl]amino}piperidine-3- carboxylate (WO 2005/066176) (2.29 g, 7.83 mmol), N,N-diisopropylethylamine (2.05 mL, 1 1.75 mmol and 2-bromoethanol (0.722 mL, 10.18 mmol) in dry acetonitrile (17 mL) was heated in the microwave at 70°C for 4.5 hours. The solvent was removed under reduced pressure and the residue taken up in ethyl acetate (200 raL) and washed with saturated aqueous sodium hydrogencarbonate solution (100 mL). The aqueous phase was back extracted once with ethyl acetate (100 mL) and the combined organic phases were dried over sodium sulfate. Chromatography on silica gel with dichloromethane/ methanol (12:1) gave 2.0 g(76%),mp73°C. MS (ES): 337.16 (MH4) for Ci7H24N2Os 'H-NMRfDMSQ-d^ 5: 1.66 (m, 2H); 2.34-2.55 (m, 5H); 2.67-2.79 (m, 2H); 3.44 (dt, 2H); 3.51 (s, 3H); 3.95 (m, 1H); 4.31 (t, 1H); 4.97 (d, 1H); 5.02 (d, 1H); 7.21 (d, 1H); 7.25- 7.38 (m, 5H). Example 16 (3IZ,4JR)-l-[2-(5,7-Difluoro-2-oxoquinolin-l(2J!ir)-yl)ethyl)-4-[(2,3- dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidine-3~carboxyIic acid Methyl (3/?,4J?)-l-[2-(5,7-difluoro-2-oxoquinolin-l(2F)-yl)ethyl]-4-[(2J3- dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidine-3-carboxylate (Example 18) (201 mg, 0.4 mmol) was saponified and converted into the bis hydrochloride salt as described for Example 12, 194 mg (87%), colorless solid, mp > 190°C. MS fESV 501.22 (MH+) for €25^2^05 'H-NMR (DMSO-d^ 5: 2.24 (m, 1H); 2.46 (m, 1H); 3.12 (m, 1H); 3.34 (m, 4H); 3.58 (m, 1H); 3.83 (m, 1H); 3.93 (m, 1H); 4.24 (d, 1H); 4.31-4.44 (m, 5H); 4.63 (m, 211); 6.66 (d, 1H); 7.26-7.31 (m, 2H); 7.69 (d, 1H); 8.02 (d, 1H); 8.25 (s, 1H); 11.51 (bs, 1H). Example 17 (37Z,4/?)-l.[2-(5,7-Difluoro-2-oxoquinolin-l(2«)-yl)cthyl]-4-{l(2JE)-3-(2,5- difluorophenyl)prop-2-en-l-yl]amino}piperidine-3-carboxylic acid Methyl (3£,4fl)-1 -[2-(5,7-difluoro-2-oxoquinolin-1 (2/f)-yl)ethyl]-4- {[(2£>3-(2,5- difluorophenyl)prop-2-en-l-yl]amino}piperidine-3-carboxylate (Example 19) (106 mg, 0.2 mmol) was treated with sodium hydroxide as described for Example 12 to give 82 mg (69 %) of the bis hydrochloride salt of the product as a colorless vsolid, mp > 205°C. MS (ES): 504.23 (MH") for 'H-NMRfDMSO-dgl 6: 2.15 (m, 1H); 2.40 (m, 1H); 3.01-3.98 (m, 10H); 4.60 (m, 2H); 6.50 (m, 1H); 6.67 (d, 1H); 6.95 (d, 1H); 7.20-7.35 (m, 3H); 7.47 (m, 1H); 7.62 (m, 1H); 8.02 (d, 1H). Example 18 Methyl (3JR,4JZ)-l-[2-(5,7-difluoro-2-oxoquinolin-l(2H)-yl)ethyl]-4-[(2,3- dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidine-3-carboxylatc Methyl (3^,4J?)-4-amino-l-[2-(5,7-difluoro-2-oxoquinolin-l(2//)-yI)ethyl]piperidine- 3-carboxylate (Intermediate 38) (195 mg, 0.53 mmol), 2,3-dihydro[l,4]dioxino[2,3- c]pyridine-7-carbaldehyde (WO 2004/058144) (88 rag, 0.53 mmol) and sodium triacetoxy borohydride (339 mg, 1.6 mmol) were reacted as described for Example 14 to give 216 mg (79%) of product as a colorless hard foam. MS fESV. 515.23 (MH) for CwHajFj^Os 'H-NMROJMSO-d^S; 1.18 (m, 1H); 1.92 (m, 1H); 2.05 (ddd, 1H); 2.14 (dd, 1H); 2.34 (ddd, 1H); 2.52 (t, 2H); 2.57 (m, 1H); 2.88 (m, 1H); 3.03 (m, 1H); 3.57 (d, 1H); 3.58 (s, 3H); 3.69 (d, 1H); 4.24-4.33 (m, 6H); 6.61 (d, 1H); 6.87 (s, 1H); 7.21 (ddd, 1H); 7.33 (m, 1H); 7.93-7.96 (m, 2H). Example 19 Methyl (3/Z,4^)-l-[2-(S,7-dinuoro-2-oxoquinolin-l(2fl)-yl)ethyl]-4-{[(2£)-3-(2,5- difluorophenyl)prop-2-en-l-yl]amino}piperidine-3-carboxylate Methyl (3^,4^)-4-amino-l-[2-(5,7-difluoro-2-oxoquinolin-l(2//)-yl)ethyl]piperidine- 3-carboxylate (Intermediate 38) (195 mg, 0.53 mmol), (2E)-3-(2,5- difluorophenyl)acrylaldehyde (FR 2872164) (90 mg, 0.53 mmol) and sodium triacetoxy borohydride (339 mg, 1.6 mmol) were reacted as described for Example 6. Chromatography on silica gel with dichloromethane/N,N-dimethylformamide (25:1 to 15:1) gave 119 nig (43%) of product as a colorless oil. MS (ESI: 518.25 (MH) for C^t^NjOa 'H-NMRfDMSO-dfil 5:1.20 (m, 1H); 1.94 (m, 1H); 2.08 (ddd, 1H); 2.16 (dd, 1H); 2.34 (ddd, 1H); 2.53 (t, 2H); 2.61 (ddd, 1H); 2.90 (m, 1H); 3.04 (m, 1H); 3.24 (dd, 1H); 3.39 (dd, 1H); 3.58 (s, 3H); 4.28 (m, 2H); 6.40 (m, 1H); 6.55-6.62 (m, 2H); 7.05-7.25 (m, 3H); 7.32 (d, 1H); 7.42 (m, 1H); 7.95 (d, 1H). Intermediate 38; Methyl (37?.4/;V4-amino-l-r2-('5.7-difluoro-2-oxoquinolin-l('2//)- vDethvl]piperjdine-3-carboxylate Methyl (3/2,4/?)-4-{[(benzyloxy)carbonyl]amino}-l-[2-(5,7-difluoro-2-oxoquinolinl( 2/0-yl)ethyl]piperidine-3-carboxylate (Intermediate 39) (535 mg, 1.07 mmol) was hydrogenated as described for Intermediate 34 to give 391 mg (quantitative) of the product as a colorless hard foam. MS (ESI: 366 (MH+) for Intermediate 39: Methl difluoro-2-oxoquinolin- 1 (2/j)-vl)ethvnpiperidine-3-carboxylate 5,7-Difluoroquinolin-2(l#)-one (Intermediate 25) (350 mg, 1.93 mmol) was deprotonated with sodium hydride (85 mg, 60% in oil, 2.13 mmol) and alkylated with methyl (3/?,4/?)-4-{[(benzyloxy)carbonyl]amino}-l-{2-[(methylsulfonyl)oxy]ethyl}piperidine-3- carboxylate (Intermediate 40) (1.93 mmol) as described for Intermediate 20 to give the product as a colorless hard foam, 538 mg (56%). MS (ES): 500.38 (MH+) for C26H27F2N3O5 'H-NMR (60°O (DMSO-dg) 8: 1.40 (dddd, 1H); 1.70 (m, 1H); 2.10-1.45 (m, 2H); 2.44 (ddd, 1H); 2.54 (t, 2H); 2.89 (m, 1H); 3.07 (m, 1H); 3.49 (s, 3H); 3.54 (m, 1H); 4.28 (m, 2H); 4.95 (d, IH); 4.99 (d, 1H); 6.61 (d, 1H); 7.21 (ddd, 1H); 7.29-7.37 (m, 711); 7.95 (d, 1H). Intermediate 40: Methyl (3J?.4J?)-4-\|f(benzyloxv)carbonyl1ammo}-l-(2- f(methylsulfonyl)oxv1ethvUpiperidine-3-carboxylate Methyl (3Rt4R)-4- {[(benzyloxy)carbonyl]amino) -1 -(2-hydroxyethyI)piperidinc-3- carboxylate (Intermediate 41) (650 mg, 1.93 mmol) was reacted with methanesulfonyl chloride (0.18 mL, 2.32 mmol) in the presence of triethylamine (0.38 mL, 2.7 mmol) as described for Intermediate 6. The crude product was used without delay for the next step. MS (ESI: 415.3 (MH+ Intermediate 41: Methyl (3^.4J?)-4-{r(benzyloxv')carbonvl]amino}-l-(2- hydroxyethyl')piperidine-3-carboxylate Methyl (3iSr,4J?)-4-{[(benzyloxy)carbonyl]amino}piperidine-3-carboxylate (WO 2005/066176) (2.0 g, 6.84 mmol), N.N-diisopropylethylamine (1.8 ml., 10.26 mmol) and 2- bromoethanol (0.63 mL, 8.9 mmol) were reacted as described for Intermediate 37 to give 1.38 g (60%) of the product as a colorless oil. MS (BS); 337.36 (MH+) for CI7H24N205 'H-NMR rDMSO-dfi-) 5: 1.43 (dddd, 1H); 1.70 (m, 1H); 1.97-2.14 (m, 2H); 2.37 (t, 2H); 2.49 (m, 1H); 2.80 (m, 1H); 2.94 (m, 1H); 3.44 (dt, 2H); 3.50 (s, 3H); 3.54 (m, 1H); 4.39 (t, 1H); 4.95 (d, 1H); 5.00 (d, 1H); 7.27-7.38 (m, 6H). Example 20 CIs(±)6-[({l-[2-(5,7-difluoro-2-oxoquinolin-l(2fl)-yl)ethyl]-3-hydroxypiperidin-4- yl}amino)methyl]-2/f-pyrido[3,2-Z»][l,4]oxazin-3(4jy)-one Cis(±)l-{2-[4-amino-3-hydroxypiperidin-l-yl]ethyl}-5,7-difluoroquinolin-2(l/f)-one (175 rag, 0.54 mmol), 3-oxo-3,4-dihyciro-2tf-pyrido[3,2-&][l,4]oxazine-6-carbaldehyde (WO 2004/058144) (96 mg, 0.54 mmol) and sodium triacetoxy borohydride (344 mg, 1.6 mmol) were reacted as described for Example 1 to give 186 mg (71%) of the free base of the product as a colorless oil. MS fBSV 486.24 (MH+) for C24H25F2N5O5 'H-NMRYMeOD^ 8: 1.-67-1.78 (m, 2H); 2.22 (m, 1H); 2.33 (d, 1H); 2.55-2.69 (m, 311); 2.90 (m, 1H); 3.06 (m, 1H); 3.75 (d, 1H); 3.79 (d, 1H); 3.91 (m, 1H); 4.30-4.46 (m, 2H); 4.59 (s, 2H); 6.61 (d, 1H); 6.93 (ddd, 1H); 6.95 (d, 1H); 7.21 (d, 1H); 7.27 (m, 1H); 7.96 (d, 1H). Intermediate 42; CisMl-{2-[4-ammo-3-hvdroxvpiperidin-l-vl]ethyl}-5.7- difluoroquinolin-2(lffl-orie Cis(±)l-{2-[4-azido-3-hydroxypiperidin-l-yl]ethyl}-5,7-difluoroquinolm-2(l/;/)-one (Intermediate 43) (190 mg, 0.54 mmol) was hydrogenated as described for Intermediate 34, for 3 hours, to give the product as a colorless oil, 175 mg (quantitative). MS (BS); 324.02 (MH+) for C16H19F2N302 'H-NMR (CDCl^ 5: 1.82 (m, 2H); 2.25 (ddd, 1H); 2.39 (d, 1H); 2.62-2.73 (m, 3H); 2.90 (m, 1H); 2.98 (m, 1H); 3.13 (m, 1H); 3.92 (m, 1H); 4.23 (ddd, 1H); 4.44 (ddd, 1H); 6.63 (d, 1HJ; 6.70 (ddd, 1H); 6.91 (d, 1H); 7.85 (d, 1H). Intermediate 43: Cis(±)l - {2-[4-azido-3-hvdroxvpiperidin-1 -yllethvl) -5.7- difluoroquinolin-2fj/:n-one 5,7-Difluoroquinolin-2(l,#)-one (Intermediate 25) (389 mg, 2.15 mmol) was deprotonated with sodium hydride (95 mg, 60% in oil, 2.36 mmol) and alkylated with cis(±) 2-(4-azido-3-hydroxypiperidin-l~yl)ethyl methanesulfonate (Intermediate 44) (2.15 mmol) as described for Intermediate 20, except after 24 hours, potassium carbonate (100 mg, 0.72 mmol) was added and the resulting mixture was stirred for another 24 hours at room temperature to give the product as a colorless hard foam, 195 mg (26%). MS (ESy- 350.15 (MH) for CwHwFaNsCfc 'H-NMR (DMSO-d^ S: 1.56 (m, IH); 1.71 (m, 1H); 2.32 (m, 1H); 2.40 (m, 1H); 2.48 (m, 1H); 2.53 (dd, 2H); 2.59 (m, 1H); 3.61-3.71 (m, 2H); 4.29 (dd, 2H); 5.05 (d, 1H); 6.61 (d, 1H); 7.21 (ddd, 1H); 7.32 (d, 1H); 7.95 (d, 1H). Intermediate 44: Cis(±)2-(4-a2ido-3-hydroxyrjiperidin-l-vl)gthvlmethapesulfonatc A solution of cis(±)4-azido-l-(2-hydroxyethyl)piperidin-3-ol (Intermediate 45) (0.4 g, 2.15 mmol) in dry dichloromethane (15 mL) and 2,6-lutidine (0.325 mL, 2.8 mmol) was treated at-20°C dropwise with a solution of methanesulfonyl chloride (0.175 mL, 2.26 mmol) in dichloromethane (5 mL). The temperature was allowed to reach 0°C and kept at 0°C for 10 hours. The resulting reaction mixture was diluted with dichloromethane (50 mL) and washed with saturated aqueous sodium hydrogen carbonate solution (10 mL). The aqueous phase was back extracted with dichloromethane (20 mL) and the combined organic phases were dried over sodium sulfate. The solvent was removed under reduced pressure, and the residue was codistilled with dry DMF (10 mL) without heating. This crude preparation of the mesylatc was used without further purification directly for the next step. MS fES): 265.02 (MH4) for C8H]6N404S Intermediate 45: CisM4-azido-l -(2-hydroxyethyDpiperidin-3-ol Cis(±)4-azidopiperidin-3-ol (prepared following the procedure described in WO 2005/066176 for the chiral material) (0.945 g, 6.65 mmol), N,N-diisopropylethylamine (1.7 mL, 10 mmol) and 2-bromoethanol (0.61 mL, 8.64 mmol) were reacted as described for Intermediate 37, except heating for one hour. The solvent was removed under reduced pressure. The residue was taken up in dichloromethane (100 mL), washed with 1M sodium hydroxide solution (30 mL) and the aqueous phase was back extracted five times with dichloromethane (5x 100 mL). The combined organic phases were dried over sodium sulfate. Chromatography on silica gel with dichloromethane/ methanol 3:1 gave 1.15 g (93%) of the product as a colorless oil. MS (ES\. 187.24 (MH4) for C7H,4N402 'H-NMR fDMSO-dfi) 8: 1.61 (m, 1H); 1.72 (m, 1H); 2.28-2.38 (m, 5H); 2.45 (m, 1H); 3.43 (ddd, 2H); 3.57 (m, 1H); 3.73 (m, 1H); 4.33 (dd, 1H); 5.01 (d, 1H). Example 21 4-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-yImethyl)aminoJpipcridin-lyl} ethyl)-6-methoxy-2#-l,4-benzoxazin-3(4jfiO-one A mixture of 4-[2-(4-aminopiperidin- 1 -yl)ethyl]-6-methoxy-2//- 1 ,4-benzoxazin- 3(4//)-one trifluoroacetate (Intermediate 46) ( 0.4 mmol), N.N-diisopropylethylamine (1 mL) and2,3-dihydro[l,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO 2004/058144) (74 mg, 0.45 mmol) in dichloroethane/methanol (1:1, 10 mL) was reacted and reduced with sodium cyanoborohydride (50 mg, 0.74 mmol) as described for Example 4. Reverse phase chromatography with water/acetonitrile/trifluoroacetic acid gave the product as the trifluoroacetic acid salt. The salt was dissolved in water and chloroform and basified with saturated sodium carbonate. The layers were separated and the aqueous was extracted with chloroform. The organic extracts were dried over magnesium sulfate and evaporated to dryness to give the free base of the title compound as a gum, 54 mg (32%). MS (ESI: 455.33 (MH+) for C^iMOs 'H-NMRfCDCU-dl 5: 1.46 (m, 2H); 1.88 (m, 2H); 2.14 (m, 2H); 2.54 (m, 1H); 2.58 (t, J = 7.3 Hz, 2H); 2.95 (m, 2H); 3.78 (s, 3H); 3.79 (s, 2H); 4.01 (t, J = 7.4 Hz, 2H); 4.29 (m, 4H); 4.52 (s, 2H); 6.50 (dd, J = 6.2, 2.7 Hz, 1H); 6.67 (d, J = 2.7 Hz, 111); 6.81 (s, 1H); 6.89 (d,J = 8.7Hz, lH);8.08(s, Intermediate 46 : 4-\|"2-(4-Aminopiperidin- 1 -vl)ethvl1-6-methoxy-2//- 1 ,4-benzoxaxin 3r4ffl-one terf-Butyl { 1 -[2-(6-methoxy-3-oxo-2,3-dihydro-4//-l ,4-benzoxazin-4- yl)ethyl]piperidine-4-yl}carbamate (Intermediate 47) (510 mg, 1.26 mmol) was reacted as described for Intermediate 14. The crude trifluoro acetate of the title compound was used without further purification for the next step (quantitative yield). MS (ESV 306 (MH+) Intermediate 47; tert-Butvl (l-[2-f6-methoxv-3-oxo-2,3-dihydro-4J/-1.4-benzoxa?:in- 4-yl)ethyl]piperidine-4-vllcarbamate 6-Methoxy-2/:M,4-benzoxazin-3(4/;/)-one (Intermediate 48) (380 mg, 2.1 mmol) was deprotonated with sodium hydride (100 mg, 60% in oil, 2.5 mmol) and alkylated with 2-{4- [(te^butoxycarbonyl)arnino]piperidin-l-yl} ethyl methanesulfonate (Intermediate 6) (2.3 mmol) as described for Intermediate 2. Chrornatography on silica gel with hexanes/ ethyl acetate (1:1) afforded 510 mg (60%) of the product. MS (ES): 406.49 (MH+) for C2iH3iN305 'H-NMR CCDCh-d) 6: 1.34 (m, 2H); 1.36 (m, 2H); 1.62 (m, 2H); 1.98 (m, 2H); 2.43 (m, 2H); 2.84 (m, 2H); 3.20 (m, 1H); 3,73 (s, 3H); 3.96 (m, 2H); 4.53 (s, 2H); 6.56 (m, 1H); 6.76 (m, 1H); 6.92 (m, 1H). Intermediate 48: 6-Methoxv-2//-1.4-benzoxazin-3(4f/)-one To a solution of ethyl (4-methoxy-2-nitrophenoxy)acetate (Intermediate 49) (1,8 g, 7.1 mmol) in acetic acid (20 mL) was added iron powder (1.1 g, 19.9 mmol). The reaction was heated at 90°C for 3 hours. It was cooled to room temperature, diluted with ethyl acetate, filtered through celite, and concentrated to dryness under reduced pressure. Silica gel chromatography with hexanes/ ethyl acetate (7:3) afforded product, 1 g (79%). MS (ES): 180.15 (MH) for C9H9N03 'H-NMRfCDCK-d) 5: 3.75 (s, 3H); 4.55 (s, 211); 6.40 (d, 1H); 6.50 (dd, 1H); 6.89 (d, 1H); 8.85 (bs, 1H). Intermediate 49; Ethyl (r4-methoxv-2-nitrophenoxv)acetate A mixture of 4-methoxy-2-nitrophenol (2 g, 11.8 mmol), cesium carbonate (7.7 g, 23.6 mmol) and 2-bromo ethyl acetate (1,31 mL, 11.8 mmol) in acetone (50 mL) was heated at 50°C overnight. The mixture was heated at 55°C for an additional 1 hour, then filtered and concentrated to dryness under reduced pressure. Silica gel chromatography with hexanes/ ethyl acetate (4:1) afforded product, 1.8 g (60%). MS rES): 256.26 (MR") for CnHnNOe 'H-NMR(CDCh-d) 5: 1.28 (t, 3H); 3.81 (s, 3H); 4.25 (q, 2H); 4.70 (s, 211); 7.04 (m, 2H); 7.39 (d, 1H). Example 22 6-[({l-{2-(6-Methoxy-3-oxo-2,3-dihydro-4JH-l,4-benzoxazin-4-yl)ethyI]piperidin- 4-yl}amino)methyI]-2#~pyrido[3,2-fiI[l,4]oxazin-3(4//)-one 4-[2-(4-aminopiperidin-1 -yl)ethyl]-6-methoxy-2/f-1,4-benzoxazin-3 (4H)-on& trifluoroacetate (Intermediate 46) (0.4 mmol), 3-oxo-3,4-dihydro-2/7-pyrido[3,2- 6][l,4]oxazine-6-carbaldehyde (WO 2004/058144) (80 mg, 0.44 mmol) and sodium cyanoborohydride were reacted as described under Example 21, but, the reaction was stirred at room temperature overnight after sodium cyanoborohydride addition to give the title compound as a free base, 30 mg (17%). MS (ES\. 468.27 (MH+) for C24H29N5O5 'H-NMRtCDCh-d) 5: 1.56 (m, 2H); 1.96 (m, 2H); 2.18 (m, 3H); 2.62 (m, 3H); 3.01 (m, 2H); 3.79 (s, 3H); 3.84 (s, 2H); 4.06 (m, 2H); 4.51 (s, 2H); 4,63 (s, 2H); 6.51 (1H); 6.67 (s, 1H); 6.89 (1H); 6.95 (1H); 7.20 (1H). Example 23 6-[({l-[2-(6-Methoxy-3-oxo-2,3-dihydro-4/f-l,4-benzothiazin-4-yl)ethyl]piperidin- 4-yl}amino)methyl]-2jy-pyrido[3,2-61[l,4]oxazin-3(4#)-one 4-[2-(4-Aminopiperidin-l-yl)ethyl]-6-methoxy-2//'-l,4-benzothiazm-3(4/ir)-one (Intermediate 50) (0.9 mmol), 3-oxo-3,4-dihydro-2#-pyrido[3,2-£][l,4]oxazine-6- carbaldehyde (WO 2004/058144) (190 mg, 1.1 mmol) and sodium cyanoborohydride (110 mg, 1,77 mmol) were reacted as described under Example 21, with stirring for 2.5 hours at room temperature after sodium cyanoborohydride addition. The title compound was obtained as a solid, 52 mg (12%). MS (ES): 484.26 (MH+) for €241^5048 'H-NMRfCDCh-d) 6: 1.49 (m, 2H); 1.91 (m, 3H); 2.16 (m, 2H); 2.54 (m, 1H); 2.61 (m, 2H); 2.96 (m, 2H); 3.33 (s, 2H); 3.81 (s, 5H); 4.09 (ra, 2H); 4.63 (s, 2H); 6.58 (dd, 1H); 6.87 (d, 1H); 6.93 (d, 1H); 7,20 (d, 1H); 7.24 (d, 1H). Intermediate SO; 4-r2-f4-Aminopiperidin-l-yl)ethyl1-6-methoxv-2^'-l,4- benzothiazin-3 f 4//)-one tert-Butyl {l-[2-(6-methoxy-3-oxo-2,3-dihydro-4//-l54-benzothiazin-4- yl)ethyl]piperidin-4-yl}carbamate (Intermediate 51) (750 mg, 1.78 mmol) was reacted as 1— described for Intermediate 14. The crude trifluoro acetate of the title compound was used without further purification for the next step (quantitative yield). MS (ES): 322 (MH+) for C,6H23N302S Intermediate 51; te/V-Butyl (l-[2-f6-methoxv-3-oxo-2,3-dihvdro-4//-1.4- benzothiazin-4-yl)ethvl1piperidin-4-vllcarbamate 6-Methoxy-2//-l,4-benzothiazin-3(4/:0-one (Intermediate 52) (410 mg, 2.1 mmol) was deprotonated with sodium hydride (100 mg, 60% in oil, 2.5 mmol) and alkylated with 2- {4-[(tert-butoxycarbonyl)amino]piperidin-l-yl}ethyl methanesulfonate (Intermediate 6) (2.3 mmol) as described for Intermediate 2. Chromatography on silica gel with hexanes/ethyl acetate (1:3) afforded 750 mg (85%) of the product, MS (ESI: 422.24 (MH4) for CziHsiNaC^S 1H-NMRfCDCK-d') 6: 1.40 (m, 2H); 1.45 (s, 9H); 1.92 (m, 2H); 2.22 (m, 2H); 2.62 (t, 2H); 2.88 (m, 2H); 3.35 (s, 2H); 3.49 (m, 1H); 3.82 (s, 3H); 4.08 (t,-2H); 4.43 (m, 1H); 6.61 (dd, 1H); 6.86 (d, 1H); 7.28 (s, 1H). Intermediate52: 6-MethQxy-2//-1.4-benzothiazin-3(4/-ir)-one Prepared from ethyl [(4-methoxy-2-nitrophenyl)thio]acetate (Intermediate S3, 3 g, 11 mmol) according to procedure described for preparation of Intermediate 48. Silica gel chromatography with hexanes/ ethyl acetate (3:2) afforded desired product, 2 g (93%). MS (ES): 196.12 (MH^ for C9H9NO2S 'H-NMR (CDClr 1H); 8.63 (bs, 1H). Intermediate S3: Ethyl [C4-methoxy-2-nitrophenvl')thio1acetate Ethyl mercaptoacetate (2.3 niL, 21.5 mmol) was dissolved in DMF (20 mL) and cooled to 0°C. Sodium hydride (1 g, 60% in oil, 25.8 mmol) was added and the reaction was stirred for 1 hour. Then a solution of l-bromo-4-methoxy-2-nitrobenzene (5 g, 21.5 mmol) in DMF (20 mL) was added at 0°C. The reaction mixture was allowed to warm to room temperature and stirred overnight. It was diluted with ethyl acetate, washed with water (four times) and with brine and then dried over magnesium sulfate. Silica gel chromatography with hexanes/ ethyl acetate (4:1) afforded the product, 3 g (52%). MS fES"): 272.14 (MH+) for CnHi3NO5S 'H-NMRfCDCh-fl 5: 1.24 (t, 3H); 3.68 (s, 2H); 3,86 (s, 3H); 4.18 (q, 2H); 7.15 (dd, 1H); 7.47 (d, 1H); 7.65 (d, 1H). Example 24 4-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]pipcridin-lyI} ethyI)-6-methoxy-2fir-l,4-benzothiazin-3(4J?)-one 4-[2-(4-Aminopiperidin-l-yl)emyl]-6-methoxy-2//-l,4-benzothiazin-3(4#)-one (Intermediate 50) (0.9 mmol), 2,3-dihydro[l,4]dioxino[2>3-c]pyridine-7-carbaldehyde (WO 2004/058144) (180 mg, 1.1 ramol), and sodium cyanoborohydride (110 rng, 1.76 mmol) were reacted as described under Example 21 to give 55 mg (13%) product as a dry film. MS fES): 471.26 (MH+) for C24H3oN404S 'H-NMR(CDClrdl 5: 1.47 (m, 2H); 1.91 (m, 2H); 2.15 (ra, 2H); 2.54 (m, 1H); 2.60 (t, J - 6.4 Hz, 2H); 2.94 (m, 2H); 3.33 (s, 2H); 3.47 (s, 2H); 3.80 (s, 5H); 4.08 (t, 2H); 4.29 (m, 4H); 6.58 (dd, 1H); 6.80 (s, 1H); 6.88 (d, 1H); 7.23 (d, 1H); 8.08 (s, 1H). Example 25 6-[({l-[2-(6-Fluoro-3-oxo-2,3-dihydro-4H-l,4-benzoxazin-4-yl)ethyl]piperidin-4- yl}amino)methyl]-2/f-pyrido[3,2-6] [1,4] oxazin-3(4fO-one 4-[2-(4-Aminopiperidin-l-yl)ethyl]-6-fluoro-2/:/-l)4-benzoxazin-3(4//)-one (Intermediate 54), (0.7 mmol), 3-oxo-3,4-dihydro-2#-pyrido[3,2-6][l,4]oxazine-6- carbaldehyde (WO 2004/058144) (150 rag, 0.84 mmol) and sodium cyanoborohydride (90 mg, 1.4 mmol) were reacted as described under Example 21 to give 51 mg (16%) product as a solid. MS (ES): 456.24 (MH4) for C23H26FN5O4 'H-NMR fCDClrd) 5: 1.52 (m, 2H); 1.94 (m, 2H); 2.15 (m, 2H); 2.57 (m, 1H); 2.59 (t, J - 7.1 Hz, 2H); 2.97 (m, 2H); 3.84 (s, 2H); 4.01 (t, J = 7.1 Hz, 2H); 4.54 (s, 2H); 4.62 (s, 2H); 6.68 (m, 1H); 6.86 (m, 1H); 6.89 (m, 1H); 6.95 (d, J = 8.1 Hz, 1H); 7.20 (d, J = 8.1 Hz, 1H). Intermediate 54: 4-r2-(4-AminQpiperidin-l-yDethvl]-6-fluoro-2/jr-l,4-benzoxazin; 3(4/f>-one tert-B\tfyl {1 -[2-(6-fluoro-3-oxo-2,3-dihydro-4flr-l,4-benzoxazin-4-yl)ethyl]piperidhi- 4-yl}carbamate (Intermediate 55) (640 mg, 1.56 mmol) was reacted as described for Intermediate 14. The crude trifluoro acetate of the title compound was used without further purification for the next step (quantitative yield). MS (ES\. 294 (MH+) for Ci Intermediate 55: fert-Butvl (l-[2-(6-fluoro-3-oxo-2.3-dihvdro-4Jjr-1.4-ben7.oxazin-4- yl)ethyl]piperidin-4-yUcarbamate Commercially available 6-fluoro-2#-l,4-benzoxazin-3(4#)-one (350 mg, 2.1 mmol) was deprotonated with sodium hydride and alkylated with 2-{4-[(tertbutoxycarbonyl) amino]piperidin-l-yl} ethyl methanesulfonate (Intermediate 6) (2.3 mniol) as described for Intermediate 2. Chromatography on silica gel with hexanes/ ethyl acetate (1:1) gave 550 mg (67%) product. MS (ES\. 394.26 (MH+) for C2oH28FN3O4 'H-NMR f CDCl?-d) 8: 1.39 (m, 2H); 1.43 (s, 9H); 1.92 (m, 2H); 2.20 (m, 211); 2.58 (t, 2H); 2.88 (m, 2H); 3.45 (m, 1H); 3.98 (t, 2H); 4.41 (m, 1H); 4.55 (s, 2H); 6.68 (m, 1H); 6.85 (m, 1H); 6.91 (m, 1H). Example 26 4-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1- yl}ethyl)-6-fluoro-2/y-l,4-benzoxazin-3(4.£0-one 4-[2-(4-Aminopiperidin-l-yl)ethyl]-6-fluoro-2//-l,4-benzoxazin-3(4//)-one (Intermediate 54) (0.7 mmol), 2,3-dihydro[l,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO 2004/058144) (140 mg, 0.84 mmol), and sodium cyanoborohydride (90 mg, 1.4 mmol) were reacted as described under Example 21 to give 100 mg (32%) product. MS HBS): 443.24 (MH4) for C23H27FN4O4 'H-NMR (CDCh-d) 8: 1.46 (m, 2H); 1.90 (m, 2H); 2.13 (m, 2H); 2.53 (m, 1H); 2.57 (t, 2H); 2.93 (m, 2H); 3.80 (s, 2H); 3.99 (t, 2H); 4.29 (m, 4H); 4.54 (s, 2H); 6.67 (td, 1H); 6.81 (s, 1H); 6.86 (dd, 1H); 6.90 (dd, 1H); 8.09 (s, 1H). Example 27 64({l-[2-(6-Chloro-3-oxo-2,3-dihydro-4/M,4-benzoxazin-4-yl)ethyl]piperidin-4- yl}ammo)methyl]-2//-pyrido[3,2-A][l,4]oxazin-3(4#)-one 4-[2-(4-Aminopiperidin-l-yl)ethyl]-6-chloro-2//-l,4-benzoxasiin-3(4/f)-one (Intermediate 56) (0.8 mmol), 3-oxo-3,4-dihydro-2#-pyrido[3,2-&][l,4]oxazine-6- carbaldehyde (WO 2004/058144) (150 mg, 0.84 mmol) and sodium cyanoborohydride (90 mg, 1.4 mmol) were reacted as described under Example 21 to give 78 mg (21%) product as a solid. MS rES): 472.24 (MH+) for C23H26C1N5O4 dl 8: 1.50 (m, 2H); 1.93 (m, 3H); 2.15 (m, 2H); 2.56 (m, 1H); 2.59 (t, 2H); 2.96 (m, 2H); 3.82 (s, 2H); 4.01 (t, 2H); 4.56 (s, 2H); 4.63 (s, 2H); 6.92 (m, 3H); 7.12 (d, 1H); 7.20 (d, 1H). Intermediate 56; 4-r2-f4-AmiDOpiperidin-l-vl)ethyn-6-chloro-2/j'-1.4-1benzoxazin- 3(4#Vone /erf-Butyl { 1 -[2-(6-chloro-3-oxo-2,3-dihydro-4/f-l ,4-benzoxazin-4-yl)ethyl]piperidin- 4-yl}carbamate (Intermediate 57) (640 mg, 1.56 mmol) was reacted as described for Intermediate 14. The crude trifluoro acetate of the title compound was used without further purification for the next step (quantitative yield). MS fBS"): 310 (MH4) for ds^oClNsOz Intermediate 57: ter/-Butvl ll-r2-f6-chloro-3-oxo-2.3-dihYdTo-4J/-l,4-benzoxagin-4- vr)ethvl]piperidin-4-yl } carbamate Commercially available 6-chloro-2//-l,4-benzoxazin-3(4//)-one (380 mg, 2.1 mmol) was deprotonated with sodium hydride and alkylated with 2-{4-[(tertbutoxycarbonyl) amino]piperidin-l-yl} ethyl methanesulfonate (Intermediate 6) (2.3 mmol) as described for Intermediate 2. Chromatography on silica gel with hexanes/ ethyl acetate (1:1) gave 640 mg (74%) product. MS (ESI: 410.22 (MH) for CzoHzgClNjC^ 'H-NMRfCDCh-d) 6: 1.43 (m, 2H); 1.43 (s, 9H); 1.92 (m, 2H); 2.21 (m, 2H); 2.58 (m, 2H); 2.88 (m, 2H); 3.45 (m, 1H); 3.99 (m, 2H); 4.41 (m, 1H); 4.56 (s, 2H); 6.91 (m, 2H); 7.13 (s, 1H). Example 28 6-[({l-[2-(6-Methoxy-3-oxo-2,3-dihydro-4/f-l,4-benzoxazin-4-yl)ethyl]piperidin- 4-yI}amino)methyl]-2flr-pyrido[3,2-6][l,4]thiazin-3(4fl)-one 4-[2-(4-aminopiperidin- 1 -yl)ethyl] -6-methoxy-2//- 1 ,4-benzoxazin-3 (4//)-oue (Intermediate 46) (0.2 mmol), 3-oxo-3,4-dihydro-2//-pyrido[3,2-6][l,4]thiazine-6- carbaldehyde (WO 2004/058144) (42 mg, 0.22 nimol) and sodium cyanoborohydride (23 mg, 0.36 mmol) were reacted as described under Example 21 to give 28 mg (32%) of product as a dry film. MS (TBS); 484.27 (MH) for Cz^NsCHS 'H-NMRfCDCh-d-) 6: 1.50 (m, 2H); 1.92 (m, 2H); 2.17 (m, 3H); 2.55 (m, 1H); 2.61 (m, 2H); 2.98 (m, 2H); 3.46 (s, 2H); 3.78 (s, 3H); 3.84 (s, 2H); 4.04 (m, 2H); 4.51 (s, 2H); 6.50 (dd, 1H); 6.67 (d, 1H); 6.89 (d, 1H); 6.98 (d, 1H); 7.57 (d, 1H). Example 29 3-Oxo-4-[2-(4-{[(3-oxo-3,4-dihydro-2fl-pyrido[3,2-6][l,41oxazin-6- yl)methyl]amino}piperidin-l-yl)ethyl]-3,4-dihydro-2F-l,4-benzoxazine-6-carbonitrile 4-[2-(4-aminopiperidin-1 -yl)ethyl]-3-oxo-3,4-dihydro-2#-1,4-benzoxazine-6- carbonitrile (Intermediate 58) (0.8 romol), 3-oxo-3,4-dihydro-2//-pyrido[3,2-6][l,4]oxa/inc- 6-carbaldehyde (WO 2004/058144) (140 mg, 0.79 mmol) and sodium cyanoborohydride (83 mg, 1.32 mmol) were reacted as described under Example 21 to give 60 mg (19%) product as a solid. MS (ES): 463.32 (MH+) for C24H26N6O4 'H-NMR (CDCh-J) 6: 1.49 (m, 2H); 1.94 (m, 2H); 2.14 (m, 2H); 2.56 (m, 1H); 2.59 (t, J = 6.7 Hz, 2H); 2.94 (m, 2H); 3.84 (s, 2H); 4.03 (t, 211); 4.62 (s, 2H); 4.67 (s, 2H); 6.94 (d, 1H); 7.03 (d, 1H); 7.19 (d, 1H); 7.30 (dd, 1H); 7.46 (d, 1H). Intermediate 58: 4-r2-(4-Aminopiperidin-l-vl)ethyl]-3-oxQ-3,4-dihydror2//-1.4- ben2oxazine-6-carbonitrile trifluoroacetate terf-Butyl {1 -[2-(6-cyano-3-oxo-2,3-dihydro-4/?-1,4-benzoxazin-4-yl)ethyl]pipcridin- 4-yl}carbamate (Intermediate 59) (610 mg, 1.52 mmol) was reacted as described for Intermediate 14. The crude trifluoro acetate of the title compound was used without further purification for the next step (quantitative, yield). MS flES): 301 (MH+) for Ci6H2oN4O2 Intermediate 59: /grt-Butyl n-r2-(6-cvano-3-oxo-2.3-dihydro-4/f-1.4-bcnzQxazin-4- vltethyripiperidin-4-yn carbamate 3-oxo-3,4-dihydro-2/f-l,4-benzoxazine-6-carbonitrile (Intermediate 60) (350 mg, 2.0 mmol) was deprotonated with sodium hydride and alkylated with 2-{4-[(tertbutoxycarbonyl) amino]piperidin-l-yl} ethyl methanesulfonate (Intermediate 6) (2.2 mmol) as described for Intermediate 2. Chromatography on silica gel with hexanes/ethyl acetate (1:3) afforded 610 mg (76%) of the product. MS (ES): 401.27 (MH4) for C2iH28N404 'H-NMR rCDClr-dl 8: 1.41 (m, 2H); 1.42 (s, 9H); 1.93 (m, 2H); 2.21 (m, 2H); 2.58 (m, 2H); 2.87 (m, 2H); 3.45 (m, 1H); 4.02 (m, 2H); 4.43 (m, 1H); 4.67 (s, 2H); 7.03 (d, 1H); 7.30 (m, 1H); 7.47 (s, 1H). Intermediate 60: 3-Oxo-3.4-dihvdro-2//-l .4-benzoxazine-6-carbonitrile The title compound was prepared similarly to literature procedure (Caliendo, G; et. al.; Bioorg, Med. Chem. Lett., 2002, 10. 2663), but in one step. Commercially available 3-amino- 4-hydroxybenzonitrile (2.5 g, 18.6 mmol) was dissolved in chloroform (300 mL) and saturated sodium bicarbonate (90 mL). The biphasic reaction mixture was cooled to 0°C and bromoacetyl bromide (2.4 mL, 28 mmol) was added dropwise. The reaction was stirred overnight at room temperature. The layers were separated and the aqueous layer was filtered to yield the desired product as a tan solid, 2.3 g (69%). MS fESV 175.11 (MH+) for CgHeNaOz 'H-NMR CPMSO-d^ 8: 4.70 (s, 2H); 7.11 (d, 1H); 7.19 (d, 1H); 7.40 (m, 1H); 10.98 (bs, 1H). Example 30 yl]ethyl}piperidin-4-yl)amino]methyl}-2Jyr-pyrido[3,2-Z>][l,4]oxazin-3(4//)-onc 4-[2-(4-Aminopiperidin-l-yl)ethyl]-6-(trifluoromethoxy)-2//'-l,4-benzoxazin-3(4//)- one (Intermediate 61) (0.55 mmol), 3-oxo-3,4-dihydro-2tf-pyrido[3,2-&][l,4]oxazine-6- carbaldehyde (WO 2004/058144) (120 mg, 0.66 mmol) and sodium cyanoborohydride (69 mg, 1.1 mmol) were reacted as described under Example 21 to give 44 mg (15%) product as a solid. MS (ES): 522.25 (MH+) for Cj^FjNsOs 'H-NMR fCDCh-d") S: 1 .53 (m, 2H); 1.95 (m, 2H); 2.14 (m, 2H); 2.59 (t, 2H); 2.59 (m, 1H); 2.96 (m, 2H); 3.85 (s, 2H); 4.02 (t, 2H); 4.59 (s, 2H); 4.63 (s, 2H); 6.85 (d, 1H); 6.96 (d, 3H); 6.97 (d, 1H); 7.20 (d, 1H). Intermediate 61: 4-r2-(4-Aminopiperidin-l-vnethvn-6-Ctrifluoromethoxy)-2//-l,4- benzoxazin-3f4flVone tert-Butyl(l-{2-[3-oxo-6-(trifluoromethoxy)-2,3-dihydro-4/:r-l,4-benzoxazin-4- yl]ethyl}piperidin-4-yl)carbamate (Intermediate 62) (790 mg, 1.72 mmol) was reacted as described for lotermediate 14. The crude trifluoro acetate of the title compound was used without further purification for the next step (quantitative yield). MS (ES): 360 (MH+) for Ci6H2oF3N303 Intermediate 62: tert-Butvl n-{2-[3-oxo-6-ftrifluoromethoxv)-2,3-dihydro-4/f-L4- benzoxazin-4-ynethyllpiperidin-4-vl)carbamate 6-(Trifluorornethoxy)-2//-l)4-benzoxazin-3(4//)-one (Intermediate 63) (490 mg, 2.0 mmol) was deprotonated with sodium hydride and alkylated with 2-{4-[(/er/- butoxycarbonyl)amino]piperidin-l-yl}ethyl methanesulfonate (Intermediate 6) (2.2 mmol) as described for Intermediate 2. Chromatography on silica gel with hexanes/ethyl acetate (2:3) afforded 790 mg (86%) of the product, MS fES); 460.26 (MH+) for C21H28F3N305 'H-NMRfCDCh-d) 5: 1.38 (m, 2H); 1.43 (s, 9H); 1.92 (m, 2H); 2.20 (m, 213); 2.57 (m, 2H); 2.87 (m, 2H); 3.45 (m, 1H); 4.00 (m, 2H); 4.41 (m, 1H); 4.58 (s, 2H); 6.85 (m, 1H); 6.95 (s, 1H); 6.99 (m, 1H). Intermediate 63; 6-(Trifluoromethoxv)-2//-1.4-benzoxaziTi-3(4J:f)-onc Ethyl [2-nitro-4-(trifluoromethoxy)phenoxy]acetate (Intermediate 64) (1,14 g, 3.7 mmol) and iron powder (510 mg, 9.2 mmol) were reacted according to procedure for Intermediate 48, but heating for only one hour. Silica gel chromatography with hexanes/ethyl acetate (4:1) afforded product, 770 mg (90%). MS (ES): 234.16 (MH+) for C9H6F3N03 'H-NMR fCDCl?- (bs, 1H). Intermediate 64; Ethyl [2-nifro-4-(trifluorornethoxy)pbenoxv1 acetate Prepared from 2-nitro-4-(trifluoromethoxy)phenol (2 g, 8.9 mmol) according to procedure for Intermediate 49. Silica gel chromatography with hexanes/ethyl acetate (4:1) afforded product, 1.14 g (41%). MS (ES): 310.12 (MH4) for CnH\|0F3N06 1H-NMRfCDCU-d>) 6: 1.28 (t, 3H); 4.26 (q, 2H); 4.78 (s, 2H); 7.03 (d, 1H); 7.40 (m, 1H); 7.78 (d, 1H). Example 31 6-[({l-[2-(6-Fluoro-3-oxo-2,3-dihydro-4flr-l,4-benzoxazin-4-yl)ethyl]piperidin-4- yl}amino)methyl]-2fl'-pyrido[3,2-Z>][l,4]thiazin-3(4//)-one 4-[2-(4-Aminopiperidin-1 -yl)ethyl] -6-fiuoro-2//-1,4-benzoxazin-3 (4#)-one (Intermediate 54) (0.7 mmol), 3-oxo-3,4-dihydro-2#-pyrido[3,2-6][l,4]thiazine-6- carbaldehyde (WO 2004/058144) (160 mg, 0.82 mmol) and sodium cyanoborohydride (90 mg, 1.4 mmol) were reacted as described under Example 21, (but the reaction mixture was refluxed overnight before reduction with sodium cyanoborohydride at room temperature for 2 hours) to give 76 mg (23%) of product. MS fESV 472.25 (MH+) for CxsHaeFNsOaS 'H-NMRfCDCh-d") 8: 1.48 (m, 2H); 1.92 (m, 2H); 2.15 (m, 2H); 2.55 (m, 1H); 2.59 (t, 2H); 2.96 (m, 2H); 3.46 (s, 2H); 3.84 (s, 2H); 4.00 (t, 2H); 4.55 (s, 2H); 6.68 (td, 1H); 6.86 (dd, 1H); 6.91 (dd, 1H); 6.98 (d, 1H); 7.57 (d, 1H). Example 32 4.(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)aminoJpiperidin-lyl} ethyl)-3-oxo-3,4-dihydro-2Jy-l,4-benzoxazine-6-carbonitrile 4-[2-(4-Aminopiperidin-l-yl)ethyl]-3-oxo-3,4-dihydro-2J!/-l,4-benzoxazine-6- carbonitrile (Intermediate 58) (2.8 mmol), 2,3-dinydro[l,4]dioxino[2,3-c]pyridine-7- carbaldehyde (WO 2004/058144) (550 mg, 3.36 mmol), and sodium cyanoborohydride (350 mg, 5.6 mmol) were reacted as described under Example 21 to give the crude free base. The product was precipitated from chloroform by addition of 2M HC1 in ether. 1'he precipitate was collected by filtration to give title compound as the bis HC1 salt, 420 mg. MS (ESI: 450.21 (MH+) for CwHfoNsC^ 1H-NMR(CDClrd>) 6: 1.43 (m, 2H); 1.89 (m, 2H); 2.12 (m, 2H); 2.48 (bs, III); 2.53 (m, 1H); 2.56 (t, 2H); 2.90 (m, 2H); 3.79 (s, 2H); 4.02 (t, 2H); 4.29 (m, 4H); 4.66 (s, 2H); 6.81 (s, 1H); 7.02 (d, 1H); 7.29 (dd, 1H); 7.37 (d, 1H); 4.66 (s, 1H). Example 33 6-[({l-[2-(6-Bromo-3-oxo-2,3-dihydro-4JH-l,4-benzoxazin-4-yl)ethyl]piperidin-4- yI}amino)methyl]-2Jy-pyrido[3,2-ft][l,4]oxazin-3(4fl)-one 4-[2-(4-Aminopiperidin-l-yl)ethyl]-6-bromo-2/:ir-l)4-benzoxazin-3(4/i)-one (Intermediate 65) (0.57 mmol), 3-oxo-3,4-dihydro-2#-pyrido[3,2-&][l,4]oxazine-6- carbaldehyde (WO 2004/058144) (120 mg, 0.67 mmol) and sodium cyanoborohydride (72 mg, 1.14 mmol) were reacted as described under Example 21 to give 65 mg (22%) product as a solid. MS (ESV. 516.22 (MH) for C23H26BrN5O4 'H-NMRCCDCh-d) 5: 1.51 (m, 2H); 1.93 (m, 2H); 2.14 (m, 2H); 2.57 (m, 1H); 2.59 (t, 2H); 2.96 (m, 2H); 3.83 (s, 2H); 4.00 (t, 2H); 4.56 (a, 2H); 4.63 (s, 2H); 6.84 (d, 1H); 6.95 (d, 1H); 7.08 (dd, 1H); 7.20 (d, 1H); 7.27 (d, 1H). Intermediate 65: 4-[2-(4-Aminopiperidin-l-yl')ethyl]-6-bromo-2//-l,4-ben/oxazin- 3f4flV-one tert-Butyl {l-[2-(6-bromo-3-oxo-2,3-dihydro-47M,4-benzoxazin-4-yl)ethyl]piperidiri- 4-yl}carbamate (Intermediate 66) (261 mg, 0.57 mmol) was reacted as described for Intermediate 14. The crude trifluoro acetate of the title compound was used without further purification for the next step (quantitative, yield). MS (ESI: 354 (MH) for Ci5H2oBrN302 Intermediate 66; tert-Butvl (l-r2-(6-bromo-3-oxo-2.3-dihvdro-4//-1.4-benzoxazin-4- vl)ethyl]piperidin-4-yl) carbamate 6-Bromo-2//-l,4-benzoxazin-3(4//)-one (Intermediate 67) (200 mg, 0.87 mmol) was deprotonated with sodium hydride and alkylated with 2-{4-[(/ertbutoxycarbonyl) amino]piperidin-l-yl}ethyl methanesulfonate (Intermediate 6) (0.96 mmol) as described for Intermediate 2. Chromatography on silica gel with hexanes/ethyl acetate (1:3) afforded 261 mg (67%) product. Intermediate 67: 6-Bromo-2J/-l,4-benzoxazin-3(4/jr)-one 2-Amino-4-bromophenol (2.1 g, 11 mmol) and bromo acetyl bromide (1.4 mL, 16.5 mmol) were reacted according to the procedure for Intermediate 60 to afford product as a solid, 2. I g (85%). MS (ESI: 228 (MH+) for CgH6BrNO2 'H-NMR (DMSO-d^ 5: 4,58 (s, 2H); 6.90 (d, 1H); 7.00 (d, 1H); 7.06 (dd, 1H); 10.9 (bs, 1H). Example 34 6-[({l-[2-(6-Hydroxy-3-oxo-2,3-dihydro-4fi-l,4-benzoxazin-4-yl)ethyl]piperidin- 4-yl}amino)methyl]-2#-pyrido[3,2-£][l,4]oxazin-3(4#)-one A solution of 6-[({1 -[2-(6-methoxy-3-oxo-2,3-dihydro-4//-1,4-benzoxazin-4- yl)ethyl]piperidin-4-yl} amino)rnethyl]-2//-pyrido[3,2-6] [ 1,4]oxazin-3(4//)-one (Example 22) (100 mg, 0.21 mmol) in dichloromethane was cooled to -78°C and treated with 1M boron tribromide (0.63 mL, 0.63 mmol) dropwise. The reaction mixture was stirred at room temperature overnight. The reaction mixture was cooled to -78°C and an additional 1 equivalent of 1M boron tribromide was added. The reaction was stirred for 4 hours at room temperature, and then quenched with saturated sodium bicarbonate. The organic layer was separated and the aqueous phase was extracted three times with dichloromethane. The combined organic extracts were dried over magnesium sulfate and concentrated to dryness under reduced pressure to afford crude product, 11 mg (11%), as a solid. MS (ES): 454.35 (MH) for CzjHavNsOs 'H-NMR (DMSO-d^ 5: 1.47 (m, 2H); 1.98 (m, 4H); 2.94 (m, 3H); 3.94 (m, 4H); 4.49 (s, 2H); 4.66 (s, 2H); 6.38 (dd, J = 6.0, 2.5 Hz, 1H); 6.60 (d, J = 2.2 Hz, 1H); 6.80 (d, J= 8.7 Hz, 1H); 7.12 (d, J- 8.1 Hz, 1H); 7.40 (d, J = 8.3 Hz, 1H); 9.33 (s, 1H); 11.29 (s, 1H). Example 35 4-{2-[4-({[2-(2,5-Difluorophenyl)cyclopropyl]methyl}amino)piperidin-l-yl]cthyl}- 3-oxo-3,4-dihydro-2//-l,4-benzoxazine-6-carbonitrile 4-[2-(4-Ammopiperidin-l-yl)ethyl]-3-oxo-3)4-dihydro-2//-l,4-benzoxazine-6- carbonitrile (Intermediate 58) (1 mmol), 2-(2,5-difluorophenyl)cyclopropanecarbaldehyde (Intermediate 68) (200 mg, 1.1 mmol) and sodium cyanoborohydride (125 mg, 2 mmol) were reacted as described under Example 21 to give 196 mg (42%) product as a gum. MS (ES): 506.35 (MH+) for C26H28F2N402 'H-NMR (CDCU-d) 8: 0.94 (m, 2H); 1.31 (m, 1H); 1.41 (m, 2H); 1.89 (m, 3H); 2.13 (m, 2H); 2.55 (m, 1H); 2.57 (t, 2H); 2.70 (d, 2H); 2.92 (m, 2H); 4.03 (t, 2H); 4.67 (s, 2H); 6.55 (m, 1H); 6.77 (m, 1H); 6.93 (m, 1H); 7.03 (d, 1H); 7.30 (dd, 1H); 7.38 (d, 1H). Intermediate 68:2-(2.S-DifluorQphenvl)cvcloprQpanecarbaldehvde To a solution of oxalyl chloride (1.2 mL, 13.5 mmol) in dichloromethane at -78°C was added dimethyl sulfoxide (1.9 mL, 27 mmol) dropwise and it was stirred at -78°C for 30 minutes. A solution of [2-(2,5-difluorophenyl)cyclopropyl]methanol (Intermediate 69) (830 mg, 4.5 mmol) in dichloromethane was added dropwise. The reaction mixture was stirred at - 78°C for 30 minutes. Triethylamine (6.3 mL, 45 mmol) was added and the reaction mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure. Silica gel chromatography with hexanes/ ethyl acetate (9:1) afforded the desired product, 546 mg (66%). GC/MS: 182 (M+) for Ci0H8F20 'H-MMR (CDClrd^ 5: 1.52 (m, 1H); 1.73 (m, 1H); 2.17 (m, 1H); 2.73 (m, 1H); 6.65 (m, 1H); 6.87 (m, 1H); 6.98 (m, 1H); 9.36 (d, 1H). Intermediate 69; [2-(2.S4)ifluorophenyl')cvclopropvl1methanol To a solution of (2^-3-(2,5-difluorophenyl)prop-2-en-l-ol (Intermediate 70) (2.12 g, 12.5 mmol) in dichloromethane at -10°C was added dropwise diethyl zinc (1M, 75 mL, 75 mmol) over 20 minutes. Diiodomethane (6 mL, 75 mmol) was added and the reaction mixture was stirred at room temperature overnight. Saturated ammonium chloride was added carefully to quench the reaction. The reaction mixture was diluted with diethyl ether and the layers were separated. The organic phase was washed with 10% aqueous hydrochloric acid, saturated sodium bicarbonate and brine, then dried over magnesium sulfate and concentrated to dryness under reduced pressure. Silica gel chromatography with hexanes/ ethyl acetate (4:1) afforded the product, 940 mg (41%). GC/MS: 184 (M+) for C,0HioF20 'H-NMR (DMSO-d^ 5: 0.92 (m, 2H); 1.36 (m, 1H); 1.91 (m, 1H); 3.43 (m, 2H); 4.64 (t, 1H); 6.82 (m, 1H); 6.97 (m, 1H); 7.15 (m, 1H). Intermediate 70; (2jg)-3-f2.S-Difluorophenvnprop-2-en-l-Ql A mixture of (2£)-3-(2,5-difluorophenyl)acrylic acid (1 g, 5.43 mmol) and N,Ndiisopropylethylamine (1.7 mL, 9.8 mmol) in tetrahydrofuran (THF) was treated with isobutyJ chloroformate (1.4 mL, 10.8 mmol) at room temperature, The reaction mixture was stirred for 30 minutes, and then filtered. The filtrate was cooled to 0°C and 2M lithium borohydride (4.1 mL, 8.2 mmol) was added dropwise. The reaction mixture was stirred at 0°C for 30 minutes then at room temperature for 30 minutes. Ice and IN hydrochloric acid were added to the reaction mixture to adjust the pH to 7. The aqueous layer was extracted with ethyl acetate twice. The combined organic extracts were dried over sodium sulfate and concentrated to dryness under reduced pressure. Silica gel chromatography with hexanes/ethyl acetate (3:2) afforded desired product, 750 mg (82%). GC/MS: 170 (M) for C9H8F2O 'H-NMRflPMSO-djQ 6:4.15 (t, 2H); 5.01 (t, 1H); 6.61 (m, 2H); 7.10 (m, 1H); 7.23 (m, 1H); 7.48 (m, 1H). Example 36 6-t({l-[2-(6,8-Difluoro-3-oxo-2,3-dihydro-4flr-l,4-benzoxazin-4-yl)ethyl]piperidin- 4-yl}amino)methyl]-2#-pyrido[3,2-A][l,4]oxazin-3(4#)-one 4-[2-(4-Aminopiperidin-l -yl)ethyl]-6,8-difluoro-2//'-1,4-benzoxazin-3 (4//)-onc (Intermediate 71) (1 rnmol), 3-oxo-3,4-dihydro-2//'-pyrido[3,2-&][l,4]oxazine-6- carbaldehyde (WO 2004/058144) (220 mg, 1.24 mmol) and sodium cyanoborohydride (130 mg, 2.1 mmol) were reacted as described for Example 21 to give 41 mg (8%) product as a dry film. MS (ES): 474.26 (MH+) for CzjIfeFaNsC^ 'H-NMR (DMSO-d^ 8: 1.19 (m, 2H); 1.74 (m, 2H); 1.96 (m, 3H); 2.34 (m, 1H); 2.42 (m, 2H); 2.82 (m, 2H); 3.65 (s, 2H); 3.97 (m, 2H); 4.59 (s, 2H); 4.70 (s, 2H); 7.00 (d, 1H); 7.09 (m, 2H); 7.28 (d, 1H); 11,16 (s, 1H). Intermediate 71.'4-[2-f4-Aminopiperidin-l-yl')ethyl1-6.8-difluoro-2/f-l14- benzoxazin-3 (4/f)-one ter/-Butyl {l-[2-(6,8-difluoro-3-oxo-2,3-dihydro-4//-l,4-benzoxazin-4- yl)ethyl]piperidin-4-yl}carbamate (Intermediate 72) (423 mg, 1 mmol) was reacted as described for Intermediate 14. The crude trifluoro acetate of the title compound was used without further purification for the next step (quantitative yield). MS fES^ 312 (MH+) Intermediate 72; tert-Butvl {l-[2-f6.8-difluoro-3-oxo-2.3-dihvdro-4/y-1.4- benzoxazin-4-yr)ethyl]piperidin-4-vUcarbamate 6,8-difluoro-2#"-l,4-benzoxazin-3(4//)-one (Intermediate 73) (205 mg, 1.11 mmol) was deprotonated with sodium hydride and alkylated with 2~{4-[(tertbutoxycarbonyl) amino]piperidin-l-yl} ethyl methanesulfonate (Intermediate 6) (1.2 mmol) as described for Intermediate 2. Chromatography on silica gel with hexanes/ethyl acetate (1 :3) afforded 423 mg (92%) product. MS (ES): 412.36 (MH+) for Intermediate 73; 6,8-Difluoro-2#'-K4-benzoxazin-3(4/f)-one Commercially available 2-amino-4,6-difluorophenol (1 g, 6.9 mmol) and bromo acetyl bromide (0.9 rnL, 10.3 mmol) were reacted according to the procedure for Intermediate 60 to afford the product as a solid, 208 mg (16%). MS (ESI: 184.34 (M-HT) for CsHsFaNC^ 1H-NMR(DMSO-dfi') 5: 4.64 (s, 2H); 6.55 (m, 1H); 6.94 (m, 1H); 10.99 (bs, III). Example 37 4-[2-(4-{[(2£)-3-(255-Difluorophenyl)prop-2-en-l-yl]amino}piperidin-l-yl)ethyll- 3-oxo-3,4-dihydro-2//-l,4-benzoxazine-6-carbonitrile 4-[2-(4-Aminopiperidin- 1 -yl)ethyl]-3-oxo-3 ,4-dihydro-2//- 1 ,4-benzoxazine-6- carbonitrile (Intermediate 58) (1.5 mmol), (2£)-3-(2,5-difluorophenyl)acrylaldehyde (202mg, 1.2 mmol) (FR 2872164) (200 mg, 1.1 mmol) and sodium cyanoborohydride were reacted as described under Example 21. Chromatography on silica gel with dichloromcthane/ methanol gave 168 mg (25%) product MS ffiS): 453 (MH+) for C25H26N4O2 'H-NMRrCDCIV) 5: 1.43 (q, 2H); 1.93 (d, 2H); 2.15 (t, 2H); 2.58 (t, 3H); 2.93 (d, 2H); 3.48 (d, 2H); 4.03 (t, 2H); 4.67 (s, 2H); 6.35 (dt, 1H); 6.65 (d, 1H); 6.88 (m, IH); 6.96 (m, IH); 7.03 (d, IH); 7.12 (m, IH); 7.30 (dd, IH); 7.40 (d, IH). Example 38 6-[({/ra/is-4-[2-(6-Methoxy-3-oxo-2,3-dihydro-4fl-l,4-benzoxazin-4- yl)ethyI]cyclohexyl}amino)methyl]-2J:f-pyrido[3,2-][l,4]oxazin-3(4JH)-one 4-[2-(7>fl77j-4-aminocyclohexyl)ethyl]-6-methoxy-2//-l,4-benzoxazin-3(4/i)-one (Intermediate 74) (310mg, 1.73 mmol), 3-oxo-3,4-dihydro-2#-pyrido[3,2-&][l,4]oxazine-6- carbaldehyde (WO 2004/058144) (1.73 mmol) and sodium cyanoborohydride were reacted as described under Example 21 to give 110 mg (24%) product. MS (ES1: 467 (MH+) for C25H3oN4O5 'H-NMR fCDCM 5: 1.05 (q, 2H); 1.19 (d, 2H); 1.35 (m, 1H); 1.53 (q, 2H); 1.86 (d, 2H); 2.00 (d, 2H); 2.47 (m, 1H); 3.77 (s, 3H); 3.84-3.91 (m, 4H); 4.50 (s, 2H); 4.61 (s, 2H); 6.47 (m, 2H); 6.90 (t, 2H); 7.18 (d, 2H). Intermediate 74: 4-[2-f/ra«j-4-Amipocvclohexvl)ethvl'\|-6-methoxv-2H-1.4- benzoxazin-3(4/f)-one terf-Butyl {fra«.y-4-[2-(6-methoxy-3-oxo-2,3-dihydro-4/:/-1,4-benzoxazin-4- yl)ethyl]cyclohexyl}carbamate (Intermediate 75) was reacted as described for Intermediate 14. The crude trifluoro acetate of the title compound was used without further purification for the next step (quantitative yield). MS ffiS"): 305 (MH+) for CI7HnN2O3 tt Intermediate 75; tert-Butyl lfrara-4-f2-r6-methoxv-3-oxo-2,3-dihvdro-4//-1.4- benzoxazin^-ynethyllcyclohexyllcarbamate 6-Methoxy-2/f-l,4-benzoxazin-3(4F)-one (Intermediate 48) (310 mg, 1.73 mmol) was deprotonated with sodium hydride and alkylated with 2-{trans-4-[(tert butoxycarbonyl)amino]cyclohexyl}ethyl methanesulfonate (Intermediate 76) (2 mmol) as described for Intermediate 2. Chromatography on silica gel with dichloromethane/ methanol (20:1) afforded the product as a solid (58%). MS (ESI: 405 (MH+) for CzzI^NzOj Intermediate 76; 2-{trans-4-\(tert Butoxvcarbonylkminolcvclohexvnethvl methanesulfonate Commercially available tert-butyl [ran^4-(2-hydroxyethyl)cyclohexyl]carbarnate (SOOmg, 2.05 mmol) was reacted according to the procedure described for Intermediate 6 to give the product as a white solid (yield 92%). 'H-NMRCCDCM 8: 1.0? (m, 4H); 1.42 (m, 9H); 1.62 (m, 3H); 1.79 (m, 3H); 1.98 (ra, 1H); 2.99 (s, 3H); 3.35 (s, br, 1H); 4.24 (t, 2H); 4.35 (s, 1H). Example 39 3-Oxo-4-[2-( yl)methyl]amino}cyclohexyl)ethyl]-3,4-diliydro-2/M,4-benzoxazine-6-carbonitrile 4-[2-(7Va7tt-4-aminocyclohexyl)emyl]-3-oxo-3,4-dihydro-2#-l,4-benzoxazine-6- carbonitrile (Intermediate 77), 3-oxo-3,4-dihydro-2f/-pyrido[3,2-6][l,4]oxazine-6- carbaldehyde (WO 2004/058144) (1.73 mmol) and sodium cyanoborohydride were reacted following the procedure described for Example 21 to give the product in 7% yield, as an offwhite solid. MS (ESI: 462 (MH+) for CjsHwNsCU 'H-NMRfCDCl-Q 8: 1.05 (q, 2H); 1.45 (m, 5H); 1.88 (d, 2H); 2.07 (d, 2H); 2.65 (t, 1H); 3.90 (m, 2H); 3.95 (s, 2H); 4.61 (s, 2H); 4.66 (s, 2H); 6.97 (d, 1H); 7.04 (d, 1H); 7.17 (d, 1H); 7.20 (d, 1H); 7.31 (dd, 1H). Intermediate 77: 4-[2-Om«J-4-Aminocyclohexyl')ethyl1-3-oxo-3.4-dihydro-2//-l,4- benzoxazine-6-carbonitrile tert-Butyl {fra/7S-4-[2-(6-cyano-3-oxo-2,3-dihydro-4//-l,4-benzoxa;dn-4- yl)ethyl]cyclohexyl}carbamate (Intermediate 78) was reacted as described for Intermediate 14. The crude trifluoro acetate of the title compound was used without further purification for the next step (quantitative yield). MS fES): 300 (MH+) for Intermediate 78: tert-Butyl ^r?-gK.y-4-[2-(6-cvano-3-oxo-2.3-dihydro-4/jr-l,4- benzoxazrn-4-yr)ethyl]cyclohexvUcarbamate 3-Oxo-3,4-dihydro-2#-l,4-benzoxazine-6-carbonitrile (Intermediate 60) (350 mg, 2.0 mmol) was deprotonated with sodium hydride and alkylated with 2-{trans-4-[(tert butoxycarbonyl)amino]cyclohexyl} ethyl methanesulfonate (Intermediate 76) as described for Intermediate 2. Chromatography on silica gel with dichloromethane/ methanol (20: 1) afforded the product as a solid (50%). MS (ES) 400 (MH) for C22H29N304 Example 40 6-Bromo-4-[2-(4-{[(3-oxo-3,4-dihydro-2flr-pyrido[3,2-6][l,4]oxazin-6- yI)methyl]amino}piperidin-l-yl)ethyl]-2^-pyrido[3,2-6][l,4]oxazin-3(4JHr)-one 4-[2-(4-Aminopiperidin-l -yl)ethyl]-6-bromo-2#-pyrido[3 ,2-b] [ 1 ,4]oxazin-3(4#)-one (Intermediate 79), 3-oxo-3,4-dihydro-2//-pyrido[3,2-&][ 1 ,4]oxazine-6-carbaldehyde (WO 2004/058144) and sodium cyanoborohydride were reacted as described under Example 21 to give the product as an off-white solid in 64% yield. MS fES): 517, 519(MH) for C22H25BrN604 'H-NMRfDMSO-d.1 5: 1.25 (q, 2H); 1.81 (d, 5H); 1.98 (t, 2H); 2.6 (s, 2H); 2.89 (m, 2H); 3.15 (s, 1H); 3.83 (s, 2H); 4.05 (t, 2H); 4.62 (s, 2H); 4.76 (s, 2H); 6.97 (d, 1H); 7.04 (d, 1H); 7.23 (d, 1H); 7.34 (dd, 2H); 11.23 (s, br, 1H) Intermediate 79: 4-[2-(4-Aminopiperidin-l-yl')ethyl]-6-brQmo-2//-pyridQf3.2- b] f 1 .4]oxazin-3(4//Vone tert-Butyl {l-[2-(6-bromo-3-oxo-2,3-dihydro-4//-pyrido[3,2-Z)][l,4]oxazin-4- yl)ethyl]piperidin-4-yl}carbamate (Intermediate 80) was reacted as described for Intermediate 14. The crude trifluoro acetate of the title compound was used without further purification for the next step (quantitative yield). MS (ES^: 3557 357 (MH4) for Intermediate 80: tert-Butvl {l-[2-(r6-bromo-3-oxo-2.3-dihvdro-4//-pvridor3.2- b] f 1 .4]oxazin-4-yDethyl]piperidin-4-yl} carbamate 6-Bromo-2/f-pyrido[3,2-6][l,4]oxazin-3(4^-one (WO 2004/058144) (935 mg, 4.08 rnmol) was deprotonated with sodium hydride and alkylated with 2-{4-[(tertbutoxycarbonyl) amino]piperidin-l-yl} ethyl methanesulfonate (Intermediate 6) (5.6 mmol) as described for Intermediate 2, but chromatography was omitted, to give the product as a solid in 92% yield. MS (BS); 455, 457 (MH4) for Ci9H27BrN4O4 Example 41 6-[({l-[2-(6-Nitro-3-oxo-2,3-dihydro-4flr-l,4-benzoxazin-4-yl)ethyl]piperidin-4- yl}amino)methyl]-2J3r-pyrido[3,2-A][l,4]oxazin-3(4J5r)-one 4-[2-(4-Aminopiperidin- 1 -yl)ethyl]-6-nitro-2.#- 1 ,4-benzoxazin-3 (4//)-one (Intermediate 81), 3-oxo-3,4-dihydro-2#-pyrido[3,2-&][l,4]oxazine-6-carbaldehyde (WO 2004/058144) and sodium cyanoborohydride were reacted as described under Example 21 to give the product as an off-white solid in 7% yield, MS fESV 483(MH+) for C23H26N606 'H-NMRCCDCl^ 8: 1.55 (q, 2H); 1.92 (d, 2H); 2.15 (t, 2H); 2.64 (t, 3H); 2.95 (d, 2H); 3.86 (s, 2H); 4.08 (t, 2H); 4.62 (s, 2H); 4.71 (s, 2H); 6.93 (d, 1H); 7.03 (d, 1H); 7.17 (d, 1H); 7.90 (dd, 1H); 8.13 (d, 1H). Intermediate 81: 4-[2-(4-Ammopiperidin-l-ynethvl]-6-nitro-2//-1.4-benzoxazin- 3(4ff)-one tert-Butyl { 1 -[2-(6-nitro-3-oxo-2,3-dihydro-4//- 1 ,4-benzoxazin-4-yl)ethyl]piperidin- 4-yl}carbamate (Intermediate 82) was reacted as described for Intermediate 14. The crude trifluoro acetate of the title compound was used without further purification for the next step (quantitative yield). MS (ESI: 32 1 (MH4) Intermediate 82; tert-Butyl n42-f6-nitro-3-oxo-2.3-dihydro-4#-1.4-benzoxazin-4- yr)ethyl]piperidin-4-vn carbamate 6-Nitro-2//-l,4-benzoxazin-3(4/;0-one (Intermediate 83) (776 mg, 4 mmol) was deprotonated with sodium hydride and alkylated with 2-{4-[(tertbutoxycarbonyl) amino]piperidin-l-yl}ethyl methanesulfonate (Intermediate 6) (5.6 mmol) as described for Intermediate 2. The product precipitated upon quenching of the reaction mixture with water and was isolated by filtration in 98% yield, yellow solid. MS fES): 421 (MH4) for Intermediate 83; 6-Nitro-2//-1.4-benzoxazin-3(4J:n-one The title compound was prepared according to the procedure described for Intermediate 60, in 28% yield, yellow solid. MS raS"): 193(M-H-)forC8H6N204 'H-NMRfDMSO-d^S: 4.80 (s, 2H); 7.18 (d, 1H); 7.75 (s, 1H); 7.85 (d, 1H); 11.10 Example 42 3-Oxo-4-[2-(4-{[(3-oxo-3,4-dihydro-2//-pyrido[3,2-6][l,4]oxazin-6- yI)methyl]amino}piperidin-l-yl)ethyl]-3,4-dihydro-2JHr-pyrido[3,2-6][l,4]oxazinc-6- carbonitrile and Example 43 3-Oxo-4-[2-(4-{[(3-oxo-3,4-dihydro-2jHr-pyrido[3,2-A][l,4]oxazin-6- yl)methyl]amino}piperidin-l-yl)ethyI]-3,4-dihydro-2J7-pyrido[3,2-6][l,4]oxazine-6- carboxamlde A mixture of 6-bromo-4-[2-(4- {[(3-oxo-3,4~dihydro-2//-pyrido[3,2-b] [ 1,4]oxazin-6- yl)methyl]amino}piperidin-1 -yl)ethyl]-2//-pyrido[3,2-6] [ 1,4]oxazin-3(4/?)-one (Example 40) (200 mg, 0,387 mmol), zinc cyanide (135 rag, 1.14mmol) and tetrakis(triphenylphosphine) palladium(O) (50 mg, 0.043mmol) in anhydrous DMF (3 mL) over molecular sieves 3A was vortexed and then heated in the microwave at 200 °C for one hour. Reverse phase chromatography and generation of the free base as described for Example 21 gave 27 mg (15%) of Example 42 and 23 mg (12%) of Example 43, both off-white solids. Example 42: MS (ES): 464(MH+) for Cz^^O* 'H-NMRfDMSO-d") 5: 1.17 (q, 2H); 1.77 (d, 2H); 20.1 (t, 2H); 2.86 (d, 2H); 3.75 (s, 2H); 4.09 (t, 2H); 4.61 (s, 2H); 4.88 (s, 2H); 7.00 (d, 1H); 7.30 (d, 1H); 7.53 (d, 1H); 7.69 (d, lH);11.20(s,br, 1H). Example 43: MS (ESV. 482(MH+) for CzsI^NvOs 'H-NMRfDMSO-d^ 5: 1.09 (q, 2H); 1.66 (d, 2H); 1.91 (t, 2H); 2.31 (m, 1H); 2.43 (m, 2H); 2.83 (d, 2H); 3.04 (s, 2H); 3.63 (s, 2H) 4.28 (t, 2H); 4.59 (s, 2H); 4.80 (s, 2H); 6.96 (d, 1H); 7.26 (d, 1H); 7.45 (d, 1H); 7.57 (s, 1H); 7.64 (d, 1H); 7.90 (s, 1H); 11.30 (s, br, 1H). Example 44 Methyl 3-oxo-4-[2-(4-{[(3-oxo-3,4-dihydro-2flr-pyrido[3,2-A][l,4]oxazin-6- yl)methyl]amino}piperidin-l-yl)ethyl]-3,4-dihydro-2ZT-l,4-benzoxazine-6-carboxylate Methyl 4-[2-(4-aminopiperidin-1 -yl)ethyrj-3-oxo-3,4-dihydro-2//-1,4-benzoxazine-6- carboxylate (Intermediate 84), 3-oxo-3,4-dihydro-2//-pyrido[3,2-&][l,4]oxazine-6- carbaldehyde (WO 2004/058144) and sodium cyanoborohydride were reacted as described under Example 21 to give the product as an off-white solid in 13% yield. MS fESy 496CMH+) for CzsHfoNsO,; 'H-NMR fCDCh) 5: 1.53 (m, 3H); 2.16 (m, 3H); 2,49 (m, 2H); 2.62 (m, 3H); 3.00 (d, 2H); 3.87 (s, 2H); 3.90 (s, 3H); 4.09 (t, 2H); 4.62 (a, 2H); 4.64 (s, 2H); 6.95 (d, 1H); 6.98 (d, 1H); 7.19 (d, 1H); 7.19 (d, 1H); 7.69 (d, 1H); 7.78 (d, 1H). Intermediate 84: Methyl 4-r2-C4-aminopiperidin-l-ynethyl1-3-oxo-3.4-dihvdro-27/- 1.4-benzoxazine-6-carboxvlate Methyl 4-(2- {4-[(/er/-butoxycarbonyl)amino]piperidin-1 -yl} ethyl)-3-oxo-3,4-dihydro- 2//-l,4-benzoxazine-6-carboxylate (Intermediate 85) was reacted as described for Intermediate 14. The crude trifluoro acetate of the title compound was used without further purification for the next step (quantitative yield). MSfES): 334(MH+) for CnlWCU Intermediate 85; Methyl 4-f2-l4-[(/e;'/-butoxvcarbonyl')amino]pipcridin-l-vUethvl)- 3-oxo-3.4-dihydro-2ff-1.4-benzoxazine-6-carboxylate Methyl 3-oxo-3,4-dihydro-2//-l,4-benzoxazine-6-carboxylate (Intermediate 86) (330 mg, 1.59 mmol) was deprotonated with sodium hydride and alkylated with 2-{4-[(tertbutoxycarbonyl) amino]piperidin-l-yl}ethyl methanesulfonate (Intermediate 6) (5.6 mmol) as described for Intermediate 2. Chromatography on silica gel with dichloromethane/ methanol (20:1) gave the product in 85% yield as a yellow solid. MS (ES^: 434 (MH) for C22H3iN3O6 Intermediate 86: Methyl 3-oxo-3.4-dihvdro-2/:/-1.4-benzoxazine-6-carboxvlate 3-Oxo-3,4-dihydro-2/f-l,4-benzoxazine-6-carbonitrile (Intermediate 60) was heated with chlorotrimethylsilane in methanol according to literature procedure (Fen-tair Luo et al. Tetrahedron Letters, 39, 1998, page 9455-9456). After removal of volatiles, the product was purified by chromatography on silica gel with methanol/dichloromethane (1 :20) and obtained as off white solid, 40% yield. MS (ES): 208 (MH+) for C,oH9NO4 'H-NMR fPMSO-d^ S: 3.80 (s, 3H); 4.67 (s, 2H); 7.03 (d, 1H); 7.50 (d, 1H); 7.55 (dd, 1H); 10.99 (s, 1H). Example 45 6-[({l-[2-(6-Acetyl-3-oxo-2,3-dihydro-4J5/-l,4-benzoxazin-4-yl)ethyl]piperidin-4- yl}amino)methyI]-2H-pyrido[3,2-6][l,4]oxazin-3(4jH)-one 6-Acetyl-4-[2-(4-aminopiperidin-l-yl)ethyl]-2/r-l,4-benzoxazin-3(4//)-one (Intermediate 87), 3-oxo-3)4-dihydro-2//-pyrido[3,2-6][l,4]oxazine-6-carbaldehyde (WO 2004/058144) and sodium cyanoborohydride were reacted as described under Example 21 to give the product as an off-white solid in 7% yield. MS (ESI: 480(MH+) for €25129^05 'H-NMR (CDCM 8: 1.49 (m, 2H); 1.98 (d, 2H); 2.13 (t, 2H); 2.57 (s, 3H); 2.60 (m, 3H); 2.94 (d, 2H); 3.82 (s, 2H); 4.09 (t, 2H); 4.60 (s, 2H); 4.64 (s, 2H); 6.90 (d, 1H); 7.01 (d, 1H); 7.16 (d, 1H); 7.58 (d, 1H); 7.74 (s, 1H). Intermediate 87 ; 6-Acetvl-4-r2-(4-aminopiperidin- 1 -yl)ethvl1-2/7- 1 .4-benzoxa?,in- /ert-Butyl {l-[2-(6-acetyl-3-oxo-2,3-dihydro-4#-l,4-benzoxazin-4-yl)ethyl]piperidin- 4-yl}carbamate (Intermediate 88) was reacted as described for Intermediate 14. The crude trifluoro acetate of the title compound was obtained as a colorless solid and used without further purification for the next step (quantitative yield). MS (ES): 318 (MH4) Intermediate 88: tert-Butyl {l-r2-(6-acetvl-3-oxp-2,3-dihydro-4//-1.4-benzoxa7in-4- yl')ethyl]piperidin-4-vU carbamate 6-Acetyl-2#-l,4-benzoxazin-3(4#)-one (Intermediate 89) (382 mg, 2.0 mmol) was deprotonated with sodium hydride and alkylated with 2-{4-[(tertbutoxycarbonyl) amino]piperidin-l-yl} ethyl methanesulfonate (Intermediate 6) (2.2 mmol) as described for Intermediate 2. Chromatography on silica gel with hexanes/ ethyl acetate (1:1) gave the product in 94% yield as a colorless solid. MS fESV 418 (MH) for C22H3iN3Oj Intermediate 89: 6-Acetvl-2/:f-1.4-benzoxazin-3f4/fi-one Ethyl (4-acetyl-2-nitrophenoxy)acetate (Intermediate 90) was reacted with iron in acetic acid as described for Intermediate 48. The crude product was obtained as an off white solid after work up. Recrystallization with ethyl acetate / methanol afforded the product as a colorless solid in 51 % yield. MS fESV. 192 (MH1) for C,0H9NO3 'H-NMRfDMSO-d^ 8:2.50 (s, 3H); 4.68 (s, 2H); 7.06 (d, 1H); 7.47 (d, 1H); 7.60 (dd, 1H); 10.88 (s, 1H). Intermediate 90: Ethyl (4-aoetvI-2-m'trophenoxy)acetate l-(4-hydroxy-3-nitrophenyl)ethanone was reacted with cesium carbonate and 2-bromo ethyl acetate as described for Intermediate 49. Chromatography on silica gel with hexanes/ ethyl acetate (1:1) gave the product in 69% yield as a pink solid MS fESV 268 (MR") for Ci2H13NO6 'H-NMRfCDClr) 8: 1.30 (t, 3H); 2.60 (s, 3H); 4.30 (q, 2H); 4.86 (s, 2H); 7.00 (d, 1H); 8.20 (d, 1H); 8.50 (s, 1H). Example 46 6-Acetyl-4-(2-{4-[(2,3-dihydro[l,4]dioxino[2,3-c]pyridin-7- ylmethyl)amino]piperidin-l-yl}ethyl)-2J?-l,4-benzoxazin-3(4£0-one 6-Acetyl-4-[2-(4-aniinopiperidm-l-yl)ethyl]-2H-l)4-benzoxazin-3(4//)-one (Intermediate 87), 2J3-dihydro[l)4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO 2004/058144) and sodium cyanoborohydride were reacted as described for Example 21. The was converted to the free base was treated with HC1 in dioxane (2M, excess) and the excess HC1 and dioxane were removed under reduced pressure to give the bis hydrochloride salt of the product, 25 mg (9%), as an off-white solid. MS fESV 467CMH4") for C23H27N705 'H-NMR fDMSO-d^ 5:2.10 (m, 2H); 2.32 (d, 1H); 2.65 (s, 3H); 3.07 (m, 2H); 3.27 (s, 3H) 3.57 (s, 1H); 3.77 (d, 2H); 4.19 (s, 2H); 4.35 (dd, 4H); 4.46 (t, 2H); 4.81 (s, 2H); 7.12 (d, 1H); 7.24 (s, 1H); 7.66 (d, 1H); 7.76 (s, 1H); 8.18 (s, 1H); 9.73 (brs, 2IT); 11.06 (brs, 1H). Example 47 4-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-lyI} ethyl)-6-methyl-2jHr-l,4-benzoxazin-3(4ff)-one 4-[2-(4-Aminopiperidin-1 -yl)ethyl]-6-methyl-2//-1,4-benzoxazin-3(4.fr)-one (Intermediate 91), 2,3-dihydro[l,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO 2004/058144) and sodium cyanoborohydride were reacted as described for Example 21 to give the product as an oil, 4.7 mg (2%). MS (ES\. 439 (MET) for C24H3oN4O4 'H-NMR (CDCIV) 8: 2.13 (m, 2H); 2.25 (s, 2H); 2.31 (s, 3H); 2.61 (s, 2H); 3.06 (m, 2H) 3.33 (m, 1H); 3.51 (m, 2H); 4.14 (s, 2H); 4.20-4.40 (m, 6H); 4.53 (s, 2H); 6.70-6.95 (m, 4H); 8.09 (s, 1H). Intermediate 91; 4-r2-(4-Aminopiperidin-1 -yl)ethvl]-6-methvl-2f/-1.4-benzoxazin- 3(4flVone tert-Butyl {1 -[2-(6-methyl-3 -oxo-2,3-dihydro-4jf/-1,4-benzoxazin-4- yl)ethyl]piperidin-4-yl}carbarnate (Intermediate 92) was reacted as described for Intermediate 14. The crude trifluoro acetate of the title compound was obtained as a colorless solid and used without further purification for the next step (quantitative yield). MS (E$): 290 (MH+) for QeHasNaOz Intermediate 92; tert-Butvl \|l-T2-(6-methyl-3-oxo-2.3-dihvdro-4ff-1.4-benzoxazin- 4-yr)ethyl]piperidin-4-yl} carbamatg Commercially available 6-methyl-2//-l,4-benzoxazin-3(4J:0-one (326mg, 2.0 mmol) was deprotonated with sodium hydride and alkylated with 2-{4~[(tertbutoxycarbonyl) amino]piperidiu-l-yl} ethyl methanesulfonate (Intermediate 6) (2.2 mmol) as described for Intermediate 2. Chromatography on silica gel with dichloromethane/ methanol (20:1) gave the product in 66% yield as a colorless solid. MS (ES): 390 (MH) for C2iH3iN304 Example 48 3-Oxo-4-[2-(6-{[(3-oxo-3,4-dihydro-2/r-pyrido[3,2-A][l,4]oxazin-6- yl)methyl]amino}-3-azabicyclo[3.1.0]hex-3-yl)ethyI)-3,4-dihydro-2/M,4-ben/oxa/inc-6- carbonitrile 4-[2-(6-Amino-3-azabicyclo[3,1.0]hex-3-yl)ethyl]-3-oxo-3,4-dihydro-2//-l,4- benzoxazine-6-carbonitrile (Intermediate 93), 3-oxo-3,4-dihydro-2//-pyrido[3,2- 6][l,4]oxazine-6-carbaldehyde (WO 2004/058144) and sodium cyanoborohydride were reacted as described under Example 21 to give the product as an off-white solid in 6% yield. MS (BS); 461(MH+) for CwHwNeC^ 'H-NMRfCDCIO 8: 2.46 (m, 4H); 2.66 (t, 2H); 3.01 (d, 2H); 3.83 (s, 2H); 3.98 (m, 3H) 4.63 (s, 2H); 4.64 (s, 2H); 6.89 (d, 1H); 7.02 (d, 1H); 7.18 (d, 1H); 7.31 (m, 2H). Intermediate 93: 4-[2-(6-Amino-3-a^abicyclo[3.L01hex-3-vl')ethvl1-3-oxo-3.4- dihvdro-2.//-1.4-ben20xazine-6-carbonitrile tert-Butyl {3-[2-(6-cyano-3-oxo-2,3-dihydro-4//-l,4-benzoxazin-4-yl)ethyl]-3- azabicyclo[3.1.0]hex-6-yl}carbamate (Intermediate 94) was reacted as described for Intermediate 14. The crude trifluoro acetate of the title compound was obtained as a colorless solid and used without further purification for the next step (quantitative yield). MS (ES): 299 (MH4) for C16HigN402. Intermediate 94: tert-Butyl l3-[2-f6-cvano-3-oxo-2.3-dihydro-4/7-1.4-bcnzoxazin-4- vnethvl]-3-azabicvclo[3.1.0]hex-6-yncarbamate 3-Oxo-3,4-dihydro-2//-l,4-benzoxazine-6-carbonitrile (Intermediate 60) (231 mg, 1.5 mmol) was deprotonated with sodium hydride and alkylated with 2-{6-[(tertbutoxycarbonyl) amino]-3-azabicyclo[3.1.0]hex-3-yl}ethyl methanesulfonate (Intermediate 95) (1.55 mmol) as described for Intermediate 2. Chromatography on silica gel with dichloromethane/ methanol (20:1) gave 442 mg (94%) product as a yellow gum. MS (ES); 399 (MH4) for C21H26N4O4 Intermediate 95: 2-{6-[f?e^-ButoxvcarbonvDamino]-3-azabicyclor3.1.01hex-3- yl} ethyl metfaanesulfonate To a mixture of ter/-butyl [3-(2-hydroxyethyl)-3-azabicyclo[3.1.0]hex-6-yl]carbamate (Intermediate 96) (376 mg, 1.55 mmol) and triethyl amine (0.283 mL, 3 mmol) in anhydrous chloroform (15 mL) was added at O°C methanesulfonyl chloride (228 mg, 3 mmol) via syringe. The reaction was allowed to warm to room temperature over 1 hr and worked up as described for Intermediate 6. The crude mesylate was used for the next step without delay. Intermediate 96: tert-Butyl r3-(2-hvdroxvethvl)-3-azabicvclo[3.1.01hex-6- vl]carbamate A mixture of tert-butyl 3-azabicyclo[3.1.0]hex-6-ylcarbamate (T. F. Braish et al. Synlett, 1996, page 1100 and T. Norris et al. J. Chem. Soc. Perkin I, 2000, page 1615-1622), 2-bromoethanol (669 mg, 3.36 mmol) and N,N-ethyldiisopropyl amine (0.087 mL) in acetonitrile (9 mL) was heated in the microwave at 70°C for 30 minutes. Chromatography on silica gel with chloroform/ methanol (20:1) gave 376 mg (46%) of the product. MS(EI) 242 for Ci2H22N203 Example 49 4-(2-{4-[(2,3-Dihydro[l,4]dioxinof2,3-c]pyridin-7-ylmethyl)amino]pipcridin-lyl} ethyl)-2/y-l,4-benzoxazin-3(4.flr)-one 4-[2-(4-Aminopiperidin-l-yl)ethyl]-2//-l ,4-benzoxazin-3(4//)-one (Intermediate 97), 2,3-dihydro[l,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO 2004/058144) and sodium cyanoborohydride were reacted as described for Example 21 to give the product as a offwhite solid, 81 mg (16%). MS (BS); 425(MH+) for C23H28N404.2HC1 'H-NMRCDMSO-d^ 8: 2.2-3.8 (m, 14H); 3.87 (s, IH); 4.42 (m, 4H); 4.75 (s, 2H); 7.11 (m, 3H); 7.40-7.60 (m, 2H); 8.29 (s, IH); 10.01 (s, 2H); 10.01 (s, 211); 11.35 (brs, III). Intermediate 97: 4-[2-C4-Aminopiperidin-1 -yl)ethyl1-2//-1,4-benzoxazin-3(4/./)-one /ert-Butyl {l-[2-(3-oxo-2,3-dihydro-4/7-l,4-benzoxazin-4-yl)ethyl]piperidin-4- yl}carbamate (Intermediate 98) was reacted as described for Intermediate 14. The crude trifluoro acetate of the title compound was obtained as a colorless solid and used without further purification for the next step (quantitative yield). MS (ES): 276 (MH+) for C15H2iN3O2 Intermediate 98; tert-Butvl vDethyl]piperidin-4-yl \ carbamate 2//-l,4-Benzoxazin-3(4ff)-one (298 mg, 2.0 mmol) was deprotonated with sodium hydride and alkylated with 2-{4-[(tert-butoxycarbonyl)amino]piperidin-l-yl}ethyl methanesulfonate (Intermediate 6) (2.0 mmol) as described for Intermediate 2. Chromatography on silica gel with dichloromethane/ methanol (20: 1) gave the product in 63% yield as a yellow gum. MS (ES): 376 (MH+) for C2oH29N3O4 Example 50 6-{[(l-{2-[6-(l-Hydroxyethyl)-3-oxo-2,3-dmydro-4#-l,4-benzoxazin-4- yl]ethyl}piperidin-4-yl)amino]methyl}-2//-pyrido [3,2-6] [1,4] oxa7in-3(4//)-one 6-[({l-[2-(6-Acetyl-3-oxo-2,3-dihydro-4/M,4-benzoxazin-4-yl)ethyl]piperidin-4- yl}anuno)methyl]-2//-pyrido[3,2-&][l,4]oxazin-3(4fl>one (Example 45) ( 309 mg, 0.645 mmol) was reduced with sodium borohydride (47 mg, 2 equivalents) in methanol (12 mL) at 0 °C. After quenching the reaction with water, the reaction mixture was concentrated under reduced pressure and extracted with chloroform. The chloroform layer was washed with brine and dried over magnesium sulfate and concentrated to dryness to give the as an off-white solid, 202 mg (95%). MS (ESV. 482(MH4) for CwHsiNjOs 'H-NMRfCDC10 5: 1.47 (d, 3H); 1.50 (q, 2H); 1.89 (d, 2H); 2.18 (m, 2H); 2.62 (m, 1H) 2.65 (t, 2H); 3.00 (d, 2H); 3.82 (s, 2H); 4.09 (t, 2H); 4.55 (s, 2H); 4.61 (s, 2H); 4.86 (q, 1H) 6,91 (m, 3H); 7.18 (d, 1H); 7.26 (s, 1H). Example 51 Ethyl Ar-{l-[2-(6-cyano-3-oxo-2,3-dihydro-4fir-l,4-benzoxazin-4- yl)ethyI]piperidin-4-yl}-7V-[(2£)-3-(2,5-difluorophenyl)prop-2-en-l-yI]glycinate To a mixture of 4-[2-(4-{[(2£)-3-(2,5-difluorophenyl)prop-2-en-l-yl]amino}piperidinl- yl)ethyl]-3-oxo-3,4-dihydro-2//-l,4-benzoxazine-6-carbonitrile (Example 37) (120 mg, 0.265 mmol) and ethyl diazoacetate (0.09 mL) in dichloromethane (5 ml) was added rhodium(II) acetate (4 mg, 0.009 mmol) at room temperature. After 72 hrs, the product was concentrated and purified by preparative TLC to give 6.7 mg of product (5%). MS fESI: 539 (MH4) 'H-NMRCCDCM 8: 1.22 (t, 3H); 1.25 (m, 2H); 1.62 (m, 4H); 1.84 (d, 2H); 2.16 (bs, 2H) 2.60 (m, 2H); 2.70 (m, 1H); 3.03 (m, 2H); 3.37 (s, 2H); 3.45 (d, 2H); 4.07 (m, 2H); 4.11 (q, 2H); 4.68 (s, 2H); 6.32 (dt, 1H); 6.67 (d, 1H); 6.86 (m, 1H); 6.97 (dm, 1H); 7.02 (d, 1H); 7.13 (m, 1H); 7.30 (dd, 1H); 7.45 (s, 1H). Example 52 6-{[(l-{2-[6-(Methylsulfonyl)-3-oxo-2,3-dihydro-4JHr-l,4-benzoxazin-4- yl]ethyI}piperidin-4-yl)amino]methyl}-2J3r-pyrido(3,2-A][l,4]oxazin-3(4JH)-one 4-[2-(4-Aminopiperidin-l-yl)ethyl]-6-(methylsulfonyl)-2/T-l,4-benzoxazin-3(4//)-one (Intermediate 99), 3-oxo-3,4-dihydro-2#-pyrido[3,2-&][l,4]oxazine-6-carbaldehyde (WO 2004/058144) and sodium cyanoborohydride were reacted as described under Example 21 to give the product as an off-white solid in 8% yield. MS (ES): 516 (MH+) for Ca-jKfoNsOeS 'H-NMRrCDChl 8: 1.53 (m, 2H); 1.87 (d, 2H); 2.13 (t, 4H); 2.54 (m, 1H); 2.60 (t, 2H) 2.93 (d, 2H); 3.05 (s, 3H); 3.82 (s, 2H); 4.08 (t, 2H); 4.60 (s, 2H); 4.66 (s, 211); 6.90 (d, 1H); 7.10 (d, 1H); 7.16 (d, 1H); 7.56 (d, 1H); 7.72 (s, 1H). Intermediate 99: 4-[2-(4-Aminopiperidin-l-vl')ethvl]-6-(methvlsulfonyl')-2/jr-1.4- benzox.azin-3(4/f)-one ter/-Butyl (1 - {2-[6-(methylsulfonyl)-3-oxo-2,3-dihydro-4//-1,4-benzoxazin-4- yl]ethyl}piperidin-4-yl)carbamate (Intermediate 100) was reacted as described for Intermediate 14. The crude trifluoro acetate of the title compound was obtained as a colorless solid and used without further purification for the next step (quantitative yield). MS (ES): 353 (MH) for C,6H23N304S Intermediate 100: tert-Butyl (l-{2-[6-(methvlsulfonvn-3-oxo-2.3-dihvdro-4//-1.4- benzoxazin-4-vl]ethyl}piperidin-4-vl)carbamate 6-(Methylsulfonyl)-2Jc/-l,4-benzoxazin-3(4//)-one (Intermediate 101) (280 mg, 1.23 mmol) was deprotonated with sodium hydride and alkylated with 2-{4-[(tertbutoxycarbonyl) amino]piperidin-l-yl} ethyl methanesulfonate (Intermediate 6) (1.62 mmol) as described for Intermediate 2. Chromatography on silica gel with dichloromethane/ methanol (20:1) gave the product in 66% yield as a yellow gum. MS (BS): 454 (MH+) for C2iH3,N3Or,S Intermediate 101: 6-(Methvlsulfonvl')-2//-l A-benzoxazin~3(4f-r>-ane 4-Methylsulfonyl-2-aminophenol (Intermediate 102) (690 mg, 3.68 mmol) was dissolved in chloroform (30 mL) and saturated sodium bicarbonate (20 mL). The biphasic reaction mixture was cooled to 0°C and bromoacetyl bromide (889 mg, 4.42 mrnol) was added dropwise. The reaction was stirred overnight at room temperature. The layers were separated and the aqueous layer was filtered to yield the desired product as a solid, 280 mg (33%). MS (ES): 228(MH+) for C9H9N04S 'H-NMR (DMSO-d^ 8: 3.16 (s, 3H); 4.73 (s, 2H); 7.15 (d, 1H); 7.41 (s, 1H); 7.50 (d, Intermediate 1Q2 4-Methvlsulfonvl-2-aminophenol The title compound was prepared by reacting 2-methoxy-5-methylsulfonyl aniline (5.0g, 24.8 mmol) with boron tribromide (26 mmol, 26 mL, 1M in dichloromethane) in chloroform (30 m L) at 0 C°. After 20 minutes, the reaction was quenched with sodium bicarbonate and the ph of the aqueous phase was adjusted to pH 7 and extracted with ethyl acetate. Concentration under reduced pressure gave 690 mg of product as an orange solid (15%). MS (ES); 188(MH) for C7H9N03S Example 53 6-{[(l-{2-[6-(EthyIsulfonyl)-3-oxo-2,3-dihydro-4fl-l,4-benzoxazln-4- yI]ethyl}piperidin-4-yl)amino]methyl}-2Jflr-pyrido[3,2-][l,4]oxazin-3(4fl)-one 4.[2-(4-Aminopiperidin- 1 -yl)ethyl]-6-(methylsulfonyl)-2//- 1 ,4-benzoxazin-3(4//)-one (Intermediate 103), 3-oxo-3,4-dmydro-2#-pyrido[3,2-6][l,4]oxazine-6-carbaldehyde (WO 2004/058144) and sodium cyanoborohydride were reacted as described under Example 21 to give the product as an off-white solid in 19% yield. MS (ES): 530(MH+) for C25H3iN5O6S 'H-NMR rDMSO-d.1 5: 1,11 (t, 3H); 1.30 (q, 2H); 1.74 (d, 2H); 2.00 (t, 2H); 2.40 (m, 3H) 2.82 (d, 2H); 3.32 (m, 4H); 3.67 (s, 2H); 4.05 (t, 2H); 4,60 (s, 2H); 4.78 (s, 2H); 7.01 (d, 1H); 7.28 (d, 1H); 7.30 (d, 1H); 7.50 (d, 1H); 7.68 (s, 1H); 11.18 (bis, 1H). Intermediate 103: 4-r2-f4-Aminopiperidin-l-vl')ethvl1-6-rinethvlsulfonvlV2^'-l,4- benzoxazin-3f4/f>-one tert-Butyl (1 - {2-[6-(ethylsulfonyl)-3-oxo-2,3-dihydro-4//- 1 ,4-benzoxazin-4- yl]ethyl}piperidin-4-yI)carbamate (Intermediate 104) was reacted as described for Intermediate 14. The crude trifluoro acetate of the title compound was obtained as a colorless solid and used without further purification for the next step (quantitative yield). MS (ESV. 368 (MH4) Intermediate 104; tert-Butyl (l-(2-[6-rethvlsulfonvlV3-oxo-2.3-dihydro-4#-l,4- benzoxazin-4-vnethyllpiperidin-4-yr)carbamate 6-(Ethylsulfonyl)-2#-l,4-benzoxazin-3(4#)-ane (Intermediate 105) (482 mg, 2 rnmol) was deprotonated with sodium hydride and alkylated with 2-{4-[(tertbutoxycarbonyl) amino]piperidin-l-yl} ethyl methanesulfonate (Intermediate 6) (2.2 mmol) as described for Intermediate 2. Chromatography on silica gel with hexanes/ ethyl acetate gave the product in 81% yield as a yellow gum. MS (ES\. 468 (MHf) for Intermediate 105: 6-fEthvlsulfonvlV2#-1.4-benzoxazin-3(4//)-one Commercially available 4-ethylsulfonyl-2-aminophenol (4.02 g, 20 mmol) was dissolved in DMF (30 mL) and mixed with cesium carbonate (6.5g, 20 mmol). The reaction mixture was cooled to 0°C and bromoacetyl bromide (4.0 g, 20 mmol) in DMF (5 mL) was added dropwise. The reaction was stirred overnight at room temperature. After aqueous work up, the product was purified by silica gel Chromatography with methanol/ dichloromethane to give the product as an orange solid, 1.7 g (35%). MS CES\. 242(MH) for C10HuNO4S 'H-NMRCDMSO-d^ 5: 1.09 (t, 3H); 3.24 (q, 2H); 4.72 (s, 211); 7.16 (d, 1H); 7.37 (s, lH);7.41(d, Example 54 6-[({l-[2-(7-Methoxy-2-oxo-2flr-3,l-benzoxazin-l(4/T)-yOethyl]piperidin-4- yl}amino)methyl]-2#-pyrido [3,2-6] [1,4] oxazin-3(4fl)-one 1 -[2-(4-Aminopiperidin- 1 -yl)ethyl]-7-methoxy- 1 ,4-dihydro-2/f-3 , 1 -benzoxazin-2-one trifluoro acetate (Intermediate 106) (324 mg, 0.78 mmol) was converted to the free base using W,.W-diisopropylethylamine for 30 minutes and reacted with 3-oxo-3,4-dihydro-2//- pyrido[3,2-fc][l,4]oxazine-6-carbaldehyde (WO 2004/058144) (153 mg, 0.86 mmol) and sodium cyanoborohydride (98 mg, 1.56 mmol) as described under Example 21. The reaction mixture was filtered through a 0.45 urn membrane and concentrated to dryness under reduced pressure. Chromatography on silica gel with dichloromethane/ methanol (9:1) gave the free base of the title compound as a colorless foam. The free base was taken up in 1,4 dioxane (2 mL), followed by addition of 4M HC1 in 1,4-dioxane (0.30 mL). The resulting precipitate was collected by filtration and gave 75 mg (48%) of the bis-hydrochloride salt of the product. MS (ES\ 468.17 (MH4) for C24H29N505 'H NMR fDMSO-dft 8 2.09 (m, 2H); 2.31 - 2.44 (m, 2H); 3.00 - 3.15 (m, 2H); 3.66 - 3.78 (m, 2H); 3.82 (s, 3H); 4.13 - 4.22 (m, 2H); 4.22 - 4.35 (m, 2H); 4.69 (s, 2H); 5.25 (s, 2H); 6.70 (d, 1H); 6.85 (s, 1H); 7.20 (dd, 2H); 7.45 (d, 1H); 9.56 - 9.71 (m, 2H); 11.05 - 11.19 (m, 1H); 11.37 (s, 1H). Intermediate 106: l-[2-(4-Aminopiperidin-l-yl')ethvl]-7-methoxy-l ,4-dihydro-2//- 3 . 1 -bepzoxazin-2-one A solution of ter/-butyl {l-[2-(7-methoxy-2-oxo-2//-3,l-benzoxazin-l(4//)- yl)ethyl]piperidin-4-yl}carbamate (Intermediate 107) (319 mg, 0.78 mmol) in dichloromethane (8 mL) was treated at room temperature under vigorous stirring with a trifluoroacetic acid (0.75 mL, 10 mmol). After 2 hours, the reaction mixture was concentrated under reduced pressure to give 324 mg (quantitative) of product as a brown oil. MS (BS); 302.24 (MH+) for Intermediate 107: tert-Butyl ll-r2-('7-methoxy-2-oxo-2//'-3.1-benzoxay,in-l(4//)- vl)ethyl]piperidin-4-vncarbamate A solution of 7-methoxyquinolin-2(l//)-one (Intermediate 108, 310 mg, 1.8 mmol) in dry N,N-dimethylformamide (5 rnL) was treated at 0°C under stirring with lithium bis(trimethylsilyl)amide (1M in tetrahydrofuran, 1.9 mL, 1.9 mmol). The mixture was then stirred for 30 minutes at room temperature and alkylated with 2-{4~[(tertbutoxycarbonyl) amino]piperidin-l-yl} ethyl methanesulfonate (Intermediate 6, 2.03 mmol) as described for Intermediate 2. Chromatography on silica gel with dichloromethane/ methanol (95:5) gave 333 mg (47%) of the product as a colorless solid. MS (ES); 406 (MII+) for 'H-NMRfCDCM 5: 1.34-1.46 (m, 11H); 1.86 (d, 2H); 2.12-2.25 (m, 2H); 2.60-2.64 (ra, 2H); 2.60-2.64 (m, 2H); 2.81-2.90 (m, 2H); 3.38-3.45 (m, 1H); 3.76 (s, 3H); 3.97 - 3.91 (m, 2H); 4.32- 4.42 (m, 1H); 5.05 (s, 2H); 6.49-6.56 (m, 2H); 6.94 (d, 1H). Intermediate 108: 7-Methoxvauinolin-2('l/f)-one A solution of (2-amino-4-methoxyphenyl)methanol (Intermediate 109,744 mg, 4.85 mmol) in toluene (25 mL) was treated with triethylamine (1.36 raL, 9.7 mmol) and triphosgene (1.58 g, 5.34 mL). The reaction was stirred at room temperature for 1.5 hours and then was heated to 110 °C for an additional 2 hours. The reaction was cooled to room temperature, diluted with water (25 mL), filtered, extracted aqueous layer with toluene (3x 30 mL) and ethyl acetate (2x 20 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. Chromatography on silica gel with hexanes/ ethyl acetate (3:2) gave 314 mg (36%) of the product as a colorless solid. 'H-NMRfDMSO-dg) 8: 3.78 (s, 3H); 5.26 (s, 2H); 6.38 (d, 1H); 6.59 (d, 1H); 6.98 (d, 1H); 8.36 (brs, 1H). Intermediate 109: (2-Amino-4-methoxyphenvl)methanQl To a solution of commercially available 4-methoxy-2-nitrobenzoic acid (4.0 g, 20.66 mmol) in tetrahydrofuran (20 mL) at -15 °C under nitrogen was added N-methylmorphorine (2.2 ml, 20 mmol) followed by isobutyl chloroformate (2.6 mL, 20 mmol) in portions. After 5 rain, the reaction was filtered and the solid was rinsed with tetrahydrofuran (20 mL). The filtrate was cooled to -15 °C and a solution of sodium borohydride in water (3 M, 10 mL) was added to the filtrate, The reaction was stirred for 5 min. The reaction mixture was partitioned between water and dichloromethane, and extracted aqueous layer with dichloromethane (3 x 100 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was redissolved in tetrahydrofuran (35 mL) and added palladium (10% on carbon, 400 mg) and stirred under hydrogen gas for 18 hours. The reaction mixture was then filtered through celite and concentrated under reduced pressure. The residue was chromatographed on silica gel with hexanes/ethyl acetate (3:2) gave 744 mg (24% yield) of product as a yellow solid. 'H-NMR(DMSO-dg) 5 3.63 (s, 3H); 4.30 (s, 2H); 4.84 - 4.96 (m, 2H); 6.08 (dd, 1H); 6.20 (d, lH);6.90(d, 1H). Example 55 7-Methoxy-3-methyl-l-[2-(4-{[(3-oxo-3,4-dihydro-2/f-pyrido[3,2-6][l,4]oxazin-6- yl)methyl]amino}piperidin-l-yl)ethyl]quinazoline-2,4(lfir,3J:0-dione l-[2-(4-Aminopiperidin-l-yl)ethyl]-7-methoxyquinazoline-2,4(l/f,3//)-dione (Intermediate 110, crude, 1 53 mg, 0.46 mmol) was converted to the free base with N,Ndiisopropylethylamine for 30 min and reacted with 3-oxo-3,4-dihydro-27/-pyrido[3,2- 6][l,4]oxazine-6-carbaldehyde (WO 2004/058144) (90 mg, 0,51 mmol) as described under Example 21. The reaction mixture was cooled to 0°C, and sodium triacetoxy borohydride (194 mg, 0.92 mmol) was added. The resulting reaction mixture was stirred at room temperature for 18 hours and then worked up as described for Example 54 to give the bishydrochloride salt of the product, 12.5 mg (25%), as a colorless solid. MS ffiS); 495 (MH+) for C2jH3oN605 'HNMRCDMSO-D6^ 6 1.85-2.32 (m, 1H); 3.68-3.88 (m, 3H); 3.89-4.08 (m, 3H); 4.10-4.43 (m, 5H); 4.50-4.78 (m, 5H); 6.91-7.44 (m, 5H); 7.99 (bs, 1H); 9.74 (br s, 211); 1 1. 16-11. 38 (m,2H). Intermediate 110: l-r2-f4-Amino-2-oxopiperidin-l-yl)ethyl]-7-methoxv-3- methylquinazoline-2.4(l.//.3/D-dione tert-Butyl {l-[2-(7-methoxy-3-methyl-2,4-dioxo-3,4-dihyaroquinazolin-l(2W)- yl)ethyl]piperidin-4-yl}carbamate (Intermediate 111, 350 mg, 0.83 mmol) was reacted as described for Intermediate 106. The crude trifluoro acetate of the title compound was obtained as a black oil, 395 mg (quantitative), and used without further purification for the next step. MS (ESV. 319 (MH4) for Intermediate 111: tert-Butyl (l-[2-(7-methoxv-3-methvl-2.4-dioxo-3,4- dihvdroquinazolin- 1 (2/f)-vDethvl]piperidin-4-yl} carbamate 7-Methoxy-3-methylquinazoline-2,4(l#,3/:/)-dione (Intermediate 112, 523 rag, 2.5 mmol) was deprotonated with lithium bis(trimethylsilyl)amide (IM in tetrahydrofuran, 1.9 mL, 1.9 mmol) and alkylated with 2-{4-[(te7-/-butoxycarbonyl)amino]piperidin-l-yl}ethyl methanesulfonate (Intermediate 6, 3.4 mmol) as described for Intermediate 2. Chromatography on silica gel with dichloromethane/ methanol (95:5) gave 200 mg (18%) of the product as a colorless solid. MS rES1: 433 (MH+) for C22H32N405. 'HNMRCCDC105 1.16-1.28 (m, 1H); 1.14-1.43 (m, 11H); 1.89-2.04 (m, 3H); 2.25- 2.47 (m, 2H); 2.80 (d, 3H); 2.94-3.14 (m, 2H); 3.77 (s, 3H); 4.22-4.36 (m, 1H); 4.40-4.56 (m, 1H); 4.99-5.09 (m, 1H); 7.02-7.03 (m, 1H); 7.31-7.47 (m, 2H). Intermediate 112: 7-Methoxv-3-methylquinazoline-2.4(ll//.3//)-dione 2-Araino-4-methoxybenzoic acid (Intermediate 113, 950 mg, 6.2 mmol) and 1,3- diraethyl urea (5.4 g, 62 mmol) were heated at 150 °C for 16 hours. The reaction was cooled to 100 °C and diluted with water. The mixture was partitioned between ethyl acetate and water, the aqueous phase extracted with ethyl acetate (3 x 20 mL) and then chloroform/2- propanol (3:1,2x 20 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. Chromatography on silica gel with hexanes/ ethyl acetate (1:2) to give a 350 mg (27%) product as an orange oil. MS fES): 205 (MH4) for Ci0H10N2O3. 'H-NMR fDMSO-oV) 5: 2.60 (d, 3H); 3.68 (s, 3H); 5.95 (d, 1H); 6.45 (dd, 1H); 6.86 (dd, 1H); 8.47 (s, 1H). Intermediate 113: 2-Amino-4-methoxvbenzoic acid 4-Methoxy-2-nitrobenzoic acid (3 g, 16.4 mmol) was hydrogenated over palladium on carbon (10%, 300 mg) in methanol (80 mL) at room temperature and normal pressure for 18 hours. The reaction mixture was filtered through celite and concentrated to dryness under reduce pressure to give 2.50 g (100%) of the product as a colorless solid. 'HNMRrPMSO-d^ 5 3.70 (s, 3H); 6.09 (dd, 1H); 6.23 (d, 1H); 7.59 (d, 1H). Example 56 4-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-2- oxopiperidin-l-yI}ethyl)-6-methoxy-2#-l,4-benzoxazin-3(4#)-onc 4-[2-(4-Amino-2-oxopiperidin-l-yl)ethyl]-6-methoxy-2//-l,4-benzoxazin-3(4//)-one trifluoroacetate (Intermediate 114, crude, 390 mg, 0.83 mmol) was converted to the free base with A^A^-diisopropylethylamine and reacted with 2,3-dihydro[l,4]dioxmo[2,3-c]pyridine-7- carbaldehyde (WO 2004/058144) (150 mg, 0.91 mmol) and sodium triacetoxy borohydride (360 mg, 1.7 mmol) as described for Example 55 to give the bis hydrochloride salt of the product as a colorless solid, 89 mg (63%). MS fES): 469.19 (MH4) for lHNMR(DMSO-dg) 6 1.84 (dd, 1H); 2.26 (d, 1H); 2.37 - 2.46 (m, 1H); 2.68 - 2.77 (m, 1H); 3.29 - 3.49 (m, 5H); 3.75 (s, 3H); 4.32-4.42 (m, 4H); 4.52 (s, 2H); 6.56 (dd, 1H); 6.91-6.98 (m, 2H); 7.22 (s, 1H); 8.23 (s, 1H); 9.52 (bs, 2H). Intermediate 114: 4-[2-(4-Amino-2-oxopiperidin-l -vnethvn-6-methoxy-2//- 1 .4- benzoxazin-3 ( 4H)-on& tert-Butyl {l-[2-(6-methoxy-3-oxo-2,3-dihydro-4#-l,4-benzoxazin-4-yl)ethyl]-2- oxopiperidin-4-yl}carbamate (Intermediate 115, 350 mg, 0.83 mmol) was reacted as described for Intermediate 106. The crude trifluoro acetate of the title compound was obtained as a black oil, 395 mg (quantitative), and used without further purification for the next step. MS (ESI: 320 (MH) for Ci6H2iN3O4. Intermediate 115: tert-Butvl U-r2-f6-methoxv-3-oxo-2.3-dihvdro-4//-1.4- bertzoxazm-4-vr)ethvn-2-oxopiperidin-4-yllcarbamate A mixture of to-/-butyl {l-[2-(6-methoxy-3-oxo-2,3-dihydro-4//-l,4-benzoxazin-4- yl)ethyl]piperidin-4-yl}carbamate (Intermediate 47, 1.39 g, 3.4 mmol) in water/ ethyl acetate (40 mL, 4:1) was treated with sodium periodate (2.8 g, 21.4 mmol) and ruthenium (IV) oxide hydrate (50 mg, .34 mmol) at room temperature. After 53 hours, the reaction was diluted with ethyl acetate, the aqueous phase was extracted with ethyl acetate (6 x 25 mL), and the combined organic layers were mixed with 2-propanol (20 mL) and stirred for 2 hours at room temperature. The reaction mixture was then filtered through celite, dried over sodium sulfate, and concentrated in vacuo. Chromatography on silica gel with dichloromethane/ methanol (95:5) gave 350 mg (25%) of the product as a colorless solid. MS test: 415 (MH"1) for C29H26N306 ^ 8: 1.37 (s, 9H); 1.51-1.56 (m, 1H); 1.81 -1.94 (m, 1H); 2.02- 2.11 (m, 1H); 2.33-2.41 (dd, 1H); 3.06-3.12 (m, 1H); 3.27-3.31 (m, 2H); 3.40-3.45 (m, 2H); 3.55-3.65 (m, 1H); 3.75 (s, 3H); 3.99 (t, 2H); 4.52 (s, 2H); 6.57 (dd, Hi); 6.90-6.98 (m, 3H). Example 57 6-[({l-[2-(6-Methoxy-3-oxo-2,3-dihydro-4jy-l,4-benzoxazin-4-yI)ethyl]-2- oxopiperidin-4-yl}amino)methyl]-2JHr-pyrido[3,2-6][l,4]oxazin-3(4//)-one 4-[2-(4-amino-2-oxopiperidin-l-yl)ethyl]-6-methoxy-2//-l,4-benzoxazin-3(4^)-one trifluoroacetate (Intermediate 114, crude, 335 mg, 1.05 mmol) was converted to the free base with W,7/-diisopropylethylamine and reacted with 3-oxo-3,4-dihydro-2H-pyrido[3,2- b][l,4]oxazine-6-carbaldehyde (WO 2004/058144) (205 mg, 1.15 mmol)and sodium triacetoxy borohydride (132 mg, 2.10 mmol) as described for Example 55 to give the bis hydrochloride salt of the product as a colorless solid, 36 mg (46%). MS CESV 482.15 (MH4) for C24H27N506 • 'H NMR (DMSO-d^ 8: 1.75-1.95 (m, 1H); 2.20-2.41 (m, 1H); 2.74 (dd, 1H); 3.76 (s, 3H); 3.92-4.07 (m, 2H); 4.12-4.23 (m, 1H); 4.53-4.62 (m, 2H); 4.69 (s, 2H); 6.57 (dd, 2.26, 1H); 6.90-6.99 (m, 2H); 7.20 (d, 1H); 7.43 (d, 1H); 9.39 (bs, 1H); 11.35 (s, 1H). Example 58 3-Oxo-4-[2-(2-oxo-4-{[(3-oxo-3,4-dihydro-2Jfir-pyrido[3,2-6][l,4]oxazin-6- yl)methyl]amlno}piperidin-l-yl)ethyl]-3,4-dihydro-2^-l,4-benzoxazine-6-carbonitrile 4-[2-(4-Amino-2-oxopiperidin-l-yl)ethyl]-3-oxo-3,4-dihydro-2//-l,4-benzoxazinc-6- carbonitrile trifluoroacetate (Intermediate 116, crude, 232 mg, 0.54 mmol) was converted to the free base with W,./V-diisopropylethylamine and reacted with 3-oxo-3,4-dihydro-2Hpyrido[ 3,2-b][l,4]oxazine-6-carbaldehyde (WO 2004/058144) (110 mg, 0.60 mmol) and sodium triacetoxy borohydride (240 mg, 1.10 mmol) as described for Example 55 to give the bis hydrochloride salt of the product as a colorless solid, 65 mg (49%). MS flSS~>: 477.35 (MH+) for C24H24N605 'HNMRfDMSQ-d^ 5 1.79-1.84 (m, 1H); 2.28-2.42 (m, 2H); 2.70-2.77 (m, 1H); 3.51-3.56 (m, 2H); 4.08-4.16 (m, 4H); 4.68 (s, 3H); 4.73 (s, 3H); 7.14-7.22 (m, 2H); 7.43-7.52 (m, 2H); 9.46 (bs, 1H); 11.35 (s, III). Intermediate 116: 4-[2-(4-Amino-2-oxopiperidin-l-vnethvl1-3-oxo-3,4-dihydro-2//- 1.4-benzoxa2Jne-6-carbonitrile tert-Butyl {l-[2-(6-cyano-3-oxo-2,3-dihydro-4/f-l,4-benzoxazin-4-yl)ethyl]-2- oxopiperidin-4-yl}carbamate (Intermediate 117, 225 mg, 0.54 mmol) was reacted as described for Intermediate 106. The crude trifluoro acetate of the title compound was obtained as a red oil, 232 mg (quantitative), and used without further purification for the next step. MS (ESI: 315 (MH4) for dyH^Ch Intermediate 117: tert-Butvl ll-r2-(6-cvano-3-oxo-2,3-dihydro-47/-1.4-benzoxay:iri- 4-vl)ethyl]-2-oxopiperidin-4-vl)carbamate ter/-Butyl {l-[2-(6-cyano-3-oxo-2,3-dihydro-4//-l,4-benzoxazin-4-yl)ethyl]piperidin- 4-yl}carbamate (Intermediate 59, 835 mg, 2.1 mmol) was reacted with sodium periodate (2.8 g, 13.1 mmol) and ruthenium (IV) oxide hydrate (30 mg, .21 mmol) as described for Intermediate 115 for 16 hours, except, chloroform was used for aqueous workup. The product was obtained as a colorless solid, 230 mg (27%), MS (ESV 415 (MH+) forC2iH26N405 'H-NMR(DMSO-d/0 5: 1.36 (s, 9H); 1.42 -1.57 (m, 2H); 1.87 (d, 1H); 2.00 (dd, 1H); 2.32 (dd, 1H); 3.38 - 3.48 (m, 2H); 3.51 - 3.63 (m, 1H); 4.07 (t, 2H); 4.72 (s, 2H); 6.94 (d, 1H); 7.14 (d, 1H); 7.48 (dd, 1H); 7.84 (d, 1H). Example 59 6-({4-[3-(7~Methoxy-2-oxo-2fir-3,l-benzoxazin-l(4/f)-y1)propyl]p»Perazin-lyl} methyl)-2£r-pyrido[3,2-6][l,4]oxazin-3(4J?)-one 7-Methoxy-1 -(3-piperazin-1 -ylpropyl)-1,4-dib.ydro-2ff-3,1 -benzoxazin-2-one trifluoroacetate (Intermediate 118, crude, 886 mg, 1.66 mmol) was converted to the free base withT/.A'-diisopropylethylamine and reacted with 3-oxo-3,4-dihydro-2H-pyrido[3,2- b][l,4]oxazine-6-carbaldehyde (WO 2004/058144) (220 mg, 1.23 mmol) and sodium triacetoxy borohydride (521 mg, 2.46 mmol) as described for Example 55 to give the free base of the product as a pink foam after chromatography on silica gel with dichloromethane/ methanol (93:7), 86 mg (21%). MS (ESV. 468.19 (MH+) for C24H29N505 IHNMRfDMSO-d^o: 1.60-1.75 (m, 2H); 2.19 - 2.44 (m, 9H); 3.37-3.43 (m, 2H); 3.72 (s, 2H); 3.83-3.96 (m, 2H); 4.53 (s, 2H); 4.60 (s, 2H); 6.56 (d, 1H); 6.78 (d, 1H); 6.88 - 7.02 (m, 2H); 7.29 (d, 1H); 11.22 (s, 1H). Intermediate 118: 6-Methoxv-4-f3-piperazin-l-ylpropyl)-2#-l .4-benzoxazin-3(4/jlone tert-Eutyl {l-[2-(7-methoxy-2-oxoquinolin-l(2/f)-yl)propyl]piperidin-4-yl}carbamate (Intermediate 119, 500 rag, 1.23 mmol) was reacted as described for Intermediate 106. The crude trifluoro acetate of the title compound was obtained as a yellow oil, 866 mg (quantitative), and used without further purification for the next step. MS fESV 306 (MH+) for Intermediate 119: fer/-Butyl4-[2-('6-methoxv-3-oxo-2.3-dihvdro-4//-1.4-benzoxaxiii- 4-vnpropvllDiperazine- 1 -carboxvlate 6-Methoxy-2//-l,4-benzOxazin-3(4//)-one (Intermediate 48, 440 mg, 2.5 mmol) was deprotonated with sodium hydride (125 mg, 60% in oil, 3.2 mmol) and alkylated with tertbutyl 4-{3-[(methylsulfonyl)oxy]propyl}piperazine-l-carboxylate (Intermediate 120, 2.5 mmol) as described for Intermediate 2. Chromatography on silica gel with dichloromethane/ 2-propanol (95:5) gave 1.25 g (quantitative) of the product as a yellow oil. MS ffiSV 406 (MH4) for C2oH29N305 'H-NMRfCDClv) 5: 1.45 (s, 9H); 1.78 - 1.90 (m, 2H) 2.36 - 2.40 (m, 6H); 3.43 (m, 4H); 3.77 (s, 3H); 3.95 (t, 2H); 4.52 (s, 2H); 6.49 (dd, 1H); 6.67 (d, 1H); 6.89 (d, 1H). Intermediate 120: tert-Butvl 4-l3-r(methvlsulfonyl')oxv1propvnpiperazine-lcarboxylate tert-Butyl 4-(3-hydroxypropyl)piperazine-l-carboxylate (Intermediate 121, 2.38 g, 9.8 mmol) was reacted with methanesulfonyl chloride (0.91 mL, 1 1.7 mmol) in the presence of triethylamine (1.9 mL, 13.7 mmol) as described for Intermediate 6. The crude product was used without further purification for the next step. IHNMRCCDCl-DS: 1.44(s,9H); 1. 94- 2.04 (m,2H); 2.43-2.51 (m,6H);3.01 (s, 3H); 3.50-3.40 (m, 4H); 4.28-4.33 (m, 2H). Intermediate 121: tert-Butvl 4-(3-hvdroxvnropvl')piperazine-l -carboxvlate A mixture of tert-bntyl piperazine-1-carboxylate (2.75 g, 14.8 mmol), l-bromo-3- propanol (1,43 mL, 16.2 mmol) and potassium carbonate (2.25 mL, 27.5 mmol) in acetonitrile (75 mL) was heated at 95°C for 4 hours. The solvent was removed under reduced pressure, and the residue was taken up in dichloromethane (300 mL) and washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure. Chromatography on silica gel with methanol in dichloromethane (0-10%) gave a tan solid 2.88 g (80% yield). MS fESV 245 (MH) for daEW^Os. 'H-NMR fCDClO 5: 1.44 (m, 9H); 1.70-1.82 (m, 2H); 2.40-2.53 (m, 2H); 2.62-2.65 (m, 2H); 3.43-3.50 (m, 4H); 2.77 (m, 2H); 3.73-3.82 (m, 2H). Example 60 4-{3-[4-(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-yImethyl)piperazin-l-yl]propyl}- 6-methoxy-2/?-l,4-benzoxazin-3(4.H)-one 7-Methoxy-l-(3-piperazin-l-ylpropyl)-l,4-dihydro-2//-3,l-benzoxazin-2-one trifluoroacetate (Intermediate 118, crude, 963 mg, 1.81 mmol) was converted to the free base with A^JV-diisopropylethylamine and reacted with 2,3-dihydro[l,4]dioxino[2,3-e]pyridine-7- carbaldehyde (WO 2004/058144) (203 mg, 123 mmol) and sodium triacetoxy borohydride (240 mg, 1.10 mmol) as described for Example 55 to give the free base of the product as an oil after chromatography on silica gel with dichloromethane/ methanol (93:7), 125 mg (22%). MS (ES): 455.15 (MH4) for CwHsMOs 'HNMRfDMSO-De'l 8:1.67 (s, 2H); 2.26 - 2.41 (m, 8H); 3.41 (s, 2H); 3.72 (s, 3H); 3.88 (s, 2H); 4.29 (d, 4H); 4.52 (s, 2H); 6.56 (d, 1H); 6.78 (s, 1H); 6.83 - 6.99 (m, 3H); 7.99 (s, 1H). Example 61 4-[2-({l-[(2£)-3-(2,5-Difluorophenyl)prop-2-en-l-yl]piperidin-4-yl}amino)ethyll- 6-methoxy-2Lff-l,4-benzoxazin-3(4fO-one 1 -[(2£)-3-(2,5-difluorophenyl)prop-2-en-1 -yl]piperidin-4-amine trifluoroacetate (Intermediate 122,430 mg, 0.85 mmol) was converted to the free base with N,Ndiisopropylethylamine and reacted with (6-methoxy-3-oxo-2,3-dihydro-4//-l,4-benzoxazin-4- yl)acetaldehyde (Intermediate 125,197 mg, 0.90 mmol) and sodium triacetoxy borohydride (132 mg, 2.10 mmol) as described for Example 55 and purified by Reverse Phase Chromatography with 20 to 75% acetonitrile/ water containing 0.1% TFA to give the trifluoroacetic acid salt of the product, 31 mg. MS (ESV. 458.27 (MH) for lHNMRfDMSO-D6)8:1.85-1.72 (m, 1H); 2.30-2.21 (m, 1H); 3.24-2.8 (m, 2H); 4.05-3.72 (m, 5H); 4.13-4.40 (m, 2H); 4.60 (br s, 2H); 6.61-6.98 (m, 2H); 7.21-7.41 (m, 2H); 7.60 (brs, 1H); 9.04 (brs, 1H). Intermediate 122: l-r(2£^-3-C2.5-Difluorophenynprop-2-en-l-vl1piperidin-4-amine ter/-Butyl {l-[(2£)-3-(2,5-difluorophenyl)prop-2-en-l-yl]piperidin-4-yl}carbamate (Intermediate 123, 299 mg, 0.85 mmol) was reacted as described for Intermediate 106. The crude trifluoro acetate of the title compound was obtained as an oil, 430 mg (quantitative), and used without further purification for the next step MS (ESV 253 (MH+) for Ci4Hi8F2N2. Intermediate 123: tert-Butvl (l-[(2g)-3-C2.5-difluorophenvnprop-2-en-lyl] piperidin-4-yn carbamate A mixture of ter/-butyl piperidin-4-ylcarbamate (248 mg, 1.2 mmol), potassium carbonate (188 mg, 1.4 mmol) and 2-[(ljE)-3-chloroprop-l-en-l-yl]-l,4-difiuorobenzene (Intermediate 124,257 mg, 1.4 mmol) in ethanol (7 mL) was heated to 80 °C for 18 hours. The mixture was concentrated under reduced pressure, the residue taken up in dichloromethane (20 mL) and water (20 mL), the aqueous phase was back extracted with dichloromethane (2 x 2C mL) and the combined organic phases were dried over sodium sulfate. Chromatography on silica gel with dichloromethane/methanol (95:5) gave 300 mg (69%) of product as a brown foam. MS (ES): 353 (MH4) for C^K^NaCb 'HNMRrCDClO 5 1.41 -1.53 (m, 11H); 1.96 (d, 2H); 2.07 - 2.21 (m, 2H); 2.92 (d, 2H); 3.18 (d, 2H); 3.48 (d, 1H); 4.45 (s, 1H); 6.27 - 6.39 (m, 1H); 6.63 (d, 1H); 6.85 - 7.01 (m, 2H); 7.12 (ddd, 1H); 7.24 - 7.28 (m, 1H). Intermediate 124: 2-r(l£)-3-Chloroprop-l-en-l-vl]-1.4-difluorobenzene A mixture of (2£>3-(2,5-difluorophenyl)prop-2-en-l-ol (Intermediate 70, 700 mg, 4.12 mmol), 1,4-dioxane (5 mL), and hydrochloric acid (12.1 M, 1 mL) was heated in the microwave at 100 °C for 3 hours. It was concentrated to dryness under reduced pressure, the residue taken up in ethyl acetate (10 mL), washed with water (1x10 mL), saturated sodium bicarbonate solution, brine and dried over sodium sulfate. The solvent was removed under reduced pressure to give 688 mg (89% yield) of product as a yellow oil. 'HNMRfCDClOS 4.24 (dd, 2H); 6.38 (dt, 1H); 6.75 (d, 1H); 6.88 - 7.04 (m, 2H); 7.13(ddd,lH). Intermediate 125; C6-Methoxy-3-oxo-2.3-dihydro-4//:-1.4-ben20xazin-4- vDacetaldehyde To a solution of oxalyl chloride (0.26 mL, 3.0 mmol) in dichloromethane (10 mL) at - 70°C was added a solution of dimethyl sulfoxide (DMSO, 0.426 mL, 6.0 mmol) in dichloromethane (10 mL), After thirty minutes a solution of 4-(2-hydroxyethyl)-6-methoxy- 2//-l,4-benzoxazin-3(4//)-one (Intermediate 126, 550 mg, 2.5 mmol) in dichloromethane (3.5 mL) was added dropwise and it was stirred for 90 minutes. Triethyl amine (1.74 ml, 12.5 mmol) was added it was stirred at -70°C for another 45 minutes. The reaction was quenched with water and warmed to 0°C. It was diluted with dichloromethane, the aqueous phase was extracted with dichloromethane (3 x 25 mL) and the combined organic phases were washed with IN HC1 (2 X 25 mL), water (25 mL), 1M sodium carbonate solution (2 X 25 mL), water, brine, dried over magnesium sulfate and concentrated at reduced pressure. Chromatography on silica gel with dichloromethane/ methanol (96:4) gave the product as a yellow oil, 292 mg (53%). MS (ES^: 221 (MH4) for CuHi2NO4 'H NMR CCDCM 5 3.71-3.78 (m, 3H); 4.63 (s, 2H); 4.69 (s, 2H); 6.22 (d, 1H); 6.53 (dd, 1H); 6.95 (d, 1H); 9.67 (s, 1H). Intermediate 126: 4-(2-Hvdroxyethvn-6-methoxv-27/-l .4-benzoxazin-3(4//)-one To a solution of 4-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-6-methoxy-2//-l,4- benzoxazin-3(4//)-one (Intermediate 127,1.38 g, 4.1 mmol) in tetrahydrofuran (40 mL) was added tetrabutyl ammonium fluoride (1M in tetrahydrofuran (THF), 4.1 mL, 4.1 mmol). The reaction was stirred at room temperature for two hours. The solvent was removed under reduced pressure and the residue was taken up in dichloromethane, washed with water and dried over magnesium sulfate. Chromatography on silica gel using dichloromethane/ methanol (95:5) gave the title compound as a yellow oil (570 mg, 62%). 'HNMRCCDClrl 5 ppm: 3.77 (s, 3H); 3.92 (t, 2H); 4.08 (t, 2H); 4.55 (s, 2H); 6.52 (dd, 1H); 6.68 (d, 1H); 6.90 (d, 1H). Intermediate 127: 4-(2-{ rterNButylfdimethvl)silvlloxv}ethvlV6-methoxv-2fl'-l .4- benzoxazin-St^flVone To a solution of 6-methoxy-2/y-l,4-benzoxazin-3(4//)-one (Intermediate 48) (800 mg, 4.5 mraol) in DMF (16 mL) was added sodium hydride (60% in mineral oil, 260 mg, 6.5 mmol). After 20 minutes, (2-bromoethoxy)(tert-butyl)dimethylsilane (1.4 mL, 6.5 mmol) was added and it was heated to 70°C in the microwave for 40 minutes. The reaction mixture was partitioned between water (100 mL) and ethyl acetate (100 mL). The aqueous phase was extracted with ethyl acetate (4 x 50 mL). The combined organic phases were washed with water (6 x 250 mL), dried over magnesium sulfate and concentrated at reduced pressure to afford the product as a yellow oil which was used without further purification. (1.38 g, 91 %). 'HNMR(CDCM 6: -0.02 (s, 6H); 0.83 (s, 9H); 3.77 (s, 3H); 3.84 - 3.91 (m, 2H); 4.01 (t, 2H); 4.52 (s, 2H); 6.50 (dd, 1H); 6.82 (d, 1H); 6.87 (d, 1H). Example 62 4-(3-{4-[(2JE)-3-(2,5-Difluorophenyl)prop-2-en-l-yl]piperazin-l-yl}propyl)-6- methoxy-2£T-l,4-benzoxazin-3(4J?)-one A solution of 6-methoxy-4-(3-piperazin-l-ylpropyl)-2//-l ,4-benzoxazin-3(4//)-one trifluoroacetate (Intermediate 118, 985 mg, 1.52 mmol) in dry ethanol (10 mL) was converted to the free base with N,N-diisopropylethylamine for 30 min and then was added 2- [(lJ^-4-chloroprop-l-en-l-yl]-l,4-difluorobenzene (Intermediate 124, 315 mg, 1.67 mmol), and potassium carbonate (230 mg, 1.67 mmol). The mixture was heated at 80°C for 18 hours, cooled to room temperature and then concentrated to dryness under reduced pressure. The residue was partitioned between water (50 mL) and dichloromethane (100 mL). The organic phase was dried over sodium sulfate and concentrated under reduced pressure. Chromatography on silica gel with dichloromethane/ methanol (95:5) gave the free base of the title compound as a yellow foam. The free base was taken up in dichloromethane(14 mL), followed by the addition of 2M HC1 in ether (0.41 mL). The precipitate was collected by filtration and to give the bis hydrochloride salt of the product as a colorless solid, 171 mg (79%). MS (ESV 458.30 (MET) for CasHjsF^Os 'HNMRfDMSO-Dei 8 1.90-2.04 (bs, 2H); 3.15-3.30 (m, 6H); 3.75 (s, 3H); 3.95 (m, 3H); 4.57 (s, 2H); 6.45-6.54 (m, 1H); 6.57-6.61 (m, 1H); 6.81 (d, 1H); 6.93 (d, J = 9Hz, 1H); 7.26-7.33 (m, 2H); 7.56 (m, 1H). Example 63 6-K{l-[2-(6-Methoxy-2-oxo-l,7-naphthyridin-l(2fi)-yl)ethyl]piperidin-4- yI}amino)methyl]-2fl-pyrido[3,2-A][l,4]oxazin-3(4fl)-one A solution of l-[2-(4-aminopiperidin-l-yl)ethyl]-6-methoxy-l,7-naphthyridin-2(l/f)- one (Intermediate 128, crude, 116 mg, 0.38 mmol) and 3-oxo-3,4-dihydro-2#-pyrido[3,2- £][l,4]oxazine-6-carbaldehyde [WO2004/058144] (82 mg, 0.46 mmol) in chloroform/methanol (6 mL, 10:1) was heated over 3 A molecular sieves at 70°C for 18 hours. The reaction mixture was cooled to 0°C, and sodium triacetoxy borohydride (180 mg, 0.84 mmol) was added. The resulting reaction mixture was allowed to warm to room temperature and stirred for 18 hours. The reaction was diluted with dichloromethane (50 raL) and water (10 mL). The aqueous phase was separated and evaporated to give a solid. The solid was suspended in methanol and filtered. The resultant solid was dissolved in dichloromethane : methanol(l: 1) and treated with 2N HC1 in ether to obtain the dihydrochloride salt. The colorless precipitate was collected by filtration and gave 28 mg (14%) of the bishydrochloride salt of the product. MSfESY1": 465 (MH)+ for CwIfegNeC^ 'H NMR rDMSQ-Dg) 5 ppm: 2.04-2.19 (m, 2H); 2.19-2.31 (m, 1H); 2.32-2.45 (m, 3H); 3.05-3.21 (m, 4H) 3.69-3.84 (m, 2H); 3.89 (a, 3H); 4.05-4.20 (m, 2H); 4.62-4.75 (m, 4H); 6.83 (d, 1H); 7.20 (s, 1H); 7.30 (d, 1H); 7.42 (d, Hi); 7.92 (d, 1H); 8.78 (s, 1H); 9.94 (s, lH);11.39(s,2H). Intermediate 128: l-[2-f4-Aminopiperidin-l-yl)ethyl]-6-methoxy-1.7-naphthyridin- 2fLHVone A solution of tert-butyl {l-[2-(6-chloro-2-oxo-l,7-naphthyridin-l(2#)- yl)ethyl]piperidin-4-yl}carbamate (Intermediate 129, 335 mg, 0.83 mmol) was treated with a solution of sodium methoxide in methanol (0.5 M, 4 mL). The reaction was sealed in a tube and heated at 150°C for 4 hours using microwave irradiation. The reaction was diluted with water and ethyl acetate. The layers were separated. The aqueous phase was washed with ethyl acetate twice. The organic extracts were combined dried over magnesium sulfate and evaporated at reduced pressure to give 116 mg (64%) of the crude product as a yellow oil. MS fES^: 303 (MH^for Intermediate 129: tert-Butvl n-[2-(7-methoxv-2-oxoquinolin-lf2fflvllethvnpiperidin- 4-yl} carbamate 6-Chloro-l,7-naphthyridin-2(l#)-one (J. Org. Chem. 1990, 55,4744-4750) (360 mg, 2.0 ramol) was deprotonated with sodium hydride (100 mg, 60% in oil, 2.4 mmol) and alkylated with 2-{4-[(ter/-butoxycarbonyl)arnino]piperidin-l-yl}ethyl methanesulfonate (Intermediate 6) 2.75 mmol) as described for Intermediate 2. Chromatography on silica gel with methanol in dichloromethane (0-10%) gave 334 mg (20%) of the product as a colorless solid. MS (ES1: 407 (MH4) for C2oH27ClN403 'H-NMR rDMSO-dg> 8: 1.19-1.32 (m, 1H); 1.36 (s, 9H); 1.56-1.70 (m, 2H); 2.01 (s, 2H); 2.51-2.57 (m, 2H); 2.67-2.75 (m, 1H); 2.83-2.93 (m, 2H); 3.10-3.25 (m, 2H); 3.29-3.31 (m, 1H); 4.30-4.40 (m, 2H); 6.71-6.80 (m, 1H); 6.91 (d, 1H); 7.87 (s, 1H); 7.91 (d, HI); 8.74 (s, 1H). Example 64 Methyl l-[(2£)-3-(2,5-difluorophenyl)prop-2-en-l-yl]-4-[3-(6-cyano-3-oxo-2,3- dihydro-4/M,4-benzoxazin-4-yl)propyl]piperidine-3-carboxylate A solution of methyl 4-[3-(6-cyano-3-oxo-2,3-dihydro-4H-l,4-benzoxazin-4- yl)propyl]piperidine-3-carboxylate trifluoroacetate (Intermediate 130, crude, 171,0.48 mmol), (2£)-3-(2,5-difluorophenyl)acrylaldehyde [FR 2872164] (81 mg, 0.48 mmol), and triethylamine (0.13 mL. 0.96 mmol) in chloroform/methanol (6 mL, 10:1) was heated over 3 A molecular sieves at 70°C for 3 hours. The reaction mixture was cooled to 0°C, and sodium triacetoxy borohydride (200 mg, 0.94 mmol) was added. The resulting reaction mixture was allowed to warm to room temperature and stir for 18 hours. The reaction was diluted with ethyl acetate (25 mL) and water (10 mL). The aqueous phase was separated and washed twice with ethyl acetate. The organic layers were combined, dried over magnesium sulfate and evaporated at reduced pressure. Chromatography on silica gel with diethyl ether gave the title compound as a off-white foam, (79 mg, 32%). MSfES^) 510 (MH)+ for CHHfoFzNsO* 'H NMR fDMSO-d^ S 1.10-1.21 (m, 1H); 1.23-1.34 (m, 1H); 1.44-1.55 (m, 3H); 1.67-1.79 (m, 2H); 1.95-2.07 (m, 1H); 2.18-2.29 (m, 1H); 2.31-2.43 (m, 1H); 2.64-2.70 (m, 1H); 2.71-2.80 (m, 1H); 2.82-2.89 (m, 1H); 3.06-3.17 (m, 2H); 3.57 (d, 3H); 3.84-3.96 (m, 2H); 4 4.77 (s, 2H); 6.40-6.51 (m, 1H); 6.56-6.63 (m, 1H); 7.12 (ddd, 1H); 7.17 (d, 2H); 7.20- 7.28 (m, 1H); 7.47-7.56 (m, 2H); 7.72 (d, 1H). Intermediate 130: Methvl 4-[3-f6-cyano-3-oxo-2.3-dihvdro-4//-1.4-benzoxazin-4- vnpropyripiperidine-3-carboxylate A solution of l-tert-bntyl 3-methyl 4-[3-(6-cyano-3-oxo-2,3-dihydro-4//-l,4- benzoxazin-4-yl)propyl]piperidine-l,3-dicarboxylate (Intermediate 131,220 mg, 0.48 mmol) was reacted as described for Intermediate 106. The crude trifluoro acetate of the title compound was used without further purification for the next step (quantitative). Intermediate 131; 1-tert-Butvl 3-methyl 4-[3-(6-cyano-3-oxo-2.3-dihydro-4//-1.4- benzoxazin-4-vnpropvl1piperidine-1.3-dicarboxvlate A solution of 3-oxo-3,4-dihydro-2//-l,4-benzoxazine-6-carbonitrile (Intermediate 60) (265 mg, 1.53 mmol) in dry ditnethylformamide (DMF) (5 mL) was treated at 0°C with sodium hydride (105 mg, 60% in oil, 2.63 mmol) and then stirred for 30 minutes at room temperature. A solution of \-tert-butyl 3-methyl 4-{3- [(methylsulfonyl)oxy]propyl}piperidine-l,3-dicarboxylate in DMF (Intermediate 132, 0.31 mmol/ mL, 5 mL, 1.53 mmol) was then added and the resulting mixture was stirred at room temperature for 96 hours. The reaction was diluted with ethyl acetate and water. The aqueous layer was adjusted to pH3 with IN HC1. The layers were separated. The aqueous phase was extracted once with ethyl acetate. The combined organic phases were washed four times with water, dried over magnesium sulfate and evaporated at reduced pressure. Chromatography on silica gel with (10 -35%) acetone in hexanes gave 445 mg (64 %) of the product as a white semi-solid (as a mixture of diastereomers). MS (ES\. 458 (MH4) for C24H3iN306 'HNMR rCPClO 5: 1.43 and 1.44 (two s, 9H); 1.47-1.9 (m, 7H); 2.56-2.83 (m, 2H); 2.94-3.2 (m, 1H); 3.65 and 3.70 (two s, 3H); 3.76-3.99 (m, 2H); 4.02-4.21 (m, 1H); 4.67 and 4.70 (two s, 2H); 7.04 (m, 1H); 7.11 and 7.18 (two brs, 1H); 7.30 (m, 1H). Intermediate 132: l-ter/-Butvl3-methvl4-(3-[(methvlsulfonvnoxv1propyl) piperidine-1.3-dicarboxvlate A mixture of l-fc/-/-butyl 3-methyl 4-(3-hydroxypropyl)piperidine-l,3-dicarboxylate (Intermediate 133, 460 mg, 1.53 mmol) in dry dichloromethane (5 mL) and triethyl aminc (0.3 mL, 2.14 mmol) was treated at 0°C with a solution of methanesulfonyl chloride (0.14 mL, 1.83 mmol) in dichloromethane (5 mL). After 2 hours minutes the reaction was complete by TLC (dichloromethane : methanol 10:1). The reaction was diluted with ethyl acetate and water. The layers were separated. The organic layer was washed with 0.1N HC1, water, saturated sodium bicarbonate, dried over magnesium sulfate. The solvent was removed under reduced pressure and the crude preparation of the mesylate was used without delay for the next step. Intermediate 133: l-te;-/-Butyl 3-methvl 4-(r3-hydroxypropyl')piperidine-1.3- dicarboxvlate A solution of 1-tert-butyl 3-methyl 4-allylpiperidine-l,3-dicarboxylate [W02002/072572] (715 mg, 2.53 mmol) in tetrahydrofuran (5 mL) at 0°C was treated with a solution of 9-BBN in tetrahydrofuran (0.5M, 10.2 mL, 5.1 mmol). After one hour the reaction mixture was allowed to warm to room temperature for 3 hours. The reaction mixture was cooled to 0°C and treated with water (3 mL), NaOH (3N, 6 mL) and hydrogen peroxide (30% solution, 6 mL). The reaction was allowed to warm to room temperature and stir for one hour. The reaction was diluted with ethyl acetate and water. The layers were separated. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated at reduced. Chromatography on silica gel with methanol in dichloromethane (0-10%) gave the product as a colorless oil as a mixture of diastereomers (460 mg, 60%). MS rest: 302(MH) for Ci5H27NO5 'HNMRrCDClOS: 1.28-1.39 (m, 1H); 1.43 and 1.44 (two s, 9H); 1.46-1.54 (m, 211); 1.56-1.67 (m, 3H); 1.73-1.85 (m, 2H); 2.58-2.63 (m, 1H); 3.02-3.12 (m, 1H); 3.27 (dd, 1H); 3.60-3.64 (m, 2H); 3.65 and 3.69 (two s, 3H); 3.71-3.81 (m, 1H); 3.87-3.98 (m, 1H). Example 65 4-[3-(6-Cyano-3-oxo-2,3-dihydro-4H-l,4-benzoxazin-4-yI)propyI]-l-[(2E)-3-(2,5- difluorophenyl)prop-2-en-l-yl]piperidine-3-carboxylicacid A solution of methyl l-[(2E)-3-(2,5-difluorophenyl)prop-2-en-l-yl]-4-[3-(6-cyano-3- oxo-2,3-dihydro-4H-l,4-benzoxaztn-4-yl)propyl]piperidine-3-carboxylate (Example 64) (73 mg, 0.143 mmol) in methanol (12 mL) and water (5 mL) was treated with sodium hydroxide solution (IN, 1 mL). After 64 hours, the pH was adjusted to 6 with IN HC1. The mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic extracts were dried over magnesium sulfate and concentrated at reduced pressure. Chromatography on silica gel using methanol in dichloromethane (0-10%) and trituration with diethyl ether gave the title compound as a colorless solid, mixture of diastereomers, 10 mg (14%). MS fES~): 496 (MH)+ for CwKfoFiNaC^ 'HNMRCCDCMS: 1.40-1.45 (m, 1H); 1.47-1.52 (m, 1H); 1.60-1.65 (m, 1H); 1.65- 1.77 (m, 3H); 2.25-2.37 (m, 2H); 2.70-2.77 (m, 1H); 3.08-3.16 (m, 1H); 3.23-3.30 (m, 1H); 3.30-3.40 (m, 2H); 3.64-3.72 (m, 1H); 3.73-3.84 (m, 1H); 3.86- 3.95 (m, 1H); 3.95-4.07 (m, 1H); 4.60-4.71 (m, 3H); 6.21-6.31 (m, 1H); 6.67 (d, 1H); 6.87-6.95 (m, 1H); 6.96-7.01 (m, 1H); 7.01-7.07 (m, 1H); 7.09-7.15 (m, 1H); 7.28-7.31 (m, 1H). Example 66 7-Fluoro-3-methyl-l-[2-(4-{[(3-oxo-3,4-dihydro-2jET-pyrido[3,2-fi][l,4]oxazin-6- yl)methyl]amino}piperidin-l-yl)ethyl]quinazoIine-2,4(lJy,3/7)-dione l-[2-(4-Aminopiperidin-l-yl)ethyl]-7-fluoro-3-methylquinazoline-2,4(l/:/,3J!:/)-dione trifluoroacetate salt (Intermediate 134) (0.476 rnrnol, 380 mg crude) was converted to the free base with ./V.N-diisopropylethylamine (0.5 mL, 3.0 mmol) and reacted with 3-oxo-3,4- dihydro-2H-pyrido[3,2-b][l,4]oxazine-6-carbaldehyde (WO 2004/058144) (102 mg, 0.571 mmol) and sodium triacetoxy borohydride (222 mg, 1.05 mmol) as described for Example 55. The reaction was diluted with dichloromethane and water. The layers were separated. The aqueous layer was extracted with dichloromethane twice. The combined organic layers were dried over magnesium sulfate and evaporated at reduced pressure. Chromatography on silica gel using methanol in dichloromethane (0-9%) with 1% concentrated ammonium hydroxide (aqueous) gave the product as a waxy material. This material was taken up in dichloromethane and washed well with water. The organic phase was dried over magnesium sulfate and evaporated to obtain the title compound as a colorless solid (48 mg, 21%). MSfES): 483 (MH)+ for Ci^vFNeC^ 'HNMRfDMSQ-De) 8: 1.14-1.28 (m, 2H); 1.71-1.82 (m, 2H); 1.94-2.06 (m, 21-1); 2.33-2.44 (m, 2H); 2.83-2.92 (m, 2H); 3.26-3.30 (m, 3H); 3.65-3.72 (m, 211); 4.17 (t, 2H); 4.60 (s, 2H); 7.00 (d, 1H); 7.13 (td, 1H); 7.29 (d, 1H); 7.36 (dd, 1H); 8.09.(dd, 1H); 11.18 (s, 1H). Intermediate 134: l-f2-f4-Aminopiperidm-l-vl)emvl1-7-fluoro-3-methylquinazoline- 2.4(m3/fl-dione tert-Butyl {l-[2-(7-fluoro-3-methyl-2,4-dioxo-3,4-dihydroquinazolin-l(2//)- yl)ethyl]piperidin-4-yl}carbamate (Intermediate 135) (200 mg, 0.476 mmol) was reacted as described for Intermediate 106. The crude trifluoro acetate of the title compound was used without further purification for the next step (quantitative). MSfES): 321 (MH)+ for Intermediate 135: tert-Butvl n-r2-C7-fluoro-3-methvI-2.4-dioxo-3.4- dihvdroquinazolin- 1 ( 2/f)-vDethvnpiperidin-4-vll carbamate 7-Fluoro-3-methylquinazoline-2,4(l//,3//)-dione [Intermediate 136] (388 mg, 2.0 mmol) was deprotonated with sodium hydride (100 mg, 60% in oil, 2.4 mmol) and alkylated with 2-{4-[(ter^butoxycarbonyl)amino]piperidin-l-yl}ethyl methanesulfonate (Intermediate 6) 2.75 mmol) as described for Intermediate 2. Chromatography on silica gel using ethyl acetate in hexanes (10-30%) gave the title compound as a yellow oil (200 mg, 24%). MS fESV 421 (MH)+ for C2iH29FN4O4 'H NMR rCDCM 8: 1.2-1.3 (m, 2H); 1.43 (s, 9H); 1.44-1.5 (m, 1H); 1.9- 2.0 (m, 2H); 2.15-2.35 (m, 2H); 2.65 (m, 2H); 2.85- 3.0 (m, 1H); 3.45 (s, 3H); 3.46- 3.52 (m, 1H); 4.15- 4.25 (m, 2H); 4.35- 4.5 (m, 1H); 6.8- 6.9 (m, 1H); 6.91-7.0 (m, 1H); 8.2-8.26 (m, 1H). Intermediate 136: 7-Fluoro-3-methylquinazoline-2.4flH.3/f)-dione A suspension of sodium hydride (60% in mineral oil, 368 mg, 9.2 mmol) in dimethylformamide (12 mL) was cooled to 0°C and treated with 2-amino-4-fluoro-A'- methylbenzamide [Intermediate 137] (0.67g, 4.0 mmol). Phenyl chloroformate (0.6 mL, 0.73 g, 4.7 mmol) was added over 40 minutes. After 1 hour a further portion of phenyl chloroformate (0.6 mL, 0.73 g, 4.7 mmol) was added. The reaction was allowed to warm to room temperature and stir for two hours. The reaction was slowly added to 200 mL of ice. The solid was filtered, washed with methanol to obtain the product (395 mg, 51%). MS (ES): 193 (M-H)' for C9H7FN202 'HNMRfDMSO-dd 8: 3.23 (s, 3H); 6.89 (dd, 1H); 7.04 (td, 1H); 7.98 (dd, 1H); 11.56(s, Intermediate 137: 2-Ammo-4-fluoro-N-rnethvlbenzamide A mixture of 2-amino 4-fluoro benzoic acid (2.5g, 16.13 mmol) and 1,3 dimethyl urea (5.85 g, 66.5 mmol) was heated at 150°C for 24 hours. The reaction was diluted with water, filtered and extracted twice with ethyl acetate. The organic extracts were dried over magnesium sulfate and concentrated at reduced pressure. Chromatography on silica gel with ethyl acetate in hexanes (0-50%) gave the title compound as a waxy solid (670 mg, 25%) MSCESV: 169 (MH) for C8H9FN20 H NMR fDMSO-Dei 8:2.69 (d, 3H); 6.29 (td, 1H); 6.43 (dd, 1H); 6.74 (s, 2H); 7.49 (dd, 1H); 8.08-8.22 (m, 1H). Example 67 7-ChIoro-l-(2-{4-[(2,3-dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino] piperidin-l-yl}ethyl)-l,8-naphthyridin-2(lH)-one 1 -[2-(4-Aminopiperidin-1 -yl)ethyl]-7-chloro-1,8-naphthyridin-2(l H)-one trifluoroacetate (Intermediate 138, crude, 405 mg, 0.76 mmol), di-isopropyl ethylamine ( 0.38 mL, 2.27 mmol), 2,3-dihydro[l,4]dioxino[2,3-c]pyridine-7-carbaldehyde [WO 2004/058144] (180 mg, 1.1 mmol) and sodium cyanoborohydride (100 mg, 1.56 mmol) were reacted as described for Example 21. Chromatography on silica gel using methanol in dichloromethane (0-20% with 1% aqueous ammonium hydroxide) followed by reverse phase Chromatography with 20-75% acetonitrile/ water/10 mM NEUOAc Buffer) gave the title compound (39 mg, 11%). MS (ES): 456 (MH)+ for C23H26C1N503 'HNMRfCDCIO 5 1.32 -1.43 (m, 2H); 1.87 (d, 2H); 2.10 - 2.21 (m, 2H); 2.51 - 2.61 (m, 1H); 2.69 (t, 2H); 3.08 (d, 2H); 3.81 (s, 2H); 4.21 - 4.32 (m, 4H); 4.58 (t, 2H); 6.68 (d, 1H); 6.78 (s, 1H); 7.11 (d, 1H); 7.58 (d, 1H); 7.75 (d, 1H); 8.05 (s, 1H). Intermediate 138; l-r2-(4-Aminopiperidin-l-yl)ethyl]-7-chloro-1.8-naphthyridin- 2flHVone tert-Butyl {1 -[2-(7-chloro-2-oxo-l ,8-naphthyridin-1 (2H)-yl)ethyl]piperidin-4- yl}carbamate (Intermediate 139, 308 mg, 0.76 mmol) was reacted as described for Intermediate 106. The crude trifluoro acetate of the title compound was used without further purification for the next step (quantitative). Intermediate 139; tert-Butvl n-r2-f7-chlQro-2-oxo-1.8-naphthvridin-l('2H')- vlkthyl]piperidin-4-yl} carbamate A solution of 7-chloro-l,8-naphthyridin-2(lH)-one FJ. Ore. Chem. 1990, 55,4744- 4750] in dry DMF (20 mL) (540 mg, 3,0 ramol) at 0°C was treated with sodium hydride (144 mg, 60% in mineral oil, 3.6 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction was cooled using an ice bath. A solution of 2- {4-[(ter/-butoxycarbonyl)amino]piperidin-lyl} ethyl methanesulfonate in DMF (Intermediate 6), 0.33 mmol/ mL, 10 mL, 3.3 mmol) was then added over 1 hour. The reaction was allowed to warm to room temperature and stirred overnight. The reaction mixture was diluted with water and extracted with dichloromethane (3 x 50 mL). The combined organic layers were washed with saturated sodium chloride solution (3x10 mL), dried over sodium sulfate and evaporated. Chromatography on silica gel using methanol in dichloromethane (0-15%) gave the title compound as a brown foam (711 mg, 58%). MS (ESI: 407 (MH)+for CzoHbClN^ 'HNMRCCDC10 5 1.42 (s, 11H); 1.84 - 1.99 (m, 2H); 2.12 - 2.22 (m, 1H); 2.22 - 2.37 (m, 2H); 2.66 - 2.80 (m, 2H); 3.03 - 3.19 (m, 1H); 3.39 - 3.55 (m, 1H); 4.34 - 4.48 (m, 1H); 4.62 (t, 2H); 6.72 (d, 1H); 7.15 (d, 1H); 7.61 (d, 1H); 7.78 (d, III). Example 68 l-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmcthyl)amino]piperidin-lyl} ethyI)-7-methoxy-l,8-naphthyridin-2(lII)-one A solution of 7-chloro-l-(2-{4-[(2,3-dihydro[l,4]dioxino[2,3-c]pyridin-7- ylmethyl)amino]piperidin-l-yl}ethyl)-l,8-naphthyridin-2(lH)-one (Example 67) (95 mg, 0.21 mmol) in methanol (5 mL) was treated with a solution of sodium methoxide (0.5 M, 1 mL, 0.5 mmol). The reaction mixture was sealed in a tube and heated at 150 C for 1 hour using microwave irradiation. The reaction mixture was concentrated at reduced pressure, partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (3 x 10 mL) and chloroform/methanol (4:1) (3 x 15 mL). The combined organic extracts were dried over sodium sulfate and concentrated at reduced pressure. Chromatography on silica gel using methanol in dichloromethane (0-50%) gave the product as a colorless solid (29 mg, 31%) MS ffiSV 452 (MH)+ 'HNMRfCDCM 8 1.39 -1.54 (m, 2H); 1.90 (d, 2H); 2.13 - 2.28 (m, 2H); 2.47 - 2.62 (m, 1H); 2.64 - 2.76 (m, 2H); 3.06 (d, 2H); 3.80 (s, 2H); 3.99 (s, 3H); 4.26 (dd, 4H); 4.55 - 4.68 (m, 2H); 6.55 (dd, 2H); 6.80 (s, 1H) 7.53 (d, 1H); 7.68 (d, 1H); 8.06 (s, 1H). Example 69 !-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-cIpyridin-7-ylmethyl)amino]piperidin-lyl} ethyl)-7-fluoroquinoxaIin-2(l/f)- A mixture of l-[2-(4-aminopiperidin-l-yl)ethyl]-7-fluoroquinoxalin-2(l//)-one (Intermediate 140, 85 mg, 0.29 ramol), 2,3-dihydro[l,4]dioxino[2,3-c]pyridine-7- carbaldehyde (WO 2004/058144) (49 mg, 0.29 mmol) and molecular sieves 3 A in dry methanol/ chloroform (1:1,10 mL) was heated to 70 °C for 3 hours. The reaction was allowed to cool to room temperature and sodium triacetoxy borohydride (190 mg, 0.88 mmol) was added. After 30 minutes, the reaction was filtered through celite, the filtrate was concentrated to dryness, taken up in 15% methanol/ chloroform, and washed with saturated sodium bicarbonate solution. The aqueous phase was reextracted twice with 15% methanol/chloroform. The combined organic phases were dried over magnesium sulfate, filtered, and concentrated to dryness. Chromatography on silica gel with 5% methanol in dichloromethane containing 0.25% ammonium hydroxide gave 70 mg (54%) of the title compound as an off-white solid. MS (ES): 440 (MH4) for CzsHjeFNsCb 'HNMR (DMSO-D6) 5 1.11 -1.24 (m, 2H); 1.73 (d, 2H); 2.00 (t, 2H); 2.18 (s, 1H); 2.25 - 2.38 (m, 1H); 2.51 - 2.56 (m, 2H); 2.87 (d, 2H); 3.64 (s, 2H); 4.24 - 4.35 (m, 6H); 6.92 (s, 1H); 7.24 (td, 1H); 7.52 (dd, 1H); 7.87 (dd, 1H); 7.99 (s, 1H); 8.18 (s, III). Intermediate 140: l-[2-(4-Aminopiperidin-l-yl)ethyl]-7-fluoroquinoxalin-2d//)-one A solution of tert-butyl {l-[2-(7-fluoro-2-oxoquinoxalin-l(2/:/)-yl)ethyl]piperidin-4- yl}carbamate (Intermediate 141,240 mg, 0.62 mmol) in dichloromethane (20 mL) was treated with trifluoroacetic acid (15 mL). After 45 minutes, the reaction was concentrated to dryness, the residue taken up in methanol/ chloroform (15:85, 30 mL) and washed with saturated sodium bicarbonate solution. The aqueous layer was re-extracted with methanol/ chloroform (15:85,3x30 mL. The combined organic phases were dried over magnesium sulfate and concentrated to dryness to give 170 mg (quantitative) of the crude product as an oil. -J3T-/3/ MS (ES\. 291 (MH+) for Ci5H]9FN4O Intermediate 141: tert-Eutvl {l-[2-(7-fluoro-2-oxoquinoxalin-lf2/f)- vl)ethyl1piperidin-4-yU carbamate and Intermediate 142; tert-Butvl n-r2-C6-fluoro-2-oxoquinoxalin-l('2//)- vDethy ripiperidin-4-vl} carbamate A suspension of a 1:1 mixture of 7-fluoroquinoxalin-2(l#)-one (Intermediate 143) and 6-fluoroquinoxalin-2(l//)-one (Intermediate 144) (1.5 g total, 9.1 mmol) was treated with sodium hydride (60% in oil, 0.44 g, 11.0 mmol) at 0°C. The reaction was allowed to stir at room temperature for 2 hours. The reaction mixture was cooled to 0 °C and 2-{4-[(tertbutoxycarbonyl) amino]piperidin-l-yl} ethyl methanesulfonate (Intermediate 6,1.33 mmol/mL, 11.0 mmol), dissolved in dry DMF (5 mL) was added and it was stirred at room temperature overnight. The reaction mixture was diluted with water and with diethyl ether (5x 50 mL). The combined organic phases were dried over sodium sulfate and concentrated to dryness under reduced pressure. Chromatography with hexanes/ acetone (5:1 to 3:1). The higher Rf material was isolated as a mixture of Intermediate 141 with an 0-alkylatcd isomcr, which was rechromatographed on silica gel with hexanes/ ethyl acetate (1:3) to give pure Intermediate 141 as a colorless solid, 0.24 g, 14%. Isolation of the lower Rf material from the first column gave 0.38 g (21%) of pure Intermediate 142 as a colorless solid. Intermediate 141: MS (BS): 391 (MH") for C2oH27FN403 'HNMRfDMSO-De^ 8 1.25-1.38 (m, 11H); 1.56-1.68 (m, 2H); 2.01 (t, 2H); 2.50- 2.56 (m, 2H); 2.82-2.93 (m, 2H); 3.16 (s, 1H); 4.27 (t, 2H); 6.72 (d, 1H); 7.23 (t, 1H); 7.50 (d, 1H); 7.83-7.91 (m, 1H); 8.17 (s, 1H). Intermediate 142: MS (ES): 391 (MH4) for CaoI^FN^ ^NMRfDMSO-De^ 5 1.24-1.38 (m, 11H); 1.65 (d, 2H); 2.03 (t, 2H); 2.51-2.58 (m, 2H); 2.88 (d, 2H); 3.11-3.26 (m, 1H); 4.31 (t, 2H); 6.75 (d, 1H); 7.57 (td, 1H); 7.63-7.71 (m, 2H); 8.29 (s, 1H). Intermediate 143: 7-Fluoroauinoxalin-2d.ff)-one and Intermediate 144; 6-Fluoroqumoxalin-2(l/fl-one A mixture of 4-fluorobenzene-l,2-diamine (5.0 g, 39.7 mmol) and ethyl oxoacetate (50 wt % in toluene, 17 mL, 79.4 mmol) in ethanol (100 mL) was stirred for two hours at room temperature. The precipitate was collected by filtration, washed with ethanol, and dried under vacuum giving 4.5 g of a solid. !H NMR revealed a 1:1 mixture of Intermediates 143 and 144. This mixture was used for the next step, MS (ES\. 165 (MH+) for C8H5FN20 Example 70 6-[({l-[2-(7-Fluoro-2-oxoquinoxalin-l(2//)-yl)ethynpiperidin-4-yl}amino)methyl]- 2#-pyrido[3,2-A\|[l,4]oxazin-3(4//)-one l-[2-(4-Aminopiperidm-l-yl)ethyl]-7-fluoroquinoxalin-2(l//)-°ne (Intermediate 140, 85 mg crude, 0.29 mmol), 3-oxo-3,4-dihydro-2#-pyrido[3,2-6][l,4]oxazine-6-carbaldehyde (WO 2004/058144) (52 mg, 0.29 mmol) and sodium triacetoxy borohydride (190 mg, 0.88 mmol) were reacted as described according to Example 69 to give 90 mg (69%) of the free base of the product. MS (ESI: 453 (MH+) for C23H2jFN6O3 1HNMRroMSO-D6') 5 1.12-1.26 (m, 2H); 1.69-1.81 (m, 2H); 2.01 (t, 2H); 2.27-2.42 (m, 1H); 2.51-2.60 (m, 2H); 2.88 (d, 2H); 3.67 (s, 2H); 4.28 (t, 2H); 4.60 (s, 2H); 7.00 (d, 1H); 7.20-7.31 (m, 2H); 7.52 (dd, 1H); 7.88 (dd, 1H); 8.19 (s, 1H); 11.16 (s, 1H). Example 71 l-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-lyl} ethyl)-6-fluoroquinoxalin-2(LF7)-one l-[2-(4-Aminopiperidin-l-yl)ethyl]-6-fluoroquinoxalin-2(l/:/)-one (Intermediate 145, 87 mg, 0.30 mmol), 2,3-dihydro[l,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO 2004/058144) (50 mg, 0.30 mmol), and sodium triacetoxy borohydride (200 mg, 0.90 mmol) were reacted as described for Example 69 to give the free base of the title compound as an oil. The free base was taken up in isopropanol (10 mL) and treated with 2.0M HC1 in ether (3 eq). Solvent was removed under reduced pressure. The resulting solid was triturated with dichloromethane/hexanes (2mL/ lOmL). The precipitate was collected by filtration to give 45 mg (29%) of the bis-hydrochloride salt of the product. MS (BSV 440 (MH+) for CzaJfefiFNsOs 1. 83-2.06 (m, 2H); 2.42 (d, 2H); 3.17 (t, 2H); 3.48-3.68 (m, 3H); 3.79-4.01 (m, 2H); 4.30-4.41 (m, 4H); 4.43-4.51 (m, 2H); 4.65-4.70 (m, 2H); T. 27-1 30 (m, 1H); 7.44-7.55 (m, 2H); 7.59 (dd, 1H); 8.20-8.25 (m, 2H). Intermediate 145: l-r2-(4-Aminopiperidin-l -vnethyl1-6-fluoroquinoxalin-2n//)-orie tert-Butyl { 1 -[2-(6-fluoro-2-oxoquinoxalin- 1 (2#)-yl)ethyl]piperidin-4-yl} carbamate (Intermediate 142, 380 mg, 0.97 mmol) was reacted with trifluoroacetic acid in dichloromethane as described for Intermediate 140 to give 260 mg (93%) of the crude product as an oil. MS fESV. 291 (MH+) for Ci5Hi9FN4O Example 72 l-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-yImethyl)amino]piperidin-lyI} ethyl)-7-methoxyquinoxalin-2(l//)-one l-[2-(4-Aminopiperidin-l-yl)ethyl]-7-methoxyquinoxalin-2(l/f)-one (Intermediate 146, 60 mg crude, 0.20 mmol), 2,3-dihydro[l,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO 2004/058144) (33 mg, 0.20 mmol), and sodium triacetoxy borohydride (130 mg, 0.60 mmol) were reacted as described for Example 69 to give the free base of the title compound as an oil. The free base was taken up in isopropanol and treated with 4.0M HC1 in dioxane (3 eq). Solvent was removed under reduced pressure to give 28 mg (27% yield) of the bishydrochloride salt of the product. MS (ESV 452 (MH+) for C24H29N504 1HNMRfD;0') 5 1.86-2.02 (m, 2H); 2.36-2.49 (m, 2H); 3.09-3.23 (m, 2H); 3.52 (t, 2H); 3.56-3.68 (m, 1H); 3.82-3.95 (m, 5H); 4.32-4.40 (m, 4H); 4.43-4.50 (m, 2H); 4.61 (t, 2H); 6.82 (d, 1H); 7.03 (dd, 1H); 7.29 (s, 1H); 7.71 (d, 1H); 7.97 (s, 1H); 8.22 (s, 1H). Intermediate 146: 1 -[2-(4-Aminor>iperidin- 1 -vr)ethvl]-7-methoxvquinoxalin-2( I/Done terf-Butyl { 1 -[2-(7-methoxy-2-oxoquinoxalin-l(2//)-yl)ethyl]piperidin-4- yl}carbamate (Intermediate 147, 190 mg, 0.47 mmol) was reacted with trifluoroacetic acid in dichloromethane as described for Intermediate 140 to give 110 mg of the crude product as an oil. MS (ES): 303 (MH+) for C^EfoN^ Intermediate 147: tert-Butvl n-[2-(7-methoxv-2-oxoquinoxalin-l(2#V vl)ethyl]piperidin-4-yl} carbamate 7-methoxyquinoxalin-2(l/0-one (Intermediate 148,300 mg, 1.70 mmol) was deprotonated with sodium hydride (100 mg, 60% in oil, 2.56 mmol) and alkylated with 2-{4- [(tert-butoxycarbonyl)amino]piperidin-l-yl} ethyl methanesulfonate (Intermediate 6) (3.4 mmol) as described for Intermediate 2. Chromatography on silica gel with 25% acetone in hexanes gave 200 mg (29%) of the product as a colorless solid. MS (ES): 403 (MH+) for C21H3oN404 'HNMRCDMSO-D6U 1.26-1.40 (m, 11H); 1.57-1.72 (m, 2H); 1.97-2.11 (m, 2H); 2.51-2.61 (m, 2H); 2.85-2.98 (m, 2H); 3.19 (s, 1H); 3.92 (s, 3H); 4.32 (t, 2H); 6.76 (d, 1H); 6.95-7.04 (ra, 2H); 7.70-7.78 (m, 1H); 8.04 (s, 1H). Intermediate 148: 7-Methoxyquinoxalin-2f Iffl-one A suspension of 2-chloro-7-methoxyquinoxaline (Intermediate 149, 720 mg, 3.70 mmol) in 5M HC1 (25 mL) was heated to 110 °C for 1 hour. The reaction was cooled to room temperature and let stand for 24 hours. The resulting precipitate was collected by filtration. A second crop of material was collected after concentration the mother liquor. The two crops were combined and crystallized from methanol to give 550 mg (85%) of the product as an oftwhite solid. MS (ES): 177 (MH+) for C9H8N2O2 'HNMR(DMSQ-D6) 5 3.83 (s, 3H); 6.76 (d, 1H); 6.91 (dd, 1H); 7.69 (d, III); 7.94 - 8.00 (m,lH); 12.32 (s, 1H). Intermediate 149: 2-Chloro-7-methoxvquinoxaline A solution of 4-methoxybenzene-l,2-diamine (16.8 g, 0.12 mmol) in ethanol (250 mL) was treated with a solution of ethyl oxoacetate (50 wt % in toluene, 50 mL, 0.23 mmol) dropwise with cooling in an ice bath. The reaction was allowed to warm to room temperature and after 2 hours, a precipitate was collected by filtration giving 15 g of a brown solid as a 2:1 mixture of 6-methoxyquinoxalin-2(l/^)-one to 7-methoxyquinoxalin-2(l//)-onc. These isomers were inseparable by TLC. The mixture was suspended in phosphorus oxychloride (150 mL) and heated to reflux for 1 hour. The reaction was cooled to room temperature and was quenched on ice. The pH of the mixture was adjusted to pH 8 with solid sodium carbonate, it was extracted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered, and concentrated to dryness to give 10.4 g of a crude mixture of 2-chloro-6- methoxyquinoxaline and the desired 2-chloro-7-methoxyquinoxaline. Chromatography on silica gel with 5% ethyl acetate in hexanes afforded 0.77 g of the product as a colorless solid. MS (ES): 195 (MH^ for C9H7C1N20 'HNMRfCDCM 5 3.96 (s, 3H); 7.29 (d, 1H); 7.41 (dd, 1H); 7.97 (d, 1H); 8.63 (s, 1H). Example 73 6-[({l-[2^7-Methoxy-2-oxoquinoxalin-l(2.H)-yl)ethyl]piperidin-4- yl}amino)methyl]-2#-pyrido[3,2-&][l,4]oxazin-3(4#)- l-[2-(4-Aminopiperidin-l-yl)ethyl]-7-methoxyquinoxalin-2(l//)-one (Intermediate 146, 60 mg crude, 0.20 mmol), 3-oxo-3,4-dihydro-2//-pyrido[3,2-6][l,4]oxazme-6- carbaldehyde (WO 2004/058144) (36 mg, 0.20 mmol), and sodium triacetoxy borohydride (130 mg, 0.60 mmol) were reacted as described according to Example 69 to give the free base of the product, which was crystallized from dichloromethane/ethyl acetate to give 45 mg (50%) as a colorless solid. MS QBS): 465 (MH4) for C24H28N604 8 1.06-1.39 (m, 2H); 1.66-1.87 (m, 2H); 2.04 (t, 2H); 2.33-2.49 (m, 1H); 2.56 (t, 2H); 2.92 (d, 2H); 3.70 (s, 2H); 3.92 (s, 3H); 4.32 (t, 2H); 4.61 (s, 2H); 6.86 - 7.09 (m, 3H); 7.30 (d, 1H); 7.75 (d, 1H); 8.04 (s, 1H); 11.18 (s, 1H). Example 74 6-[({l-[2-(7-Methoxy-2-oxoquinoxalin-l(2/?)-yI)ethyl]piperidin-4- yl}amino)methyl]-2flr-pyrido[3,2-A][l,4]thiazin-3(4£0-one l-[2-(4-Aminopiperidin-l-yl)ethyl]-7-methoxyquinoxalin-2(l/Z)-one (Intermediate 146, 250 mg crude, 0.83 mmol), 3-oxo-3,4-dihydro-2#-pyrido[3,2-Z>][l,4]thiazme-6- carbaldehyde (WO 2004/058144) (160 mg, 0.83 mmol), and sodium triacetoxy borohydride (530 mg, 2.50 mmol) were reacted as described according to Example 69. Chromatography on silica gel with 10% methanol in dichloromethane containing 0.25% ammonium hydroxide afforded the free base of the product. This was triturated with dichloromethane and the precipitate was collected by filtration giving 230 mg (58%) of the title compound as a colorless solid. MS fBSV 481 (MH+) for C24H28N603S 'HNMRnDMSO-D6> 5 1.27 (s, 2H); 1.69 -1.90 (m, 2H); 2.04 (t, 2H); 2.39-2.48 (m, 1H); 2.56 (t, 2H); 2.93 (d, 2H); 3.53 (s, 2H); 3.75 (s, 2H); 3.92 (s, 3H); 4.33 (t, 2H); 6.91 - 7.05 (m, 2H); 7.10 (d, 1H); 7.67 - 7.83 (m, 2H); 8.04 (s, 1H); 10.88 (s, 1H). Example 75 l-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-lyl} ethyl)-6,7-difluoroquinoxaIin-2(l/7)-one l-[2-(4-Aminopiperidin-l-yl)ethyl]-6,7-difluoroquinoxalm-2(l/i)-one (Intermediate 150,190 mg, 0.62 rnrnol), 2,3-dihydro[l,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO 2004/058144) (100 mg, 0.62 mmol), and sodium triacetoxy borohydride (390 mg, 1.90 mmol) were reacted as described according to Example 69. Chromatography on silica gel with 10% methanol in dichloromethane containing 0.25% ammonium hydroxide gave the free base of the product as an oil. The free base was taken up in dichloromethane (2 mL) and diluted with diethyl ether (10 mL). A solution of HC1 in diethyl ether (2M, 2.2 eq) was added. The resulting precipitate was collected by filtration to give 180 mg (55%) of the bis-hydrochloride salt of the product. MS (ES): 458 (MH+) for CaH^NjOs 'HNMR(D7CD 5 1.82 - 2.06 (m, 2H); 2.40 (d, 2H); 3.16 (t, 2H); 3.48-3.68 (m, 311); 3.89 (d, 2H); 4.27-4.38 (m, 4H); 4.39-4.49 (m, 2H); 4.63 (t, 2H); 7.15-7.28 (m, 1H); 7.44-7.61 (m, 1H); 7.69-7.85 (m, 1H); 8.10-8.28 (m, 2H). Intermediate 150: l-r2-f4-Aminopiperidin-l-vl')ethvl]-6.7-difluoroquinoxalin-2(l//)- one tert-Eutyl {1 -[2-(6,7-difluoro-2-oxoquinoxalin-1 (2#)-yl)ethyl]piperidin-4- yl}carbamate (Intermediate 151, 500 mg, 1.23 mmol) was reacted with trifluoroacetic acid in dichloromethane as described for Intermediate 140 to give 380 mg (quantitative) of the crude product as an oil. MS flBS): 309 (MH1) for Intermediate 151: tert-ButvI (142-('6.7-difluoro-2-oxoquinoxalin-l(2.flV ynetfayyipip6ridin-4-yUcarbamate 6,7-Difluoroquinoxalin-2(l//)-one (Intermediate 152, 1.0 g, 5.50 mmol) was deprotonated with sodium hydride (60% in oil, 0.26 g, 6.60 mmol) and alkylated with 2-{4- [(ter/-butoxycarbonyl)amino]piperidin-l-yl} ethyl methanesulfonate (Intermediate 6) (6.6 mmol) as described for Intermediate 2. Chromatography on silica gel with 5% toluene/ethyl acetate gave 500 mg (23%) of the product as a colorless solid, MS (ES): 409 (MH+) for €20^2^03 'HNMRfDMSQ-D6^ 5 1.10-1.45 (m, 11H); 1.54-1.75 (m, 2H); 1.90-2.13 (m, 2H); 2.52-2.59 (m, 2H); 2.86 (d, 2H); 3.16 (s, 1H); 4.28 (t, 2H); 6.75 (d, 1H); 7.81 (dd, 1H); 7.96 (dd, 1H); 8.25 (s, 1H). Intermediate 152: 6.7-Difluoroquinoxalin-2(l/in-one To a stirred solution of 4,5-difluorobenzene-l,2-diamine (4.7 g, 32.6 mmol) in ethanol (75 mL) was added ethyl oxoacetate (50 wt % in toluene, 13,3 mL, 65.3 mmol). The reaction was stirred at room temperature overnight. The resulting precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give 4.3 g (73%) of the product as a colorless solid. MS (ES): 183 (MH+) for CgH4F2N2O H NMR (DMSO-D6) 5 7.23 (dd, 1H); 7.93 (dd, 1H); 8.19 (s, 1H); 12.54 (s, 1H). Example 76 6-[({l-[2-(6,7-Difluoro-2-oxoquinoxalin-l(2iO-yl)ethyl]piperidin-4- yl}amino)methyl]-2#-pyrido[3,2-i][l,4]oxazin-3(4#)-one 1 -[2-(4-Aminopiperidin- 1 -yl)ethyl]-6 ,7-difluoroquinoxalin-2( 1 //)-one (Intermediate 150, 190 mg, 0.62 mmol), 3-oxo-3,4-dihydro-2//-pyrido[3,2-&][l,4]oxazine-6-carbaldehyde (WO 2004/058144) (1 10 mg, 0.62 mmol), and sodium triacetoxy borohydride (390 mg, 1.90 mmol) were reacted as described according to Example 69 to give 180 mg (62%) of the free base of the product as a colorless solid. MS (ES): 471 (MH) for CasKWy^Os 5 1.12-1.26 (m, 2H); 1.69-1.83 (m, 2H); 2.01 (t, 2H); 2.42 (s, 1H); 2.53 (t, 2H); 2.88 (d, 2H); 3.69 (s, 2H); 4.29 (t, 2H); 4.60 (s, 2H); 7.01 (d, 1H); 7.30 (d, 1H); 7.82 (dd, 1H); 7.97 (dd, 1H); 8.25 (s, 1H); 11.18 (s, 1H). Example 77 l-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-clpyridin-7-ylmethyl)amino]piperidin-lyl} ethyl)-7,8-difluoroquinoxalin-2(l//)-one l-[2-(4-Aminopiperidin-l-yl)ethyl]-7,8-difluoroquraoxalin-2(l/f)-one (Intermediate 153,130 mg, 0.42 mmol), 2>3-dihydro[l,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO 2004/058144) (70 mg, 0.42 mmol), and sodium triacetoxy borohydride (270 mg, 1.30 mmol) were reacted as described according to Example 71 to give 35 mg (16%) of the bishydrochloride salt of the product as a colorless solid. MS (ESV. 458 (MH+) for CzsHbFaNsOj 'HNMRfD2C» 5 1.89-2.02 (m, 2H); 2.43 (d, 2H); 3.18 (t, 2H); 3.52-3.64 (m, 3H); 3.88 (d, 2H); 4.29-4.34 (m, 4H); 4.38-4.43 (m, 2H); 4.71-4.77 (m, 2H); 7.17 (s, 1H); 7.27 - 7.38 (m, 1H); 7.62-7.69 (m, 1H); 8.15 (s, 2H). Intermediate 153: l-r2-(4-Aminopiperidin-l-vl')ethvn-7.8-difluoroquinQxalin-2(l/Jr)- pne tert-Butyl {1 -[2-(7,8-difluoro-2-oxoquinoxalin-1 (2#)-yl)ethyl]piperidin-4- yl}carbamate (Intermediate 154, 320 mg, 0.78 mmol) was reacted with trifluoroacetic acid in dichloromethane as described for Intermediate 140 to give 240 mg (quantitative) of the crude product as an oil. MS (ESY. 309 (MH+) for CisHigF^O Intermediate 154: tert-Butyl ll-r2-(7.8-difluoro-2-oxoquinoxalin-l(2/7V ynethyl]piperidin-4-yl)carbamate 7,8-Difluoroquinoxalin-2(l.ff)-one (Intermediate 155 - a mixture of regioisomers containing 30% 5,6-difluoroquinoxalin-2(l//)-one, 1.0 g, 5.50 mmol) was deprotonated with sodium hydride (60% in oil, 0.26 g, 6.60 mmol) and alkylated with 2-{4-[(tertbutoxycarbonyl) amino]piperidin-l-yl}ethyl methanesulfonate (Intermediate 6) (6.6 mmol) as described for Intermediate 2. Chromatography on silica gel with 70-100% ethyl acetate in hexanes gave 320 mg of the product as a colorless solid. MS fES): 409 (MH+) for €20^2^03 'HNMRfDMSO-Dei 5 1.30 (d, 2H); 1.37 (s, 911); 1.64 (d, 2H); 2.07 (t, 2H); 2.59 (t, 2H); 2.81 (d, 2H); 3.20 (s, 1H); 4.36 (t, 2H); 6.76 (d, 1H); 7.48 (td, 1H); 7.72 (ddd, 1H); 8.23 (s, 1H). Intermediate 155: 7.8-Difluoroquinoxalin-2(l/f)-one 3,4-Difluorobenzene-l,2-diamine (4.6 g, 31.6 mmol) and ethyl oxoacetate (50 wt % in toluene, 13.0 mL, 63.2 mmol) were reacted as described for Intermediate 152 to give 3.7 g of product as an off white solid, mixture with 30% of the regioisomer 5,6-difiuoroquinoxalin- 2(l.H)-one. The mixture was carried on to the next step. MS fES): 183 (MH) Example 78 6-[({l-[2-(7,8-Difluoro-2-oxoquinoxalin-l(2J2>yl)ethyl]piperidin-4- yl}amino)methyl]-2/f-pyrido[3,2-A)[l,4]oxazin-3(4/T)-one l-[2-(4-Aminopiperidin-l-yl)ethyl]-7,8-difluoroquinoxalin-2(l/f)-one (Intermediate 153, 130 mg, 0.42 mmol), 3-oxo-3,4-dmydro-2#-pyrido[3,2-Z>][l,4]oxazine-6-carbaldehyde (WO 2004/058144) (70 mg, 0.42 mmol), and sodium triacetoxy borohydride (270 mg, ] .30 mmol) were reacted as described for Example 69 to give 82 mg (41%) of the free base of the product. MS CBS): 471 (MH4) for Caal^NeCb lHNMRfDMSO-Dfl5 1.07-1.22 (m, 2H); 1.69 (d, 2H); 1.98 (t, 2H); 2.35 (s, IH); 2.52 (t, 2H); 2.76 (d, 2H); 3.63 (s, 2H); 4.30 (t, 2H); 4.54 (s, 2H); 6.95 (d, IH); 7.24 (d, IH); 7.35-7.47 (m, IH); 7.61-7.71 (m, IH); 8.17 (s, IH); 11.12 (s, IH). Example 79 6-[({l-[2-(6,7-Dimethoxy-2-oxoquinoxalin-l(2fl)-yl)ethyl]piperidin-4- yI}araino)methyl]-2#~pyrido[3,2-&][l,4]oxazin-3(4#)-one 1 -[2-(4-Aminopiperidin- 1 -yl)ethyl]-6,7-dimethoxyquinoxalin-2( l//)-one (Intermediate 156, 75 mg, 0.23 mmol), 3-oxo-3,4-dihydro-2#-pyrido[3,2-6][l,4]oxazine-6- carbaldehyde (WO 2004/058144) (40 mg, 0.23 mmol), and sodium triacetoxy borohydride (150 mg, 0.69 mmol) were reacted as described according to Example 69 to give 78 mg (68%) of the free base of the product as a colorless solid. MS (ES): 495 (MH4) for C2sH3oN605 'HNMRfDMSO-D6^ 5 1.06-1.38 (m, 2H); 1.65-1.85 (m, 2H); 1.95-2.13 (m, 2H); 2.29-2.42 (m, IH); 2.51-2.64 (m, 2H); 2.92 (d, 2H); 3.67 (s, 2H); 3.85 (s, 3H); 3.88-4.04 (m, 3H); 4.24-4.45 (m, 2H); 4.52-4.66 (m, 2H); 6.94-7.09 (m, 2H); 7.21-7.37 (m, 2H); 7.98-8.11 (m, 1H);1 1.06 -11.23 (m, IH). Intermediate 156: l-[2-(4-Aminopiperidin-l-yl)ethvl1-6j-dimethoxvquinoxalintert- Butyl { I - [2-(6,7-dimethoxy-2-oxoquinoxalin- 1 (2#)-yl)ethyl]piperidin-4- yljcarbamate (Intermediate 157, 100 mg, 0.23 mmol) was reacted with trifluoroacetic acid in dichloromethane as described for Intermediate 140 to give 75 mg (quantitative) of the crude product as an oil. ^: 333 (Mtf) for CnHaMOs Intermediate 157: tert-Butvl (l-r2-f6.7-dimethoxv-2-oxoquinoxalin-l('2//)- vl)ethvnpiperidin-4-vU carbamate 6,7-Dimethoxyquinoxalin-2(l/0-°ne (Intermediate 158, 540 mg, 2.60 mmol) was deprotonated with sodium hydride (60% in oil, 2.90 mmol) and alkylated with 2-{4~[(tertbutoxycarbonyl) arnino]piperidin-l-yl} ethyl methanesulfonate (Intermediate 6) (3.9 mmol) as described for Intermediate 2. Chromatography on silica gel with 20-50% acetone in hexanes gave 310 mg (28%) of the product as an off-white solid. MS (ES^: 433 (MH1) for Cxfk^Os 'HNMRfDMSO-Dei 8 1.25-1.39 (m, 11H); 1.63 (d, 2H); 1.98 - 2.12 (m, 2H); 2.57 (t, 2H); 2.92 (d, 2H); 3.19 (s, 1H); 3.84 (s, 3H); 3.95 (s, 3H); 4.35 (t, 2H); 6.75 (d, 1H); 7.04 (s, 1H); 7.31 (s, 1H); 8.05 (s, 1H). Intermediate 158: 6.7-Dimethoxyquinoxalin-2n/fl-one A mixture of l,2-dimethoxy-4,5-dinitrobenzene (5.7 g, 25.0 mmol) in ethanol/ acetic acid (140 mL, 1:1) was hydrogenated over palladium on carbon (10%, 1 g) at normal pressure and room temperature for 3 hours, then filtered through a pad of celite. The filtrate containing the crude diamine was treated with ethyl oxoacetate (50 wt % in toluene, 10 mL, 50 mmol) and the reaction was stirred at room temperature overnight. The resulting precipitate was collected by filtration. This material was suspended in a mixture of methanol/dichloromethane and solvent was removed under reduced pressure to remove traces of acetic acid to give 2.0 g (38%) of product as a solid. MS (ESV. 207 (MH) for CioHioN2O3 'HNMRfDMSO-D6) 5 3.81-3.83 (m, 3H); 3.83-3.85 (m, 3H); 6.78-6.81 (m, 1H); 7.25-7.27 (m, 1H); 7.97-8.01 (m, 1H); 12.26-12.34 (m, 1H). Example 80 6-[({l-[2-(7-Methoxy-3-methyl-2-oxoquinoxaIin-l(2fl)-yl)ethyI]piperidin-4- yl}amino)methyl]-2Jy-pyrido[3,2-)[l,4]oxazin-3(4/0-one l-[2-(4-Aminopiperidin-l-yl)ethyl]-7-methoxy-3-methylquinoxalin-2(l//)-°ne (Intermediate 159, 75 mg, 0.24 mmol), 3-oxo-3,4-dihydro-2fl-pyrido[3,2-&][l,4]oxazine-6- carbaldehyde (WO 2004/058144) (42 mg, 0.24 mmol), and sodium triacetoxy borohydride (150 mg, 0.72 mmol) were reacted as described according to Example 69 to give 80 mg (73% yield) of the free base of the product. MS fESV 479 (MB1) for QwHjoNeC^ 'HNMRrDMSO-D61 5 1.23 (q, 2H); 1.77 (d, 2H); 2.04 (t, 2H); 2.31 - 2.45 (m, 4H); 2.51 - 2.61 (m, 2H); 2.91 (d, 2H); 3.68 (s, 2H); 3.89 (s, 3H); 4.31 (t, 2H); 4.60 (s, 2H); 6.85- 7.10 (m, 3H); 7.29 (d, 1H); 7.59 - 7.73 (m, 1H); 11.17 (s, 1H). Intermediate 159: l-r2-(4-Aminopiperidin-l-vl)ethvl1-7-methoxv-3- methylquinoxalin-2(l//)-one tert-Butyl {l-[2-(7-methoxy-3-methyl-2-oxoquinoxalin-l(2//)-yl)ethyl]piperidin-4- yl}carbamate (Intermediate 160, 100 mg, 0.24 mmol) was reacted with trifluoroacetic acid in dichloromethane as described for Intermediate 140 to give 75 mg (99% yield) of the crude product as an oil. MS (ES): 317 (MH+) for Ci7H24N402 Intermediate 160: tert-Butvl {l-r2-(7-methoxy-3-methvl-2-oxoquinoxalin-l(2J7)- yl)ethyl]piperidin-4-yll carbamate 7-Methoxy-3-methylquinoxalin-2(l//)-one (Intermediate 161, 500 mg, 2.60 mmol) was deprotonated with sodium hydride (60% in oil, 2.90 mmol) and alkylated with 2-{4- [(/ert-butoxycarbonyl)amino]piperidin-l-yl}ethyl methanesulfonate (Intermediate 6) (3.9 mmol) as described for Intermediate 2. Chromatography on silica gel with 70% ethyl acetate in hexanes, followed by a second chromatography on silica gel with 20% acetone in hexanes gave 110 mg (10%) of the product as a colorless solid. MS (ESY 417 (MH) for CaEfezN^ 'HNMRfDMSO-D6) 8 1.21-1.46 (m, 11H); 1.65 (d, 2H); 2.05 (t, 2H); 2.38 (s, 3H); 2.51-2.59 (m, 2H); 2.92 (d, 2H); 3.18 (s, 1H); 3.90 (s, 3H); 4.31 (t, 2H); 6.77 (d, 1H); 6.91- 7.00 (m, 2H); 7.58-7.73 (m, 1H). Intermediate 161: 7-Methoxy-3-methvlauinoxalin-2n.fcn-one A suspension of 3-chloro-6-methoxy-2-methylquinoxaline (Intermediate 162, 1.5 g, 7.21 mmol) in 5M HC1 (30 mL) was heated to 1 10 °C for 1 hour. The reaction mixture was neutralized with saturated sodium carbonate solution, diluted with water and extracted with ethyl acetate (3 times). The combined organic phases were dried over magnesium sulfate and concentrated to a small volume under reduced pressure. The precipitate was collected by filtration to give 1.0 g (71%) of product as an off-white solid. MS (ES\. 191 (MH4) for CjoHidNjCfc 'HNMR(DMSO-D6) 8 2.34 (s, 3H); 3.80 (s, 3H); 6.73 (d, 1H); 6.83-6.89 (m, 1H); 7.59 (d,lH); 12.19 (s,lH). Intermediate 162: 3-Chloro-6-methoxy-2-methvlquinoxaline A suspension of 4-methoxybenzene-l,2-diamine (5.0 g, 36.2 mmol) in water (100 mL) was heated under sonication for 5 minutes. 2-Oxopropanoic acid (2.5 mL, 36.2 mmol) was added and it was stirred for 2 hours. The precipitate was collected by filtration and dried under vacuum and heating, over phosphorus pentoxide, to give 3.0 g of a mixture of the product together with 6-methoxy-3-methylquinoxalin-2(l.ff)-one. This mixture was suspended in phosphorus oxychloride (30 mL) and heated to 1 15 °C for 30 min. The mixture was quenched on ice and neutralized with solid sodium carbonate. The aqueous mixture was extracted with ethyl acetate (4 times). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated to dryness under reduced pressure. Chromatography on silica gel with 5% ethyl acetate in hexanes and isolation of the higher migrating regioisomer gave 0.9 g of product as an off-white solid. MS (BSV 209 (MH+) for Ci0H9ClN20 'HNMRfDMSO-Det 8 2.71 (s, 3H); 3.93 (s, 3H); 7.39 (d, 1H); 7.49 (dd, 1H); 7.95 Example 81 l.(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridm-7-ylmethyl)amino]piperidin-lyl} ethyl)qumolin-2(lfl)-°ne l-[2-(4-Aminopiperidin-l-yl)ethyl]quinolin-2(l#)-one (Intermediate 1.63, 170 mg crude, 0.63 mmol), 2,3-dihydro[l,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO 2004/058144) (100 mg, 0.63 mmol), and sodium triacetoxy borohydride (400 mg, 1.90 mmol) were reacted as described according to Example 69 to give the free base of the product as an oil. The free base was taken up in dichloromethane (2 mL) and ethanol (8 mL) and treated with a solution of 4M HCl/dioxane (2 eq). The resulting precipitate was collected by filtration to give 188 mg (60%) of the bis-hydrochloride salt of the product as a colorless solid. MS (ES\ 421 (MHT1) for QwHjMOs 6 1.86 - 2.06 (m, 2H); 2.36 - 2.54 (m, 2H); 3.06 - 3.27 (m, 2H); 3.46 - 3.70 (m, 3H); 3.89 (d, 2H); 4.29 - 4.42 (m, 4H); 4.42 - 4.53 (m, 2H); 4.65 - 4.70 (m, 2H); 6.66 (d, 1H); 7.29 (s, 1H); 7.34 (t, 1H); 7.47 (d, 1H); 7.59 - 7.78 (m, 2H); 7.95 (d, 1H); 8.22 (s, 1H). Intermediate 163 : 1 -r2-(4-Aminopiperidin- 1 -yr)ethvl]quinolin-2( IfD-one To a solution of tert-butyl {l-[2-(2-oxoquinolin-l(2#)-yl)ethyl]piperidin-4- yl}carbamate (Intermediate 164, 220 mg, 0.59 mmol) in dioxanc (5 mL) was added a solution of HC1 in dioxane (4M, 9 mL), followed by water (1 mL) and it was stirred at room temperature over night. An addition 5 mL of HCl/dioxane was added to the reaction. After 1 hr, the reaction was concentrated to dryness. The crude product was partitioned between 10% methanol/dichloromethane (50 mL) and 1M sodium hydroxide (50 mL). The aqueous phase was back extracted with 10% methanol/dichloromethane (50 mL) and the combined organic phases were washed with brine, dried over sodium sulfate and concentrated under reduced pressure to give 170 mg (quantitative) of the crude product as an oil. MS (ES\. 212 (MH+) for Ci6H2iN30 Intermediate 164: tert-Butvl n-r2-(2-oxoquinolin-l(2ffl-vl)ethvl1piperidin-4- vDcarbamate Quinolin-2(l/:/)-one (250 mg, 1.7 mmol) was deprotonated with sodium hydride (60% in oil, 70 mg, 1.7 mmol) and alkylated with 2-{4-[(/er/-butoxycarbonyl)amino]piperidin-lyl} ethyl methanesulfonate (Intermediate 6) (1.7 mmol) as described for Intermediate 141. Chromatography on silica gel with 0-5% methanol in dichloromethane gave 220 mg (35%) of product as a colorless solid. MS (ESI: 372 (MH) for C2,H29N3O3 Example 82 l-(2-{4-[(2,3-Daiydro[l,4]dioxinoI2,3-c]pyridin-7-ylmethyl)amino]piperidin-lyI} ethyl)qiiinolin-4(lH)-one l-[2-(4-Aminopiperidin-l-yl)ethyl]quinolin-4(l//)-one (Intermediate 165,180 mg crude, 0.66 mmol), 2,3-dihydro[l,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO 2004/058144) (110 mg, 0.66 mmol), and sodium triacetoxy borohydride (420 mg, 2.0 mmol) were reacted as described according to Example 81 to give the bis-hydrochloride salt of the product 53 mg (16%) as a colorless solid. MS fESV 421 (Mtf) for CwKMtyOa 'HNMR(D2C» 5 1.90-2.13 (m, 2H); 2.44 (d, 2H); 3.22 (t, 2H); 3.58-3.70 (m, 3H); 3.77 (d, 2H); 4.33-4.40 (m, 2H); 4.42 (s, 2H); 4.46 - 4.53 (m, 2H); 4.75-4.86 (m, 2H); 6.47 (d, 1H); 7.36 (s, 1H); 7.51 (t, 1H); 7.68 (d, 1H); 7.77-7.89 (m, 1H); 8.11-8.21 (m, 2H); 8.25 (s, 1H). Intermediate 165: l-r2-(4-Aminopiperidin-l-yl')ethyl]quinolin-4(']//)-one ter/-Butyl (l-[2-(4-oxoquinolin-l(4//)-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 166,480 mg crude, 1.29 mmol) was reacted with 4M HCl/dioxane in dioxane as described for Intermediate 163 to give 180 mg (51%) of the crude product as an oil. MS (ES^ 272 (MH4) for Ci6H2iN30 Intermediate 166: tert-Butvl (l-\|'2-('4-oxoquinolin-l(4^D-vl')ethyl]piperidin-4- vncarbamate Quinolin-4(l//)-one (250 mg, 1.7 mmol) was deprotonated with sodium hydride (60% in oil, 70 mg, 1.7 mmol) and alkylated with 2-{4-[(tert-butoxycarbonyl)amino]piperidin-] - yl} ethyl methanesulfonate (Intermediate 6) (1.7 mmol) as described for Intermediate 141. The precipitate formed in the reaction mixture was collected by filtration to give 480 mg (76 %) of product as a colorless solid. MS (ESV. 372 (MH+) for Example 83 Cis(±)6-[({l-[2-(5,7-difluoro-2-oxoquinoUn-l(2fl)-yOethyl]-3-methoxypiperidin-4- yl} amino)methyl]-2//-pyrido [3,2-6] [1,4] oxazin-3(4J?)-one Cis(±)l-[2-(4-amino-3-methoxypiperidin-l-yl)ethyl]-5,7-difluorocluinoIin-2(l//)-one (Intermediate 167, 140 mg, 0.42 mmol), 3-oxo-3,4-dihydro-2/;/'-pyrido[3J2-i][l,4]oxazine-6- carbaldehyde (WO 2004/058144) (75 mg, 0.42 mmol) and sodium triacetoxy borohydride (250 mg, 1.20 mmol) were reacted as described according to Example 69. Chromatography on silica gel with 5% methanol in dichloromethane containing 0.50% ammonium hydroxide gave 120 mg (57%) of the free base of the product. MS test: 500 (MH+) for CwIfcvFjNjOA 'HNMRfCDCl^ 5 1.66-1.87 (m, 2H); 2.22-2.44 (m, 2H); 2.55-2.83 (m, 3H); 2.93 (d, 1H); 3.14 (d, 1H); 3.34-3.45 (m, 3H); 3.47-3.56 (m, 1H); 3.80 - 3.86 (m, 2H); 4.25-4.49 (m, 2H); 4.63 (s, 2H); 6.65 (d, 1H); 6.67-6.77 (m, 1H); 6.99 (t, 2H); 7.21 (d, 1H); 7.88 (d, 1H). Intermediate 167: Cisf±')l-r2-('4-amino-3-methoxvpiperidin-l-vl')ethvl1-5.7- difluoroquinolin-2f l//Vone Cis(±)l-{2-[4-(dibenzylamino)-3-methoxypiperidin-l-yl]ethyl}-5,7-difluoroquinolin- 2(l/i)-one (Intermediate 168, 240 mg, 0.46 mmol) was hydrogenated in methanol/ acetonitrile (10 mL, 9:1) over palladium hydroxide on carbon (20%, 120 mg) at room temperature and normal pressure for 4 hours. The reaction mixture was filtered through celite and the filtrate was concentrated to dryness under reduced pressure to give 140 mg (90%) of crude product. This was used without further purification. MS (ES): 338 (MH+) for Intermediate 168: Cis(±M-(2-r4-rdibenzvlamino)-3-methoxvpiperidin-l-vHethvU- 5.7-difluoroquinolin-2nJ:f)-one A solution of 5,7-difluoroquinolin-2(l#)-one (Intermediate 25, 300 mg, 1.70 mmol) in dry DMF (10 mL) was treated with sodium hydride (60% in oil, 80 mg, 2.00 mmol) with cooling in an ice bath. The reaction was stirred at room temperature for 90 min. The reaction was again cooled in an ice bath and treated with a solution of cis(±)2-[4-(dibenzylamino)-3- methoxypiperidin-l-yl]ethyl methanesulfonate in dry DMF (10 mL) (Intermediate 169, 1.2 eq, 2.00 mmol). The reaction was stirred at room temperature overnight. It was quenched with a small amount of water and concentrated to dryness. Residual DMF was removed by coIk evaporating with toluene and the residue was partitioned between ethyl acetate (50 mL) and water (20 mL). The biphasic mixture was filtered, the phases separated and the aqueous phase was back extracted two times with ethyl acetate (2x 50 mL). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated to dryness. Chromatography on silica gel with a gradient of 10-20% acetone in hexanes gave 240 mg (27%) of product as a colorless solid. MS (ESV 518 (MH4) for CaiH^NsOa 'HNMRfDMSO-Det 8 1.49-1.60 (m, 1H); 1.70-1.84 (m, 1H); 1.92-2.06 (m, 2H); 2.37-2.47 (m, 2H); 2.99-3.12 (m, 1H); 3.16-3.22 (m, 1H); 3.25 (s, 3H); 3.30-3.40 (m, 1H); 3.56 (s, 1H); 3.59-3.86 (m, 4H); 4.28 (t, 2H); 6.62 (d, 1H); 7.15-7.24 (m, 3H); 7.24-7.41 (m, 9H);7.96(d,lH). Intermediate 169: Cis^2-r4-fdibenzvlammoV3-methoxvDroeridiri- 1-vllethvl methanesulfonate Cis(±)2-[4-(dibenzylamino)-3-methoxypiperidni-l-yl]ethanol (Intermediate 170, 740 mg, 2.1 mmol) was reacted with methanesulfonyl chloride (0.20 mL, 2.5 mmol) in the presence of triethylamine (0.41 mL, 2.9 mmol) as described for Intermediate 6. The crude product was presumed to be unstable and was used without further purification directly for the next step. Intermediate 170: Cis(±^2-r4-fdibenzvlaminoV3-memoxvpiperidin-l-vllethanol A mixture of cis(±)^V-diben2yl-3-methoxypiperidin-4-amine (1.7 g, 5.5 mmol) (WO 2005/068461), bromoethanol (0.5 mL, 7.1 mmol), and//^/-diisopropylethylamine (1.4 mL, 8.3 mmol) were reacted as described for Intermediate 37, but heating for one hour at 70°C. Chromatography on silica gel with 5% methanol in dichloromethane containing 0.25% ammonium hydroxide gave 1.3 g (68%) of product as a colorless solid. MS fESV 355 (NOT1) for CaHsoNjOz >HNMRfDMSO-D6>> 8 1.44 -1.58 (m, 1H); 1.64 (d, 1H); 1.79 - 2.08 (m, 2H); 2.32 (t, 2H); 2.36 - 2.45 (m, 1H); 2.88 (d, 1H); 3.13 (d, 1H); 3.30 (s, 3H); 3.40 - 3.49 (m, 2H); 3.56 (s, 1H); 3.59 - 3.87 (m, 4H); 4.34 (s, 1H); 7.11 - 7.24 (m, 2H); 7.24 - 7.40 (m, 8H) Example 84 7-Fluoro-2-oxo-l-[2-(4-{[(3-oxo-3,4-dihydro-2^-pyrido[3,2-6][l,4]oxazin-6- yl)raethylJamino}piperidin-l-yl)ethyl]-l,2-dihydroquinoline-5-carbonitrile and Example 85 5-Fluoro-2-oxo-l-[2-(4-{[(3-oxo-3,4-dihydro-2^-pyrido[3,2-/;][l,4]oxazin-6- yl)tnethyl]amino}piperidin-l-yl)ethyl]-l,2-dihydroquinolinc-7-carbonitrile A mixture of the regioisomers l-[2-(4-aminopipcridin-l-yl)ethyl]-7-fluoro-2-oxo-l,2- dihydroquinoline-5-carbonitrile (major isomer) and l-[2-(4-aminopiperidin-l-yl)ethyl]-5- fluoro-2-oxo-l,2-dihydroquinoline-7-carbonitrile (minor isomer) (Intermediates 171 and 172,120 mg, 0.38 mmol), 3-oxo-3,4-dihydro-2#-pyrido[3,2-6][l,4]oxazine-6-carbaldehyde (WO 2004/058144) (68 mg, 0.38 mmol) and sodium triacetoxy borohydride (230 mg, 1.1 mmol) were reacted as described according to Example 69. Chromatography on silica gel with 10% methanol in dichloromethane containing 0.5% ammonium hydroxide followed by reverse phase HPLC on a 50x250 mm ODS AQ column eluting with an isocratic gradient of 15% acetonitrile in water containing 0.1% TFA to give the bis TFA salts of Example 84 (68 mg) and Example 85 (21 mg), both as colorless solids. Example 84: MS CBS): 477 (MH) for Cas^sFNeOa 'H NMR (DMSO-D6) 8 1.09 - 1.27 (m, 2H); 1.67 - 1.83 (m, 2H); 2.00 (t, 2H); 2.31 - 2.44 (m, IH); 2.51 - 2.55 (m, 2H); 2.87 (d, 2H); 3.67 (s, 2H); 4.33 (t, 2H); 4.53 - 4.64 (m, 2H); 6.81 (d, IH); 7.00 (d, IH); 7.28 (d, IH); 7.78 - 7.92 (m, 211); 7.98 (d, III); 11.16 (s, IH). Example 85: MS CES): 477 (MH) for CijHjsFNeOs 'HNMRfDMSO-De) 8 1.12 - 1.30 (m, 2H); 1.69 - 1.83 (m, 2H); 1.95 - 2.10 (m, 2H); 2.33 - 2.46 (m, IH); 2.51 - 2.57 (m, 2H); 2.89 (d, 2H); 3.68 (s, 2H); 4.31 - 4.43 (m, 2H); 4,57 - 4.64 (m, 2H); 6.84 (d, IH); 7.01 (d, III); 7.29 (d, IH); 7.70 (d, IH); 7.99 (s, 111); 8.06 (d, 1.17(s, IH). Intermediate 171: 1 -r2-(4-Aminopiperidin-1 -vr)ethvn-7-fluoro-2-oxo-1,2- dihvdroquinoline-5-carbonitrile (major isomer) and Intermediate 172: l-[2-f4-Aminopiperidin-l-vnethyl]-5-fluoro-2-oxo-1.2- dihvdroquinoline-7-carbonitriIe A mixture of tert-butyl {l-[2-(5-cyano-7-fluoro-2-oxoquinolin-l(2#)- yl)ethyl]piperidin-4-yl}carbaraate and tert-butyl {l-[2-(7-cyano-5-fluoro-2-oxoquinolinl( 2#)-yl)ethyl]piperidin-4-yl} carbamate (Intermediates 173 and 174, 170 mg, 0.41 mmol) was reacted with trifluoroacetic acid in dichloromethane as described for Intermediate 140 to give 120 mg (92% yield) of the mixture of regioisomers as an oil. This mixture was carried on without further purification to the next step. MS (ES): 315 (MH+) for Ci7Hi9FN40 Intermediate 173: tert-Butvl ll-r2-(5-cvano-7-fluoro-2-oxoquinolin-l(2fflvl) ethyl]piperidin-4-yl} carbamate and Intermediate 174: tert-Butyl (l-r2-(7-cyano-5-fluoro-2-oxoquinolip-l('2/-/)- vl)ethyl]piperidin-4-vncarbamate A mixture of tert-butyl {l-[2-(5-bromo-7-fluoro-2-oxoquinolin-l(2//)- yl)ethyl]piperidin-4-yl}carbamate and tert-buty\ {l-[2-(7-bromo-5-fluoro-2-oxoquinolinl( 2/i)-yi)ethyl]piperidin-4-yl}carbamate (Intermediates 175 and 176, 460 mg, 0.98 mmol) was reacted with potassium cyanide (96 mg, 1.5 mmol), tributyl tin chloride (14 uL/mL in heptane, 0.90 jiL, 0.003 mmol), 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (XANTPHOS) (3.0 mg, 0.005 mmol) and tris(dibenzylideneacetone)dipalladium (0) (5.0 mg, 0.005 mmol) as described for Intermediate 15. Chromatography on silica gel with acetone/ hexanes (1:4) gave 170 mg of the mixture of regioisomers. This mixture was carried on directly to the next step. MS CBS): 415 (MH+) for Intermediate 175: tert-Butvl n-[2-C5-bromo-7-fluoro-2-oxoquinplin-l(2/f)- yl)ethyl]piperidin-4-yl)carbamate and Intermediate 176: tert-Butvl IH2-f7-bromo-5-fluoro-2-oxoquinolin-l(2f/); yl)ethyl1piperidin-4-vl)carbamate A mixture of 5-bromo-7-fluoroquinolin-2(l.f/)-one and 7-bromo-5-fluoroquinolin- 2(l//)-one (Intermediate 177 and 178, 3.0 g, 9.4 mmol) was reacted with sodium hydride (60% in oil, 0.20 g, 5.0 mmol) and 2-{4-[(/erC-butoxycarbonyl)amino]piperidin-l-yl}ethyl methanesulfonate (Intermediate 6, 9.4 mmol) as described for Intermediate 141. Chromatography on silica gel with a gradient of 50-75% ethyl acetate in hexanes gave 0.63 g (33%) of the regioisomeric product mixture, which was carried on without further purification to the next step. MS (ES\. 468, 470 (MET) for Intermediate 177: 5-Bromo-7-fluoroquinolin-2(l/f)-one and Intermediate 178: 7-Bromo-5-fluoroquinolin-2(l//)-one The compounds were prepared from (2£)-AL(3-bromo-5-fluorophenyl)-3- phenylacrylamide (Intermediate 179, 3.0 g, 9.4 mmol) and aluminium trichloride (6.2 g, 46.9 mmol) as described for Intermediate 17, but the reaction mixture was heated to 90 °C for 30 min, to give 1.5 g of 3:1 mixture of 5-Bromo-7-fluoroquinolin-2(l//)-onc and 7-bromo-5- fluoroquinolin-2(l/:/)-one. This mixture was carried on to the next step without further purification. MS (RS): 242, 244 (MH1) for C9H5BrFNO Intermediate 179: (2£r)-JV-(3-Bromo-5-fluorophenyn-3-phenvlacrvlamide The compound was prepared from 3-bromo-5-fluoroaniline (Intermediate 180, 5.3 g, 27.9 mmol) and cinnamoylchloride (5.6 g, 33.5 mmol) in the presence of 2,6-lutidine (5.0 mL, 41 .9 mmol) as described for Intermediate 18 to give the product as a colorless solid, 7.6 g (85% yield). MS (BS): 320, 322 (MH+) for CuHnBrFNO 'HNMRfDMSO-Pe) 56.77 (d, 1H); 7.18 - 7.30 (m, Hi); 7.40 - 7.52 (m, 3H); 7.55 - 7.70 (m, 4H); 7.75 (s, 1H); 10.56 (s, 1H). Intermediate 180: 3-Bromo-S-fluoroaniline To a solution of Af-(3-bromo-5-fluorophenyl)acetamide (Intermediate 181, 8.7 g, 37.4 mmol) in ethanol (30 mL) was added concentrated hydrochloric acid (80 mL). The reaction was heated to 100 °C for 1 hr. It was cooled to room temperature and neutralized with 5N sodium hydroxide. The crude product was extracted with ethyl acetate (2x 100 mL), the combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated to dryness. Chromatography on silica gel with a gradient of 5-10% ethyl acetate in hexanes gave 5.3 g (75%) of the product as a yellow oil. MS (ESI: 190, 192 (MH+) for C6H5BrFN 'H NMR (DMSO-D615 5.46 - 6.00 (m, 2H); 6.24 - 6.37 (m, 1H); 6.44 - 6.53 (m, III); 6.54 - 6.61 (m, 1H). Intermediate 181: Af-C3-Bromo-5-fluoroprienyl)acetarnidc A mixture of acetamide (2.8 g, 47.2 mmol), palladium acetate (0.50 g, 0.80 mmol), XANTPHOS (0.68 g, 1.2 mmol) and cesium carbonate (18 g, 55.2 mmol) was degassed and purged with nitrogen twice. Dry dioxane (50 mL) was added followed by l,3-dibromo-5- fluorobenzene (10 g, 39.4 mmol). The reaction was heated to 105 °C overnight and then allowed to cool to room temperature. Dichloromethane was added and the mixture was stirred vigorously for 1 hr. The mixture was filtered. The filtrate was concentrated to dryness. Chromatography on silica gel with 25% ethyl acetate in hexanes gave 4.0 g (44%) of the product as a colorless solid. MS (ESV. 232, 234 (Mil1') for C8H7BrFNO 1HNMR(T)MSO-D6) 8 2.01 - 2.13 (m, 311); 7.13 - 7.24 (m, 111); 7.42 - 7.54 (m, I I I ) ; 7.57 - 7.67 (m, 1H); 10.22 - 10.35 (m, 1H). Example 86 7-Fluoro-l-[2-(4-{[(2-oxo-l,2-dihydroquinolin-3-yI)methyI]amino}piperidin-lyl) ethyl] quinoxalin-2(l//)-one A mixture of l-[2-(4-aminopiperidin-l-yl)ethyl]-7-fluoroqinnoxalin-2(ljy)-onc (Intermediate 140, 130 mg, 0.448 mmol), 2-oxo-l,2-dihydroquinolinc-3-carbaldehyde (65 mg, 0.448 mmol) and 3A molecular sieves (100 mg) in methanol (6.0mL) was heated at reflux for 2.5 hours under nitrogen atmosphere. It was cooled to 0°C and sodium triacctoxy borohydride (189.5 mg, 0.996 mmol) was added and the mixture was allowed to warm to room temperature and stirred overnight. The mixture was filtered and purified through silica gel plug (eluting with 15% methanol in methylene chloride) to give title compound (71 mg). MS fES); 448.52 (MH) for C25H26FN5O2 'HNMRrDMSO-D6) 5 1.13 -1.32 (m, 2H); 1.79 (d, 2H); 2.02 (t, 2H); 2.35 - 2.45 (m, IH); 2.52 - 2.59 (m, 2H); 2.90 (d, 2H); 3.61 (s, 2H); 4.27 (t, 2H); 7.15 (t, IH); 7.24 - 7.33 (m, 2H); 7.43 (t, IH); 7.51 (d, IH); 7.63 (d, IH); 7.79 - 7.92 (m, 2H); 8.17 (s, IH). Examples 87-96 The following compounds were synthesized following the procedure described for Example 86, except the compounds were purified by reverse phase HPLC with methanol/ water, containing 0.1% TFA to give the TFA salts of the final products. Ex 87 88 Compound l-[2-(4-{[(2,2-Dimethyl- 3,4-dihydro-2#- chromen-6-yl)methyl] amino}piperidin-lyl) ethyl]-5,7-difluoro quinolin-2(l//)-one l-[2-(4-{[(l,3-Dimethyl- 2-oxo-2,3 -dihydro- 1 Hbenzimidazol- 5-yl) methyl]amino}piperidinl- yl)ethyl]-5,7- difluoroquinolin-2(l H)- one 'H NMR (DMSO-D6) 8 ppm 1. 27 (s,6H); 1.64-1. 89 (m,4H); 2.21 - 2.39 (m, 2H); 2.73 (t, 2H); 2.95 - 3.18 (m, 2H); 3.80 (s, 2H); 4.08 (s, 2H); 4.53 (s, 211); 6.67 (d, IH); 6.76 (d,lH); 7.19 (d, IH); 7.24 (s, IH); 7.31 (t, IH); 7.43 (d, IH); 8.03 (d, IH); 9.02 (s, 2H); 9.75 (s, IH) 1. 80 (s,2H); 2.34 (s,2H); 3.01 - 3.18 (m,2H); 3.45 (s, 6H); 3.80 (s, 2H); 4.24 (s, 2H); 4.53 (s, 2H); 6.67 (d, 1 H); 7.22 (s,2H); 7.25- 7.36 (m, 2H); 7.43 (d, IH); 8.03 (d, lH);9.18(s, 2H) ES 482 (MH)+ 482 (MII)+ Aldehyde 2,2-dimethyl chromane-6- carbaldehyde 1,3-dirnethyl- 2-oxo-2,3- dihydro-lf/- benzirnidazolc; -5- carbaldchydc Ex 89 90 91 92 Compound 5,7-Difluoro-l-(2~{4- [(5,6,7,8-tetrahydronaphthalen- 2-ylmethyl) amino]piperidin- 1 -yl} ethyl)quinolin-2( 1 H)-onc 5,7-Difluoro-l-[2-(4- {[(6-fluoro-4//-l,3- benzodioxin-8-yl)methyl] amino} piperidin- 1 -yl) ethyl]quinolin-2(l//)-one 5,7-Difluoro-l-(2-{4- [(l/Wndol-6-yImethyl) amino]piperidin- 1 - yl} ethyl)quinolin-2( 1 H)- one l-(2-{4-[(2,3-Dihydro- 17/-inden-5-ylmethyl) amino]piperidin-l - yl}etb.yl)-5,7- difluoroquinolin-2( 1 //)- one 'H NMR (DMSO-D6) 5 ppm 1. 72 (s,4H); 1.77-1. 92 (m, 2H); 2.32 (s, 2H); 2.71 (s, 4H); 3.09 (s, 2H); 3.58 (s, 2H); 3.79 (s, 2H); 4.12 (s, 2H); 4.54 (s, 2H); 6.66 (d, lH);7.07-7.14(ra, IH); 7.20 (s, 2H); 7.30 (t, IH); 7.43 (d, IH); 8.02 (d, IH); 9.23 (s, 2H) 1.84 (d, 2H); 2.33 (s, 2H); 3.09 (s, 2H); 3.29 - 3.44 (m, 2H); 3.80 (s, 2H);4.16(s,2H);4.54(s, 2H); 4.91 (s, 2H); 5.32 (s, 2H); 6.66 (d, IH); 7.01- 7.14 (m, 1H);7.19- 7.34 (m,2H); 7.43 (d,lH); 8.01 (d, IH); 9.35 (s, 2H) 1.85 (d, 2H); 2.35 (s, 2H); 3.09 (s, 2H);3.31 (s, 2H); 3.80 (s, 2H); 4.30 (s, 2H); 4.54 (s, 2H); 6.45 (s, HI); 6.66 (d, III); 7.13 (d, IH); 7.29 (t, IH); 7.42 (s, 2H); 7.50 - 7.68 (m,2H); 8.0 1 (d, IH); 9.22 (s,2H); 11.39(s, III) 1.73 - 1.89 (m, 2H); 1.94-2.09 (m, 211); 2.22 - 2.41 (m, 2H); 2.86 (t, 4H); 3.28 (s,2H); 3.43 -3.54 (m, 2H); 3.78 (s, 211); 4.16 (s, 2H); 4.53 (s, 2H); 6.67 (d, IH); 7.20-7.31(111, 311); 7.37 (s, Hi); 7.42 (d, IH); 8.02 (d, IH); 9.15 (s, 2H) ES 452 (MH)+ 474 (MH)+ 437 (MH)+ 438 (Mil)' Aldehyde 5,6,7,8- tetrahydronaphthalene- 2- carbaldehydc 6-fluoro-4//- 1,3- benzoclioxine- 8- carbaldehyde l//-indolc-6- carbaldehydc iI indane-5- carbaldehyde 4 $-3 Ex 93 94 95 96 Compound 5,7-Difluoro-l-[2-(4- {[(1-methyl- 1/7-1,2,3- benzotriazol-5-yl)methyl] amino} piped din- 1- yl)ethyl]quinolin-2(l//)- one 5,7-Difluoro-l-(2-{4- [(ljy-indol-5-ylmethyl) amino]piperidin-lyl} ethyl)quinolin-2(l//)- one 5,7-Difluoro-l-[2-(4- { [(4-methyl-3 ,4-dihydro- 2H-1 ,4-benzoxazin-7-yl) methyl]amino} piperidinl- yl)ethyl]quinolin- 2(l//)-one l-(2-{4-[(2,l,3- Benzoxadiazol-5- ylraethyl)amino] piperidin- 1 -yl} ethy l)-7- fluoroquinoxalin-2 ( 1 II)- one 1H NMR (DMSO-D6) 8 ppm 1. 72-1. 95 (m,2H); 2.35 (s,2H); 2.99- 3.18 (m, 211); 3.31 (s, 2H); 3.79 (s, 2H); 4.32 (s, 3H); 4.41 (s, 2H); 4.54 (s, 2H); 6.66 (d, IH); 7.29 (t, IH); 7.42 (d, IH); 7.69 (d, IH); 7.94 (d,!H); 8.02 (d, IH); 8.23 (s, IH); 9.43 (s, 2H) 1.80(s,2H);2.36(s,2H);3.11 (s, 2H); 3.40 (s, 2H); 3.80 (s, 2H); 4.26 (s, 2H); 4.52 (s, 2H); 6.47 (s, IH); 6.67 (d, IH); 7.21 (d, IH); 7.3 l(t,!H); 7.37- 7.52 (m,3H); 7.70 (s, IH); 8.03 (d, IH); 9.04 (s, IH NMR (DMSO-D6) 8 ppm 1 .73 (s, 2H); 2.30 (s, 211); 2.83 (s, 3H); 2.97-3.15(m,2H);3.24(s,2H); 3.30 - 3.38 (m, 2H); 3.79 (s, 2H); 4.03 (s, 2H); 4.22 (s, 2H); 4.53 (s, 2H); 6.63 - 6.75 (m, 211); 6.85 (s, IH); 6.90 (d, IH); 7.31 (t, IH); 7.43 (d, IH); 8.04 (d, IH); 8.90 (s, IH) 1.13-1.29(m,2H); 1.78(d,2H); 1. 95 - 2.07 (m,2H); 2.3 1-2.43 (m, IH); 2.51- 2.58 (m,2H); 2.89 (d, 2H); 3.82 (s, 2H); 4.27 (t; 2H); 7.23 (td, 1 H); 7.5 1 (dd, IH); 7.58 (d, IH); 7.80 - 7.89 (m, 2H); 7.96 (d, 1H);8.18(S,1H) ES 453 (MH)+ 437 (MH)+ 469 (MH)H 423 (MH)+ Aldehyde 1 -methyl- IH- 1,2,3- benzotriazolc- 5- carbaldehyde l/f-indole-5- carbaldehyde 4-methy 1-3,4- dihydro-2//- 1,4- ben/oxazine- 7- carbaldehydc 2,1,3- bcnzoxadiaxol e-5- carbaldehydc Example 97 1 ,4-bcnzodioxine-6-sulfonamide To a solution of l-[2-(4-aminopiperidin-l-yl)ethyl]-7-fluoroquinoxalin-2(I//)-one (Intermediate 140, 130 mg, 0.448 ramol) in rnethylene chloride (10 mL) was added diisopropylethylamine (0.156 mL, 0.996 ramol) and 2,3-dihydro-l,4-benzodioxine-6-sulfonyl chloride (1 16 mg, 0.493 mmol) and the reaction was stirred for 2.5 hours at room temperature. It was washed with saturated sodium bicarbonate solution and brine, dried over sodium sulfate, and concentrated. The residue was dissolved in HC1 in dioxane (4M, 8.0 mL), concentrated, suspended in ethyl acetate and filtered to give the HC1 salt of title compound (15.9 rag). MS (ESV 489 (MH+) for QaHfoF^OsS 'H NMR (DMSO-D61 8 1.62 - 1.83 (m, 3H); 2.92 - 3.11 (m, 211); 3.16 - 3.28 (m, 3H); 3.41 - 3.50 (m, 3H); 3.59 (d, 2H); 4.47 - 4.59 (m, 2H); 7.05 (d, 1H); 7.23 - 7.34 (m, 2H); 7.78 (dd, 1H); 7.83 - 7.96 (m, 2H); 8.15 - 8.23 (m, 1H); 10.61 (s, 1H). Example 98 A'-{l-[2-(7-FIuoro-2-oxoquinoxaIin-l(2//)-y))ethyl]pipcridin-4-yl}-3-oxo-3,4- dihydro-2//-l,4-ben/oxazinc-6~sulfonamide l-[2-(4-Aminopiperidin-l-yl)ethyl]-7-fluoroquinoxalin-2(l//)-onc (Intermediate 140, 130 mg, 0.448 mmol) was reacted as described for Example 97 with 3-oxo-3,4-dihydro-2/fl, 4-benzoxazine-6-sulfonyl chloride (122 mg, 0.493 mmol) to give the HC1 salt of title compound (89 mg). MS fESV 502 (Mil") for C23H24FN505S 'H NMR (DMSO-D6) 8 1.55 - 1.93 (m, 3I-T); 2.94 - 3.09 (m, 2H); 3.17 - 3.30 (m, 211); 3.50 (d, 1H); 3.61 (d, 2H); 4.53 (d, 211); 4.69 (s, 2H); 7.12 (d, Hi); 7.28 (t, 1H); 7.32 - 7.42 (m, 2H); 7.73 (d, 1H); 7.83 - 7.95 (m, 1H); 8.02 (d, 1H); 8.20 (s, 1H); 10.14 (s, III); 1 1.04 (s, 1H). Example 99 5-FIuoro-A'-{l-[2-(7-fluoro-2-oxoquinoxaIin-l(2J:0-yl)ethyI]pipcridin-4-yl}-l//- indoIe-2-carboxamide A mixture of l-[2-(4-aminopiperidin-l-yl)ethyl]-7-fluoroquinoxalin-2(l//)-one (Intermediate 140, 130 mg, 0.448 mmol), 5-fluoro-l//-indole-2-carboxylic acid (96.3 mg, 0.538 mmol), AK3-Dimethylaminopropyl)-7V'-ethylcarbodiimide (EDC)(124mg, 0.645 mmol) and 1-Hydroxybenzotriazole hydrate (HOBT) (87mg, 0.645 mmol) in dichloromethane/ DMF (4:1, 10 mL) was stirred for 2.5 hours at room temperature. The solvent was removed under reduced pressure and the residue was suspended in methanol, stirred for 45 minutes and then filtered to give title compound (161 mg). MS (ES): 452 (MH+) for €24^2^02 'HNMR fDMSO-Dei 5 1. 78 - 2.15 (m, 4H); 3.10 - 3.29 (m, 2H); 3.57 (s, 1H); 3.75 (d, 2H); 4.07 (s, 1H); 4.61 (s, 2H); 6.95 - 7.10 (m, 1H); 7.19 (s, 1H); 7.23 - 7.34 (m, 1H); 7.39 (d, 2H); 7.75 - 7.88 (m, 1H); 7.88-7.98 (m, 1H); 8.23 (s, 1H); 8.67 (d, 1H); 10.44 (s, 111); 11.74(8, 1H). Example 100 4-ylnicotinamide l-[2-(4-Aminopiperidin-l-yl)ethyl]-5,7-difluoroquino]in-2(lf/)-one (Intermediate 23, 100 mg, 0.326 mmol) was reacted as described for Example 99 with 6-morpholin-4- ylnicotinic acid (81mg, 0.391mmol), EDC (94 mg, 0.489 mmol) and IIOBT (66 mg, 0.489 mmol) to give title compound (43.6 mg). MS (ESV 498 (MH) for QasHWFiiNsOa 6 1.81 - 2.12 (m, 5H); 3.09 - 3.24 (m, 2H); 3.46 - 3.60 (in, 4H); 3.62 - 3.78 (m, 6H); 3.97 - 4.18 (m, 1H); 4.63 (s, 2H); 6.67 (d, 1H); 6.85 (d, 1H); 7.30 (t, 1H); 7.74 (d, 1H); 7.93 - 8.07 (m, 2H); 8.37 (d, 1H); 8.63 (s, 1H); 10.66 (s, 1H). Example 101 A^-{l-[2-(5,7-Difluoro-2-oxoquinolin-l(2//)-yl)ethyl]piperidin-4-yl}-2,3-dihydro- 1 ,4-benzodioxine-2-carhoxamide l-[2-(4-Aminopiperidin-l-yl)ethyl]-5,7-difluoroquinolui-2(l//)-one (Intermediate 23, 100 mg, 0.326 mmol) was reacted as described for Example 99 with 2,3-dihydro-l,4- benzodioxine-2-carboxylic acid (71 mg, 0.391 mmol), EDC (94 mg, 0.489 mmol) and HOBT (66 mg, 0.489 mmol) to give title compound (73.9 mg). MS (ES^: 470 (MH+) for CzsHzsFaNsCU 1HNMR(T)MSO-D6>) 8 1.71 - 2.05 (m, 4H); 3.06 - 3.21 (m, 2H); 3.22 - 3.29 (m, 2H); 3.67 (s, 1H); 3.80 - 4.03 (m, 1H); 4.17 (dd, 1H); 4.31 - 4.45 (m, 1H); 4.51 - 4.67 (m, 211); 4.70 - 4.79 (m, 1H); 6.58 - 6.73 (m, 1H); 6.85 (d, 2H); 6.92 - 7.02 (m, 1H); 7.30 (t, 1H); 7.65 (d, 1H); 8.03 (d, 1H); 8.41 (d, 1H); 10.19 (s, 1H). Example 102 Ar-{l-[2-(5,7-Difluoro-2-oxoquinolin-l(2JH)-yl)ethyl]piperidin-4-yI}-l-methyI-1//- l,2,3-benzotriazole-5-carboxamide l-[2-(4-Aminopiperidin-l-yl)ethyl]-5,7-difluoroqumolin-2(l//)-one (Intermediate 23, 100 mg, 0.326 mmol) was reacted as described for Example 99 with 1-methyl-l//-l,2,3- benzotriazole-5-carboxylic acid (70 mg, 0.391mmol), EDC (94 mg, 0.489 mmol) and HOBT (66 mg, 0.489 mol) to give title compound (67.6 mg). MS QBS): 467 (MH+) for CaiEWWiCfe 'HNMR(DMSO-D6^ 5 1.86 - 2.03 (m, 2H); 2.07 (s, 2H); 3.12 - 3.25 (m, 2H); 3.42 - 3.61 (m, 1H); 3.73 (d, 2H); 4.09 (s, 1H); 4.33 (s, 3H); 4.64 (t, 2H); 6.68 (d, 1H); 7.30 (t, 1H); 7.73 (d, 1H); 7.92 (d, 1H); 8.05 (t, 2H); 8.61 (s, 1H); 8.76 (d, 1H); 10.60 (s, III). Example 103 jV-{l-[2-(5,7-Difluoro-2-oxoquinolin-I(2//)-yI)cthyI]piperidin-4-yI}-3-(2-inethyll, 3-thiazol-4-yl)benzamide l-[2-(4-Aminopiperidin-l-yl)ethyl]-5,7-difluoroquinolin-2(l//)-one (Intermediate 23, 100 mg, 0.326 mmol) was reacted as described for Example 99 with 3-(2-methyl-l,3-thiazol- 4-yl)benzoic acid (86 mg, 0.391 mmol), EDC (94 mg, 0.489 mmol) and HOBT (66 mg, 0.489 mmol). Solvent removed and the obtained solids were stirred in HCl/dioxane (8.0 mL, 4M) and then filtered to give the HC1 salt of title compound (39 mg). MS (ES): 509 (MH+) for C27H26F2N4O2S 'HNMRfDMSQ-De) 6 1.91 - 2.17 (m, 4H); 2.73 (s, 3H); 3.10 - 3.39 (m, 3H); 3.50 (s, 1H); 3.71 (d, 2H); 4.64 (s, 2H); 6.68 (d, 1H); 7.30 (t, III); 7.51 (t, 1H); 7.72 - 7.89 (m, 2H); 7.98 - 8.13 (m, 3H); 8.42 (s, 1H); 8.73 (d, 1H); 10.85 (s, 1H). Example 104 ^-{l-[2-(5,7-Difluoro-2-oxoquinoIin-l(2/7)-yl)ethyl]pipcridin-4-y]}-4-(5-methyll, 2,4-oxadiazol-3-yI)benzamide 1 -[2-(4-Aminopiperidin- 1 -yl)ethyl]-5,7-difluoroquinolin-2( l//)-one (Intermediate 23 , 100 mg, 0.326 ramol) was reacted as described for Example 99 with 4-(5-methyl- 1,2,4- oxadiazol-3-yl)benzoic acid (80 mg, 0.391 mmol), EDC (94 mg, 0.489 mmol) and HOBT (66 mg, 0.489 mmol). Solvent removed and the obtained solids were suspended in ethyl acetate and then filtered to give title compound (71,9 mg). MS CBS): 494 (MH) for CaOfc^NsOa 5 1.77 - 1.97 (m, 2H); 1.98 - 2.15 (m, 2H); 2.68 (s, 3H); 3.10 - 3.27 (m, 2H); 3.75 (d, 2I-I); 4.05 (s, 1H); 4.60 (t, 2H); 6.69 (d, 1H); 7.32 (t, 1H); 7.46 - 7.68 (m, 1H); 7.96 - 8.15 (m, 5H); 8.72 (d, 1H); 9.86 (s, 1H). Example 105 3-Oxo-4-[2-((2JR,51S)-5-{[(3-oxo-3,4-dihydro-2flr-pyrido[3,2-6][l,4]oxazin-6- yl)methyl]amino}piperidin-2-yl)ethyl]-3,4-dihydro-21T-l,4-benzoxa/ine-6-carbonitrilc To a solution of fer/-butyl (2^,5iS)-2-[2-(6-cyano-3-oxo-2,3-dihydro-4#-l,4- benzoxazin-4-yl)ethyl] -5 - { [(3 -oxo-3 ,4-dihydro-2W-pyrido[3 ,2-b] [ 1 ,4] ox azin-6- yl)methyl]amino}piperidine-l-carboxylate (Intermediate 182, 0.138 g) in dioxane (2 mL) was added 4M HCl/dioxane (1 mL). After 1 hour at room temperature, the reaction was concentrated and evaporated twice from methanol. The solid was suspended in methanol and filtered to yield 73 mg of the name compound as a bis HC1 salt. MS (BSI) 463 (MTI+) for Ca^eNeC^ 1.58 - 1.63 (m, 1H); 1.65 - 1.74 (m, HI); 1.75 - 1.86 (m, 1H); 1.92 - 2.03 (m, 1H); 2.13 - 2.23 (m, 1H); 2.29-2.38 (m, 1H); 3.02 - 3.14 (m, 1H); 3.14 - 3.24 (m, 3H); 3.59 - 3.70 (m, 1H); 3.70 - 3.78 (m, 1H); 4.01 - 4.13 (m, 211); 4.1 8 - 4.28 (m, 211); 4.70 (s, 2H); 4.82 (s, 2H); 7.19 (d, 1H); 7.26 (d, 1H); 7.46 (d, 1H); 7.54 (dd, 1H); 7.77 (d, 1H); 9.51 (s, 1H); 9.70 (s, 1H); 9.82 (s, 1H); 11.36 (s, 1H). Intermediate 182: tert-Butvl C2/;.5^-2-[2-C6-cvano-3-oxo-2.3-dihvdro-4//-1.4- benzoxazin-4-vl')ethyn-5-ir('3-oxo-3.4-dibvdro-2//-pvrido[3.2-6][1.4]oxazin-6- vl)methyl]amino)piperidine-l-carboxylate A mixture of tert-butyl (2^,55)-5-amino-2-[2-(6-cyano-3-oxo-2)3-dihydro-4/f-l,4- benzoxazin-4-yl)ethyl]piperidine-l-carboxylate (Intermediate 183, 0.14 g), 3-oxo-3,4- dihydro-2#-pyrido[3,2-Z>][l,4]oxazine-6-carbaldehyde (WO 2004/058144) (75 mg) and 3 A molecular sieves powder (70 mg) in methanol (8 mL) was heated at 80 °C for 1 hour. The solution was cooled to 0°C and NaCNBHa (33 mg) was added. After stirring at room temperature overnight, the reaction was filtered and concentrated. The residue was purified chromatography on silica gel with a gradient of 0-5% methanol in methylene chloride to give 0.14 g. MS fESD 563 (MH+) for CwH^NsC^ 'HNMRf CDC1Q8 1.37 -1.43 (m. 1H): 1.44-1.51 (s, 9H);1.70- 1.81 (m,2H);2.11 (m, 1H); 2.89 - 3.00 (m, 1H); 3.01 - 3.12 (m, 1H); 3.94 - 4.05 (m, 1H); 4.20 - 4.32 (m, 1H); 4.33 - 4.44 (m, 1H); 4.64 (s, 2H); 4.67 (s, 2H); 6.99 (d, 1H); 7.04 (d, 1H); 7.17 - 7.24 (m, 211); 7.32 (dd, 1H). Intermediate 183: /erf-Butyl (2&5SV5-ammo-2-[2-(6-cyano-3-oxo-23-dihydro-4/'-/'- 1,4-benzoxazin-4-yl)ethynpiperidine-1 -carboxylate tert-Butyl(2/?,55)-5-azido-2-[2-(6-cyano-3-oxo-2,3-dihydro-4//-l,4-hen7.oxazin-4- yl)ethyl]piperidine-l-carboxylate (Intermediate 184, 0.31 g) was hydrogenated in methano] (10 mL) over 10% Pd/C (90 mg) at normal pressure and room temperature overnight. The reaction was degassed, filtered and purified by chromatography on silica gel with a gradient of 0-10% methanol in methylene chloride to give 0.29 g. MS (ESI) 401 (Mil) for CjiIfcgN^ Intermediate 184: tert-Butvl f2&5SV5-azido-2-f2-f6-cvano-3-oxo-2.3-dihydro-4#- 1.4-benzoxazin-4-yl)ethyl]piperidine-1 -carboxylate To a solution of ter/-butyl (2#,57?)-2-[2-(6-cyano-3-oxo-2,3-dihydro-4//-l,4- benzoxazin-4-yl)ethyl]-5-hydroxypiperidine-l-carboxylate (Intermediate 185, crude, 0.8 g) in THF (20 mL) were successively added triphenylphosphine (1.30 g), diisopropylazodicarboxylate (1 mL) and diphenyl phosphoryl azide (0.90 g). After 4 hours, the reaction was diluted with ethyl acetate, washed with saturated solution of sodium hydrogen carbonate (NaHCOs) and brine, dried over sodium sulfate and concentrated. Chromatography on silica gel with a gradient of 0-5% methanol in methylene chloride gave 0.31 g of product. MS (ESTi 427 (MH4) for Intermediate 185: fert-Butyl (2^5#)-2-[2-(6-cvano-3-oxo-2.3-dihvdro-4#-1.4- benzoxazin-4-ynethyl1-5-hvdroxvpiperidine- 1 -carboxylate To a solution of tert-butyl (2^,5/?)-5-{[/er?-butyl(dimethyl)silyl]oxy}-2-[2-(6-cyano- 3-oxo-2,3-dihydro-4//-l,4-benzoxazin-4-yl)ethyl]piperidine-l-carboxylate (Intermediate 186, 1.01 g) in THF (10 mL) was added tetrabutylammonium fluoride (TBAF) (4 mL). After 5 hours, the reaction was diluted with ethyl acetate, washed with NaHCOa and brine, dried over sodium sulfate and concentrated. The crude reaction mixture was used without further purification in the next step. MS (ESP 402 (MH+) for C2iH27N3O5 Intermediate 186: tert-Butyl (2&5^)-5-{[te;^butyl(;dimethvlXsilyl]oxY}-2-f2-(6- cyano-3-oxo-2.3-dihydro-4//- 1 .4-benzoxazin-4-ynethyl]piperidine- 1 -carboxylate To a solution of tert-butyl (2/?,5^)-5-{[/er/-butyl(dimethyl)silyl]oxy}-2-(2- hydroxyethyl)piperidine-l -carboxylate (Intermediate 187, 1.27 g) in methylene chloride (15 mL) at 0 °C were added diisopropylethylamine (1.2 mL) and methanesulfonyl chloride (0.50 mL). At the same time in a separate flask, to a solution of3-oxo-3,4-dihydro-2/7-l ,4- benzoxazine-6-carbonitrile (Intermediate 60) (0.66 g) in DMF (8 mL) at 0 °C was added 60% suspension in oil of NaH (0.25 g). After 30 minutes, the mesylate solution was diluted with methylene chloride, washed with NaHCOa and brine, dried over sodium sulfate and concentrated. This residue was dissolved in DMF (5 mL) and added to the sodium salt of Intermediate 60. The reaction was stirred over the weekend, diluted with ethyl acetate, washed with NaHCCb and brine, dried over sodium sulfate and concentrated to give the product. MS (ESP 516 (MH1) for Intermediate 187: /ert-Butvl (2/;.5^V5-(rfer/-butvl(dimethvl)silvl]oxyl-2-(2- hydroxvethyDpiperidine- 1 -carboxylate To a solution of tert-bnlyl (lR,5^)-5-{[ier/-butyl(dimethyl)silyl]oxy}-2- vinylpiperidine-1 -carboxylate (Intermediate 188, 1.39 g) in THF (20 mL) at 0 °C was added 9-BBN (0.5 M, 15 mL). After 45 minutes, the reaction was diluted with water (3 mL), 3 N NaOH (12 mL) and 30% H^Oa (12 mL). After 15 minutes, the reaction was allowed to warm to room temperature. After 30 minutes, the reaction was diluted with ethyl acetate, washed with 1 N HC1, NaHCOa and brine, dried (NazSO,)), filtered and concentrated. Chromatography on silica gel with a gradient of 0-5% methanol in methylene chloride gave 1. 27 g of product. MS fESn 360 (MH4) for Intermediate 188: ferf-Butyl(2J?.5/?)-S-{[ vinvlpiperidine- 1 -carboxylate To a suspension of /.inc dust (12.2 g) in THF (200 mL) and diiodomethane (5 mL) at 0 °C was added trimethyl aluminium (2M in hexanes, 6 mL). After the addition the reaction was carefully warmed to room temperature (exothermic reaction!). The reaction was then cooled with an ice bath and a solution of tert-buiyl (2/Z,5/Z)-5-{[/er/-butyl(dimethyl)silyl]oxy}-2- formylpiperidine-1 -carboxylate (Intermediate 189, 6.84 g) in THF (40 mL) was added. After 6 hours it was warmed to room temperature, the reaction was diluted with ethyl acetate and slowly quenched with a saturated aqueous solution of NaHCOs. The organic phase was collected and washed with NaHCOs and brine, dried (NajSO^, filtered and concentrated. Chromatography on silica gel with a gradient of 0-100% methylene chloride in hexanes gave 3.96 g of product. MS (ESP 341 (MH+) for QgHssNOaSi 'HNMRfCDCIO 5 0.06 (s, 6H); 0.87 (s, 911); 1.42 - 1.44 (m, 1H); 1.44 (s, 9H); 1 .63 - 1.81 (m, 2H); 2.44 - 2.73 (m, 1H); 3.43 - 3.63 (m, 1H); 3.77 - 4.16 (m, 1H); 4.50 - 4.92 (m, 1H); 4.97 - 5.13 (m, III); 5.13 - 5.26 (m, 1H); 5.58 - 5.84 (m, 1H). Intermediate 189: ter/-Butyl f2/?.SJ?)-S-{[ter/-butylfdimethvl)silyl]oxy}-2- formylpiperidine- 1 -carboxylate To a solution of oxalyl chloride (2.4 mL) in methylene chloride (75 mL) at -78 °C was slowly added dimethylsulfoxide (3 mL) in methylene chloride (25 mL). After 10 minutes, a solution of tert-butyl (2/?,5-R)-5-{[tert-butyl(dimethyl)silyl]oxy}-2- (hydroxymethyl)piperidine-l-carboxylate (Intermediate 190, 7.60 g) in methylene chloride (40 mL) was slowly added. After 30 minutes at -78 °C, diisopropylethylamine (10 mL) was added and the reaction warmed to room temperature. The reaction was diluted with ethyl acetate, washed with 0.5 M HC1, NaHCOa and brine solutions, dried QS^SCU), filtered and concentrated. Chromatography on silica gel with a gradient of 0-30% ethyl acetate in hexanes gave 6.84 g of product. MS (ESP 344 (MH+) for Intermediate 190: /er/-ButyU2J?.5^)-5-([/erf-butvlfdimethyl)silvl1oxvl-2- ( hydroxymethvDpiperidine- 1 -carboxvlate To a solution of 1-re/Y-butyl 2-ethyl (2R,5R)-5-{[tertbutyl( dimethyl)silyl]oxy}piperidine-l,2-dicarboxylate (Intermediate 191, 9.99 g) in THF (100 mL) was added lithium aluminium hydride (1M in THF, 30 mL). After 2 hours, the reaction was quenched with ethyl acetate, washed with 1 N HC1, NaHCC-3 and brine solutions, dried (NaaSC^), filtered and concentrated yielding 7.9 g of product. MS (ESP 346 (MH4) for Ci7H3sNO4Si Intermediate 191: 1-tert-Butvl 2-ethvl (2R.5K\-5-Utertbutyl( dimethvl)silvl]oxylpiperidine-1.2-dicarboxylate To a solution of l-/ert-butyl 2-ethyl (2fl)-5-oxopiperidine-l ,2-dicarboxylate (8.8 g) (Bioorganic & Medicinal Chemistry Letters (2002), 12(1 0), 1387-1390) in mcthanol (200 mL) at 0 °C was added sodium borohydride (1.80 g). After 2 hours, the reaction was concentrated to dryness. The residue was dissolved in ethyl acetate and washed with 1 N HC1, NaHCOa and brine solutions, dried (Na2SO4), filtered and concentrated. The crude alcohol was dissolved in DMF (200 mL) and tread with imidazole (7.5 g) and t-BDMSCl (1 1.5 g). After stirring overnight at room temperature, the reaction was diluted with ethyl acetate and washed with 1 N HC1, NaHCOs and brine solutions, dried (Na2SO4), filtered and concentrated. Chromatography on silica gel with a gradient of 0-25% ethyl acetate in hexanes gave 9.99 g of product. MS (ESP 388 (MH) for Ci^NOsSi IHNMRfCDCIO 8 (rotamers) 0.06 (m, 6H); 0.86 & 0.87 (s, 9H); 1 .22 - 1 .30 (rn, 3H); 1.42 & 1.46 (s, 9H); 1.61 - 1.73 (m, 1H); 1.77 - 1.91 (m, 1H); 2.18 - 2.31 (m, 1H); 2.58 & 2,69 (dd, 1H); 3.42 - 3.62 (m, 1H); 3.97 & 4.13 (dd, 1H); 4.14 - 4.25 (m, 2H); 4.60 & 4.81 (d, 1H). Example 106 yl)methyl]amino}piperidin-2-yl)ethyl]-3,4-dihydro-2//-l,4-benzoxazine-6-carbonitriIc The title compound was prepared following the procedure described for Example 105, except, starting from l-tert-butyl 2-methyl (25)-5-oxopiperidine-l,2-dicarboxylate (Bioorganic & Medicinal Chemistry Letters (2002), 12(10), 1387-1390). MS (BSD 463 (MH4) for C24H26N6O4 'H NMR (DMSO-D61 S 1.58 - 1.63 (m, 1H); 1.65 - 1.74 (m, 1H); 1.75 - 1.86 (m, 1H); 1.92 - 2.03 (m, 1H); 2.13 - 2.23 (m, 1H); 2.29 - 2.38 (m, 1H); 3.02 - 3.14 (m, 1H); 3.14 - 3.24 (m, 3H); 3.59 - 3.70 (m, 1H); 3.70 - 3.78 (m, 1H); 4.01 - 4.13 (m, 2H); 4.18 - 4.28 (m, 2H); 4.70 (s, 2H); 4.82 (s, 2H); 7.19 (d, 1H); 7.26 (d, III); 7.46 (d, 1H); 7.54 (dd, 1H); 7.77 (d, III); 9.51 (s, 1H); 9.70 (s, 1H); 9.82 (s, 1H); 1 1.36 (s, III). Example 107 6-[({l-[2-(5,7-Difluoro-2-oxoquinoxalin-l(2//)-yl)ethyl]pipcridin-4- yl}amino)methyl]-2//-pyrldo[3,2-A][l,4Joxa/in-3(4//)-onc To a solution of l-[2-(4-minopiperidin-l-yl)ethyl]-5,7-diiluoroqumoxalin-2(l//)-one (Intermediate 192, 0.158 g) in methanol (10 mL) were added 3 A molecular sieve power (0.15 g) and 3-oxo-3,4-dihydro-2#-pyrido[3,2-&][l,4]oxazine-6-carbaldchyde (WO 2004/058144) (92 mg). After 2 hours at reflux, the reaction was cooled to 0°C and NaBH(OAc)3 (0.19 g) was added. The reaction was allowed to warm to room temperature and was stirred overnight. It was diluted with ethyl acetate, filtered, washed with saturated solutions of NaaCOa and brine, dried over sodium sulfate and concentrated. Chromatography on silica gel with 0-20% methanol in dichloromethane. Fractions containing product were collected, concentrated, dissolved in a minimum of CPIzCk, precipitated with diethyl ether, and filtered to yield 104 mg of product. MS (ESI) 471 (MH) for Czal^NfA 'H NMR (CDCM 6 1.15 - 1.35 (m, 2H); 1.73 - 1.88 (m, 2H); 1.93 - 2.09 (m, 2H); 2.51 - 2.58 (m, 2H); 2.83 - 2.95 (m, 2H); 3.16 (d, 1H); 3.71 - 3.84 (m, 1H); 4.21 - 4.34 (m, 2H); 4.61 (s, 2H); 7.02 (d, 1H); 7.26 - 7.48 (m, 1H); 8.19 (s, IE), Intermediate 192: l-f2-('4-Aminopiperidin-l-vl')ethvl]-5.7-difluoroquinoxalin-2(l^none To a solution of tert-butyl {l-[2-(5,7-difluoro-2-oxoquinoxalin-l(2/i)- yl)ethyl]piperidin-4-yl}carbamate (Intermediate 193, 0.21 g) in dioxane (3 mL) and water (1 mL) was added 4 M HCl in dioxane (1 mL). After 30 minutes, additional 4 M HCl/dioxane (3 mL) was added. After 1 hour, the reaction was diluted with chloroform and poured into a saturated solution of Na2CC>3. The organic solution was collected, dried (Na2S04), filtered and concentrated yielding 0.158 g of crude titled compound, MS ("BSD 309 (MH4) for Ci5Hi8F2N40 Intermediates 193: tert-Butyl (l-[2-f5,7-difluoro-2-gxoquinoxalin-l(2//)- vl)ethyl]piperidin-4-yUcarbamate and Intermediate 194: tert-Butyl n-[2-(6,8-difluoro-2-oxoquinoxalin-U2/JV vnethyl]piperidin-4-yl}carbamate A mixture of 5,7-difluoroquinoxalin-2(l//)-one and 6,8-difluoroquinoxalin-2(l//)-one (Intermediate 195) (1.05 g, 5.77 mmol) was deprotonated with sodium hydride (0.31 g, 60% in oil, 7.75 mmol) and alkylated with 2-{4-f(?er/'-butoxycarbonyl)amino]piperidin-l-yl} ethyl methanesulfonate (Intermediate 6) (5.8 mmol) as described for Intermediate 2. The residue obtained after aqueous workup was titurated in diethyl ether and filtered yielding 0.73 g of /e/V-butyl {1 -[2-(5,7-difluoro-2-oxoquinoxalin-1 (2#)-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 193). The filtrate was concentrated and the residue was purified by chromatography on silica gel with 0-20% acetone in dichloromethanc to yield 111 mg of tertbutyl {1 -[2-(6,8-difluoro-2-oxoquinoxalin-1 (2#)-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 194). Intermediate 193: MS (BSD 409 (Mir) for CrolfeeFMOs 'HNMRfCDCIO 5 1.33 -1.42 (m, 2H); 1.44 (s, 9H); 1.89 -1.97 (m, 2H); 2.24 (td, 2H); 2.65 (t, 2H); 2.84 - 2.89 (m, 2H); 3.41 - 3.52 (m, III); 4.27 (t, 2H); 4.41 (s, Hi); 6.87 (td, 1H); 6.93 (dt, 1H); 8.23 (s, 1H). Intermediate 194: MS (ESI) 409 (MH4) 'HNMRfCDCM 8 1.31 -1.42 (m, 211); 1.44 (s, 9H); 1.86 -1.96 (m, 2H); 2.23 (td, 2H); 2.67 (t, 2H); 2.84 - 2.91 (m, 2H); 3.39 - 3.51 (m, 1H); 4.34 - 4.45 (m, 1H); 4.46 - 4.53 (m, 2H); 7.13 (ddd, 1H); 7.36 - 7.44 (m, 1H); 8.30 (s, 1H). Intermediate 195; 5.7-Difluoroquinoxalin-2(l#Vone and 6.8-difluoroquinoxaliii- To a solution of l,2-diamino-3,5-difluorobenzene (5.11 g) in methanol (100 mL) was added ethylglyoxalate (16 mL). After 6 hours at room temperature, the precipitate was collected by filtration and washed with methanol yielding 2.1 g products, 1:1 mixture of 5,7- difluoroquinoxalin-2(l//)-oneand6,8-difluoroquinoxalin-2(l/f)-one. MS (ESP 182 (MH+) for C8H4F2N2O Example 108 6-[({l-I2-(6,8-Difluoro-2-oxoquinoxalin-l(2//)-yl)ethyl]piperidin-4- yl}amino)methyl]-2flr-pyrido[3,2-6] [1,4] oxazin-3(4/J)-one l-[2-(4-Aminopiperidin-l-yl)ethyl]-6,8-difluoroquinoxalin-2(l//)-one (Intermediate 196, 52 mg) was reacted with 3-oxo-3,4-dihydro-2//-pyrido[3,2-k][l,4]oxazine-6- carbaldehyde (WO 2004/058144) and sodium acetoxyborohydride as described for Example 107 yielding 29 mg of the title compound. MS (ESP 471 (MH+) for C23H24F2N6O3 'HNMR(DMSQ-D6) 8 1.16 -1.28 (m, 2H); 1.71 - 1.82 (m, 2H); 2.04 (t, 2H); 2.35 - 2.47 (m, 2H); 2.54 - 2.61 (m, 2H); 2.81 - 2.90 (m, 2H); 3.70 (s, 2H); 4.32 - 4.42 (m, 211); 4.61 (s, 2H); 7.02 (d, 1H); 7.30 (d, 1H); 7.61 (d, III); 7.72 (ddd, 1H); 8.33 (s, III); 11.17 (s, III). Intermediate 196: 1 -[2-(4-Aminopiperidin-1 -yl)e1hyl1-6.8-difluoroquinoxajfa-20ff)-. one ter/-Butyl {1 -[2-(6,8-difluoro-2-oxoquinoxalin-l (2//)-yl)ethyljpiperidin-4- yljcarbamate (Intermediate 194) was deprotected with HC1 in dioxane as described for Intermediate 192. MS (ESP 309 (MH+) for CUH18F2N4O Example 109 2-Oxo-l-[2-(4-{[(3-oxo-3,4-dihydro-2flr-pyrido[3,2-6][l,4]oxa/in-6- yl)methyl]amino}piperidin-l-yl)ethyl]-l,2-dihydroquinoxaline-6-carbonitriIc 1 -[2-(4-Aminopiperidin~1 -yl)etliyl]-2-oxo-1,2-dihydroquinoxaline-6-carbcmitrile (Intermediate 197,0.125 g) was reacted with 3-oxo-3,4-dihydro-2#-pyrido[3,2- 6][l,4]oxazine-6-carbaldehyde (WO 2004/058144) (0.17 g) and NaBH(OAc)3 (0.27 g) as described for Example 107. The residue was purified by reverse phase HPLC with acetonitrile in water containing 0.1% TFA. Fractions containing product were concentrated to remove acetonitrile, neutralized with NaaCOj solid, extracted with ethyl acetate, dried (NajSO^, filtered and concentrated. The residue was suspended in diethyl ether and filtered to yield 127 mg of a colorless solid. MS fESD 460 (MH+) for C24H25N703 'HNMRfDMSO-.D6) 5 1.14 - 1.25 (m, 2H); 1.70 - 1.80 (m, 211); 1.96 - 2.07 (m, 2H); 2.33 - 2.43 (m, IH); 2.51 - 2.57 (m, 2H); 2.87 (d, 2H); 3.67 (s, 2H); 4.33 (t, 2H); 4.61 (s, 2H); 7.01 (d, IH); 7.30 (d, III); 7.79 (d, IH); 8.05 (dd, IH); 8.36 (d, 211); 11.16 (s, III). Intermediate 197: l-[2-(4-Aminopiperidin-l-yl)ethyn-2-oxQ-1,2-djhydroquinoxaline- 6-carbonitrile To a solution of /e;-/-butyl {l-[2-(6-cyano-2-oxoquinoxalin-l(27/)-yl)ethyl]pipcridin- 4-yl}carbamate (Intermediate 198, 0.38 g) in methylene chloride (4 mL) was added at 0°C TFA (2 mL). After 1 hour, the reaction was diluted with chloroform, washed with saturated solution of NajCOs, dried (Na2SO4), filtered and concentrated yielding 0.25 g of crude product. MS (ESI) 298 (MH+) for C,6Hi9N50 Intermediate 198: tert-Butyl {1 -[2-(6-cvano-2-oxoquinoxalin-1 (211)- ynethyIjpiperidin-4-yl} carbamate and Intermediate 199: te/-/-Butyl {l-r2-(7-cyano-2-oxoquinoxalin-V(2fflyl) ethyl]piperidin-4-yl) carbamate A mixture of 2-oxo-l,2-dihydroquinoxaline-6-carbonitrile and 3-oxo-3,4- dihydroquinoxaline-6-carbonitrile (Intermediate 200, 0.83 g, 4.8 mmol) was deprotonatcd with sodium hydride (0.30 g, 60% in oil) and alkylated with 2-{4-[(tertbutoxycarbonyl) amino]piperidin-l-yl}ethyl methanesulfonate (Intermediate 6) (4.8 inmol) as described for Intermediate 2. Chromatography on silica gel with 0-25% acetone in dichloromethane gave 38 mg of tert-butyl {l-[2-(7-cyano-2-oxoquinoxalin-l(2//)- yl)ethyl]piperidin-4-yl}carbamate (Intermediate 199) and 0.39 g of te/7-butyl {l-[2-(6- cyano-2-oxoquinoxalin-l(2//)-yl)ethyl]piperidin-4-yl}carbarnate (Intermediate 198). MS (ESP 398 (MH+) for C2iH27N5O3 Intermediate 198: 'HNMR(CDCIV) 8 1.31 -1.41 (m, 2H); 1.44 (s, 9H); 1.88 - 1.98 (m, 2H); 2.19 - 2.29 (m, 2H); 2.67 (t, 2H); 2.83 - 2.93 (m, 2H); 3.41 - 3.52 (m, 1H); 4.35 (t, 2H); 4.43 (m, HI); 7.48 (d, 1H); 7.80 (dd, 1H); 8.20 (d, 1H); 8.35 (s, III). Intermediate 199: 'HNMRfCDC1061.32 - 1.42 (m, 2H); 1.44 (s, 9H); 1.89 - 1.97 (m, 2H); 2.19 - 2.30 (m, 2H); 2.68 (t, 2H); 2.83 - 2.93 (m, 2H); 3.42 - 3.53 (m, 1H); 4.33 (t, 211); 4.42 (s, 1H); 7.59 (dd, 1H); 7.79 (s, 1H); 7.97 (d, 1H); 8.37 (s, 1H). Intermediate 200: 2-Oxo-1.2-dihvdroquinoxalinc-6-carbonitrile and 3-oxo-3.4- dihvdroquinoxaline- 6-carbonitrile To a solution of 3,4-diaminobenzonitrile (0.99 g) in methanol (20 mL) was added ethylglyoxalate (3.5 mL). After stirring overnight at room temperature, the precipitate was collected and washed with methanol. The filtrate was concentrated to give a second crop of product yielding 0.83 g from both batches, 1:1 mixture of 2-oxo-l,2-dihydroquinoxaline~6- carbonitrile and 3-oxo-3,4-dihydroquinoxaline-6-carbonitrile as a brown solid. MS (ESP 172 (MH1) for C9H5N30 Example 110 3-Oxo-4-[2-(4-{[(3-oxo-3,4-dihydro-2#-pyrido[3,2-6][l,4]oxazin-6- yl)methyl]amino}piperidin-l-yl)ethyl]-3,4-dihydroquinoxaline-6-carbonitrilc 1 -[2-(4-Aminopiperidin-l -yl)ethyl]-2-oxo-1,2-dihydroquinoxaline-7-carbonitrile (Intermediate 201, O.llg) was reacted with 3-oxo-3,4-dihydro-2/:/-pyrido[3,2- 6][l,4]oxazine-6-carbaldehyde (WO 2004/058144) and sodium acetoxyborohydride as described for Example 107 yielding 17 mg of a colorless solid. MS (ESP 460 (MH+) for 1HNMR(DMSQ-D6U 1.22 -1.33 (m, 2H); 1.80 -1.91 (m, 2H); 1.98 - 2.08 (m, 2H); 2.55 - 2.67 (m, 3H); 2.90 - 3.01 (m, 2H); 3.79 - 3.90 (m, 1H); 4.35 (t, 2H); 4.64 (s, 2H); 7.05 (d, 1H); 7.34 (d, 1H); 7.79 (d, 1H); 7.99 (d, 1H); 8.21 (s, 1H); 8.38 (s, 1H); 11.23 (s, 1H). Intermediate 201; 1 -f 2-(4-Aminopiperidin-1 -yl)ethyl]-2-oxo-1.2-dihvdroquinoxaline- 7-carbonitrile tert-Butyl {1 -[2-(7-cyano-2-oxoquinoxalin-1 (2//)-yl)ethyl]piperidin-4-yl} carbamate (Intermediate 199) was deprotected with TFA as described for Intermediate 197 to give the crude free base of the product. MS fESI) 298 (MH4) for Ci6Hi9N5O Example 111 6-[({l-[2-(6-Methoxy-3-oxopyrido[2,3-A]pyrazin-4(3//)-yI)ethyl]piperidin-4- yl}amino)methyl]-2#-pyrido[3,2-A][l,4]oxazin-3(4#)-one 4-[2-(4-Aminopiperidin-l-y])ethyl]-6-methoxypyrido[2,3-6]pyrazin-3(4//)-onc (Intermediate 202, 0.125 g) was reacted with 3-oxo-3,4-dihydro-2//-pyrido[3,2- 6][l,4]oxazine-6-carbaldehyde (WO 2004/058144) (50 rag) and sodium acetoxyborohydridc (110 mg) as described for Example 107. Chromatography on silica gel with 0-20% methanol in dichloromethane and trituration of the product from ether gave 37.6 mg of the title compound as acetic acid salt. MS (ESP 466 (MH+) for CalfotyC^ 'H NMR (DMSQ-D6) 8 1.18 (q, 2H); 1.74 (d, 2H); 2.03 (t, 2H); 2.32 - 2.41 (m, HI); 2.61 (t, 2H); 2.90 (d, 2H); 3.66 (s, 2H); 3.98 (s, 3H); 4.41 (t, 2H); 4.59 (s, 2H); 6.83 (d, 1H); 6.99 (d, 1H); 7.27 (d, 1H); 8.10 (s, 1H); 8.12 (d, 1H); 11.15 (s, 1H). Intermediate 202; 4-[2-(4-Aminopiperidin-1 -yl)ethyl]-6-mcthpxypyrido[2,3- fcjpyrazin-S^ffi-one /e/-/-Butyl {l-[2-(6-methoxy-3-oxopyrido[2,3-A]pyrazm-4(3//)-yl)ethyl]piperidin-4- yl}carbamate (Intermediate 203,0.213 g) was deprotected with TFA as described for Intermediate 197 to give the crude free base of the product, 0.15 g. MS (ESP 304 (MET) for Ci5H2iN502 Intermediate 203: te^-ButvHl-['2-(6-methoxv-3-oxopyridof2J-A1pyrazin-4(3//)_- vl)ethyI]piperidin-4-yl)carbamate 6-Methoxypyrido[2,3-6]pyrazin-3(4H)-one (Intermediate 204, 0.085 g, 0.48 mmol) was deprotonated with sodium hydride (0.030 g, 60% in oil, 0.7.5 mmol) and alkylatcd with 2-{4-[(ter/-butoxycarbonyl)amino]piperidin-l-yl}ethyl methanesulfonate (Intermediate 6) (1.05 mmol) as described for Intermediate 2, Chromatography on silica gel with 0-25% acetone in dichloromethane gave 0.13 g of the title compound. MSfESD 404 (MH+) for C2oH29N504 H NMR fCDCM 5 1.31 -1.40 (m, 2H); 1.40 -1.46 (m, 9H); 1.87-1.95 (m, 2H); 2.15 - 2.27 (m, 2H); 2.69 - 2.75 (m, 2H); 2.93 - 3.02 (m, 2H); 3.40 - 3.51 (m, 1H); 4.02 (s, 3H); 4.35 - 4.46 (m, 1H); 4.51 - 4.60 (m, 2H); 6.73 (d, 1H); 8.02 (d, 1H); 8.15 (s, 1H). Intermediate 204: 6-Methoxvpvridor2.3-/;]pyra7in-3(4//)-one To a solution of 3,4-diamino-6-methoxypyridine (1.11 g) in mcthanol (20 mL) was added ethylglyoxalate (3.5 mL). After stirring overnight at room temperature, it was filtered and washed with methanol (the precipitate contained the undesired regioisomer, 6- methoxypyrido[2,3-Z>]pyrazin-2(l//)-one). The filtrate was concentrated and suspended in diethyl ether to give 0.18 g product. MS (BSD 178 (MH4) for C8H7N302 'HNMR(DMSO-D6) 8 6.77 (d, 1H); 8.01 (s, 1H); 8.07 (d, III); 12.83 (s, 1H). Example 112 4-(2-{4-[(2,3-DihydroIl,41dioxino[2,3-c]pyridin-7-ylmethyl)amino]pipcridin-lyl} ethyl)-6-methoxypyrido[2,3-6]pyrarin-3(4/3>one 4-[2-(4-Aminopiperidin-l-yl)ethyl]-6-methoxypyrido[2,3-i]pyrazin-3(4/;/)-one (Intermediate 202, 75 mg) was reacted with 2,3-dihydro[l,4]dioxino[2,3-c]pyridine-7- carbaldehyde (WO 2004/058144) (48 mg) and sodium acetoxyborohydride (0.11) as described for Example 107. Chromatography on silica gel with 0-2% methanol in dichloromethane to give 72 mg of the product. MS (BSD 453 (MH1) for C^H^NeC^ 'HNMRfDMSQ-D6) 8 1.18 (q, 2H); 1.74 (d, 2H); 2.02 (t, 2H); 2.30 - 2.40 (m, 1H); 2.60 (t, 2H); 2.89 (d, 2H); 3.65 (s, 2H); 3.98 (s, 3H); 4.26 (dd, 2H); 4.29 - 4.34 (m, 2H); 4.40 (t, 2H); 6.83 (d, 1H); 6.92 (s, 1H); 7.98 (s, 1H); 8.10 (s, 1H); 8.12 (d, 1H). Example 113 6-[({l-[2-(6-ChIoro-l-oxido-3-oxo-l,2,4-benzotriazin-4(3/0-yl)ethyl]piperidin-4- yI}amino)methyl]-2/y-pyrido[3,2-£][l,4]oxazin-3(4i9)-one 4-[2-(4-Aminopiperidin-l-yl)ethyl]-6-chloro-l,2,4-benzotriazin-3(4//)-one 1-oxide (Intermediate 205, 0.517 g) was reacted with 3-oxo-3,4-dihydro-2H-pyrido[3,2- 6][l,4]oxazine-6-carbaldehyde (WO 2004/058144) (117 mg) and sodium acetoxyborohydride (340 mg) as described for Example 107. Chromatography on silica gel with 0-20% methanol in dichloromethane gave 60 mg of the title compound as acetic acid salt. MS (ESP 486 (MH1) for CjoBtwClNvCU 'H NMR (DMSO-Dei 8 1.13 -1.24 (m, 2H); 1.69 -1.79 (m, 2H); 2.02 (t, 2H); 2.31 - 2.42 (m, 1H); 2.57 (t, 211); 2.88 (d, 2H); 3.27 - 3.39 (m, 2H); 3.67 (s, 2H); 4.26 (t, 2H); 4.60 (s, 2H); 7.00 (d, 1H); 7.28 (d, 1H); 7.43 (dd, 1H); 7.91 (d, 1H); 8.20 (d, 1H); 11.15 (s, 1H). Intermediate 205: 4-r2-(4-Aminopiperidm-l-vl)ethvn-6-chloro-l,2.4-benzotriazin- 3(4/f)-one 1-oxide tert-Butyl {1 -[2-(6-chloro-1 -oxido-3-oxo-1,2,4-benzotriazin-4(3fl>yl)cthyl]pipcridin- 4-yl}carbamate (Intermediate 206,0.65 g) was deprotected with TFA as described for Intermediate 197 to give the crude free base of the product, 0.517 g. MS (ESI) 324 (MH+) for Ci4Hi8ClN502 Intermediate 206: terf-Bytyl (l-r2-(6-chlQro-l-oxido-3-oxo-1.2.4-benzotriazin- 4(3//)-yl)ethyl]piperidin-4-yUcarbamate 6-Chloro-l,2,4-benzotriazm-3(4//)-one 1-oxide (FR 2621583, 1.50 g) was deprotonated with sodium hydride (0.42 g, 60% in oil) and alkylated with 2- {4-[(tertbutoxycarbonyl) amino]piperidin-l-yl}ethyl methanesulfonate (Intermediate 6) (1 equivalent) as described for Intermediate 2. The residue obtained after aqueous work up was suspended in diethyl ether and filtered to yield 1.30 g of product, MS (ESP 424 (Mil1) for Ci9H26ClNs04 'HNMR(CDCIV) 6 1.30 - 1.41 (m, 2H); 1.44 (s, 9H); 1.88 - 1.96 (m, 211); 2.21 - 2.30 (m, 2H); 2.74 (t, 2H); 2.83 - 2.92 (m, 2H); 3.41 - 3.52 (m, 1H); 4.27 (t, 211); 4.34 - 4.45 (m, 1H); 7.30 (dd, 1H); 7.53 (d, 1H); 8.27 (d, 1H). Example 114 6-Chloro-4-(2-{4-[(2,3-dihydro[l,4]dioxino[2,3-c]pyridin-7- ylmethyl)amino]piperidin-l-yI}ethyl)-l,2,4-benzotriazin-3(4/0-onel-oxide 4-[2-(4-Aminopiperidm-l-yl)ethyl]-6-chloro-l,2,4-benzotriazin-3(4#)-one 1-oxide (Intermediate 205, (0.25 g) was reacted with 2,3-dmydro[l,4]dioxino[2,3-c]pyridine-7- carbaldehyde (WO 2004/058144) (0.14 g) and sodium acetoxyborohydride (0.34 g) as described for Example 107. Chromatography on silica gel with 0-20% methanol in dichloromethane gave 60 mg of the title compound as acetic acid salt (0.37 g). MS (ESP 473 (MH4) for CzjIfcClNfiC^ IH NMR rPMSO-Pe^ 6 1.14 -1.25 (m, 2H); 1.68 - 1.78 (m, 2H); 2.02 (t, 2H); 2.31 - 2.42 (m, IH); 2.57 (t, 2H); 2.88 (d, 2H); 3.67 (s, 2H); 4.22 - 4.30 (m, 4H); 4.33 (dd, 2H); 6.93 (s, IH); 7.44 (dd, IH); 7.91 (d, IH); 8.00 (s, IH); 8.21 (d, IH). Example 115 6-[({l-[2-(6-Chloro-3-oxo-l,2,4-ben/otriazin-4(3«)-yl)ethyl]piperidin-4- yl}amino)methyl]-2//-pyrido[3,2-A][l,4]oxazin-3(4/J)-one 4-[2-(4-Aminopiperidin-l-yl)ethyl]-6-chloro-l,2,4-benzotriazin-3(4//)-one (Intermediate 207, 67 mg) was reacted with 3-oxo-3,4-dihydro-2//-pyrido[3,2- 6][l,4]oxazine-6-carbaldehyde (WO 2004/058144) (360 mg) and sodium acetoxyborohydridc (76 mg) as described for Example 107. Chromatography on silica gel with 0-20% methanol in dichloromethane and trituration from ether gave 33 mg of the title compound. MS (ESP 470 (MHH) for C22H24C1N703 'HNMRfPMSQ-P61 5 1.30 -1.42 (m, 2H); 1.88 -1.97 (m, 2H); 1.98 - 2.08 (m, 211); 2.58 - 2.67 (m, 2H); 2.90 - 3.02 (m, 2H); 3.28 - 3.34 (m, 2H); 3.95 - 4.07 (m, 2H); 4.26 (t, 2H); 4.66 (s, 2H); 7.08 (d, IH); 7.39 (d, IH); 7.56 (dd, IH); 7.87 (d, IH); 8.43 (d, IH); 11.27 (s, IH). Intermediate 207: 4-[2-C4-Aminopiperidin-l-yl)ethyl1-6-chloro-l1214-benxotriazin- 3(4//)-one tert-Butyl {l-[2-(6-chloro-3-oxo-l,2,4-benzotriazin-4(3//)-yl)ethyl]piperidin-4- yl}carbamate (Intermediate 208, 74 mg) was deprotected with TFA as described for Intermediate 197 to give the crude free base of the product, 67 mg. MS (ESP 307 (MH") for Ci4Hi8ClN50 Intermediate 208; tert-Butvl I l-[2-(6-chloro-3-oxo-1.2,4-benzotriazin-4r3#)- vnethyl]piperidin-4-yl} carbamate To a solution of /ert-butyl {l-[2-(6-chloro-l-oxido-3-oxo-l,2,4-benzotriazin-4(3//)- yl)ethyl]piperidin-4-yl} carbamate (Intermediate 206) (0.43 g) in acetic acid (8 inL) arid water (2 mL) was added zinc dust (0.50 g). After 30 minutes, the solution was filtered and the filtrate concentrated. The residue was then treated with potassium ferricyanide (1.0 g) in water (20mL). After 2 hours, the reaction was diluted with ethyl acetate. The aqueous layer was collected, the pH adjusted with solid Na2CC>3 and extracted with ethyl acetate. The combined organic washes were dried (NajSO^, filtered and concentrated. The residue was purified by chiomatography on silica gel with 0-25% acetone in dichloromethane to yield 66 mg of the product. MS (ESP 407 (MH+) for dsH^ClNsOs 'H NMR (CDCK) 8 1.32 -1.40 (m, 2H); 1.44 (s, 9H); 1.91 (d, 2H); 2.20 - 2.30 (m, 2H); 2.75 (t, 2H); 2.87 (d, 2H); 3.40 - 3.52 (m, 1H); 4.24 (t, 2H); 4.40 (s, 1H); 7.42 (dd, III); 7.46 (s,!H); 8.38 (d,!H). Example 116 4-(2-{(21S',57Z)-S-\|(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7- ylmethyl)amino]piperidin-2-yl}ethyl)-3-oxo-3,4-dihydro-2//-l,4-benzoxazine-6- carbonitrile The product was obtained following the procedure described for Example 105, except, the enantiomer of Intermediate 183, tert-butyl (25,5/?)-5-amino-2-[2-(6-cyano-3- oxo-2,3-dihydro-4//-l,4-benzoxazin-4-yl)ethyl]piperidine-l-carboxylate (prepared by the exact route as Intermediate 183, but starting from l-?ert-butyl 2-ethyl (2S,5S)-5-{[tertbutyl( dimethyl)silyl]oxy}piperidine-l,2-dicarboxylate, the enantiomer of Intermediate 191) was reacted with 2,3-dihydro[l,4]dioxino[2,3-c]pyridine-7-carbaldehyde to yield the named compound. MS (ESP 449 (MH) for Ca^NsC^ 'H NMR (DMSO-D61 5 ppm 1.42-1.81 (m, 3H); 1.85 - 2.03 (m, Hi); 2.16 (d, 1 H); 2.28 (d, 1H); 2.98 - 3.11 (m, 1H); 3.38 - 3.58 (m, 111); 3.68 (d, 211); 4.28 (s, 2H); 4.38 (dd, 4H); 4.80 (s, 2H); 7.18 (d, 1H); 7.31 (s, 1H); 7.52 (d, 1H); 7.75 (s, III); 8.26 (a, 111); 9.46 - 9.79 (m, 2H); 9.98 (s, 1H). -^^ Example 117 6-[(1-[2-(7-Bromo-l-oxo-2,3-dihydro-lH-pyrido[2,3-b][1,4]oxazin-lyl) ethyl]piperidin-4-yl}amino)methyl]-2/f-pyrido[3,2-b][l,4]oxazin-3(4H)-one l-[2-(4-Aminopiperidin-l-yl)ethyl]-7-bromo-lH'-pyrido[2,3-b)][l,4]oxazin-2(3//)-one (Intermediate 209) (2.0 mmol), (3-oxo-3,4-dihydro-2H-pyrido[3,2-b][l,4]oxazine-6- carbaldehyde (WO 2004/058144) (356 mg, 2.0 mmol) and sodium cyanoborohydride (496 ing, 4 equiv) were reacted as described under Example 21 to give the product as an off-white solid 420mg( 41% yield), MS (ESP); 517. 52 (MH4) for C22H25BrN604 1'H-NMR(DMSO-d6) δ 1.13 (t, 2H); 1.34 (q, 5H); 1.85 (d, 2H); 1.98 (t, 211); 2.45 (m, 2H); 2.71 (m, 1H); 2.91 (d, 2H); 3.00 (m, 2H); 3.89 (m, 2H); 3.99 (m, 211); 4.63 (s, 2H); 4.85 (s, 2H); 7.05 (d, 1H); 7.35 (d, 1H); 7.94 (dd, 1H); 11.25 (bs, 1H). Intermediate 209 : l-r2-(4-Aminopiperidin-l-vl)ethvl1-7-bromo-l //-pyrido[2.3- 6in .41oxazin-2f 3#)-onc ter/-Butyl {l-[2-(7-bromo-2-oxo-2,3-dihydro-l//-pyrido[2,3-6][l,4]oxazin-lyl) ethyl]piperidin-4-yl}carbamate (Intermediate 210) (0.85 g) was reacted as described for Intermediate 14. The crude trifluoro acetate of the title compound was used without further purification for the next step (quantitative yield). MS (ESP'): 3557 357 (MH) for Ci4Hi9BrN402 Intermediate 210:tert-Butyl {l-r2-(7-bromo-2-oxo-2,3-dihydro- t//-pyrido[2,3- b] [ 1,4]oxazin-1 -vnethyl]piperidin-4-yl} carbamate 6-Bromo-2H-pyrido[3)2-6][l,4]oxazin-3(4/f)-one (Intermediate 21.1) (460 mg, 2.0 mmol) was deprotonated with sodium hydride and alkylated with 2-{4-[(tertbutoxycarbonyl) amino]piperidin-l-yl}ethylmethanesulfonate (Intermediate 6) (2.1 mmol) as described for Intermediate 2. Chromatography on silica gel with methanol/ dichloromethane gave the product as an oil (0.85 g, 93% yield). MS (ESP): 455, 457 (MH4) for Ci9H27BrN404 Intermediate 211: 7-Bromo-l//-pyrido[2.3-^][l,41oxazin-2r3/jr)-one Ethyl [(5-bromo-3-nitropyridin-2-yl)oxy]acetate (intermediate 212) (4.3g, 14.1 mmol) was dissolved in anhydrous THF (10 mL) and concentrated HC1 (10 mL) was added at ?& 0 ° C. Tin chloride (5.0 g, 26.4 mmol) was added in small portions. The reaction was stirred for 1 hr and heated at 65 °C overnight. The reaction mixture was concentrated under reduced pressure, extracted with chloroform, dried over magnesium sulfate and concentrated. Chromatography on silica gel with methanol/ chloroform gave the product as a light pink solid (1.2 g, 37% yield). MS (ESP): 229/231(MH+) for C7H5BrN2O2 1H-NMR (DMSO-d6) δ: 4.80 (s, 2H); 7.32 (s, 1H); 7.87 (s, 1H); 10.94 (bs, III). Intermediate 212: Ethyl [(5-bromo-3-nitropyridin-2-yl)oxt]acetate A mixture of 5-bromo-2-chloropyridin-3-ol (4.73 g, 19.9 mmol) and ethyl glycolate (2.9 g, 27. 8mrnol) in anhydrous dioxane (20 rnL) was treated with sodium hydride (1.12 g, 60% in mineral oil, 28 mmol) in portions (exothermic reaction!). The reaction was then quenched with water and extracted with chloroform and dried over magnesium sulfate. Chromatography on silica gel with ethyl acetate/ hexanes gave the product as a light yellow solid (4.8 g, 79% yield). MS (ESP): 305, 307(Mtf) for C9H9BrN2O5 1H-NMR (PMSO-d6) δ ppm: l.l7 (t, 3H); 4.12 (q, 2H); 5.10 (s, 211); 8.64 (s, 1H); 8.76 (s, 1H). Example 118 2-Oxo-l-[2-(4-{f(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][l,4]oxazin-6- yl)methyl]amino}piperidin-l-yI)ethyl]-2,3-dihydro-lH-pyrido\|2,3-i][l,4)oxazinc-7- carbonitrile and Example 119 2-Oxo-l-[2-(4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][l,4]oxazin-6- yl)methyl]amino}piperidin-l-yl)ethyl]-2,3-dihydro-lH-pyrido[2,3-b]ll,4]oxazine-7- carboxamide A mixture of 6-[({l-[2-(7-bromo-2-oxo-2,3-dihydro-l//-pyrido[2,3-&][ 1,4]oxazin-1 - yl)ethyI]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-i][l,4]oxaxin-3(4H-oac (Example 117) (110 mg, 0.21 mmol), zinc cyanide (80 mg, 0.683mmol) and tetrakis(triphenylphosphinc) palladium(O) (25 mg, 0.0215mmol) in anhydrous DMF (2.5 mL) over molecular sieves 3A was vortexed and then heated in the microwave at 200 °C for one hour. Reverse phase chromatography and generation of the free base as described for Example 21 gave 20 mg (20%) of Example 118 and 20 mg (20%) of Example 119, both as off-white solids, Example 118 MS (ESP):. 464(MII+) for C23H25N704 1H-NMR(DMSO-d6) δ: 1.74 (m, 2H); 2.18 (m, 2H); 3.02 (m, 2H); 3.80 (m, 2H); 3.90 (m, 2H); 4.23 (m, 4H); 4.70 (s, 2H); 5.01 (s, 2H); 7.11 (d, 1H); 7.44 (d, 1H); 8.08 (s, 1H); 8.40 (s, 1H); 9.28 (s, 1H); 9.75 (bs, 1H); 11.35 (bs, 1H). Example 119: MS (ESP): 482(MH+) for C23H27N7O5 1H-NMR (DMSO-d6) δ 1.74 (m, 2H); 2.36 (m, 2H); 3.10 (m, 2H); 3.80 (m, 2H); 4.23 (m, 2H); 4.32 (m, 4H); 4.56 (s, 2H); 4.70 (s, 2H); 4.94 (s, 4H); 7.11 (d, 1H); 7.44 (d, 1H); 7.62 (s, 1H); 7.91 (s, 1H); 8.08 (s, 1H); 8.38 (s, III); 9.30 (bs, 2H); 9.60 (bs, 1H); 11.35 (bs, 1H). Example 120 l-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-2- methylpiperidin-l-yl}ethyl)-5,7-difluoroquinolin-2(lH)-one A solution of l-[2-(4-amino-2-methylpiperidin-l-yl)emyl]-5,7-difluoroquinolin- 2(lH)-one (Intermediate 213, crude, 220 mg, 0.69 mmol) and 2,3-dihydro[l,4]dioxino[2,3- c]pyridine-7-carbaldehyde (WO 2004/058144) (114 mg, 0.69 mmol) in dry dichloroethane/methanol (4 mL, 4:1) was heated over 3 A molecular sieves at 80 °C for 3 hours. The reaction mixture was cooled to 0°C, and sodium triacetoxy borohydride (299 mg, 1.38 mmol) was added. The resulting reaction mixture was stirred at room temperature for 16 hours and then was filtered through a 0.45 urn membrane and concentrated to dryness under reduced pressure. The residue was taken up in dichloromethane (20 mL) and saturated aqueous sodium hydrogen carbonate solution (5 mL). The pH of the aqueous phase was adjusted to pH~10 with 1M aqueous sodium hydroxide solution. The aqueous phase was back extracted twice with dichloromethane (4x 20 mL) and the combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. Chromatography on silica gel with dichloromethane/methanol (17:3) gave 195 mg (69%) of the title compound as a white foam. MS (ESP): 471.22 (MH+) for C25H28F2 N403 1H NMR (300 MHz. DMSO-d^ 8: 0.82-0.91 (m,4H); 1.16-1.26 (m, HI); 1.74-1.90 (m, 2H); 2.16-2.25 (m, 2H); 2.34 -2.42 (m, 2H); 2.85-2.95 (m, 1H); 3.08 (d, 1H, J = 11.5 Hz); 3.76 (s, 2H); 4.27-4.34 (m, 6H); 6.63 (d, 1H, J= 9.8 Hz); 6.96 (s, 1H); 7.18-7.32 (m, 2H); 7.94 (d, 1H, J = 9.8 Hz); 8.03 (s, 1H), The intermediates for Example 120 were prepared as follows: Intermediate 213: l-[2-(4-Amino-2-methvlpiperidin-l-vl')ethvl]-5.7-difluoroquinolin- 2d/fl-one A solution of l-{2~[4-(dibenzylamino)-2-methylpiperidin-l-yl]ethyl}-5,7- difiuoroquinolin-2(l//)-one (Intermediate 214 358 mg, 0,71 mmol) in methanol (6 mL) was treated with palladium hydroxide on carbon (100 mg). The reaction was stirred at room temperature under hydrogen gas for 18 hours, filtered through celite, rinsed with methanol (100 mL), and concentrated under reduced pressure to afford 225 mg (96%) of a yellow oil. MS (ESP): (MH+) for C17H21F2N3O. 1H-NMR(DMSO-d6) δ: 0.74-0.87 (m, 4H); 1.04-1.17 (dq, III, J= 12.1, 11.9, 3.7 H/.); 1.54-1.67 (m, 2H); 2.16-2.26 (m, 2H); 2.30-2.39 (m, 1H); 2.84-2.95 (m, HI); 3.02-3.08 (ra, 1H); 4.26 (t, 2H, J Hz). Intermediate 214; 1- {2-[4-(Dibenzylamino)-2-methylpipcndin- l-yllethyll -5.7- difluoroqumolin-2( H)-one A solution of 5,7-difluoroquinolin-2(1H)-one (40 mg, 1.9 mmol) in dry dimethylformamide (DMF) (5 mL) was treated at 0 °C with a cooling bath under stirring with sodium hydride (80 mg, 60% in oil, 2.0 mmol). The cooling bath was removed and the mixture was stirred for 30 minutes at room temperature. A solution of 2-[4-(benzylamino)-2- methylpiperidin-1-yl]ethyl methanesulfonate in DMF (Intermediate 215, 0.58 mmol/ mL, 3.5 mL, -2,03 mmol) was then added and the resulting mixture was stirred over night at room temperature. The DMF was removed under reduced pressure, and the residue was taken up in ethyl acetate (100 mL) and saturated aqueous sodium hydrogencarbonate solution (30 mL). The aqueous phase was back extracted once with ethyl acetate (50 mL). The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. Chromatography on silica gel with hexanes/acetone (2:1) gave 365 mg (39% yield) of the product as a yellow solid. )^ ?&9\'T MS (ESP): 502 (MH+) for C3,H33F2N30 1H-NMR (DMSO-d6) δ: 0.89 (d, 3H, J = 5.5 Hz); 1.10-1.23 (m, 1H); 1.46-1.54 (m, 1H); 1.70 (t, 2H, J - 14.3 Hz); 2.10-2.16 (m, 2H); 2.35-2.44 (m, 211); 2.82-2.89 (m, 1H); 3.12 (d, 1H, J « 10.4 Hz); 3.54 (s, 4H); 4.21-4.26 (m, 2H); 6.61 (d, 1H, 9.8 Hz); 7.16-7.34 (m, 12H); 7.95 (d, 1H). Intermediate 215: 2-[4-(Dibenzvlamino)-2-metbylpiperidin-l -yl]ethyl methanesulfpnate A mixture 2-[4-(dibenzylainino)-2-methylpiperidin-l-yl]ethanol (Intermediate 216, 660 mg, 1,9 mmol) in dry dichloromethane (6 mL) and triethyl amine (0.375 mL, 2.7 mmol) was treated at 0°C with rnethanesulfonyl chloride (0.175 mL, 8.4 mmol). After 45 minutes the reaction was complete by TLC (chloroform/methanol 6:1, rf 0.54). Potassium phosphate buffer (pH 7, 1M, 25 mL) was added, dichloromethane was removed under reduced pressure and it was extracted with ice cold ethyl acetate (2 x 100 mL) and dried over sodium sulfate. The solvent was removed under reduced pressure and the crude preparation of the mesylate was used without delay for the next step. MS (ESP): 417.18 (MH+) for C23H32N2O3S. Intermediate 216; 2-F4-(Dibenzvlamino)2-methylpiperidin-1 -yllethanol To a solution of N,N-dibenzyl-2-methyIpiperidin-4-amine (Intermediate 217, 880 mg, 3.0 mmol) in acetonitrile (6 mL) was added triethylamine (0.85 ml, 6.0 mmol) and 2- bromoethanol (0.32 mL, 4.5 mmol). The reaction is stirred at 70°C at 300 watts in the microwave for 20 minutes. Acetonitrile was removed under reduced pressure, the residue was taken up in dichloromethane (100 mL) and saturated aqueous sodium hydrogen carbonate solution (30 mL) and the aqueous phase was back extracted three times with dichloromethane (3x 70 mL). The combined organic phases were dried over sodium sulfate and concentrated to dryness under reduced pressure. Chromatography of the residue on silica gel with dichloromethane/methanol (10:1) gave 660 mg (65% yield) of the product as an orange solid. MS (ESP): 339.22 (MH4) for C22H3oN2O. 1H-NMR(DMSO-d6)δ: 1.01 (d, 3H, J=5.8 Hx), 1.22-1.34 (m, 1H); 1.48-1.56 (m, 1H); 1.69 (d, 2H, J- 11.1 Hz); 1.95-2.11 (m, 2H); 2.14-2.30 (m,. 1H); 2.38-2.43 (m, 1H); 2.64- 2.80 (m, 1H); 2.84-3.00 (m, 1H); 3.37-3.41 (m, 1H); 3.55 (s, 4H); 4.24-4.35 (m, 1H); 7.15- 7.22 (m, 2H); 7.24-7.34 (m, 8H). Intermediate 217: N.N-Dibenzvl-2-methvlpiperidin-4-amine A mixture of ethyl 4-(dibenzylamino)-2-methylpiperidine-l-carboxylate (Intermediate 218,1.28 g, 3.78 mmol) in dry isopropyl alcohol (30 mL) was added potassium hydroxide (0.65 mL, 8.4 mmol). The reaction was stirred at 105 °C for 6 hours. 2- Propanol was removed under reduced pressure, the residue was taken up in dichloromethane (100 mL), filtered through a 0.5 μm membrane, and concentrated under reduced pressure. Chromatography of the residue on silica gel with dichloromethane/methanol/ammonium hydroxide (85:15:0.1) gave 882 mg (79% yield) of the product as a red oil. MS (ESP): 295.18 (MH+) for C2oH26N2. 1H-NMR(DMSO-d6) δ: 0.98 (d, 3H, J= 5.8 Hz); 1.07-1.14 (m, 1H); 1.37 (dq, 1H, J =12.0,4.2 Hz); 1.68 (t, 2H, J= 13 Hz); 2.26-2.36 (m, 2H); 2.40-2.46 (m, 1H); 2.91-2.97 (m, 1H); 3.56 (s, 4H); 7.16-7.20 (m, 2H); 7.25-7.34 (m, 8H). Intermediate 218: Ethvl 4-rdibenzvlamino')-2-methvlpiperidine-1 -carboxvlate A mixture of ethyl 4-(benzylamino)-2-methylpiperidine-l-carboxylate (Intermediate 219,1.57 g, 5.7 mmol), cesium carbonate (3.72 g, 11.4 mmol) and benzyl bromide (1.36 mL, 11.4 mmol) in dry DMF (20 mL) was heated at 80°C for 16 hours. The DMF was removed under reduced pressure, the residue was taken up in ethyl acetate (150 mL) arid water (75 mL) and the aqueous phase was back extracted once with ethyl acetate (3x150 mL). The combined organic phases were washed with brine (100 mL) and were dried over sodium sulfate. Chromatography on silica gel with hexanes/ethyl acetate (3:2) gave 1.43 g (68% yield) of the product as a yellow oil. MS (ESP): 367 (MH+) for C23H30N2O2. 1H-NMR (DMSO-d6) δ: 1.07-1.16 (m, 6H); 1.47-1.61 (m, 2H); 1.72-1.93 (m, 2H); 2.56-2.70 (m, 1H); 3.11-3.19 (m, 1H); 3.48-3.63 (m, 6H); 3.89-4.00 (m, 2H); 7.17-7.21 (m, 2H); 7.29-7.38 (m, 8H). Intermediate 219: Ethyl 4-(benzvlamino)-2-methylpiperidine-l-carboxvlate A solution of ethyl 2-methyl-4-oxopiperidine-l-carboxylate (2.20 grams, 11.9 mmol) and benzyl benzylamine in dichloroethane/methanol (4:1, 50 mL) was heated over 3 A molecular sieves at 90°C for 16 hours. The reaction mixture was cooled to 0°C, and sodium triacetoxy borohydride (5.03 g, 23.8 mmol) was added. The resulting reaction mixture was stirred at room temperature for 30 minutes and then was filtered through a 0.45 urn membrane -JtfTand concentrated to dryness under reduced pressure. The residue was taken up in aqueous IN HC1 solution and washed with ether (2 x 50 mL). The pH of the aqueous phase was adjusted to apH of approximately 7 with 1M aqueous sodium bicarbonate solution. The aqueous phase was back extracted twice with ether (4x 50 mL) and the combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. Chromatography on silica gel with dichloromethane/methanol (94:6) gave 1.57 g (47% yield) of a yellow oil. MS (ESP): 277 (MH+) for C16H24N2O2 1'H-NMR (DMSO-d£) δ: US (t, 3H, J = 7.1 Hz); 1.30 (d, 3H, J = 6.8 Hz); 1.52-1.59 (m, 3H); 1.61-1.71 (m, 1H); 2.80-2.82 (m, 1H); 3.22-3.27 (m, 1H); 3.57-3.73 (m, 3H); 3.95- 4.06 (m, 3H); 7.18-7.34 (m, 5H). Example 121 l-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-lyl} ethyl)-2-oxo-l,2-dihydroquinoline-7-carbonitrile A mixture of 7-chloro-l-(2-{4-[(2,3-dihydro[l,4]dioxino[2,3-c]pyridin-7- ylmethyl)amhio]piperidin-l-yl}ethyl)quinolin-2(lH)-one (2.11 g, crude, ~3.47 mmol) and zinc cyanide (244 mg, 2.1 mmol) in dry DMF (8 mL) was degassed and flushed with nitrogen three times. Zinc (174 mg, 0.059 mmol, 51.6 mM solution in heptane) was added, followed by 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (63 mg, 0.11 mmol) and tris(dibenzylideneacetone)dipalladium (0) (100 mg, 0.11 mmol) and it was degassed and flushed with nitrogen like above. The mixture was stirred for 30 minutes at room temperature and then degassed and flushed with nitrogen again. It was heated at 120°C for 3 hours. The solvent was removed under reduced pressure and the residue taken up in chloroform/isopropyl alcohol (3:1,50 mL) and filtered through celite and concentrated under reduced pressure. Chromatography by reverse phase (Column: Atlantis Hilic; Gradient: 90% ACE/0.1% TFA; 5% Water/0.1% TFA; and 5% IsopropanoVO.1% TFA; Flow Rate: 1 mL/min.) afforded 418 mg (20%) of a brown oil as a TFA salt. MS fESPV 447.14 (MH+) for C24H26N603 1H NMR (300 MHz. DMSO-d6) δ:1.75-1.87 (m, 2H); 2.29-2.38 (d, 2H, .7=12.6 Hz); 3.00-3.20 (m, 2H); 3.37-3.49 (m, 2H); 3.90 (d, 2H, .7=12.6 Hz); 4.24 (br s, 2H); 4.35 (d, 2H, J = 4.6 Hz); 4.39 (d, 2H, J = 4.6 Hz); 4.62-4.72 (m, 2H); 6.95 (d, 1H, 1 = 9.6); 7.12 (s, 1H); 8.02 (d, 1H, J = 7.7 Hz); 8.11 (d, 1H, J = 9.6 Hz); 8.21 (s, 1H); 8.47 (d, 1H, J = 7.7); 9.18- 9.45 (m, 2H). Example 122 Cis±l-[(2E)-3-(2,5-difluorophenyl)prop-2-en-l-yl}-4-[3-(6-methoxy-3-oxo-2,3- dihydro-4;H-l,4-benzoxazin-4-yl)propyl]piperiduie-3-carboxylic acid A solution of methyl Cis(±)-l-[(2£)-3-(2,5-difluorophenyl)prop-2-en-l-yl]-4-[3-(6- methoxy-3-oxo-2,3-dihydro-4H-l,4-benzoxazin-4-yl)propyl]piperidine-3-carboxylate (Example 123) (105 mg, 0.204 mraol) in methanol (1 mL) was treated with a solution of sodium hydroxide (IN, 1 mL) the reaction was warmed to 30 °C for 18 hours. The temperature was increased to 60 °C for 6 hours. The solvents were evaporated, the reaction was diluted with ethyl acetate and water. The pH was adjusted to 7 with IN HC1. The layers were separated. The aqueous phase was extracted with ethyl acetate (2 X 20mL). The organic layers were combined dried over magnesium sulfate and concentrated at reduced pressure. The residue was taken up and dichloromethane and precipitated with ether in a dry ice/acetone bam. The solvent was decanted. The solid was dried under high vacuum to obtain 21 mg (20%) of an off-white solid. MS(ESP'): 501 (MH+) for C27H3oF2N205 1H-NMR (400 MHZ.DMSO-d6) δ114 -1.26 (m, IH) 1.41 -1.53 (m, 1H) 1.57 -1.68 (m, 2H) 1.74 - 1.84 (m, III) 1.98 - 2.10 (m, IH) 2.89 - 2.97 (m, IH) 2.98 - 3.04 (m, IH) 3.04 - 3.12 (m, IH) 3.12 - 3.20 (m, IH) 3.22 - 3.34 (m, IH) 3.34 - 3.45 (m, 2H) 3.71 (s, 3H) 3.81 - 3.86 (m, IH) 3.88 - 3.96 (m, 3H) 4.46 (s, 2H) 6.47 - 6.58 (m, 2H) 6.63 (s, IH) 6.85 (d, 2H) 7.06 - 7.18 (m, 2H) 7.39 - 7.48 (m, IH) 8.11 (s, IH) Example 123 Methyl cis(±)l-[(2E)-3-(2,5-difluorophenyl)prop-2-en-l-yll-4-[3-(6-methoxy-3- oxo-2,3-dihydro-4H-l,4-benzoxazin-4-yl)propyl]piperidine-3-carboxyIatc A solution of methyl 4-[3-(6-methoxy-3-oxo-2,3-dihydro-4//-l,4-benzoxazin-4- yl)propyl]piperidine-3-carboxylate (Intermediate 220) (150 mg, 0.414 mmol) in ethanol (2 mL) was treated with K2CO3 (63 mg, 0.455 mmol) followed by a solution of 2-[(lE)-3- chloroprop-l-en-l-yl]-l,4-difluorobenzene (Intermediate 124) (86 mg, 0.455 mmol) in ethanol (1 mL). The reaction was warmed to 40°C for 18 hours. The reaction was partitioned between ethyl acetate and water. The aqueous layer was extracted with dichloromethane (2 X 20 mL). The organic extracts were combined, dried over MgSO4 and concentrated at reduced pressure to obtain a yellow oil. Chromatography on silica gel eluting with (0-2.5%) methanol in dichloromethane gave the title compound as a yellow oil (120 mg, 56 %). MS(ESP):515 (MH4) for C28H32F2N205 ( 1H-NMR (400 Mz. DMSQ-d6 δ 1.19 -1.30 (m, 2H) 1.39 -1.49 (m, 2H) 1.49 -1.61 (m, 2H) 1.66 - 1.78 (m, 2H) 2.16 - 2.28 (m, 1H) 2.36 (s, 1H) 2.64 - 2.75 (m, 1H) 3.03 - 3.15 (m, 2H) 3.54 (s, 3H) 3.73 (s, 3H) 3.81 - 3.92 (m, 2H) 4.52 (s, 2H) 6.39 - 6.51 (m, 1H) 6.56 (dd, 7=8.6,2 Hz, 2H) 6.71 (d, ,7=2 Hz, 1H) 6.92 (d, 7=8.6 Hz, 1H) 7.07 - 7.18 (m, 1H) 7.18 - 7.30 (m, 1H) 7.46 - 7.57 (m, 1H). The intermediates for Example 2 were prepared as follows: Intermediate 220; Methyl 4-[3-(6-methoxv-3-oxo-2.3-dihvdro-4H-1.4-benzoxazin-4- yl)propvl1piperidme-3-carboxvlate To an ice-cooled solution of 6-methoxy-2H-l,4-benzoxazin-3(4H)-one (Intermediate 48) (407 mg, 2.29 mmol) in DMF was added sodium hydride (110 mg, 2.75 mmol). After stirring for 2 hours a solution of l-tert-butyl 3-methyl 4-{3- [(methylsulfonyl)oxy]propyl}piperidine-l,3-dicarboxylate (868 mg, ~2.29 mmol) (Intermediate 132) hi DMF (5 mL) was added. The reaction was allowed to stir at room temperature for five days. The reaction was diluted with ethyl acetate and water. The pH was adjusted to approximately 3 with IN HC1. The layers were separated. The aqueous layer was extracted with ethyl acetate (3 X 30 mL). The combined organic layers were washed with water (4X 50 mL), dried over magnesium sulfate and concentrated at reduced pressure to obtain a semi-solid. Chromatography on silica gel eluting with (0-2.5 %) methanol in dichloromethane gave the product as a mixture of diastereomers. Reverse phase separation using a 50-60 % gradient of acetonitrile in water with 0.1% trifluoroacetic acid gave the cis diastereomer as the faster eluting peak. Upon evaporation of the organic components and extraction of the aqueous with 20% methanol in dichloromethane 150 mg of the cis diastereomer was obtained. 1HNMR(CDCl3): δ1.19 -1.30 (m, 1H); 1.32 -1.40 (m, 2H); 1.64 -1.75 (m, 2H); 1.77 -1.89 (m, 2H); 1.94 - 2.04 (m, 1H); 2.93 - 3.01 (m, 1H); 3.06 - 3.11 (m, 1H); 3.13 - 3.20 (m, 1H); 3.47 - 3.53 (m, 1H); 3.54 - 3.60 (m, 1H); 3.74 (s, 3H); 3.79 (s, 3H); 3.82 - 3.90 (m, 1H); 3.90 - 4.00 (m, 1H); 4.49 - 4.57 (m, 2H); 6.49 - 6.56 (m, 2H); 6.89 - 6.97 (m, 1H). The trans compound was obtained as a mixture of amine and Boc protected material (138 mg) through neutralization of the aqueous layer with sodium bicarbonate before extraction with 20% methanol in dichloromethane. The mixture was dissolved in ethanol (3 mL) and heated in the microwave at 150°C for four hours. MS(ESP): 363 (MH+) for C19H26N2O5 Example 124 l-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-lyI} ethyl)-7-methoxy-3,4-dihydroquinoxalin-2(lH)-one To a solution of l-(2-{4-[(2,3-dihydro[l,4]dioxino[2,3-c]pyridin-7- ylmethyl)amino]piperidin-l-yl}ethyl)-7-methoxyquinoxalin-2(lH)-one (Example 72, 0.125 g) in ethanol (4 mL) was added sodium borohydride (40 mg). After 3 hour at room temperature, additional sodium borohydride (47 mg) was added. After 30 minutes the reaction was quenched with acetone and concentrated. Chromatography on silica gel with a gradient of dichloromethane to 20% methanol in dichloromethane gave 108 mg of the product as a colorless solid. MS (ESI) 454 (MH4) for C24H31N504 1HNMR (DMSO-D6) δppm): 1.36 (m, 2H); 1.78 - 1.88 (m, 2H); 1.98 (t, 2H); 2.41 (t, 2H); 2.52 - 2.60 (m, 1H); 2.89 (d, 2H); 3.63 (d, 2H); 3.67 (s, 3H); 3.77 - 3.87 (m, 211); 3.88 - 3.95 (m, 2H); 4.25 - 4.30 (m, 2H); 4.31 - 4.36 (m, 2H); 5.65 (s, 1H); 6.46 (dd, 1H); 6.62 (d, 1H); 6.66 (d, 1H); 6.95 - 7.01 (m, 1H); 8.05 (s, 1H). Example 125 5,7-Difluoro-l-[2-(4-{[(l-oxo-l,3-dihydro-2-benzofuran-5-yl)methyl]amino} piperidin-l-yl)ethyl]quinolin-2(lH)-one The compound was prepared following the procedure described for Examples 87-96. MS (ES). 454 (MH+) for C25H25N3O3 1HNMR (DMSO-D6) δ(ppm): 1.83 (s, 2H); 2.32 (s, 2H); 3.07 (s, 1H); 3.31 (s, 2H); 3.45 (s, 2H); 3.80 (s, 2H); 4.39 (s, 2H); 4.53 (s, 2H); 5.45 (s, 2H); 6.66 (d, 1H); 7.29 (t, 1H); 7.42 (d, 1H); 7.73 (d, 1H); 7.80 (s, 1H; 7.94 (d, 1H); 8.01 (d, 1H); 9.49 (s, 1H). Example 126 6-[({l-[2-(7-Methoxy-2-oxoquinoxalin-l(2H)-yl)propyl]piperidin-4- yl}amino)methyl]-2H-pyrido[3,2-b][l,4]oxazin-3(4H)-one l-[2-(4-ammopiperidin-l-yl)-l-methylethyl]-7-methoxyquinoxalin-2(l/0-°ne (Intermediate 221) (160 mg crude, 0.51 mmol), 3-oxo-3,4-dihydro-2H-pyrido[3,2- 6][l,4]oxazine-6-carbaldehyde (WO 2004/058144) (91 mg, 0.51 mmol), and sodium triacetoxy borohydride (320 mg, 1.5 mmol) were reacted as described according to Example 69. Chromatography on silica gel eluting with 5% methanol/dichloromethane containing 0.25% ammonium hydroxide gave 105 mg (63%) of the title compound as an off-white solid. MS (ESP): 479 (MH4) for C25H30N6O4 1HNMR (DMSO-D6) δ(ppm): 0.96 (d, 3H); 0.99 - 1.14 (m, 2H); 1.71 (t, 2H); 1.95 (s, 1H); 2.10 (t, 1H); 2.22 - 2.41 (m, 2H); 2.89 - 3.01 (m, 1H); 3.03 - 3.14 (m, 1H); 3.64 (s, 2H); 3.90 (s, 3H); 4.11 (q, 1H); 4.27 - 4.40 (m, 1H); 4.55 - 4.66 (m, 2H); 6.93 - 7.04 (m, 3H); 7.23 - 7.33 (m, 1H); 7.69 - 7.80 (m, 1H); 8.04 (s, 1H); 11.16 (s, 1H). Intermediate 221; l-[2-(4-Aminopiperidin4-vl)-l-methvlethvl]-7- metfapxyquinoxarm-2( lH)-one A solution of tert-butyl {l-[2-(7-methoxy-2-oxoquinoxalin-l(2/f)-yl)propyl]piperidin- 4-yl}carbamate (Intermediate 222,200 mg, 0.48 mmol) in dichloromethane (30 mL) was treated with trifluoroacetic acid (3 mL). After 2 hours, the reaction was concentrated to dryness, The residue was partitioned between 15% methanol/chloroform. The aqueous phase was re-extracted 3x with 15% methanol/chloroform. The combined organic phases were dried over magnesium sulfate, filtered, and concentrated to dryness giving 160 mg (100%) of the crude product as an oil. MS (ESP):. 317 (MH+) for C17H24N4O2 Intermediate 222; tert-Butvl {1-[2-(7-methoxy-2-oxoquinoxalin-l(2H)- vl)propyl]piperidin-4-yl} carbamate A solution of 7-methoxyquinoxalin-2(lH)-one (Intermediate 148, 590 mg, 3.35 mmol) in dry DMF (10 mL) was cooled in an ice bath under nitrogen and treated with sodium hydride (60%, 160 mg, 4.02 mmol). The reaction was stirred at room temperature for ~90 minutes. The reaction was again cooled in an ice bath and treated with a solution of 2-{4- [(tert-butoxycarbonyl)amino]piperidin-l-yl}-l-methylethyl methanesulfonate in dry DMF (Intermediate 223, ~0.43 mmol/ml, 4.3 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was concentrated to dryness. Residual DMF was coevaporated Ix with toluene. The resulting residue was partitioned between ethyl acetate and water. The aqueous phase was re-extracted 3x with ethyl acetate. The organic phases were combined, dried over magnesium sulfate, filtered, and concentrated to dryness. Chromatography on silica gel with 25% acetone/hexanes gave 410 mg (29%) of product which contained ~10% starting material (7-methoxyquinoxalin-2(1H)~one). This material was used directly in the next step. MS (ESP): 417 (MH+) for C22H32N404 1HNMR (DMSO-D6) δ (ppm): 0.96 (d, 3H); 1.10 -1.26 (m, 2H); 1.31 -1.42 (m, 9H); 1.53 - 1.72 (m, 2H); 2.14 (t, 1H); 2.37 (t, 1H); 2.94 (d, 1H); 3.04 - 3.15 (m, 2H); 3.87 - 3.96 (m, 3H); 4.06 - 4.20 (m, 2H); 4.32 (dd, 1H); 6.71 (d, 1H); 6.95 - 7.05 (m, 2H); 7.71 - 7.78 (m, 1H); 8.04 (s, 1H). Intermediate 223; 2- (4-[(tert-Butoxvcarbonyl)amino]piperidin-1 -yl) -1 -methvlethyl methanesulfonate tert-Butyl [l-(2-hydroxypropyl)piperidin-4-yl]carbamate (Intermediate 224,1.1 g, 4.3 mmol), triethylamine (0.90 mL, 6.5 mmol) and methanesulfonyl chloride (0.37 mL, 4.7 mmol). Were reacted as described for Intermediate 6. The crude mesylate was directly used for the next step. Intermediate 224; tert-Butvl ri-f2-hydroxypropvr)piperidin-4-vncarbamate tert-Butyl piperidin-4-ylcarbamate (2.0 g, 10.0 mmol), l-bromopropan-2-ol (2.8 g, 20.0 mmol, commercial product which also contained 30% of the regioisomer 2- bromopropan-1-ol), triethylamine (4.2 mL, 30.0 mmol), and acetonitrile (15 mL) were combined in a microwave vial and heated to 70 °C for 4 hours. The reaction mixture was concentrated to dryness. The crude product was partitioned between ethyl acetate/water. The aqueous phase was re-extracted 2x with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered, and concentrated to dryness. The product was purified by flash chromatography on silica gel eluting with a gradient of 20-30% methanol in dichloromethane to give 1.7 g of the desired product as an oil. 1HNMR (DMSO-D6) δppm 1.01 (d, 3H); 1.26 -1.48 (m, 11H); 1.64 (d, 2H); 1.85 - 2.04 (m, 2H); 2.03 - 2.27 (m, 2H); 2.78 (d, 2H); 3.09 - 3.29 (m, 1H); 3.62 - 3.81 (m, 1H); 4.23 (d, 1H); 6.75 (d, 1H). Example 127 S,7-Dlfluoro-l-(2-{4-[(5,6,7,8-tetrahydro-l,8-naphthyridin-2- ylmethyl)amino]piperidin-l-yl}ethyl)quinolin-2(1H)-one l-[2-(4-Aminopiperidin-l-yl)ethyl]-5J7-difluoroquinolin-2(lH)-one (Intermediate 23) (126 mg, 0.410 mmol), 5,6,7,8-tetrahydro-l,8-naphthyridine-2-carbaldehyde (JOG 2004, 69,1959-1966) (66 mg, 0.410 mmol) and sodium triacetoxy borohydride (52 mg, 0.82 mmol) were reacted as described for Example 6, to give 84.82 mg of the mono acetate salt of the product as a pale yellow foam. MS (ES): 454.54 (MH4) forC25H29F2N50 1HNMR (DMSO-D6) δ (ppm): 1.12 -1.27 (m, 2H); 1.67 -1.79 (m, 4H); 2.01 (t, 2H); 2.29 - 2.42 (m, 1H); 2.60 (t, 2H); 2.88 (d, 2H); 3.22 (t, 2H); 3.51 (s, 2H); 4.29 (t, 2H); 6.28 (s, 1H); 6.40 (d, 1H); 6.61 (d, 1H); 7.05 (d, 1H); 7.16 - 7.26 (m, 1H); 7.31 (d, 1H); 7.96 (d, 1H). All cited publications, patents, and patent documents are incorporated by reference herein, as though individually incorporated by reference. The invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope of the invention. CLAIMS What is claimed is: 1. A compound of formula I: (Formula Removed) or a pharmaceutically acceptable salt thereof, or N-oxides thereof, wherein: L is a group of formula L1-L15: (Formula Removed) wherein indicates the point of attachment; Z3, Z6, and Z7 are C or N provided that when Z3, Z6, or Z7 is N, then R2a, R2C, or R2d are absent; and R2a, R2b, R2c, R2d, R2e, and R2f, are each independently H, halo, cyano, carboxy, nitro, carbamoyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkyl, hydroxy, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, (C1-C6)alkoxy, NHCO-(C1-C6)alkyl, SO2(C1-C6)alkyl) S02NH(C1-C6)alkyl, or S02N((C1-C6)alkyl)2; R2g, Rag1, and Rag" are each independently H, (C1-C6)alkyl, or halo(C1-C6)alkyl; U1 is CRaRb — CRcRd or CRaRb— CRcRd— CReRf, wherein Ra, Rb, Rc, Rd, Re, and Rf are each independently hydrogen or (C1-C6)alkyl; M is a group of formula M1-M5: (Formula Removed) wherein R2 is H or carboxy, and wherein indicate points of attachment; Ry and Ry1 are each independently H, halo, hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy, CO2R", wherein R" is H, (C1-C6)alkyl, or halo(C1-C6)alkyl, or Ry and Ry' together with the carbon to which they are attached form C=0; or Ry and Ry' together form a bridge; X and Y are each independently CH2, 0, or NR'; " " is a bond or is absent; n is 1, or 2, or 3; when M is a group of formula Ml or M4, U2 is NR1— W, wherein W is CH2, CO, SO2, (Formula Removed) ^ , CH2CH2, CH2CH=CH, or CH2OC, wherein each hydrogen may be optionally replaced by halo or (C1-C6)alkyl; when M is a group of formula M2, M3, or M5, U2 is W wherein W is as defined herein above; R1 at each occurrence is independently H, (C1-C6)alkyl, -CO-(C1-C6)alkyl, -(C1-C6)alkylcarboxy, -C02(C1-C6)alkyl, -CO-NH(C1-C6)alkyl, -CO-N(C1-C6)alkyl)2, or SO2(C1-C6)alkyl, any of which may be optionally substituted on carbon with halo, hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy, SO2(C1-C6)alkyl,NH2,NII(C1-C6)alkyl, or N((C1-C6)alkyl)2; when W is CH2, CO or S02, R is aryl, heteroaryl, heterocyclyl or ortho-fused bicyclic (Formula Removed) heteroaryl, or when W is CH2CH2, CH2CH=CH, or CH2C=C, R is aryl, heteroaryl, heteroaryloxy, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylamino; wherein any R may be optionally substituted on carbon; and wherein any ring nitrogen in R may be optionally substituted by (C1-C6)alkyl; and any of L, U1, M, U2, or R may be optionally substituted on carbon by one, two or three substituents selected from halo, nitro, cyano, hydroxy, oxo, trifluoromethoxy, trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulphamoyl, methyl, ethyl, ethenyl, ethynyl, methoxy, ethoxy, methoxycarbonyl, ethoxycarbonyl, heteroaryl, heterocyclyl, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, or acetylamino; with the proviso that when L is a group of formula L8 or L15, W is not CO. 2. A compound or a pharmaceutically acceptable salt thereof, according to claim 1, wherein L is: (Formula Removed) , wherein indicates the point of attachment; Z is CH or N when " ---- " is a bond, or Z is 0 or NH when "---- "is absent; and R2a, R2b R2c, and R2d are each independently H, halo, cyano, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkyl, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, (C1-C6)alkoxy, NHCO-(C1-C6)alkyl, SO2(C1-C6)alkyl, SO2NH(C1-C6)alkyl, orso2N((C1-C6)alkyl)2. 3. A compound or a pharmaceutically acceptable salt thereof, according to either claim 1 or 2, wherein (Formula Removed) L is .wherein" "indicates the point of attachment; and ZisCHorNwhen" is a bond, or, when " ' is absent, Z is 0 or NH. 4. A compound or a pharmaceutically acceptable salt thereof, according to any one of claims 1-3, wherein U1—M— U2 is: (Formula Removed) wherein " '""* " uidicates the point of attachment; Ry is H, F, hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy, or carboxy; and R1 is H, (C1-C6)alkyl, -(C1-C6)alkylcarboxy, -CO-(C1-C6)alkyl, -C02(C1-C6)alkyl, -CO-NH(C1-C6)alkyl, -CO-N((C1-C6)alkyl)2, or SO2(C1-C6)alkyl. 5. A compound or a pharmaceutically acceptable salt thereof, according to any one of claims 1-4, wherein Ry is H, hydroxy, fluoro, or methoxy. 6. A compound or a pharmaceutically acceptable salt thereof, according to any one of claims 1-5, wherein R is 2,1,3-benzothiadiazol-5-yl; 3-oxo-3,4-dihydro-2H-1,4-benzothiazin-6-yl; 2,3-dihydro-benzo[l,4]dioxin-6-yl; 1,2,3-benzothiadiazol-5-yl; 3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl; 7-fluoro-3-oxo-3,4-dihydro-2tf-l,4-benzoxazin-6-yl; 2-oxo-2,3-dihydro-lH-pyrido[2,3-b][l,4]thiazin-7-yl; 2,3-dihydro-[l,4]dioxino[2,3-c]pyridin-7-yl; 3-oxo-3,4-dihydro-2H-pyrido[3,2-b] [ 1,4]oxazin-6-yl; [l,2,3]thiadiazolo[5,4-b]pyridin-6-yl; 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][l,4]thiazin-6-yl; 7-chloro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][l,4]thiazin-6-yl; 7-fluoro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][l,4]thiazin-6-yl; 2-thienylthio; or 2,5-difluorophenyl. 7. A compound or a pharmaceutically acceptable salt thereof, according to any one of (Formula Removed) claims 1-6, wherein R is , wherein indicates the point of attachment. 8. A compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1-3 which is a compound of formula II: (Formula Removed) R2a, R2b, R2C, and R2d are each independently H, fluoro, chloro, cyano, (C1-C6)alkyl, halo(C1-C6)alkyl, halo(C1-C66)alkoxy, (C1-C6)alkoxy; Z is CH orN when " " is a bond, or Z is O or NH when " — " is absent; M is a group of formula M1a or M2-M5: (Formula Removed) in the trans configuration relative to "*"; Ry and Ry1 are each independently H, hydroxy, fluoro, chloro, methoxy, carboxy, CO2(C1-C6)alkyl, or (C1-C6)alkyl, or together with tlie carbon to which they are attached form C=0; or Ry and Ry' together form a bridge; X is CH2, NH, N(C1-C6)aIkyl, N[CO-(C1-C6)alkyl], N[SO2(C1-C6)alkyl] or O; Y is CH2, NH, N(C1-C6)alkyl, N[CO-(C1-C6)alkyl], N[SO2(C1-C6)alkyl] or O; when M is a group of formula Mia or M4, U2 is NR'-W, wherein R' is IT, (C1-C6)alkyl, -(C1-C6)alkylcarboxy, -CO-(C,-C6)alkyl, -CO2(C,-C6)alkyl, -CO-NH(C1-C6)alkyl, -CO-N((C1-C6)alkyl)2, any of which may be optionally substituted on carbon with halo, hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy, S02(C1-C6)alkyl, NII2, NH(C1-C6)alkyl, or N((C1-C6)alkyl)2; and W is CH2, CO, SO2, CII2CH2, CH2CH=CH, or CII2C=C, wherein each hydrogen may he optionally replaced by halo or (C1-C6)alkyl; when M is a group of formula M2, M3, or M5, U2 is W wherein W is as defined herein above; and when W is CH2) CO or S02, R is aryl, hetcroaryl, heterocyclyl or ortho-fused bicyclic heteroaryl, or when W is CH2CH2, CH2CH-CH, or CH2CsC, R is aryl, hcteroaryl, heteroaryl(C1-C6)alkyloxy, heteroaryl(C1-C6)alkylthio, heteroaryl(C1-C6)alkylsulfinyI, heteroaryl(C1-C6)alkylsulfonyl, heteroaryl(C1-C6)alkylamino; wherein any R may be optionally substituted on carbon; and wherein any ring nitrogen in R may be optionally substituted by (C1-C6)alkyl. 9, A compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1-3 or 5-7 which is a compound of formula III: (Formula Removed) wherein R2a, R2b, R2c, and R2d are each independently H, fluoro, chloro, cyano, (C1-C6)alkyl. halo(C1-C6)alkyl, halo(C1-C6)alkoxy, (C1-C6)alkoxy; Z is CH or N when " is a bond, or, when is absent, Z is 0 or NH; Y1 is N or CRj, wherein R2 is H, hydroxy, or carboxy; U2 is NR'-W, wherein W is CH2, CO, SO2, CH2CH2, CH2CH=CH, or CH2CsC, wherein each hydrogen may be optionally replaced by halo or (C1-C6)alkyl; and (Formula Removed) R is , wherein" indicates the point of attachment. 10. A compound, or a phannaceutically acceptable salt thereof, according to any one of claims 1-7 which is a compound of formula IV: (Formula Removed) wherein R2a, R2b, R2c, and R2d are each independently H, fluoro, chloro, cyano, nitro, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkyl, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, (C1-C6)alkoxy,NHCO-(C1-C6)alkyl> S02(C1-C6)alkyl, S02NH(C1-C6)alkyl, or S02N((C1-C6)alkyl)2; Z is CH or N when " "" " is a bond, or, when " "-- "is absent, Z is 0 or NH; R'isHor(C1-C6)alkyl; W is CO, SO2, or CH2, wherein each hydrogen may be optionally replaced by halo or (C1-C6)alkyl; and (Formula Removed) R is , wherein indicates the point of attachment. 11, A compound according to any one of claims 1-7 or 9, or a pharmaceutically acceptable salt thereof, which is a compound of formula V: (Formula Removed) wherein R2a, R2b, R2C, and R2d are each independently H, fluoro, chloro, cyano, nitro, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkyl, halo(C1-C6)allcyl, halo(C1-C6)alkoxy, (C1-C6)alkoxy, NHCO-(Ci-C6)alkyl, S02(C1-C6)alkyl, S02NH(C1-C6)alkyl, or S02N((C1-C6)alkyl)2; Z is CH or N when " " is a bond, or, when " "is absent, Z is O or NH; and (Formula Removed) 12. A compound, or a pharmaceutically acceptable salt thereof, which is l-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-l-yl}ethyl)-7-methoxyquinolin-2(lH)-one; l-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)ainino]piperidin-l-yl}ethyl)-7-methoxyquinolin-4(lH)-one; Methyl l-(2-{4-[(2,3-dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1 -yl} ethyl)-6-methoxy- lH-indole-2-carboxylate; 6-[({ 1 -[2-(7-Methoxy-2-oxoquinolin-1 (2H)-yl)ethyl]piperidin-4-yl} amino)methyl]-2H-pyrido[3,2-b] [ 1,4]oxazin-3 (4H)-one; 1 -(2- {4-[(2,3-Dihydro[ 1,4]dioxino[2,3-c]pyridin-7-ylmethyl)arnmo]piperidin-1 -yl} ethyl)-2-oxo-1,2-dihydroquinoline-7-carbonitrile; 2-Oxo-1 -[2-(4- {[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b] [ 1,4]oxazin-6-yl)methyl]amino} piperidin-1 -yl)ethyl]-1,2-dihydroquinoline-7-carbonitrile; 6-[({l-[2-(7?8-Difluoro-2-oxoquinolin-l(2H)-yl)ethyl]piperidin-4-yl}amino)methyl]-2#-pyrido[3,2-b][l,4]oxazin-3(4H)-one; 6-[({l-[2-(5,7-Difluoro-2-oxoquinolin-l(2H)-yl)ethyl]piperidin-4-yl}amino)methylj-2//-pyrido[3,2-6][l,4]oxazin-3(4H)-one; 6-[({l-[2-(7-Fluoro-2-oxoquinolin-l(2H)-yl)ethyl]piperidin-4-yl}amino)methyl]-2//-pyrido[3,2-b] [1,4]oxazin-3(4H)-one; l-(2-{4-[(2)3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-l-yl}ethyl)-7-fluoroquinolin-2(l,H)-one; 6-[( {1 -[2-(7-Methoxy-2-oxo-3,4-dihydroquinolin-1 (2H)-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][l,4]oxazin-3(4H)-one; (3S,4R)-l-[2-(5>7-Difluoro-2-oxoquinolin-l(2H-yl)ethyl]-4-[(2,3-dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidine-3-carboxylic acid; (3S,4R)- l-[2-(5,7-Difluoro-2-oxoquinolin-1 (2H)-yl)ethyl]-4- {[(2E)-3-(2,5-difluorophenyl)prop-2-en-1 -yl]amino}piperidine-3-carboxylic acid; Methyl (3S',4R)-l-[2-(5,7-difluoro-2-oxoquuiolin-l(2H)-yl)ethyl]-4-[(2,3-dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidine-3-carboxylate; Methyl (3S,4R)-l -[2-(5,7-difluoro-2-oxoquinolin-l(2H-yl)ethyl]-4- {[(2E)-3-(2,5-difluorophenyl)prop-2-en-1 -yl]amino}piperidine-3-carboxylate; (3R)4R)-l-[2-(5,7-Difluoro-2-oxoquinolin-l(2H)-yl)ethyl]-4-[(2,3-dihydro[l,4]dioxino[2,3-6']pyridin-7-ylmethyl)amino]pipcridinc-3-carboxylic acid; (3R,4R)-l-[2-(5,7-Difluoro-2-oxoquinolin-l(2H)-yl)ethyl]-4-{[(2E)-3-(2,5-difluorophenyl)prop-2-en-l-yl]amino}piperidine-3-carboxylic acid; Methyl (3R,4R)-l-[2-(5,7-difluoro-2-oxoquinolin-l(2H)-yl)ethyl]-4-[(2,3-dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidine-3-carboxylate; Methyl (3S,4R)-l-[2-(5,7-difluoro-2-oxoquinolin-l(2H)-yl)ethyl]-4-{[(2E)-3-(2,5-difluorophenyl)prop-2-en-l-yl]amino}piperidine-3-carboxylate; Cis(±)6-[({l-[2-(5,7-Difluoro-2-oxoquinolin-l(2H)-yl)ethyl]-3-hydroxypiperidin-4-yl}amino)methyl]-2H-pyrido[3,2-6][l,4]oxazin-3(4H)-one; 4-(2-{4-[(2)3-Dihydro[l,4]dioxino[213-c]pyridin-7-ylmethyl)amino]pipendin-l-yl}ethyl)-6-methoxy-2H-l,4-benzoxazin-3(4H)-one; 6-[({l-[2-(6-Methoxy-3-oxo-2,3-dihydi-o-4H-l,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2b][l,4]oxazin-3(4H)-one; 6-[({l-[2-(6-Methoxy-3-oxo-2,3-dihydro-4H-l,4-benzothia7.in-4-yl)ethyl]piperidin-4-yl}araino)methyl]-2H-pyrido[3,2-b][l,4]oxazin-3(4H)-one; 4-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylraethyl)amino]piperidin-l-yl}ethyl)-6-methoxy-2H-1,4-benzothiazin-3(4H)-one; 6-[({l-[2-(6-Fluoro-3-oxo-2,3-dihydro-4H-l,4-benzoxazin-4-yl)cthyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][l,4]oxazin-3(4H)-one; 4-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-l-yl} cthyl)-6-fluoro-2H-1,4-benzoxazin-3 (4H)-onc; 6-[({l-[2-(6-Chloro-3-oxo-2,3-dihydro-4H-l,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][l,4]oxazin-3(4H)-one; 6-[({l-[2-(6-Methoxy-3-oxo-2,3-dihydro-4H-l,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-Z)][lJ4]thiazin-3(4H)-one; 3-Oxo-4-[2-(4-{[(3-oxo-3,4-dihydro-2H-pyrido[3)2-b][l,4]oxazin-6-yl)methyl]amino}piperidin-l-yl)ethyl]-3,4-dihydro-2H-l,4-benzoxazinc-6-carbonitrile; 6-{[(l-{2-[3-Oxo-6-(trifluoromethoxy)-2,3-dihydro-4H-ls4-benzoxazin-4-yl]ethyl}piperidin-4-yl)aTnino]methyl}-2H-pyrido[3,2-b)][l,4]oxazin-3(4H)-one; 6-[({l-[2-(6-Fluoro-3-oxo-2,3-dihydro-4H'-l,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}amino)methyl]-2H'-pyrido[3,2-Z)][l)4]thiazin-3(4H)-one; 4-(2-{4-[(2,3-Dihydro[l,4]dioxino[2(3-c]pyridin-7-ylmethyl)amirio]piperidin-l-yl}ethyl)-3-oxo-3,4-dihydro-2H-l,4-benzoxazine-6-carbonitrile; 6-[({l-[2-(6-Bromo-3-oxo-2,3-dihydro-4H-l)4-benzoxazin-4-yl)ethyl]piperidin-4-yl} amino)methyl]-2H-pyrido[3,2-b] [ 1,4]oxazin-3(4H)-one; 6-[( {1 -[2-(6-Hydroxy-3 -oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidin-4-yl} amino)methyl]-2//-pyrido[3,2-b] [ 1,4]oxazin-3(4H)-one; 4-{2-[4-({[2-(2,5-Difluorophenyl)cyclopropyl]methyl}amino)piperidin-l-yl]ethyl}-3-oxo-3,4-dihydro-2/f-l,4-benzoxazine-6-carbonitrile; 6-[({l-[2-(6,8-Difluoro-3-oxo-2,3-dihydro-4H-l,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}amino)metb.yl]-2Hr-pyrido[3,2-6][l,4]oxazin-3(4H)-one; 4-[2-(4-{[(2E)-3-(2,5-Difluorophenyl)prop-2-en-l-yl]amino}piperidin-l-yl)ethyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile; 6-[(trans-4-[2-(6-Methoxy-3-oxo-2,3-dihydro-4H-l,4-benzoxazin-4-yl)ethyl]cyclohexyl} amino)methyl]-2H-pyrido[3,2-b] [ 1,4]oxazin-3(4H)-one; 3-Oxo-4-[2-(tran.s-4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][l,4]oxazin-6-yl)raethyl]amino}cyclohexyl)ethyl]-3,4-dihydro-2H-l)4-benzoxazine-6-carbonitrile; 6-Bromo-4-[2-(4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][l,4]oxazin-6-yl)methyl]amino}piperidin-1 -yl)ethyl]-2tf-pyrido[3,2-b] [ 1,4]oxazin-3(4H)-one; 6-[({l-[2-(6-Nitro-3-oxo-2,3-dihydro-4//-l)4-benzoxazin-4-yl)ethyl]piperidin-4-yl} amino)methyl]-2H-pyrido [3,2-b] [ 1,4] oxazin-3 (4H)-one; 3-Oxo-4-[2-(4-{t(3-oxo-3,4-dihydro-2H'-pyrido[3,2-b][l,4]oxazin-6-yl)methyl] amino} piperid in-1 -yl)ethyl]-3,4-dihydro-2//-pyrido [3,2-b] [ 1,4]oxazine- 6-carbonitrile; 3-Oxo-4-[2-(4-{[(3-oxo-3,4-dihydro-2Hr-pyrido[3)2-b][l,4]oxazin-6-yl)methyl]amino}piperidin-l-yl)ethyl]-3,4-dihydro-2H-pyrido[3,2-i][l,4]oxazinc-6-carboxamide; Methyl 3-oxo-4-[2-(4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-i][l,4]oxaxin-6-yl)methyl]amino}piperidin-l-yl)ethyl]-3,4-dihydro-2H-l,4-benzoxazine-6-carboxylate; 6-[({l-[2-(6-AcetyI-3-oxo-2,3-dihydro-4H-l,4-bcnzoxazin-4-yl)ethyl]piperidin-4-yl} amino)methyl]-2H-pyrido[3,2-b] [ 1,4]oxazin-3 (4H)-one; 6-Acetyl-4-(2-{4-[(2,3-dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1 -yl} ethyl)-2H-1,4-benzoxazin-3 (4H)-one; 4-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]pipcridin-l-yl} ethyl)-6-methyl-2H-1,4-bcnzoxazin-3(4H)-one; 3-Oxo-4-[2-(6-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-A][l,4]oxazin-6-yl)methyl]amino}-3-azabicyclo[3.1.0]hex-3-yl)ethyl]-3,4-dihydro-2//-l,4-benzoxazine-6-carbonitrile; 4-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-l-yl} etiayl)-2H-1,4-benzoxazin-3(4H)-one; 6-{[(l-{2-[6-(l-Hydroxyethyl)-3-oxo-2,3-dihydro-4H-l,4-benzoxazin-4-yl]ethyl}piperidin-4-yl)amino]methyl}-2H-pyrido[3,2-b][l,4]oxazin-3(4H)-one; Ethyl N- {1 -[2-(6-cyano-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidiri-4-yl} -N-[(2E)-3 -(2,5-difluorophenyl)prop-2-en-1 -yl]glycinate; 6-{[(l-{2-[6-(Methylsulfonyl)-3-oxo-2,3-dihydro-4H-l,4-benzoxazin-4-yl]ethyl}piperidin-4-yl)amino]methyl}-2H-pyrido[3,2-b][l,4]oxazin-3(4H)-one; 6-{[(l-{2-[6-(Ethylsulfonyl)-3-oxo-2,3-dihydro-4H-l,4-bcnzoxazin-4-yl]ethyl}piperidin-4-yl)amino]methyl}-2H-pyrido[3,2-b][l,4]oxazm-3(4H)-one; 6-[( {1 -[2-(7-Methoxy-2-oxo-2H-3,1 -benzoxazin-1 (4H)-yl)ethyl]piperidin-4-yl} amino)methyl]-2H-pyrido[3,2-b)][l ,4]oxazin-3(4H)-one; 7-Methoxy-3-methyl-l-[2-(4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][l,4]oxazin-6-yl)methyl]amino}piperidin-l-yl)ethyl]quinazoline-2,4(lH,3H-dione; 4-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-2-oxopiperidin-l--yl} ethyl)-6-methoxy-2H-1,4-benzoxazin-3(4H)-one; 6-[({ 1 -[2-(6-Methoxy-3-oxo-2,3-dihydro-4H-l ,4-benzoxazin-4-yl)ethyl]-2-oxopiperidin-4-yl}amino)methyl]-2Hr-pyrido[3,2-H][l)4]oxazin-3(4H)-oue; 3-Oxo-4-[2-(2-oxo-4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][l,4]oxazin-6-yl)methyl]amino}piperidin-1 -yl)ethyl]-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile; 6-( {4-[3-(7-Methoxy-2-oxo-2H~3,1 -benzoxazin-1 (4H)-yl)propyl]piperazin-1 -yl}methyl)-2H-pyrido[3,2-b][l,4]oxazin-3(4H)-one; 4-{3-[4-(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)piperazin-l-yl]propyl}-6-methoxy-2H-1,4-benzoxazin-3 (4H)-one; 4-[2-({l-[(2E)-3-(2,5-Difluorophenyl)prop-2-en-l-yl]piperidin-4-yl}amino)ethyl]-6-methoxy-2H-l,4-benzoxazin-3(4H\|)-one; 4-(3-{4-[(2E)-3-(2,5-Difluorophenyl)prop-2-en-l-yl]piperazin-l-yl}propyl)-6-raethoxy-2H-1,4-benzoxazin-3(4H)-one; 6-[({l-[2-(6-Mcthoxy-2-oxo-l,7-naphthyridin-l(2H)-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][l,4]oxazin-3(4H)-one; Methyl l-[(2E)-3-(2,5-difluorophenyl)prop-2-en-l-yl]-4-[3-(6-cyano-3-oxo-2,3-dihydro-4/f-l,4-benzoxazin-4-yl)propyl]piperidine-3-carboxylate; 4-[3-(6-Cyano-3-oxo-2,3-dihydro-4H-l34-benzoxazin-4-yl)propyl]-l-[(2E)-3-(2,5-difluorophenyl)prop-2-en-l -yl]piperidine-3-carboxylic acid; 7-Fluoro-3-methyl-l-[2-(4-{[(3-oxo-3,4-dihydro-2H-pyridof3)2-b][l,4]oxazin-6-yl)methyl]amino}piperidin-l-yl)ethyl]quinazoline-2,4(lH,3H)-dione; 7-Chloro-1-(2-{4-[(2,3-dibydro[l ,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-l-yl}ethyl)-l,8-naphthyridin-2(lH)-one; l-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-l-yl} ethyl)-7-methoxy-1,8-naphthyridin-2( 1 H)-one; l-(2-{4-[(2,3-Dihydro[l,4]dioxmo[2,3-c]pyridin-7-ylmethyl)araino]piperidin-l-yl}ethyl)-7-fluoroquinoxalin-2(lH)-one; 6-[({l-[2-(7-Fluoro-2-oxoquinoxalin-l(2H)-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-6][l,4]oxazin-3(4H)-one; 1 -(2- {4-[(2,3-Dihydro[ 1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1 - yl}ethyl)-6-fluoroquinoxalin-2(lH)-one; l-(2-{4-[(2>3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-l-yl}ethyl)-7-methoxyquinoxalin-2(lH)-one; 6-[({l-[2-(7-Methoxy-2-oxoquinoxaIin-l(2H)-yl)ethyl]piperidin-4-yl}amino)methyl\|-2H-pyrido[3,2-b][l,4]oxazin-3(4H)-one; 6-[( {1 -[2-(7-Methoxy-2-oxoquinoxalin-1 (2H)-y l)ethyl]piperidin-4-yI} amino)methj'l j-2H-pyrido[3,2-6][l,4]thiazin-3(4H)-one; l-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmeth}'l)amino]piperidin-l-y 1} ethyl)-6,7-difluoroquinoxalin-2( lH)-one; 6-[({l-[2-(6,7-Difluoro-2-oxoquinoxalin-l(2H)-yOetM]piperid'n-4-yl}amino)methyl]-2H-pyrido[3,2-b][l,4]oxazin-3(4H)-one; l-(2-{4-[(213-Dihydro[l)4]dioxino[2,3-c]pyridin-7-ylmcthyl)amino]piperidin-l-yl}ethyI)-7,8-difluoroquinoxalin-2(lH)-one; 6-[({l-[2-(7J8-Difluoro-2-oxoquinoxalin-l(2H)-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][l,4]oxazin-3(4H)-one; 6-[({l-[2-(6J7-Dimethoxy-2-oxoquinoxalin-l(2H)-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,-2b][ 1,4]oxazin-3(4H)-one; 6-[({l-[2-(7-Methoxy-3-methyl-2-oxoquinoxalin-l(2H)-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][l,4]oxazin-3(H)-one; l-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]pipcridin-l- yl} ethyl)quinolin-2(1H)-°neJ l-(2-{4-[(2,3-Dihydrofl,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-l-yl} ethyl)quinolin-4( 1 H) -one; Cis(±)6-[({l-[2-(5,7-difluoro-2-oxoquinolin-l(2H)-yI)ethyl]-3-methoxypiperidin-4-yl}amino)methyl]-2H-pyrido[3)2-6][l,4]oxazin-3(4H)-oric; 7-Fluoro-2-oxo-l-[2-(4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-6][l>4]oxazin-6-yl)methyl]amino}piperidin-l-yl)ethyl]-l,2-dihydroquinoline-5-carbonitrile; 5-Fluoro-2-oxo-l-[2-(4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][l,4]oxazin-6-yl)methyl]amino}piperidin-l-yl)ethyl]-l,2-dihydroquinoline-7-carbonitrile; 7-Fluoro-l-[2-(4-{[(2-oxo-l,2-dihydroquinolin-3-yl)methyl]amino}piperidin-l-yl)ethyl]quinoxalin-2( 1H)-one; 1 -[2-(4-{[(2,2-Dimethyl-3,4-dihydro-2H-chromen-6-yl)methyl]amino}piperidin- 1 -yl)ethyl]-5,7-difluoroquinolin-2(lH)-one; l-[2-(4-{[(l,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)methyl]amino}pipcridin-l-yl)ethyl]-57-difluoroquinolin-2(lH)-one; 5,7-Difluoro-l -(2- {4-[(5,6)7,8-tetrahydronaphthal6n-2-ylraethyl)amino]pipcridin- 1 -yl}ethyl)quinolin-2(l//)-one; 5,7-Difluoro-l -[2-(4-{[(6-fluoro-4H:-l,3-benzodioxin-8-yl)methyl]amino}piperidin-l- yl)ethyl]quinolin-2(lH)-°ne; 5,7-Difluoro- 1 -(2- {4-[ClH"-indol-6-ylraethyl)atnino]piperidin-l-yl} ethyl)quinolin- 2(lH)-one; l-(2-{4-[(2,3-Dihydro-1H-inden-5-ylmethyl)amino]piperidin-l-yl}ethyl)-5,7-difluoroquinolin-2(lH)-one; 5,7-Difluoro-l-[2-(4-{[(l-methyl-lH-l,2,3-benzotriazol-5-yl)methyl]amino}pipt;ridin-1 -yl)ethyl]quinolin-2( lH)-one; 5,7-Difluoro-1-(2-{4-[( lH-indol-5-ylmethyl)amino]piperidin-1-yl} ethyl)quinolin- 2(lfl)-one; 5,7-Difluoro-l-[2-(4-{[(4-methyl-3,4-dihydro-2H-l,4-ben/oxazin-7-yl)methyl]amino}piperidin-l-yl)cthyl]quinolin-2(lH)-one; 1 -(2- {4-[(2,1,3-Benzoxadiazol-5-ylmethyl)aminojpiperidin-1 -yl} ethyl)-7-fluoroquinoxalin-2(lH)-one; N- {l-[2-(7-Fluoro-2-oxoquinoxalin-l (2H)-yl)ethyl]piperidin-4-yl} -2,3-dihydro-1,4-benzodioxine-6-sulfonamide; N- {1 -[2-(7-Fluoro-2-oxoquinoxalin-1 (2H)-yl)ethyl]piperidin-4-yl} -3-oxo-3,4-dihydro-2H-l,4-benzoxazine-6-sulfonamide; 5-Fluoro-N- {1 -[2-(7-fluoro-2-oxoquinoxalin-1 (2H)-yl)ethyl]piperidin-4-yl} - IH-indole-2-carboxamide; N-{l-[2-(5,7-Difluoro-2-oxoquinolin-l(2H)-yl)ethyl]piperidin-4-yl}-6-inorpholin-4-yhiicotinamide; N- {1 -[2-(5,7-Difluoro-2-oxoquinolin-l (2H)-yl)ethyl]piperidin-4-yl} -2,3-dihydro-1,4-benzodioxine-2-carboxamide; N- {1 -[2-(5,7-Difluoro-2-oxoquinolin-1 (2H)-yl)ethyl]piperidin-4-yl) -1 -methyl-1H-l,2,3-benzotriazole-5-carboxamide; N-{l-[2-(5,7-Difluoro-2-oxoquinolm-l(2H)-yl)ethyl]piperidm-4-yl}-3-(2-methyl-l,3-thiazol-4-yl)benzamide; N- {1 -[2-(5,7-Difluoro-2-oxoquino lin-1 (2H)-y l)ethyl]piperidin-4-yl} -4-(5-mcthyl-1,2,4-oxadiazol-3-yl)benzamide; 3-Oxo-4-[2-((2R;5S)-5-{[(3-oxo-3)4-dihydro-2H-pyrido[3,2-][l>4]oxazin-6-yl)methyl]amino}piperidin-2-yl)ethyl]-3,4-dihydro-2H-l,4-benzoxazine-6-carbonitrile; 3.0xo-4-[2-((2S,5R)-5-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-6][l,4]oxazin-6-yl)methyl]amino}piperidin-2-yl)ethyl]-3,4-dihydro-2H-l,4-benzoxazine-6-carbonitrile; 6-[( {1-[2-(5,7-Difluoro-2-oxoquinoxalin-1 (2H)-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-6][l,4]oxazin-3(4H)-one; 6-[({l-[2-(6,8-Difluoro-2-oxoquinoxalin-l(2H)-yl)ethyl]piperidin-4-yl} amino)methyl]-2//-pyrido[3,2-6] [ 1,4]oxazin-3 (4H)-one; 2-Oxo-l-[2-(4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-6][l,4]oxazin-6-yl)methyl]amino}piperidin-l-yl)ethyl]-l,2-dihydroquinoxaline-6-carbonitrile; 3-Oxo-4-[2-(4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-6][l,4]oxazin-6-yl)methyl]amino}piperidin-l-yl)ethyl]-3,4-dihydroquinoxaline-6-carbonitrile; 6-[({l-[2-(6-Methoxy-3-oxopyrido[2,3-b]]pyrazin-4(3H)-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3J2-b][l,4]oxazin-3(4H)-one; 4-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-l-yl}ethyl)-6-methoxypyrido[2,3-6]pyrazin-3(4H)-one; 6-t({l-[2-(6-Chloro-l-oxido-3-oxo-l,2,4-benzotriazin-4(3H)-yl)etliyl]piperidin-4-yl} amino)methyl]-2H-pyrido[3,2-b] [1,4]oxazin-3(4H)-one; 6-Chloro-4-(2-{4-[(2,3-diihydro[l,4]dioxmo[2)3-c]pyridin-7-ylmethyl)amino]piperidin-1 -yl} ethyl)-1,2,4-benzotriazin-3 (4H)-one 1 -oxide; 6-[({l-[2-(6-Chloro-3-oxo-l,2,4-benzotriazin-4(3H-yl)ethyl]piperidin-4-yl} amino)methyl]-2H-pyrido[3,2-b][ 1,4]oxazin-3(4H)-one; 4-(2-{(2S)5R)-5-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-2-yl}ethyl)-3-oxo-3,4-dihydro-2H-l,4-benzoxazine-6-carbonitrile; 6-[({l-[2-(7-Bromo-2-oxo-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-l-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-6][l,4]oxazin-3(4H)-one; 2-Oxo-l-[2-(4-{[(3-oxo-3,4-dihydro-2H-pyrido[3)2-i][l,4]oxazin-6-yl)methyl]amino}piperidin-l-yl)ethyl]-2,3-dihydro-lH-pyrido[2,3-6][l,4]oxazine-7-carbonitrile; 2-Oxo-1 -[2-(4- {[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b] [ 1,4]oxazin-6-yl)methyl]amino}piperidin-l-yl)ethyl]-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazine-7-carboxamide; l-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-2-methylpiperidin-l-yl}ethyl)-5,7-difluoroquinolin-2(lH)-one; 1 -(2- {4-[(2,3-Dihydro[l ,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1 -yl}ethyl)-2-oxo-l,2-dihydroquinoline-7-carbonitrile; Cis±4(l-[(2H)-3-(2,5-difluorophenyl)prop-2-en-l-yl]-4-[3-(6-methoxy-3-oxo-2,3-dihydro-4/f-l,4-benzoxazin-4-yl)propyl]piperidine-3-carboxylicacid; Methyl (Cis±4)-l-[(2H)-3-(2,5-difluofophenyl)prop-2-en-l-yl]-4-[3-(6-methoxy-3-oxo-2,3-dihydro-4H-l,4-benzoxazin-4-yl)propyl]piperidine-3-carboxylate; Cis±l-(2-{4-[(2,3-dihydro[l,4]dioxino[2,3-c]pyridm-7-ylmethyl)amino]-3-hydroxypiperidin-1 -yl} ethyl)-2-oxo-1,2-dihydroquinoline-7-carbonitrile; Cis±l-[2-(3-hydroxy-4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][l,4]oxazin-6-yl)methyl]amino}piperidin-l-yl)ethyl]-2-oxo-l,2-dihydroquinoline-7-carbonitrile; 5,7-Difluoro-1 -(2- {4-[(5,6,7,8-tetrahydro-1,8-naphthyridin-2-ylmethyl)amino]piperidin-1 -yl} ethyl)quinolin-2(lH)-one; Cis±l-(2-{4-[(2,3-dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3-methoxypiperidin-1 -yl} ethyl)-2-oxo-1,2-dihydroquinoline-7-carbonitrile; Cisil-[(2-[3-methoxy-4-{[(3--oxo-3,4-dihydro-2H-pyridotS^-Altl.^oxazin-e-yl)methyl]amino}piperidin-1 -yl)ethyl]-2-oxo-l ,2-dihydroquinoline-7-carbonitrile; Cis±l-(2-{4-[(2,3-dihydro[l,4]dioxmo[2,3-c]pyridin-7-ylmethyl)amino]-3-fluoropiperidin-l-yl}ethyl)-2-oxo-l,2-dihydroquinoline-7-carbonitrile; Cis±l-[2-(3fluoro-4-{[(3-oxo-3,4-dihydro-2H'-pyrido[3,2-A][l,4]oxazin-6-yl)methyl]amino}piperidin-l-yl)ethyl]-2-oxo-l,2-dihydroquinoline-7-carbonitrile; Cis±l-(2-{4-[(2,3-dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3-hydroxypiperidin-l-yl}ethyl)-7-fluoroquinoxalin-2(lH)-one; Cis±6-[({l-[2-(7-fluoro-2-oxoquinoxalin-l(2H)-yl)ethyl]-3-hydroxypiperidin-4-yl}amino)methyl]-2flr-pyrido[3,2-6][l,4]oxazin-3(4fl)-one; Cis±l -(2- {4-[(2,3 -dihydro[l ,4]dioxino[2,3-c]pyridin-7-ylmethyl)araino]-3-methoxypiperidin-1 -yl} ethyl)-7-fluoroquinoxalin-2(lH)-one; Cis±6-[({l-[2-(7-fluoro-2-oxoquinoxalin-l(2H)-yl)ethyl]-3-methoxypiperidin-4-yl} amino)methyl]-2H-pyrido[3,2-b] [ 1,4]oxazin-3 (4H)-one; Cis±l-(2-{4-[(2,3-dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3-fluoropiperidin-l-yl}ethyl)-7-fluoroquinoxalin-2(lH)-one; Cis±6-[({l-[2-(7-fluoro-2-oxoquinoxalin-l(2H)-yl)ethyl]-3-fluoropiperidin-4-yl}amino)methyl]-2Hr-pyrido[3,2-6][l,4]oxazin-3(4H-one; Cis± l-(2- {4-[(2,3-dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3-hydroxypiperidin-1 -yl} ethyl)-7-methoxyquinoxalin-2(lH)-one; Cis±6-[({l-[2-(7-methoxy-2-oxoquinoxalin-l(2H)-yl)ethyl]-3-hydroxypiperidin-4-yl}amino)methyl]-2H-pyrido[3,2-6][l,4]oxazin-3(4H)-one; Cis±l -(2- (4-[(2,3-dihydro[l ,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3-metboxypiperidin-l-yl}ethyl)-7-methoxyquinoxalin-2(lH)-one; Cis±6-[({l-[2-(7-methoxy-2-oxoquinoxalin-l(2H)-yl)ethyl]-3-methoxypiperidin-4-yl}amino)methyl]-2H-pyrido[3,2-6][l,4]oxazin-3(4H)-one; Cis±l-(2-{4-[(2,3-dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3-fluoropiperidin-1 -yl} ethyl)-7-methoxyquinoxalin-2( 1 H)-one; Cis±6-[({l-[2-(7-methoxy-2-oxoquinoxalin-l(2H)-yl)ethyl]-3-fluoropiperidin-4-yl}amino)methyl]-2//-pyridot3,2-b][l,4]oxazin-3(4H)-one; Cis±4-[2-(3-hydroxy-4-{[(3-oxo-3,4-dihydro-2/ir-pyrido[3)2-b][l,4]oxazin-6-yl)methyl]amino}piperidin-l-yl)ethyl]-3-oxo-3,4-dihydro-2H-l,4-benzoxazine-6-carbonitrile; Cis±4-[2-(3-methoxy-4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-fe][l,4]oxazin-6-yl)methyl]amino}piperidin-l-yl)ethyl]-3-oxo-3,4-dihydro-2H'-l,4-benzoxazine-6-carbonitrile; Cis±4-[2-(3-fluoro-4-{[(3-oxo-3,4-dihydro-2H-pyrido[3)2-6][l,4]oxazin-6-yl)methyl]amino}piperidin-l-yl)ethyl]-3-oxo-3,4-dihydro-2H-l,4-benzoxazine-6-carbonitrile; 1 -(2- {4-[(2,3-Dihydro[l ,4]dioxino[2,3-c]pyridin-7-ylmetliyl)amino]piperidin-1 -yl} ethyl)-7-methoxy-3,4-dihydroquinoxalin-2( lH)-one; 5,7-Difluoro-l -[2-(4- {[(1 -oxo-1,3-dihydro-2-benzofuran-5-yl)methyl]amino}piperidin-l-yl)ethyl]quinolin-2(lH)-one; 6-[({l-[2-(7-Methoxy-2-oxoquinoxalin-l(2^0-yl)propyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-6][l,4]oxazin-3(4H)-°ne; or 5,7-Difluoro-l-(2-{4-[(5,6,718-tetrahydro-l,8-naphthyridin-2-ylmethyl)amino]piperidin-1 -yl} ethyl)quinolin-2(lH)-one. 13. A pharmaceutical composition comprising a compound according to any one of claims 1-12, or a pharmaceutically acceptable salt thereof, admixed with a pharmaceutically acceptable adjuvant, carrier, or excipient. 14. A method of treating a bacterial infection comprising administering a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1-12 to a mammal in need thereof. 15. A method of treating a bacterial infection in a warm-blooded animal, such as a human being, in need of such treatment, which comprises administering to said animal an effective amount of a compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1-12 or a pharmaceutically-acceptable salt thereof. 16. A method for inhibiting bacterial DNA gyrase in a warm-blooded animal, such as a human being, in need of such treatment which comprises administering to said animal an effective amount of a compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1-12 or a pharmaceutically acceptable salt. 17. A compound, ot a pharmaceutically acceptable salt thereof, according to any one of claims 1-12 or a pharmaceutically acceptable salt thereof for use as a medicament. 18. The use of a compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1-12 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the production of an anti-bacterial effect in a warm-blooded animal such as a human being. 19. The use of a compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1-12 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of a bacterial infection hi a warm-blooded animal such as a human being. 20. A process for making a compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1-12, comprising one of the following: (a) N-alkylation of L with X-U1M, wherein X is a leaving group in the presence of a base to form LU1M, wherein U1 is CH2CH2, followed by attachment of U2 and R via functional group manipulation, alkylation, or reductive amination; (Formula Removed) (b) N-alkylation of L with HO-U1M, under Mitsunobu conditions to form LU1M, followed by attachment of U2and R via functional group manipulation, alkylation, or reductive amination; (Formula Removed) (c) N-alkylation of L with bromo- or chloroacetic acid or a derivative thereof to form (Formula Removed) followed by (Formula Removed) activation of the acid moiety in ii) amide coupling to form LU1M, wherein U1 is CH2CO, iii) attachment of U2 and R via functional group manipulation, alkylation, or reductive animation; and iv) optional reduction of the carbonyl moiety in Ui to form a compound wherein (Formula Removed) (d) N-alkylation of L with X-(CH2)nCH=CH2 wherein X is a leaving group and n is 1 or 2 to form L-(CH2)nCH=CH2, followed by: i) oxidative cleavage using an oxidant such as ozone or sodium periodate (with reductive workup) to form L-(CH2)nCH2OH; ii) conversion of the alcohol moiety in L-(CH2)nCH2OH to a leaving group; iii) reaction of L--(CH2)nCH2-Y with M, in the presence of a base to form LUjM; and iv) attachment of U2 and R via functional group manipulation, alkylation, or reductive amination; (Formula Removed) X,Y = leaving group n= 1 or 2 (e) N-alkylation of L with X-(CH2)nCH=CH2 wherein X is a leaving group and n is 1 or 2 to form L-(CH2)nCH=CH2, followed by: i) hydroboration followed by an oxidative workup to form to form L- (Formula Removed) ii) conversion of the alcohol moiety in L-CH2CH2OH to a leaving group; iii) reaction of L-CH2CH2-"LG" with M, hi the presence of a base to form LUiM; and iv) followed by attachment of U2 and R via functional group manipulation, alkylation, or reductive animation; or (Formula Removed) X,Y = leaving group n- 1 or 2 (0 Oxidation of the alcohol intermediate in d) and e) supra to the aldehyde (Formula Removed) .followed by i) reductive animation with MU2; to form LUiMU2, wherein Ul is CH2CH2; ii) reductive animation with R. (Formula Removed) 21. A compound of formula (I) and/or a pharmaceutical composition and/or a method of treating and/or the use of a compound and/or a process substantially as herein described with reference to the given examples.

Full Text

COMPOUNDS FOR THE TREATMENT OF MULTI-DRUG RESISTANT BACTERIAL INFECTIONS
BACKGROUND OF THE INVENTION
The international health community continues to express serious concern that the
evolution of antibacterial resistance will result in strains against which currently available
antibacterial agents will be ineffective. For example, resistant strains of Gram-positive
pathogens such as methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant
coagulase-negative staphylococci (MRCNS), penicillin-resistant Streptococcus pneumoniae
and multiple resistant Enterococcus faecium are both difficult to treat and difficult to
eradicate. Consequently, in order to overcome the threat of widespread multi-drug resistant
organisms, there is an on-going need to develop new antibiotics, particularly those with either
a novel mechanism of action and/or containing new pharmacophoric groups,
SUMMARY OF THE INVENTION
These and other needs are met by the invention disclosed herein which is directed to a
compound of formula I:
L— Uj— M— U2— R
I
or a pharmaceuticaUy acceptable salt thereof, or N-oxides thereof, wherein:
L is a group of formula LI -LI 5:
R2a f R2a R2a
f R r^ 6'7 >T R 6 R r> 6'7^ W R P R ,1 r\2 ^ Ii 2 "^2 I 2 2r '^'T97'
R2d R2e R2d 0 R2d R.,d R2e
) J t
LI L2 L3 L4
R2a j» R2a f R2a ^ R2a f
IN ,2 Rr\ 2Cc - 6^' Z NIN' Rn 2cc^
R2d j9 R2d R2gR29 R2d R2d
» > J
L5 L6 L7 L8
R2a f R2a { R2a f R2a f
R cxZ6'Z;YN>R g R c^'ZfNC.0 R c^'Z^^\ ^ R-jc'^'Z^^A^ '
R2d O R2d R2g z9 R2d Rse R2d R2e
J ) ) 3
L9 L10 Lll L12
R2a * R2a > R2a ,
•7 ^L x/ -7 ^L /=:
R2C^6'ZPN R2c"Z6'zf^N
R,d R2B R,d R,d 22 ,or Rz9
L13 L14 L15
wherein " "*** " indicates the point of attachment;
Zs, Zfi, and Z? are C or N provided that when Zs, Ze, or Z? is N, then R2a, R2C, or
are absent;
Rza, Rab, R2C, R2d, R2e, and R2f, are each independently H, halo, cyano, carboxy,
nitro, carbamoyl, -CO-(Ci-C6)alkyl, CO2-(CrC6)alkyl, (CrC6)alkyI, hydroxy,
halo(Ci-C6)alkyl, halo(Ci-C6)alkoxy, (d-C6)alkoxy, NHCO-(Ci-C6)alkyl, SO2(C|-C6)a1kyl,
S02NH(Ci-C6)alkyl, or S02N((Ci-C6)alkyl)2;
Rag) Rag', and R2g" are each independently II, (Ci-C6)alkyl, or halo(Ci-C6)allcyl;
Ui is CRaRb— CRcRd or CRaRb— CRcRd— CReRf, wherein Ra, Rb, Re, Rd, Re, and
Rf are each independently hydrogen or (Ci-Cfi)alkyl;
M is a group of formula M1-M5:
M3
1
,and
M4 M5
wherein R2 is H or carboxy, and wherein " "**** " indicate points of attachment;
Ry and Ry1 are each independently H, halo, hydroxy, (Ci-C6)alkyl, (Ci-C6)alkoxy,
CO2R", wherein R" is H, (Ci-C6)alkyl, or halo(C]-C6)alkyl, or Ry and Ry1 together with the
carbon to which they are attached form C=0; or Ry and Ry' together form a bridge;
X and Y are each independently CH2, O, or NR';
" — " is a bond or is absent;
nis 1, or 2, or 3;
when M is a group of fonnula Ml or M4, U2 is NR'—W, wherein W is CH2, CO, SO2,
A /-ITT TIT-' OTJ
2 , CH2CH2, CH2CH=CH, or CttiCsC, wherein each hydrogen may be optionally
replaced by halo or (Ci-C6)alkyl;
when M is a group of formula M2, M3, or M5, U2 is W wherein W is as defined
herein above;
R1 at each occurrence is independently H, (Ci-C6)alkyl, -(Cj-C^alkylcarboxy,
-CO-(Ci-C6)alkyl, -C02(C,-C6)alkyl, -CO-NH(Ci-C6)alkyl, -CO-N((Ci-C6)alkyl)2, or
SO2(Ci-C6)alkyl, any of which may be optionally substituted on carbon with halo, hydroxy,
(Ci-C6)alkyl, (CrC6)alkoxy, SO2(Ci-C6)alkyl, NH2, NH(Ci-Q)alkyl, or N((CrC6)alkyl)2;
when W is CH2, CO or SOi, R is aryl, heteroaryl, hetcrocyclyl or ortho-iused bicyclic
A
heteroaryl, or when W is CH2HC-CH
t CH2CH2j CH2CH=CH, or CH2CsC, R is aryl,
heteroaryl, heteroaryloxy, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl,
heteroarylamino; wherein any R may be optionally substituted on carbon; and wherein any
ring nitrogen in R may be optionally substituted by (Ci-C6)alkyl; and
any of L, Ui, M, U2, or R may be optionally substituted on carbon by one, two or three
substituents selected from halo, nitro, cyano, hydroxy, oxo, trifluoromethoxy, trifluoromethyl,
amino, carboxy, carbamoyl, mercapto, sulphamoyl, methyl, ethyl, ethenyl, ethynyl, methoxy,
ethoxy, methoxycarbonyl, ethoxycarbonyl, heteroaryl, heterocyclyl, acetyl, acetoxy,
methylamino, ethylamino, dimethylamino, diethylamino, //-methyl-jV-ethylamino, or
acetylamino;
with the proviso that when L is a group of formula L8 or L15, W is not CO.
What is also provided is a compound of formula I which is a compound of formula II:
R0a U—M-U-R
R2b>
II
or a pharmaceutically acceptable salt thereof, wherein
R23, R2b, Rac, and Rjd are each independently H, fluoro, chloro, cyano, (Cihalo(
Ci-C6)alkyl, halo(CrC6)alkoxy, (Ci-C6)alkoxy;
" " is a bond or is absent;
Z is CH or N when "— " is a bond, or Z is 0 or NH when "— "isabsent;
Ui is CRaRb—CRcRd or CRaRb—CRcRd—CReRf, wherein Ra, Rb, Re, Rd, Re and
Rf are each independently hydrogen or (Ci-C M is a group of formula Mia or M2-M5:
M3 M4
Ryx /Ry'
~.hRv' [UJ^N
, or
Mia M5
in the trans configuration relative to "*", wherein R2 is H or carboxy;
Ry and Ry1 are each independently H, hydroxy, fluoro, chloro, methoxy, carboxy,
CO2(Ci-Q)alkyl, or (Ci-C6)alkyl, or together with the carbon to which they are attached form
C^O; or Ry and Ry' together form a bridge;
X is CH2, NH, N[CO-(Ci-C6)alkyl], N[SO2(C1-C6)alkyl], N(C,-C6)alkyl, or O;
Y is CH2, NH, N[CO-(Ci-G0alkyl], N[SO2(C1-C(i)alkyl], N(CrC6)alkyl, or 0;
" " is a bond or is absent;
nis 1, 2, or 3;
when M is a group of formula Mia or M4, U2 is NR'-W, wherein R' is H,
(C]-C6)aIkyl, -(Ci-C6)alkylcarboxy, -CO-(Ci-C6)alkyl, -C02(Ci-Cfi)alkyl,
-CO-NH(Ci-C6)alkyl, -CO-N((Ci-C6)alkyl)2) any of which may be optionally substituted on
carbon with halo, hydroxy, (Ci-C6)alkyl, (C]-C6)alkoxy, SO2(Ci-C6)alkyl, NH2,
NH(C,-C6)alkyl, orN((C,-C6)alkyl)2;
W is CH2, CO, SO2) CH2CH2, CHaCH^CH, or CH2CsC, wherein each hydrogen may
be optionally replaced by halo or (Ci-Cs)alkyl;
when M is a group of formula M2, M3, or M5, U2 is W; and
when W is CH2, CO or SO2, R is aryl, heteroaryl, heterocyclyl or ortho-fused bicyclic
heteroaryl, or when W is CH2CH2) CH2CH=CH, or CH2CsC, R is aryl, heteroaryl,
heteroaryl(Ci -C6)alkyloxy, heteroaryl(Ci -C6)alkylthio, heteroaryl(C i -C^alkylsulfiny 1,
heteroaryl(Ci-C6)alkylsulfonyl, heteroaryl(Ci-C6)alkylamino; wherein any R may be
optionally substituted on carbon; and wherein any ring nitrogen in R may be optionally
substituted by (Ci-C6)alkyl.
What is also provided is a compound of formula I which is a compound of formula III:
Ry,
III
or a pharmaceutically acceptable salt thereof, wherein
R2a, R2b, R2c, and R2d are each independently H, fluoro, chloro, cyano, (C]-C6)alkyl,
halo(C]-C6)alkyl, halo(Ci-C6)alkoxy, (C,-C6)alkoxy;
Z is CH or N when " — - " is a bond, or, when " " " "is absent, Z is O or NH;
V is N or CR2, wherein R2 is H, hydroxy, or carboxy;
U2 is NR'-W, wherein W is CH2, CO, SO2, CII2CH2, CH2CH=CH, or CH2CsC,
wherein each hydrogen may be optionally replaced by halo or (Ci-Cfi)alkyl; and
H .0 H .0
0
Ris ,or
What is also provided is a compound of formula I which is a compound of formula IV:
RV \ ,R
N-W
IV
or a pharmaceutically acceptable salt thereof, wherein
Rja, Rjb, R2c, and R2d are each independently H, fluoro, chloro, cyano, nitro,
(Ci-Qj)alkanoyl, (Ci-Cfi)alkoxycarbonyl, (C,-C6)alkyl, halo(Ci-C6)alkyl, halo(Ci-C6)alkoxy,
(Ci-C6)alkoxy,NHCO-(Ci-C6)alkyl, S02(C,-C6)alkyl, S02NH(C,-C6)a]kyl, or
S02N((C1-C6)alkyl)2;
Z is CH orN when " "" " is a bond, or, when " --" " is absent, Z is O or NH;
R'isHor(C,-C6)alkyl;
W is CO, SO2, or CH2, wherein each hydrogen may be optionally replaced by halo or
(CVC6)alkyl; and
H .0 H .0
N-
\\ /-o
Ris N , — ,or
What is also provided is a compound of formula I which is a compound of formula V:
R'R2b
V
or a pharmaceutically acceptable salt thereof, wherein
Rja, Rab, Rac, and R2d are each independently H, fluoro, chloro, cyano, nitro,
(Ci-Cfi)alkanoyl, (Ci-C6)alkoxycarbonyl, (Ci-C6)alkyl, halo(Ci-C6)alkyl, halo(C,-C6)alkoxy,
(Ci-C6)alkoxy,NHCO-(Ci-C6)alkyl, S02(C]-C6)alkyl, S02NH(Ci~C6)alkyl, or
S02N((C,-C6)alkyl)2;
Z is CH or N when " ' ' " " is a bond, or, when " • " " "is absent, Z is 0 or NH; and
H O H 0 M N= _
Ris N , — , or
What is also provided by the invention is a compound which is:
1 -(2- {4-[(2,3-Dihydro[ 1 ,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin- 1 -
yl}ethyl)-7-methoxyquinolin-2(l/f)-one;
l-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-lyl}
ethyl)-7-methoxyquinolin-4(l//)-one;
Methyl l-(2-{4-[(2,3-dthydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-
1 -yl} etbyl)-6-methoxy- l//-indole-2-carboxylate;
6-[({l-[2-(7-Methoxy-2-oxoquinolin-l(2//)-yl)ethyl]piperidin-4-yl}amino)methyl]-
2/f-pyrido[3,2-6][l,4]oxazin-3(4/:0-one;
l-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-lyl}
ethyl)-2-oxo-l,2-dihydroquinoline-7-carbonitrile;
2-Oxo-l-[2-(4-{[(3-oxo-3,4-dihydro-2//-pyrido[3)2-6][l,4]oxazin-6-
yl)methyl]amino}piperidin-l-yl)ethyl]-l,2-dihydroquinoline-7-carbonitrile;
6-[({ 1 -[2-(7,8-Difluoro-2-oxoquinolin- 1 (2#)-yl)ethyl]piperidin-4-yl} amino)methyl] -
2//-pyrido[3,2-6][l,4]oxazin-3(4^-one;
6-[({l-[2-(5,7-Difluoro-2-oxoquinolin-l(2//)-yl)ethyl]piperidin-4-yl}amino)rnethyl]-
2#-pyrido[3,2-&][l,4]oxazin-3(4#)-one;
6-[( { 1 -[2-(7-Fluoro-2-oxoquinolin- 1 (2#)-yl)ethyl]piperidin-4-yl } amino)methyl]-2//-
pyrido[3,2-6][l,4]oxazin-3(4//)-one;
l-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)arnino]piperidin-lyl}
ethyl)-7-fluoroquinolin-2(!Ar)-one;
6-[({ l-[2-(7-Methoxy-2-oxo-3,4-dihydroquinolin- 1 (2//)-yl)ethyl]piperidin-4-
yl}amino)methyl]-2//-pyrido[3,2-6][l,4]oxazin-3(4//)-one;
(36',4^)-l-[2-(5)7-Difluoro-2-oxoquinoUn-l(2JW)-yl)ethyl]-4-[(2,3-
dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidine-3-carboxylic acid;
(3.S',4^)-l-[2-(5,7-Difluoro-2-oxoquinolin-l(2W)-yl)etbyl]-4-{[(2J?)-3-(2,5-
difluorophenyl)prop-2-en- 1 -yl]amino}piperidine-3-carboxylic acid;
Methyl (35r,4^)-l-[2-(5)7-difluoro-2-oxoquinolin-l(2H)-yl)ethyl]-4-[(2)3-
dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidine-3-carboxylate;
Methyl (3S,4R)-1 -[2-(5,7-difluoro-2-oxoquinolin-l (2J¥)-yl)ethyl]-4- {[(2£)-3-(2,5-
difluorophenyl)prop-2-en-l-yl]amino}piperidine-3-carboxylate;
(3^,4^)-l-[2-(5,7-Difluoro-2-oxoquinolin-l(2//)-yl)ethyl]-4-[(2s3-
dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)ainino]piperidine-3-carboxylicacid;
(3/?)4^)-l-[2-(5,7-Difluoro-2-oxoquinolin-l(2W)-yl)ethyl]-4-{[(2E)-3-(2J5-
difluorophenyl)prop-2-en-l-yl]amino}piperidine-3-carboxylic acid;
Methyl (3/?,4^)-l-[2-(5,7-difluoro-2-oxoquinolin-l(2^)-yl)ethyl]-4-[(2,3-
dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidine-3-carboxylate;
Methyl (3^,4^)-l-[2-(5,7-difluoro-2-oxoquinolin-l(2/i)-yl)ethyl]-4-{[(2£)-3-(2J5-
difluorophenyl)prop-2-en-l-yl]amino}piperidme-3-carboxylate;
Cis(±)6-[({l-[2-(5,7-Difluoro-2-oxoquinolin-l(2//)-yl)ethyl]-3-hydroxypiperidin-4-
yl} amino)methyl]-2#-pyrido[3,2-b] [ 1,4]oxazin-3 (4/f)-one;
4-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-lyl}
ethyl)-6-methoxy-2/f-l,4-benzoxazin-3(4//)-one;
6-[({l-[2-(6-Methoxy-3-oxo-2,3-dihydro-4flr-l,4-benzoxazin-4-yl)ethyl]piperidin-4-
yl} amino)methyl]-2//-pyrido[3,2-b] [ 1,4]oxazin-3(4/7)-one;
6-[( {1 -[2-(6-Methoxy-3 -oxo-2,3-dihydro-4//-1,4-benzothia/dn-4-yl)cthyl ]pipcridin-4-
yl} amino)methyl]-2/f-pyrido[3,2-b] [ 1,4]oxazin-3(4/:/)-one;
4-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin"lyl}
ethyl)-6-methoxy-2#-l,4-benzothiazin-3(4#)-one;
6-[( {1 -[2-(6-Fluoro-3-oxo-2,3-dihydro-4/7-1,4-benzoxazin-4-yl)ethyl]piperidin-4-
yl} amino)methyl]-2H-pyrido[3,2-b] [ 1,4]oxazin-3(4#)-one;
4-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-lyl}
ethyl)-6-fluoro-2/f-1,4-benzoxazin-3(4//)-one;
6-[({l-[2-(6-Chloro-3-oxo-2,3-dihydro-4//-l)4-benzoxazin-4-yl)cthyl]pipcridin-4-
yl}amino)methyl]-2flr-pyrido[3,2-i][l,4]oxazin-3(4//)-one;
6-[({l-[2-(6-Methoxy-3-oxo-2,3-dihydro-4//-l,4-benzoxazin-4-yi)ethyl]piperidm-4-
yl} amino)methyl]-2H-pyrido[3,2-b][ 1,4]thiazin-3(4//)-one;
3-Oxo-4-[2-(4-{[(3-oxo-3,4-dihydro-2//-pyrido[3,2-6][l,4]oxazin-6-
yl)methyl]amino}piperidin-1 -yl)ethyl]-3,4-dihydro-2//-1,4-benzoxazine-6-carbonitrile;
6-{[(l-{2-[3-Oxo-6-(trifluoromethoxy)-2I3-dihydro-4//-l,4-benzoxazin-4-
yl]ethyl}piperidin-4-yl)amino]methyl}-2/7-pyrido[3,2-6][l,4]oxazin-3(4/i)-one;
6-[({l-[2-(6-Fluoro-3-oxo-2,3-dihydro-4/f-l,4-benzoxazin-4-yl)ethyl]piperidin-4-
yl}amino)methyl]-2//-pyrido[3J2-6][l,4]thiazin-3(4//)-one;
4-(2-{4-[(2,3-Dihydro[l,4]dioxinot2,3-c]pyridin-7-ylmethyl)amino]piperidin-lyl}
ethyl)-3-oxo-3,4-dihydro-2//-l,4-benzoxazine-6-carbonitrile;
6-[( {1 -[2-(6-Bromo-3 -oxo-2,3 -dihydro-4#-1,4-benzoxazin-4-yl)ethyl]piperidin-4-
yl}amino)methyl]-2/:/'-pyrido[3,2-6][l)4]oxazin-3(4J:0-one;
6-[({l-[2-(6-Hydroxy-3-oxo-2,3-dihydro-4/f-l,4-benzoxazin-4-yl)ethyl]piperidin-4-
yl} amino)methyl]-2#-pyrido[3,2-b][l ,4]oxazin-3(4fl)-one;
4- {2-[4-({[2-(2,5-Difluorophenyl)cyclopropyl]methyl} amino)piperidin-l -yl]ethyl} -3-
oxo-3,4-dihydro-2//-1,4-benzoxazine-6-carbonitrile;
6-[({l-[2-(6,8-Difluoro-3-oxo-2,3-dihydro-4//-l,4-benzoxazin-4-yl)ethyl]piperidin-4-
yl} amino)methyl]-2//-pyrido[3,2-6] [ 1,4]oxazin-3(4//)-one;
4-[2-(4-{[(2£)-3-(2,5-Difluorophenyl)prop-2-en-l-yl]amino}piperidin-l-yl)ethyl]-3-
oxo-3,4-dibydro-2/f-1,4-benzoxazine-6-carbonitrile;
6-[( { yl)ethyl]cyclohexyl} amino)methyl]-2//-pyrido[3,2-b][ 1,4]oxazin-3(4//)-one;
3-Oxo-4-[2-(fra«5-4-{[(3-oxo-3,4-dihydro-2/;f-pyrido[3,2-i][l,4]oxazin-6-
yl)methyl]amino}cyclohexyl)ethyl]-3,4-dihydro-2H-l,4-benzoxazine-6-carbonitrile;
6-Bromo-4-[2-(4-{[(3-oxo-3,4-dihydro-2//-pyrido[3,2-&][l,4]oxazin-6-
yl)methyl]amino}piperidm-l-yl)ethyl]-2W-pyrido[3,2-6][l,4]oxazin-3(4/3r)-one;
6-[({l-[2-(6-Nitro-3-oxo-2,3-dihydro-4//'-l,4-benzoxazin-4-yl)ethyl]piperidin-4-
yl} amino)methyl]-2H-pyrido[3,2-b][ 1,4]oxazin-3(4J:/)-one;
3-Oxo-4-[2-(4-{[(3-oxo-3)4-dihydro-2//-pyrido[3)2-6][l)4]oxaziu-6-
yl)methyl]amino} piperidin-1 -yl)ethyl]-3,4-dihydro-2//-pyrido [3,2-b] [ 1,4] oxazine-6-
carbonitrile;
3-Oxo-4-[2-(4-{[(3-oxo-3,4-dihydro-2//-pyrido[3,2-i][l>4]oxazin-6-
yl)metbyl]amino}piperidin-l-yl)ethyl]-3,4-dihydro-2//-pyridot3,2-&][l,4]oxazine-6-
carboxamide;
Methyl 3-oxo-4-[2-(4-{[(3-oxo-3,4-dihydro-2//-pyrido[3,2-6][l ,4]oxazin-6-
yl)methyl]amino}piperidin-l-yl)ethyl]-3,4-dihydro-2//-l,4-benzoxa/,ine-6-carboxylate;
6-[({l-[2-(6-Acelyl-3-oxo-2,3-dihydro-4/7-l,4-benzoxazin-4-yl)e%l]piperidin-4-
yl} amino)methyl]-2flr-pyrido[3,2-Z>] [ 1 ,4]oxazin-3 (4/f)-one;
6-Acetyl-4-(2-{4-[(2,3-dihydro[l)4]dioxiao[2,3-c]pyridin-7-
ylraethyl)amino]piperidin-l-yl}ethyl)-2^-l,4-benzoxazin-3(4fl')-one;
4.(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-lyl}
ethyl)-6-methyl-2W- 1 ,4-benzoxazin-3(4/:/)-one;
3-Oxo-4-[2-(6-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-6][l,4]oxazui-6-
carbonitrile;
4-(2-{4-[(2,3-Dihydro[l,4]dioxino[2>3-c]pyridin-7-ylmethyl)amino]piperidin-lyl}
ethyl)-2/f-l,4-benzoxazin-3(4#)-one;
6- {[(1- {2-[6-(l -Hydroxyetbyl)-3-oxo-2,3-dihydro-4/f- 1 ,4-benzoxazin-4-
yl]ethyl}piperidin-4-yl)amino]methyl}-2//-pyrido[3,2-fo][l,4]oxazin-3(4//)-onc;
Ethyl 7/-{l-[2-(6-cyano-3-oxo-2,3-dihydro-4//-l,4-benzoxazin-4-yl)ethyl]pipcridin-4-
yl}-A^-[(2£)-3-(2,5-difluorophenyl)prop-2-en-l-yl]glycinate;
6-{[(l-{2-[6-(Methylsulfony])-3-oxo-2,3-dihydro-4/:/-l,4-benxoxazin-4-
yl]ethyl}piperidin-4-yl)amino]methyl} -2//-pyrido[3 ,2-b] [ 1 ,4]oxazin-3 (4/f)-one;
6-{[(l-{2-[6-(Ethylsulfonyl)-3-oxo-2,3-dihydro-4/7-l,4-bcnzoxazin-4-
yl]ethyl}piperidin-4-yl)amino]methyl}-2//-pyrido[3,2-i]tl,4]oxazin-3(4f/)-onc;
6-[( { 1 -[2-(7-Methoxy-2-oxo-2//-3 , 1 -benzoxazin- 1 (4ff) -yl)etbyl]piperidin-4-
yl} amino)methyl]-2//-pyrido[3 ,2-b] [ 1 ,4]oxazm-3(4ff)-one;
7-Methoxy-3-methyl-l-[2-(4-{[(3-oxo-3,4-dihydro-2F-pyrido[3,2-^][l,4]oxazin-6-
yl)methyl]amino}piperidin- 1 -yl)ethyl]quinazoline-2,4( \H,3H)-diaw,
4-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-2-oxopii5eridin-lyl}
ethyl)-6-methoxy-2//- 1 ,4-benzoxazin-3 (4/f)-one;
6-[({l-[2-(6-Methoxy-3-oxo-2)3-dihydro-47f-l,4-benzoxazin-4-yl)ethyl]-2-
oxopiperidin-4-yl}amino)methyl]-2//-pyrido[3,2-fo][l,4]oxazin-3(4//)-one;
3-Oxo-4-[2-(2-oxo-4-{[(3-oxo-3J4-dihydro-2//-pyrido[3,2-i][l,4]oxazin-6-
yl)methyl]amino}piperidin- l-yl)ethyl]-3,4-dihydro-2//- 1 ,4-benzoxazine-6-carbonitrile;
6-( {4-[3-(7-Methoxy-2-oxo-2//-3, 1 -benzoxazin- 1 (4/^)-yl)propy l]piperazin- 1 -
yl}methyl)-2//-pyrido[3,2-*][l,4]oxazin-3(4//)-one;
4-{3-[4-(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)piperazin-l-yl]propyl}-6-
methoxy-2H- 1 ,4-benzoxazin-3 (4//)-one;
1 -[(2£)-3-(2,5-Difluorophenyl)prop-2-en-1 -yl]piperidin-4-yl} amino)ethyl]-6-
methoxy-2//-1,4-benzoxazin-3 (4H)-on&;
4-(3.{4.[(2£)-3-(2,5-Difluorophenyl)prop-2-en-l-yl]piperazin-l-yl}propyl)-6-
methoxy-2#-l,4-benzoxazin-3(4W)-one;
6-[({ 1 -[2-(6-Methoxy-2-oxo-1,7-naphthyridin-1 (2#)-yl)ethyl]piperidin-4-
yl}ammo)methyl]-2#-pyrido[3,2-6][l,4]oxazm-3(4#)-one;
Methyl l-[(2£)-3-(2,5-difluorophenyl)prop-2-en-l-yl]-4-[3-(6-cyano-3-oxo-2,3-
dihydro-4#-1,4-benzoxazin-4-yl)propyl]piperidine-3 -carboxylate;
4-[3-(6-Cyano-3-oxo-2,3-dihydro-4H-l,4-benzoxazin-4-yl)propyl]-l-[(2E)-3-(2,5-
difluorophenyl)prop-2-en-1 -yl]piperidine-3-carboxylic acid;
7-Fluoro-3-methyl-l-[2-(4-{[(3-oxo-3,4-dihydro-27/-pyrido[3,2-6][lJ4]oxazin-6-
yl)metbyl]amino}piperidin-1 -yl)ethyl]quinazoline-2,4( lH,3H)-dians;
7-Chloro-l-(2-{4-[(2,3-dihydro[l,4]dioxino[2,3-c]pyridin-7-
ylmethyl)araino]piperidin-1 -yl} ethyl)-1,8-naphthyridin-2(l H)-one;
l-(2-{4-[(2,3-Dihydro[l)4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-lyl}
ethyl)-7-methoxy-1,8-naphthyridin-2( 1 H)-one;
l-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)araino]piperidm-lyl}
ethyl)-7-fluoroquinoxalin-2( l//)-one;
6-[({ 1 -[2-(7-Fluoro-2-oxoquinoxalin-1 (2//)-yl)ethyl]piperidin-4-yl) amino)methyl]-
2//-pyrido[3,2-6][l,4]oxazin-3(4/^)-one;
l-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-lyl}
ethyl)-6-fluoroquinoxalin-2(l/f)-one;
1 -(2- {4-[(2,3-Dihydro[ 1 ^dioxinop^-cJpyridin^-ylmetiiyOaminoJpiperidin-1 -
yl}ethyl)-7-methoxyquinoxalin-2(l/:/)-one;
6-[({l-[2-(7-Methoxy-2-oxoquinoxalin-l(27:r)-yl)ethyl]piperidin-4-yl}amino)methyl]-
2#-pyrido[3,2-6][l,4]oxazin-3(4#)-one;
6-[({l-[2-(7-Methoxy-2-oxoquinoxalin-l(2//)-yl)ethyl]piperidin-4-yl}amino)mothyl]-
2/f-pyrido[3J2-6][l>4]thiazin-3(4^)-one;
l-(2-{4-[(2,3-Dihydrotl,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-lyl}
ethyl)-6,7-difluoroquinoxalin-2( llf)-one;
6-[({l-[2-(6,7-Difluoro-2-oxoquinoxalin-l(2F)-yl)ethyl]piperidin-4-
yl)amino)methyl]-2Jcf-pyrido[3,2-fc][l,4]oxazin-3(4//)-one;
l-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-lyl}
ethyl)-7,8-difluoroquinoxalin-2(l.fr)-one;
6-[( {1 -[2-(7,8-Difluoro-2-oxoquinoxalin-1 (2^f)-yl)ethyl]piperidin-4-
yl}amino)methyl]-2Jy-pyrido[3,2-fc][l,4]oxazin-3(4/f)-one;
6-[({l-[2-(6,7-Dimethoxy-2-oxoquinoxalin-l(2/:/)-yl)ethyl]piperidin-4-
yl}amino)methyl]-2#-pyrido[3,2-6][l,4]oxazin-3(4Jy)-one;
6-[({l-[2-(7-Methoxy-3-methyl-2-oxoquinoxalin-l(2^)-yl)ethyl]piperidin-4-
yl} amino)methyl]-2/f-pyrido[3,2-b] [ 1,4]oxazin-3(4#)-one;
1 -(2- {4-[(2,3-Dihydro[ 1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1 -
yl}ethyl)quinolin-2(l//)-one;
l-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-lyl}
ethyl)quinolin-4(l/0-one;
Cis(±)6-[({l-[2-(5,7-difluoro-2-oxoqumolin-l(27J)-yl)ethyl]-3-mcthoxypiperidin-4-
yl} amino)methyl]-2//'-pyrido[3,2-b][ 1,4]oxazin-3(4//)-one;
7-FIuoro-2-oxo-l-[2-(4-{[(3-oxo-3,4-dihydro-27/-pyrido[3,2-6][l,4]oxazin-6-
yl)methyl]amino}piperidin-1 -yl)ethyl]-l ,2-dihydroquinoline-5-carbonitrile;
5-Fluoro-2-oxo-l-[2-(4-{[(3-oxo-3,4-dihydro-2//-pyrido[3,2-/?][l,4]oxa/in-6-
yl)methyl]amino}piperidin-l-yl)ethyl]-l,2-dihydroquinoline-7-carbonitrile;
7-Fluoro-1 -[2-(4- {[(2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino} piperidin-1 -
yI)ethyl]quinoxalin-2(l//)-one;
l-[2-(4-{[(2,2-Dimethyl-3)4-dihydro-2//-chromen-6-yl)raethyl]araino}piperidin-lyl)
ethyl]-5,7-difluoroquinolin-2(l/f)-one;
l-[2-(4-{[(l,3-Dimethyl-2-oxo-2,3-dihydro-l//'-benziinidazol-5-
yl)methyl]amino}piperidin-l-yl)ethyl]-57-difluoroquinolin-2(l/:0-one;
5,7-Difluoro-l-(2-{4-[(5,6,7,8-tetrahydronaphthalen-2-ylmethyl)amino]piperidin-lyl}
ethyl)quinolin-2(l^T)-one;
5,7-Difluoro-l-[2-(4-{[(6-fluoro-4flr-l,3-benzodioxin-8-yl)methyl]amino}piperidin-lyl)
ethyl]quino!in-2(l//)-one;
5,7-Difluoro-l-(2-{4-[(l//P-indol-6-ylmethyl)amino]piperidin-l-yl}ethyl)quinolin-
2(lH)-one;
l-(2-{4-[(2,3-Dihydro-l//-inden-5-ylmethyl)amino]piperidin-l-yl}ethyl)-517-
di£luoroquinolin-2(lJ:0-onc;
5,7-Difluoro-l-[2-(4-{[(l-methyl-l//-l,2,3-benzotriazol-5-yl)methyl]amino}piperidinl-
yl)ethyl]quinolin-2(l#)-one;
5,7-Difluoro-1 -(2- {4-[( l//-indol-5-ylmethyl)amino]piperidin-1 -yl} ethyl)quinolin-
2(l#)-one;
5,7-Difluoro-l-[2-(4-{[(4-methyl-3>4-dihydro-2//-l)4-benzoxazin-7-
yl)methyl]amino}piperidin-l-yl)ethyl]quinolin-2(l/f)-one;
1 -(2- {4-[(2,1,3-Benzoxadiazol-5-ylmethyl)amino]piperidin-1 -yl} ethyl)-7-
fluoroquinoxalin-2( l//)-one;
AT-{l-[2-(7-Fluoro-2-oxoquinoxalin-l(2//)-yl)ethyl]piperidin-4-yl}-2,3-dihydro-l,4-
benzodioxine-6-sulfonamide;
N- {1 -[2-(7-Fluoro-2-oxoquinoxalin-1 (2#)-yl)ethyl]piperidin-4-yl} -3 -oxo-3,4-
dihydro-2/f-l,4-benzoxazine-6-sulfonamide;
5-Fluoro-^-{l-[2-(7-fluoro-2-oxoquinoxalin-l(2Jy)-yl)ethyl]piperidin-4-yl}-l/:/-
indole-2-carboxamide;
A^{l-[2-(5,7-Difluoro-2-oxoquinolin-l(2//)-yl)ethyl]piperidin-4-yl}-6-morpholin-4-
ylnicotinamide;
N- {1 -[2-(5,7-Difluoro-2-oxoquinolin-1 (2#)-yl)etkyl]piperidin-4-yl} -2,3-dihydi'O-1,4-
benzodioxine-2-carboxamide;
N- {l-[2-(5,7-Difluoro-2-oxoquinolin-1 (2ff)-yl)ethyl]piperidin-4-yl} -1 -methyl-1/7-
1,2,3-benzotriazole-5-carboxamide;
N- {l-[2-(5,7-Difluoro-2-oxoquinolin-l (2//)-yl)ethyl]pipcridin-4-yl} -3-(2-methyl-1,3-
thiazol-4-yl)benzamide;
A^{l-[2-(557-Difluoro-2-oxoquinoHn-](2/f)-yl)ethyl]piperidin-4-yl}-4-(5-methyl-
1,2,4-oxadiazol-3-yl)benzamide;
3-Oxo-4-[2-((2/?,55)-5-{[(3-oxo-3,4-dihydro-2//-pyrido[352-6][l,4]oxazin-6-
yl)methyl]amino}piperidin-2-yl)ethyl]-3,4-dihydro-2//-l,4-benzoxazine-6-carbonitrile;
3-Oxo-4-[2-((25,5/?)-5-{[(3-oxo-3,4-dihydro-2//-pyrido[3,2-6][l,4]oxazin-6-
yl)methyl]amino}piperidin-2-yl)ethyl]-3,4-dihydro-2//-l,4-benzoxazine-6-carbonitrile;
6-[({l-[2-(5J7-Difluoro-2-oxoquinoxalin-l(2/0-yl)ethy1]PiPeridin-4-
yl}amino)methyl]-2//-pyrido[3,2-6][l,4]oxazin-3(4//)-one;
6-[({ 1 -[2-(6,8-Difluoro-2-oxoquinoxalin-l (2//)-yl)ethyl]piperidin-4-
yl} amino)methyl]-2//-pyrido[3,2-6] [ 1,4]oxazin-3 (4#)-one;
2-Oxo-1 -[2-(4- {[(3 -oxo-3,4-dihydro-2#-pyrido[3,2-b] [ 1,4]oxazin-6-
yl)methyl]amino}piperidin-l-yl)ethyl]-l,2-dihydroquinoxaline-6-carbonitrile;
3-Oxo-4-[2-(4-{[(3-oxo-3,4-dihydro-2//-pyrido[3,2-i][l,4]oxazin-6-
yl)rnethyl]amino}piperidin-l-yl)ethyl]-3,4-dihydroquinoxaline-6-carbonitrile;
6-[({l-[2-(6-Methoxy-3-oxopyrido[2,3-6]pyrazin-4(3//)-yl)ethyl]piperidin-4-
yl}amino)methyl]-2//-pyrido[3)2-i][lJ4]oxazin-3(4^)-one;
4-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-lyl}
ethyl)-6-methoxypyrido[2,3-i]pyrazin-3(4/f)-one;
6-[( {1 -[2-(6-Chloro-1 -oxido-3-oxo-1 )2,4-benzotriazin-4(3J:/)-yl)ethyl]piperidin-4-
yi} amino)methyl]-2J7-pyrido[3,2-b] [ 1,4]oxazin-3(4//)-one;
6-Chloro-4-(2-{4-[(2,3-dihydro[l,4]dioxino[2,3-c]pyridin-7-
ylmethyl)amino]piperidin-1 -yi} ethyl)-1,2,4-benzotriazin-3 (4//)-one 1 -oxide;
6-[( {1 -[2-(6-Chloro-3-oxo-1,2,4-benzotriazin-4(3//)-yl)ethyl]piperidin-4-
yl}amino)methyl]-2//-pyrido[3,2-i][l,4]oxazin-3(47/)-one;
4-(2-{(2iS',5J?)-5-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-
2-yl} ethyl)-3-oxo-3,4-dihydro-2/f-1,4-benzoxazine-6-carbonitrile;
6-[({l-[2-(7-Bronio-2-oxo-2,3-dihydro-l//-pyrido[2,3-6][l,4]oxazin-lyl)
ethyl]piperidin-4-yl} amino)methyl]-2//-pyrido[3,2-b] [ 1,4]oxay;in-3 (4H)-one;
2-Oxo-1 -[2-(4- {[(3-oxo-3,4-dihydro-2tf-pyrido[3,2-b] [ 1,4]oxazin-6-
yl)methyl]amino}piperidin-1 -yl)ethyl]-2,3-dihydro- l^T-pyrido[2,3-b] [ 1,4]oxazine-7-
carbonitrile;
2-Oxo-l-[2-(4-{[(3-oxo-3>4-dihydro-2flr-pyrido[3,2-i][l)4]oxazin-6-
yl)methyl]amino}piperidin-l-yl)ethyl]-2,3-dihydro-l//-pyrido[2,3-3][l,4]oxazine-7-
carboxamide;
l-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-2-
methylpiperidin-l-yl}ethyl)-5,7-difluoroquinolin-2(l//)-°ne;
l-(2-{4-[(2,3-Dihydro[l ,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino jpiperidin-1-
yl} ethyl)-2-oxo-1,2-dihydrbquinoline-7-carbonitrile;
Cis±4(l-[(2JS)-3-(2,5-difluorophenyl)prop-2-en-l-yl]-4-[3-(6-methoxy-3-oxo-2,3-
dihydro-4fl'-l,4-benzoxazin-4-yl)propyl]piperidine-3-carboxylic acid;
Methyl (Cis±4)-l-[(2£)-3-(2,5-difluorophenyl)prop-2-en-l-yl]-4-[3-(6-methoxy-3-
oxo-2,3-dihydro-47/-l,4-benzoxazin-4-yl)propyl]piperidine-3-carboxylate;
Cis±l-(2-{4-[(2,3-dihydro[l54]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3-
hydroxypiperidin-l-yl}ethyl)-2-oxo-l,2-dihydroquinoline-7-carbonitrile;
Q8±l-|>xo-3,4-dihydro-2fl'-pyrido[3>2-6][l,4]oxazin-6-
yl)methyl]amino}piperidin- 1 -yl)ethyl]-2-oxo- 1 ,2-dihydroquinoline-7-carbonitrile;
5,7-Difluoro-l -(2- {4-[(5,6,7,8-tetrahydro- 1 ,8-naphthyridin-2-
ylmethyl)amino]piperidin-l-yl}ethyl)quinolin-2(l#)-one;
Cis±l-(2-{4-[(2>3-dihydro|;i)4]dioxino[2J3-c]pyridin-7-ylmethyl)amino]-3-
methoxypiperidin-l-yl}ethyl)-2-oxo-l,2-dihydroquinoline-7-carbonitrile;
yl)methyl]amino}piperidin- 1 -yl)ethyl]-2-oxo- 1 ,2-dihydroquinoline-7-carbonitrile;
Cis±l-(2-{4-[(2,3-dihydro[lJ4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3-
fluoropiperidin- 1 -yl} ethyl)-2-oxo- 1 ,2-dihydroquinoline-7-carbonitrile;
yl)metbyl]araino}piperidin- 1 -yl)ethyl]-2-oxo- 1 ,2-dihydroquinoline-7-carbonitrile;
Cis±l-(2-{4-[(2,3-dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3-
hydroxypiperidin-l-yl}ethyl)-7-fluoroquinoxalin-2(l//)-one;
Cis±6-[({l-[2-(7-fluoro-2-oxoquinoxalin-l(2//)-yl)ethyl]-3-hydroxypiperidin-4-
yl} araino)methyl]-2/:/-pyrido[3J2-i][l ,4]oxazin-3(4/0-one;
Cis±l-(2-{4-[(2,3-dihydro[l,4Jdioxino[2,3-c]pyridin-7-ylmethyl)amino]-3-
methoxypiperidin- 1 -y 1} ethyl)-7-fluoroquinoxalin-2( 1 H)-one;
Cis±6-[({l-[2-(7-fluoro-2-oxoquinoxalin-l(2//)-yl)ethyl]-3-methoxypiperidin-4-
yl} amino)methyl]-2#-pyrido[3 ,2-6] [ 1 ,4]oxazin-3 (4J7)-one;
Cis±l-(2-{4-[(2,3-dihydro[l,4]dioxino[2)3-c]pyridin-7-ylmethyl)amino]-3-
fluoropiperidin-l-yl}ethyl)-7-fluoroquinoxalin-2(l^)-one;
Cis±6-[( { 1 -[2-(7-fluoro-2-oxoquinoxalin- 1 (2//)-yl)ethyl]-3-fluoropiperidin-4-
yl} amino)methyl]-2^r-pyrido[3 ,2-b] [ 1 ,4]oxazin-3 (4//) -one;
Cis±l-(2-{4-[(2,3-dihydro[l,4]dioxmo[2,3-c]pyridin-7-yln]ethyl)amino]-3-
hydroxypiperidin- 1 -yl} ethyl)-7-methoxyquinoxalin-2( l//)-one;
Cis±6-[({l-[2-(7-methoxy-2-oxoquinoxalin-l(2fl)-yl)ethyl]-3-hydroxypiperidinyl}
amino)methyl]-2//-pyrido[3)2-i][l,4]oxazin-3(4//)-one;
Cis±l-(2-{4-[(2,3-dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3-
methoxypiperidin-]-yl}ethyl)-7-methoxyquinoxalin-2(l//)-one;
Cis±6-[({l-[2-(7-methoxy-2-oxoquinoxalin-l(2/f)-yl)ethyl]-3-methoxypiperidin-4-
yI}ammo)memyl]-2//-pyrido[3,2-6][l,4]oxazin-3(4#)-one;
Cis±l-(2-{4-[(2,3-dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3-
fluoropiperidin- 1-yl} ethyl)-7-methoxyquinoxalin-2(l.#)-one;
Cis±6-[({l-[2-(7-methoxy-2-oxoquinoxalin-l(2H)-yl)ethyl]-3-fluoropiperidin-4-
yl}amino)methyl]-2/^pyrido[3,2-&][l,4]oxazin-3(4#)-one;
Cis±4-[2-(3-hydroxy-4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-6][l,4]oxazin-6-
yl)methyl]amino}piperidin-l-yl)ethyl]-3-oxo-3,4-dihydro-2//-l,4-benzoxazine-6-carbonitrilc;
Cis±4-[2-(3-methoxy-4-{[(3-oxo-3,4-dihydro-2/7-pyrido[3,2-6][I,4]oxazm-6-
yl)methyl]amino}piperidin-l-yl)ethyl]-3-oxo-3,4-dihydro-27/-l,4-benzoxazme-6-carbonitrile;
Cis±4-[2-(3-fluoro-4-{[(3-oxo-3,4-dihydro-2//-pyrido[3,2-6][l,4]oxazin-6-
yl)methyl]amino}piperidin- l-yl)ethyl]-3-oxo-3,4-dihydro-27/-1,4-benzoxazine-6-carbonitrilc;
l-(2-{4-t(2,3-Dihydro[l ,4]dioxino[2,3-c]pyridin~7-ylmethyl)amino]piperidin-1 -
yl} ethyl)-7-methoxy-3,4-dihydroquinoxalin-2( 1 //)-one;
5,7-Difluoro-1 -[2-(4- {[(1 -oxo-1,3-dihydro-2-benzofuran-5-
yl)methyl]amino}piperidin-l-yl)ethyl]quinolin-2(l/:f)-one;
6-[({l-[2-(7-Methoxy-2-oxoquinoxalin-l(2//)-yl)propyl]piperidin-4-
yl}amino)methyl]-2//-pyrido[3,2-/)][l,4]oxazin-3(4//)-one; or
5,7-Difluoro-l-(2- {4-[(5,6,7,8-tetrahydro-l ,8-naphthyridin-2-
ylmethyl)amino]piperidin-l-yI}ethyI)quinolin-2(l//)-one.
The invention also provides a pharmaceutical composition comprising a compound of
formulas I-V admixed with a pharmaceutically acceptable adjuvant, carrier, or excipient.
The invention also provides a method of treating a bacterial infection comprising
administering a therapeutically effective amount of a compound of formulas I-V to a mammal
in need thereof.
The invention also provides a method of treating a bacterial infection in a
warm-blooded animal, such as a human being, in need of such treatment, which comprises
administering to said animal an effective amount of a compound of formulas I-V or a
pharmaceutically-acceptable salt thereof.
The invention also provides a method for inhibiting bacterial DNA gyrase in a
warm-blooded animal, such as a human being, in need of such treatment which comprises
administering to said animal an effective amount of a compound of formulas I-V or a
pharmaceutically acceptable salt.
The invention also provides a compound of formulas I-V and pharmaceutically
acceptable salts thereof for use as a medicament.
The invention also provides the use of a compound of formulas I-V or a
pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the
production of an anti-bacterial effect in a warm-blooded animal such as a human being.
The invention also provides the use of a compound of formulas I-V or a
pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the
treatment of a bacterial infection in a warm-blooded animal such as a human being.
The invention also provides a process for making a compound of formulas I-V,
comprising one of the following:
(a) N-alkylation of L with X-UjM, wherein X is a leaving group in the presence of a base
to form LUiM, wherein Uj is CHaCHa, followed by attachment of Uj and R via
functional group manipulation, alkylation, or reductive animation;
X-UrM U2
—»- L-UrM *•
Base
R
L-UrM-U2 L-UrM-U2-R
(b) N-alkylation of L with HO-U]M, under Mitsunobu conditions to form LU]M,
followed by attachment of Ua and R via functional group manipulation, alkylatioa, or
reductive amination;
HO-UrM U2
L — *• L-UrM *-
Mitsunobu
R
L-UrM-U2 *• L-UrM-U2-R
(c) N-alkylation of L with bromo- or chloroacetic acid or a derivative thereof to form
L-CH2C02H ... ,.
* * followed by
• ,• *.*. -A • „ • L-CH2C02i) activation of the acid moiety in * H;
ii) amide coupling to form LUiM, wherein Ui is CHzCO,
iii) attachment of Ua and R via functional group manipulation, alkylation, or
reductive amination; and
iv) optional reduction of the carbonyl moiety in Ui to form a compound wherein
Ui is CH2CH2.
XCH2C02H
X= Cl, Br M
L ». L-CH2CO2H *"
Base
L-CH2COM - *• L-CHZCO-M-U2
U2
L-CH2COM-U2-R - *• L-CH2CH2M-U2-R
(d) N-alkylation of L with X-(CH2)nCH=CH2 wherein X is a leaving group and n is 1 or 2
to form L-(CH2)nCH=CH2, followed by:
i) oxidativc cleavage using an oxidant such as ozone or sodium periodatc (with
reductive workup) to form L-(CH2)nCH2OH;
ii) conversion of the alcohol moiety in L-(CHi)nCH2OH to a leaving group;
iii) reaction of L--(CH2)nCH2-Y with M, in the presence of a base to form LUjM;
and
iv) attachment of U2 and R via functional group manipulation, alkylation, or
reductive animation;
X-(CH2)n-CH=CH2 L— (-Op [O] L— (
L _
Base — V~OH
L— (-\)n
U2 R
•- L-UrM-U2 *- L-UrM-U2-R
X,Y = leaving group n= 1 or 2
(e) N-alkylation of L with X-(CH2)nCH=CH2 wherein X is a leaving group and n is 0 or 1
to form L-(CH2)nCH=CH2, provided that when n is 0, a metal catalyst is optionally
used, followed by:
i) hydroboration followed by an oxidative workup to form to form
L-(CH2)nCH2CH2OH;
ii) conversion of the alcohol moiety in L-(CH2)nCH2CH20H to a leaving group;
iii) reaction of L-(CH2)nCH2CH2-"LG" with M, in the presence of a base to form
LUiM; and
iv) followed by attachment of U2 and R via functional group manipulation,
alkylation, or reductive amination;
X-(CH2)n-CH=CH2 L—(-Jn Hydroboration L—(-\)n
Base ^= Oxidative Workup
OH
L—(-v)n M
L-UrM
Y
U2 R
- L-UrM-U2 ^ L-UrM-U2-R
X,Y = leaving group n= 1 or 2
L—v
(f) Oxidation of the alcohol intermediate in d) and e) supra to the aldehyde
L—vy=o
H .followed by
i) reductive amination with MUz; to form LU]MU2, wherein Ul is '
ii) reductive amination with R; or
L^ [O] L
^-OH
H
R
L-UrM-U2 *- L-UrM-U2-R
(g) N-alkylation of L with X-(CH2)nCH2CH20H, wherein X is a leaving group and n is 0
or 1 to form the intermediate L-(CH2)nCH2CH20H as depicted in (e), supra, followed
by
i) conversion of the alcohol moiety in L-(CH2)nCH2CH2OH to a leaving group;
ii) reaction of L-(CH2)nCH2CH2-"LG" with M, in the presence of a base to form
LUiM; and
iii) followed by attachment of Ua and R via functional group manipulation,
alkylation, or reductive amination.
L—(-y)n M
Y
U2 R
L-U,-M - »- L-UrM-U2 - „ L-UrM-U2-R
X,Y = leaving group n= 1 or 2
DETAILED DESCRIPTION OF THE INVENTION
Unless otherwise stated, the following terms used in the specification and claims have
the following meanings.
Definitions
"Alky!" means a linear saturated monovalent hydrocarbon radical of one to six carbon
atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms,
e.g., methyl, ethyl, propyl, 2-propyl, pentyl, and the like, that may be optionally substituted.
"Alkenyl" means a linear monovalent hydrocarbon radical of two to six carbon atoms
or a branched monovalent hydrocarbon radical of three to six carbon atoms, containing at
least one double bond, e.g., ethenyl (-CH=CH2), propenyl, and the like that may be optionally
substituted.
"Alkylene" means a linear saturated divalent hydrocarbon radical of one to six carbon
atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms, e.g.,
methylene (-CHa-), ethylene (-CKfoCHa-), propylene, 2-methylpropylene, pentylene, and the
like that may be optionally substituted.
"Acyl" means a radical ~C(O)R where R is hydrogen, alkyl, alkenyl, cycloalkyl,
heteroalkyl, haloalkyl, aryl, aralkyl, heteroaralkyl or heteroaryl, e.g., acetyl, benzoyl, thienoyl,
and the like that may be optionally substituted.
"Acyloxy" means a radical — OC(O)R where R is hydrogen, alkyl, alkenyl,
cycloalkyl, heteroalkyl, haloalkyl or optionally substituted phenyl, e.g, , acetoxy, benzoyloxy,
and the like that may be optionally substituted.
"Halo" means fluoro, chloro, bromo or iodo.
"Haloalkyl" means alkyl substituted with one or more same or different halo atoms,
e.g., —CH2C1, —CF3> —CH2CF3) ~-CH2CCl3, and the like.
"Cycloalkyl" means a saturated monovalent cyclic hydrocarbon radical of three to six
ring carbons, e.g., cyclopropyl, cyclohexyl, and the like that may be optionally substituted.
"Amine" or "amino" refers to radicals of the general formula —NRR', wherein R and
R' are independently selected from hydrogen or a hydrocarbyl radical, or wherein R and R'
combined form a heterocycle, Examples of amino groups include: —Ntfe, methyl amino,
diethyl amino, anilino, benzyl amino, piperidinyl, piperazinyl and indolinyl.
"Monosubstituted amino" means a radical —NHR where R is alkyl, heteroalkyl,
haloalkyl, cycloalkyl, cycloalkylalkyl or optionally substituted phenyl, e.g., methylamino,
(l-methylethyl)amino, phenylamino, and the like.
"Disubstituted amino" means a radical -NRR' where R and R' are independently alkyl,
alkenyl, heteroalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl or optionally substituted phenyl.
Representative examples include, but are not limited to, dimethylamino, methylethylamino,
di(l-methylethyl)amino, methylbenzylamino, and the like.
"Aryl" means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical of 6
to 10 ring atoms, and optionally substituted independently with one or more substituents,
preferably one, two or three substituents selected from alkyl, haloalkyl, heteroalkyl,
cycloalkyl, cycloalkylalkyl, halo, cyano, nitro, acyloxy, alkoxy, optionally substituted phenyl,
heteroaryl, heteroaralkyl, amino, monosubstituted amino, disubstituted amino, acylamino,
hydroxyamino, amidino, guanidino, cyanoguanidinyl, hydrazino, hydrazido, —OR [where R
is hydrogen, alkyl, haloalkyl, alkenyl, cycloalkyl, cycloalkylalkyl, optionally substituted
phenyl, heteroaryl or heteroaralkyl], —S(O)nR [where n is an integer from 0 to 2 and R is
hydrogen, alkyl, haloalkyl, alkenyl, cycloalkyl, cycloalkylalkyl, optionally substituted phcnyl,
heteroaryl, heteroaralkyl, amino, mono or disubstituted amino], —NRSC^R' (where R is
hydrogen or alkyl and R' is alkyl, amino, monosubstituted or disubstituted amino) —C(O)R
(where R is hydrogen, alkyl, alkenyl, cycloalkyl, heteroalkyl, haloalkyl or optionally
substituted phenyl), —COOR (where R is hydrogen, alkyl, optionally substituted phenyl,
heteroaryl or heteroaralkyl), — (alkylene)-COOR (where R is hydrogen, alkyl, optionally
substituted phenyl, heteroaryl or heteroaralkyl), methylenedioxy, 1,2-ethylenedioxy, —
CONR'R" or—(alkylene)CONR'R" (where R' and R" are independently selected from
hydrogen, alkyl, cycloalkyl, haloalkyl, cycloalkylalkyl, optionally substituted phenyl,
heteroaryl and heteroaralkyl). More specifically the term aryl includes, but is not limited to,
phenyl, 1-naphthyl, 2-naphthyl, and derivatives thereof.
The term "ortho-fused" as used in the phrase "ortho-fused bicyclic subunit" means a
bicyclic saturated, partially aromatic or fully aromatic, fully unsaturated or partially saturated,
carbocyclic or heterocyclic ring system wherein the two rings have only two atoms and one
bond in common. Both rings may be aromatic; for example, such as in naphthalene, pteridine,
cinnoline, quinazoline, quinoxaline, naphthyridine, phthalazine, quinoline, isoquinoline,
quinolizine, purine, indazole, indole, isoindole, indolizine, or pyrrolizine and the like.
"Heteroaryl" means a monovalent monocyclic or bicyclic aromatic radical of 5 to 10
ring atoms containing one, two, or three ring heteroatoms selected from N, 0, or S, the
remaining ring atoms being C. For the avoidance of doubt, "heteroaryl" includes "ortho-fused
bicyclic heteroaryl". The aromatic radical is optionally substituted independently with one or
more substituents, preferably one or two substituents selected from oxo, alkyl, haloalkyl,
heteroalkyl, cycloalkyl, cycloalkylalkyl, halo, cyano, nitro, acyloxy, optionally substituted
phenyl, amino, monosubstituted amino, disubstituted amino, acylamino, hydroxyamino,
amidino, guanidino, cyanoguanidinyl, hydrazino, hydrazido, —OR [where R is hydrogen,
alkyl, haloalkyl, alkenyl, cycloalkyl, cycloallcylalkyl or optionally substituted phenyl], —
S(O)nR [where n is an integer from 0 to 2 and R is hydrogen, alkyl, haloalkyl, alkenyl,
cycloalkyl, cycloalkylalkyl, optionally substituted phenyl, amino, mono or disubstituted
amino], —C(O)R (where R is hydrogen, alkyl, alkenyl, cycloalkyl, heteroalkyl, haloalkyl or
optionally substituted phenyl), —COOR (where R is hydrogen, alkyl, or optionally
substituted phenyl), —(alkylene)-COOR (where R is hydrogen, alkyl or optionally substituted
phenyl), methylenedioxy, 1,2-ethylenedioxy,—CONR'R" or —(alkylene)-CONR'R" (where
R' and R" are independently selected from hydrogen, alkyl, cycloalkyl, haloalkyl,
cycloalkylalkyl or optionally substituted phenyl). The term heteroaryl includes, but is not
limited to pyridyl, pyrrolyl, thiopbene, pyrazolyl, thiazolyl, imidazolyl, pyrimidinyl,
thiadiazolyl, indolyl, carbazolyl, azaindolyl, benzofuranyl, benzotriazolyl, benzisoxazolyl,
purinyl, quinolinyl, benzopyranyl, and derivatives thereof.
"Heterocycle" or "Heterocyclyl" means a saturated, partially unsaturated or fully
unsaturated cyclic radical of 3 to 8 ring atoms in which one or two ring atoms are heteroatoms
selected from N, O, or S(O)n (where n is an integer from 0 to 2). The heterocyclo ring may be
optionally substituted independently with one, two or three substituents selected from alkyl,
haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, halo, cyano,
acyl, acylamino, amino, monosubstituted amino, disubstituted amino, —COOR (where R is
hydrogen or alkyl), —XR (where X is 0 or S(0),, where n is an integer from 0 to 2 and R is
hydrogen, alkyl, haloalkyl, cyoloalkyl, aralkyl, aryl, heteroaryl or heteroarallcyl) or —
CONRH" (where R' and R" are independently selected from hydrogen or alkyl).
Representative examples include, but are not limited to tetrahydropyranyl, piperidino,
l-(4-chlorophenyl)piperidino, and the like.
In one aspect of the invention "Ry and Ry1 together form a bridge". A bridge is a
bond, a carbon atom or two carbon atoms connecting two different ring atoms of M which are
meta or para to each other. Particularly the bridge is a bond. Particularly the bridge is one
carbon atom. Alternatively the bridge is two carbon atoms. Examples of M where"Ry and Ry'
together form a bridge" are:
(Ml, bridge is a bond, atoms of M are meta to each other),
(M2, bridge is one carbon atom, atoms of M are meta to each other),
(M4, bridge is two carbon atoms, atoms of M are para to each other),
(M5, bridge is a bond, atoms of M are meta to each and other). •\ ~"Aralkyl" means a radical —Ra—Rb where Ra is bound to Rb and Ra is an alkylcne
group and Rb is an aryl group as defined above e.g., benzyl, phenylethyl,
3-(3-chlorophenyl)-2-methylpentyl, and the like.
"Heteroaralkyl" means a radical —Ra—Rb where Ra is bound to Rb and R alkylene group and Rb is a heteroaryl group as defined above e.g., pyridin-3-ylmethyl,
3-(benzofuran-2-yl)propyl, and the like.
"Alkoxy", "aryloxy" or "heteroaryloxy" means a radical —OR where R is an alkyl,
aryl or heteroaryl, respectively as defined above e.g., methoxy, phenoxy, pyridin-2-yloxy and
the like.
"Alkylthio" and "heteroarylthio" respectively mean an alkyl group or heteroaryl group
attached via a thioether linkage.
"Alkylsulfinyl" and "heteroarylsulfmyl" respectively mean an alkyl group or
heteroaryl group attached via a sulfinyl linkage.
"Alkylcarbonyloxy" refers to an alkyl group attached to a COa group, as in
alkyl-COj—, alkenyl-CO2—, aryl-CCV, respectively, where alkyl is as defined herein. For
example, alkylcarbonyloxy includes but is not limited to, acetoxy, ethylcarbonyloxy, n- or
iso-propylcarbonyloxy, n-, iso-, sec- or tert-butylcarbonyloxy, n-pentylcarbonyloxy,
n-hexylcarbonyloxy.
"Optionally substituted" means that the group at issue is optionally substituted
independently with one, two or three substituents selected from halo, nitro, cyano, hydroxy,
trifluoromethoxy, trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulphamoyl, methyl,
ethyl, ethenyl, ethynyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino,
dimethylamino, diethylamino, JV-methyl-A^-ethylamino, acetylamino, or as otherwise
provided,
"Amino-protecting group" refers to those organic groups intended to protect nitrogen
atoms against undesirable reactions during synthetic procedures e.g., benzyl,
benzyloxycarbonyl (CBZ), t-butoxycarbonyl (BOC), trifluoroacetyl, and the like.
Compounds that have the same molecular formula but differ in the nature or sequence
of bonding of their atoms or the arrangement of their atoms in space are termed "isomers".
Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers".
Stereoisomers that are not mirror images of one another are termed "diastereomers" and those
that are non-superimposable mirror images of each other are termed "enantiomers". When a
compound has an asymmetric center, for example, it is bonded to four different groups, a pair
of enantiomers is possible. An enantiomer can be characterized by the absolute configuration
of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and
Prelog, or by the manner in which the molecule rotates the plane of polarized light and
designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral
compound can exist as either individual enantiomer or as a mixture thereof. A mixture
containing equal proportions of the enantiomers is called a "racemic mixture".
The compounds of this invention may possess one or more asymmetric centers; such
compounds can therefore be produced as individual (R)- or (S)-stereoisomers or as mixtures
thereof. For example, if the Y and Y' substituents in a compound of formula I are attached to
the same carbon are different, then the carbon to which they are attached is an asymmetric
center and the compound of formula I can exist as an (R)- or (S)-stereoisomer relative to that
carbon. Unless indicated otherwise, the description or naming of a particular compound in the
specification and claims is intended to include both individual enantiomers and mixtures,
racemic or otherwise, thereof. The methods for the determination of stereochemistry and the
separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of
"Advanced Organic Chemistry", 4th edition J. March, John Wiley and Sons, New York,
2001).
A "pharmaceutically acceptable excipient" means an excipient that is useful in
preparing a pharmaceutical composition that is generally safe, non-toxic and neither
biologically nor otherwise undesirable, and includes an excipient that is acceptable for
veterinary use as well as human pharmaceutical use. A "pharmaceutically acceptable
excipient" as used in the specification and claims includes both one and more than one such
excipient.
A "pharmaceutically acceptable counterion" means an ion having a charge opposite to
that of the substance with which it is associated and that is pharmaceutically acceptable.
Representative examples include, but are not limited to, chloride, bromide, iodide,
methanesulfonate, p-tolylsulfonate, trifluoroacetate, acetate, and the like.
A "pharmaceutically acceptable salt" of a compound means a salt that is
pharmaceutically acceptable and that possesses the desired pharmacological activity of the
parent compound. Such salts include:
1) acid addition salts, formed with inorganic acids such as hydrochloric acid,
hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed
with organic acids such as acetic acid, propionic acid, hexanoic acid,
cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid,
succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic
acid, 3-(4-hydroxyben?,oyl)benzoic acid, cinnamic acid, mandelic acid,
methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid,
2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid,
2-napthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid,
4-methylbicyclo[2,2,2]oct-2-ene-l-carboxylic acid, glucoheptonic acid,
4,4'-metbylenebis-(3-hydroxy-2-ene-l-carboxylic acid), 3-phenylpropionic acid,
trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid,
glutamic acid, hydroxynapthoic acid, salicylic acid, stearic acid, muconic acid, and the
like; or
2) salts formed when an acidic proton present in the parent compound either is
replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum
ion; or coordinates with an organic base such as ethanolamine, diethanolamine,
triethanolamine, tromethamine, N-methylglucamine, and the like.
3) "Leaving group" has the meaning conventionally associated with it in synthetic
organic chemistry i.e., an atom or group capable of being displaced by a nucleophile
and includes halogen(such as chloro, bromo, iodo), alkanesulfonyloxy (such as
mesyloxy or trifluorosulfonyloxy) or arenesulfonyloxy (such as tosyloxy), ester, or
amino, and the like.
"Pro-drugs" means any compound which releases an active parent drug according to
formula I in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a
compound of formula I are prepared by modifying functional groups present in the compound
of formula I in such a way that the modifications may be cleaved in vivo to release the parent
compound. Prodrugs include compounds of formula I wherein a hydroxy, thio or amino group
in compound I is bonded to any group that may be cleaved in vivo to regenerate the free
hydroxy, amino, or thio group, respectively. Examples of prodrugs include, but are not limited
to esters (e.g., acetate, formate, and benzoate derivatives), carbamates (e.g.,
N,N-dimethylaminocarbonyl) of hydroxy functional groups in compounds of formula I, and
the like.
"Treating" or "treatment" of a disease includes:
1) preventing the disease, i.e. causing the clinical symptoms of the disease not to
develop in a mammal that may be exposed to or predisposed to the disease but does
not yet experience or display symptoms of the disease;
2) inhibiting the disease, i.e., arresting or reducing the development of the disease
or its clinical symptoms; or
3) relieving the disease, i.e., causing regression of the disease or its clinical
symptoms.
A "therapeutically effective amount" means the amount of a compound that, when
administered to a mammal for treating a disease, is sufficient to effect such treatment for the
disease. The "therapeutically effective amount" will vary depending on the compound, the
disease and its severity and the age, weight, etc., of the mammal to be treated.
Invention Compounds
Referring again to a compound of the invention, the following specific values are
disclosed.
In a compound of formula I, a specific value for L is ' »indicates the point of attachment and Z is CH or N. Other specific values for L
include the following structures, wherein " ~**f* " has the same meaning.
R2d O
R,a
R2b
f
Yo
|N2" f R2a £
,-N^^.O R2bv.x4^,N R
2
b^
|| | /^"R2^
R -.' -s^ \x\ 'R2f R p'^v^^f R2c y ^\ R2c y N RR r'
2c ,
R2d Kze R2d Kze R2d R2e
R2d ,or R2d
A specific value for R2b is H. Other specific values for Rab include halo,
(d-CsJalkanoyl, cyano, carboxy, (Ci-C6)alkoxycarbonyl, (Ci-C6)alkyl, hydroxy,
halo(Ci-C6)alkyl, halo(CrC6)alkoxy, (Ci-C6)alkoxy, NHCO-(CrC6)alkyl, SO2(Ci-C6)alkyl,
S02NH(Ci-C6)alkyl, or SO2N((Ci-C6)alkyl)2.
To that end, specific values for R2b include H, methoxy, cyano, fluoro, chloro,
trifluoromethoxy, bromo, hydroxy, CONH2, C02Me, MeCO, methyl, 1-hydroxyethyl,
2-hydroxyethyl, SO2Me, and SO2Et.
A specific value for R2a, is H. Other specific values for R2a include halo,
(Ci-C6)alkanoyl, cyano, carboxy, (Cj-CeJalkoxycarbonyl, (Ci-C$)alkyl, hydroxy,
halo(Ci-C6)alkyl, halo(C,-C6)alkoxy, (C)-C6)alkoxy, NHCO-(CrC6)alkyl, SO2(CI-C6)alkyl)
SO2NH(Ci-C6)alkyl, or S02N((Ci-C6)alkyl)2.
To that end, specific values for R2a include H, methoxy, cyano, fluoro, chloro,
trifluoromethoxy, bromo, hydroxy, CONH2, CO2Me, MeCO, methyl, 1-hydroxyethyl,
2-hydroxyethyl, SO2Me, and SO2Et.
A specific value for R2c is H. Other specific values for R2c include halo,
(C]-C6)alkanoyl, cyano, carboxy, (Ci-CgJalkoxycarbonyl, (Ci-C6)alkyl, hydroxy,
halo(CrC6)alkyl, halo(Ci-C6)alkoxy, (Ci-C6)alkoxy,NHCO-(Ci-C6)alkyl, SO2(CrC6)alkyl,
SO2NH(C,-C6)alkyl, or SO2N((CrC6)alkyl)2.
To that end, specific values for R2c include H, methoxy, cyano, fluoro, chloro,
trifluoromethoxy, bromo, hydroxy, CONH2, C02Me, MeCO, methyl, 1-hydroxyethyl,
2-hydroxyethyl, SO2Me, and SO^t.
A specific value for R2d is H. Other specific values for R2d include halo,
(Ci-Cfi)alkanoyl, cyano, carboxy, (Ci-C6)alkoxycarbonyl, (Ci-C6)alkyl, hydroxy,
halo(CrC6)alkyl, halo(Ci-C6)alkoxy, (Ci-C6)alkoxy, NHCO-(Ci-C6)alkyl, SO2(d-C6)alkyl,
S02NH(C,-C6)alkyl, or SO2N((d-C6)alkyl)2.
To that end, specific values for R2d include H, methoxy, cyano, fluoro, chloro,
trifluoromethoxy, bromo, hydroxy, CONH2, C02Me, MeCO, methyl, 1-hydroxyethyl,
2-hydroxyethyl, SO2Me, and SO^t.
A specific value for R2e is H. Other specific values for R2e include halo,
(Cj-CeJalkanoyl, cyano, carboxy, (Ci-C6)alkoxycarbonyl, (CpCeJalkyl, hydroxy,
halo(CrC6)alkyl, halo(CrC6)alkoxy, (Ci-C6)alkoxy, NHCO-(Ci-C6)alkyl, SO2(Ci-C6)alkyl,
S02NH(Ci-C6)alkyl, or S02N((Ci-C6)alkyl)2.
To that end, specific values for R2e include H, methoxy, cyano, fluoro, chloro,
trifluoromethoxy, bromo, hydroxy, CONH2> CO2Me, MeCO, methyl, 1-hydroxyethyl,
2-hydroxyethyl, SO2Me, and SO2Et.
A specific value for R2f is H. Other specific values for R2f include halo,
(C|-C6)alkanoyl, cyano, carboxy, (Ci-C6)alkoxycarbonyl, (Ci-CeXlkyl, hydroxy,
halo(CrC6)alkyl, halo(CrC6)alkoxy5 (Ci-C6)alkoxy, NHCO-(C,-C6)allcyl) SO2(C,-C SO2NH(Ci-C6)alkyl, or S02N((C,-C6)alkyl)2.
To that end, specific values for R2f include H, methoxy, cyano, fluoro, chloro,
trifluoromethoxy, bromo, hydroxy, CONH2, C02Me, MeCO, methyl, 1-hydroxyethyl,
2-hydroxyethyl, SO2Me, and SO2Et.
A specific value for R2g and R2g' is H. Other specific values for R2g and R2g' include
(Ci-C6)alkyl, andhalo(CrC6)alkyl.
A specific value for Uj is CH2CH2. Other specific values for Ui include CH2CH2CH2
and CH2CH(Me). A further specific value for U] is CH(Me)CH2.
RyN
Y"
C( »
A specific value for M is 1 , wherein Y is 0, NH or CH2 and
is absent or is a bond. Other specific values for M include a group of formula MS
DO V-^'-^
which is , M3 , a group of formula M4 which is
XA
g^N V^v [U
, or a group of formula M2 which is , wherein
" uidicates the point of attachment and [Ui] and 112 is H or carboxy, n is 1, 2, or 3, and
Ry is H, F, hydroxy, (Ci-C6)alkyl, (Ci-C6)alkoxy, or carboxy.
A specific value for M is a group of formula M4 which is
^^N V^vv
>0
HO Other specific values for M include groups of formula M.4 which are
/ v y v
[UJ^-N VM- [Ujjv-N V"*
V.^
OH
OMe , wherein " "^ " indicates the point of attachment.
When M is a group of formula Ml or M4, a specific value for [M]-Ua is [MJ-NHCEfe.
When M is a group of formula Ml or M4, other specific values for [M]-U2 include
OA
[M]— r f^
[M]-NHCH2CH=CH, [M]-NHS02>
n , when M is a group of formula M2, M3,
or M5, a specific value for [M]-U2 is [M]-CH2CH=CH- or [M]-CH2CH2-.
A specific value for R is 2,l,3-oenzothiadiazol-5-yl;
3-oxo-3 ,4-dihydro-2/f- 1 ,4-benzothiazin-6-yl;
2,3-dihydro-benzo[l,4]dioxin-6-yl;
1 ,2,3 -benzothiadiazol-5 -yl;
3-oxo-3,4-dihydro-2//'-l,4-benzoxazin-6-yl;
7-fluoro-3-oxo-3,4-dihydro-2//-l,4-benzoxazin-6-yl;
2-oxo-2,3-dihydro-lH-pyrido[2,3-b][l,4]thiazm-7-yl;
2,3-dihydro-[l,4]dioxmo[2,3-c]pyridin-7-yl;
3-oxo-3 ,4-dihydro-2H-pyrido[3 ,2-b] [ 1 ,4]oxazin-6-yl;
[l,2,3]thiadiazolo[5,4-b]pyridin-6-yl;
3-oxo-3 ,4-dihydro-2H-pyrido[3,2-b] [ 1 4] thiazin-6-yl;
7-chloro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][l,4]thiazin-6-yl;
7-fluoro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][l,4]thiazin-6-yl;
2-thienylthio; or
2,5-difluorophenyl.
H O H O
_ More specifically R is IN , , or wherein
" indicates the point of attachment.
A specific group of compounds of the invention are compounds wherein L is
, wherein " "^ " indicates the point of attachment;
" ' is a bond or is absent;
Z is CH or N when " " is a bond, or, when " — "is absent, Z is 0 or NH;
R2a, Rzb, Rzc, and R2d are each independently H, halo, cyano, (Ci-C(i)alkanoyl,
carboxy, (Cj-C6)alkoxycarbonyl, (Ci-C6)alkyl, halo(C|-C6)alkyl, halo(Cj-C6)alkoxy,
(C1-C6)alkoxy,NHCO-(C1-C6)alkyl1 S02(Ci-C SO2N((C1-C6)alkyl)2.
A specific group of compounds of the invention are compounds wherein Ui—M—U2
RyN
Y*
[L]
is
N[SO2(Ci-C6)alkyl] or CH2 and " "is absent or is a bond. Other specific groups of
compounds of the invention are compounds wherein Ui-M-U: is
Ry
Rev Rf
Pa
" l x/ -N N-W-*v ">1-N >—NR1 «-„/-»- ^ lLlr7 Re Rd Ra „ en-
Re Rf X-^xCH .
\^W^v
^ Rd
)
wherein
"[L] ^^ " indicates the point of attachment to L and " "~M' indicates the point of
attachment to R, and wherein R2 is H or carboxy and n is 1, 2, or 3;
Ra, Rb, Re, Rd, Re, and Rf are each independently H or (Ci-C(
Ry is H, F, hydroxy, (Ci-C6)alkyl, (d-CeJalkoxy, or carboxy;
R1 is H, (Ci-C6)alkyl, or -(C1-C6)alkylcarboxy; and
W is CH2, CO, SO2) CH2CH2, CH2CH=CH, or CH2CsC, wherein each hydrogen may
be optionally replaced by halo or (C)-C6)alkyl;
X is CH2, NH, N(C,-C6)alkyl, N[CO-(C,-C6)alkyl], N[SO2(Ci-C6)alkyl] or 0.
A specific group of compounds of the invention are compounds of formula I which are
compounds of formula II:
R2a U—M-U2-R
II
or a pharmaceutically acceptable salt thereof, wherein
R2a, R2b, R2c, and R2d are each independently H, fluoro, chloro, cyano, (Ci-Cf,)alkyl,
halo(CrC6)alkyl, halo(C]-C6)alkoxy, (Ci-C6)alkoxy;
" " is a bond or is absent;
Z is CH or N when " " is a bond, or Z is 0 or NH when " — "is absent;
Uj is CRaRb—CRcRd or CRaRb—CRcRd—CReRf, wherein Ra, Rb, Re, Rd, Re and
Rf are each independently hydrogen or (Ci-Cs
M is a group of formula Mia or M2-M5:
[U,]'
Mia M5
in the trans configuration relative to "*", wherein R2 is H or carboxy;
Ry and Ry' are each independently H, halo, (Ci-C6)alkyl, or together with the carbon
to which they are attached form C=0; or Ry and Ry' together form a bridge;
X is CH2, or provided n is 2 or 3, X is NH, N(C}-C6)alkyl, or O;
Y is CH2, NH, N(C,-C6)alkyl, or O;
« .» jg a b0n£j OJ. jg absgjjtnisi,
2, or 3;
when M is a group of formula Mia or M4, Ife is NR1—W, wherein R' is H,
, or _ md w.,
CH2CH2, CEfeCKNCH, or CHaCsC, wherein each hydrogen may be optionally replaced by
halo or (Ci-CeJalkyl, provided that when M is a group of formula M2, M3, or M5, U2 is W;
and
when W is CHa, CO or SOz, R is aryl, heteroaryl, heterocyclyl or ortho-fused bicyclic
A
C^M T-fO f1T-f
heteroaryl, or when W is 2 " , CH2CH2, CH2CH=CH, or CHjOC, R is aryl,
heteroaryl, heteroaryl(CrC6)alkyloxy, heteroaryl(Ci-C6)alkylthio,
heteroaryl(Ci-C6)alkylsulfinyl, heteroaryl(Ci-C6)alkylsulfonyl, heteroaryl(Ci-C6)alkylamino
wherein any R may be optionally substituted on carbon; and wherein any ring nitrogen in R
may be optionally substituted by (Ci-C6)alkyl.
A specific group of compounds of the invention are compounds of formula I which are
compounds of formula III:
III
or a pharmaceutically acceptable salt thereof, wherein
Rja, Rib, R2C, and Rjd are each independently H, fluoro, chloro, cyano, (Ci-C6)alkyl,
halo(Ci-C6)alkyl, halo(d-C6)alkoxy, (Ci-C6)alkoxy;
Z is CH or N when " ' is a bond, or, when " — "is absent, Z is 0 or NH;
V is N or CRa, wherein R2 is H or carboxy;
Ry is H, fluoro, hydroxy, methoxy, carbomethoxy, or carboxy;
U2 is NR'—W, wherein R' is H, (Ci-C6)alkyl,
(C.-C^alkyl
, or
-0(C,-C6)alkyl ^ ^ ^ and w .g ^ CQ> ^ CH2CH2j CH2cH=CHj or CH2OC, wherein
each hydrogen may be optionally replaced by halo or (Ci-CeJalkyl; and
R is 2,l,3-benzothiadiazol-5-yl;
3-oxo-3,4-dihydro-27/-l,4-benzothiazin-6-yl;
2,3-dihydro-benzo[l,4]dioxin-6-yl;
1,2,3-benzothiadiazol-5-yl;
3-OXO-3,4-dihydro-2/f-1,4-benzoxazin-6-yl;
7-fluoro-3 -oxo-3,4-dihydro-277-1,4-benzoxazin-6-yl;
2-oxo-2,3-dihydro-lH-pyrido[2,3-b][l,4]thiazin-7-yl;
2,3-dihydro-[l,4]dioxino[2,3-c]pyridin- 7-yl;
3-oxo-3,4-dihydro-2H-pyrido[3,2-b] [ 1,4]oxazin-6-yl;
[l,2,3]thiadiazolo[5,4-b]pyridin-6-yl;
3-oxo-3,4-dihydro-2H-pyrido[3,2-b][ 1,4] thiazin-6-yl;
7-chloro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][l,4]thiazin-6-yl;
7-fluoro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][l,4]thiazin-6-yl;
2-thienylthio; or
2,5-difluorophenyl.
A specific group of compounds of the invention are compounds of formula I which are
compounds of formula IV:
R'sN-W
IV
or a pharmaceutically acceptable salt thereof, wherein
is H, halo, cyano, nitro, (Ci-C6)alkanoyl, carboxy, (C|-C6)alkoxycarbonyl,
(Ci-C6)alkyl, hydroxy, halo(CrC6)alkyi, halo(CrC6)alkoxy, (Ci-C6)alkoxy,
NHCO-(C,-C6)alkyl, SO2(C,-C6)alkyl, S02NH(Ci-C6)alkyl, or SO2N((C,-C6)alkyl)2;
Z is CH or N when " " " " is a bond, or, when " -'" • "is absent, Z is 0 or NH;
Ry is H, fluoro, hydroxy, methoxy, carbomethoxy, or carboxy;
R1 is H or (Ci-C6)alkyl;
W is CO, SO2, or CEfe, wherein each hydrogen may be optionally replaced by halo or
(Ci-C6)alkyl; and
H O H O
Ris N , ^ ,or
A specific group of compounds of the invention are compounds of formula V:
RV ,R
V
or a pharmaceutically acceptable salt thereof, wherein
R2b is H, halo, cyano, nitro, (Ci-C6)alkanoyl, carboxy, (C]-C6)alkoxycarbonyl,
(Ci-C6)alkyl, hydroxy, halo(Ci-C6)alkyl, halo(C]-C6)alkoxy, (d-C6)alkoxy,
NHCO-(Ci-C6)alkyl, SO2(C,-C6)alkyl, S02NH(C,-C6)alkyl, or SOzNCCC^alkyFh;
Z is CH or N when " " is a bond, or, when " "is absent, Z is 0 or Nil;
Ry is H, fluoro, hydroxy, methoxy, carbomethoxy, or carboxy;
R1 is H or (Ci-C6)alkyl; and
H O H.O
,or
A specific group of compounds of the invention are compounds wherein L is a group
of formula LI.
A specific group of compounds of the invention are compounds wherein L is a group
of formula L2.
A specific group of compounds of the invention are compounds wherein L is a group
of formula L3.
A specific group of compounds of the invention are compounds wherein L is a group
of formula L4.
A specific group of compounds of the invention are compounds wherein L is a group
of formula L5.
A specific group of compounds of the invention are compounds wherein L is a group
of formula L6.
A specific group of compounds of the invention are compounds wherein L is a group
of formula L7.
A specific group of compounds of the invention are compounds wherein L is a group
of formula L8.
A specific group of compounds of the invention are compounds wherein L is a group
of formula L9.
A specific group of compounds of the invention are compounds wherein L is a group
of formula LI 0.
A specific group of compounds of the invention are compounds wherein L is a group
of formula LI 1.
A specific group of compounds of the invention are compounds wherein L is a group
of formula LI 2.
A specific group of compounds of the invention are compounds wherein L is a group
of formula LI 3.
A specific group of compounds of the invention are compounds wherein L is a group
of formula L14.
A specific group of compounds of the invention are compounds wherein L is a group
of formula LI 5.
A specific group of compounds of the invention are compounds wherein M is a group
of formula Ml.
A specific group of compounds of the invention are compounds wherein M is a group
of formula Ml a.
A specific group of compounds of the invention are compounds wherein M is a group
of formula M2.
A specific group of compounds of the invention are compounds wherein M is a group
of formula M3.
A specific group of compounds of the invention are compounds wherein M is a group
of formula M4.
A specific group of compounds of the invention are compounds wherein M is a group
of formula M5.
A specific group of compounds of the invention are compounds wherein when M is a
group of formula Ml or M2, W is CH2l CO or SO2.
Preparation of Invention Compounds
In a further aspect, the present invention provides a process for preparing a compound
of the invention or a pharmaceutically-acceptable salt or an in-vivo hydroly sable ester thereof.
It will be appreciated that during certain of the following processes, certain substituents may
require protection to prevent their undesired reaction. The skilled chemist will appreciate
when such protection is required, and how such protecting groups may be put in place and
later removed.
Examples of protecting groups are disclosed in, for example, 'Protective Groups in
Organic Synthesis' by Theodora Green (John Wiley & Sons, 1999). Protecting groups may be
removed by any convenient method described in the literature or known to the skilled chemist
as appropriate for the removal of the protecting group in question, such methods being chosen
so as to effect removal of the protecting group with minimum disturbance of groups
elsewhere in the molecule.
Thus, if reactants include, for example, groups such as amino, carboxy or hydroxy it
may be desirable to protect the group in some of the reactions mentioned herein.
A suitable protecting group for an amino or alkylamino group is, for example, an acyl
group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a
methoxycarbonyl, ethoxycarbonyl or /-butoxycarbonyl group, an arylmethoxycarbonyl group,
for example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The deprotection
conditions for the above protecting groups necessarily vary with the choice of protecting
group.
Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an
aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali
metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such
as a f-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid
as hydrochloric, sulfuric or phosphoric acid or trifluoroacetic acid and an
arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for
example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with
a Lewis acid for example boron tris(trifluoroacetate). A suitable alternative protecting group
for a primary amino group is, for example, a phthaloyl group that may be removed by
treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.
A suitable protecting group for a hydroxy group is, for example, an acyl group, for
example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an
arylmethyl group, for example benzyl. The deprotection conditions for the above protecting
groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl
group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with
a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
Alternatively an arylmethyl group such as a benzyl group may be removed, for example, by
hydrogenation over a catalyst such as palladium-on-carbon.
A suitable protecting group for a carboxy group is, for example, an esterifying group,
for example a methyl or an ethyl group which may be removed, for example, by hydrolysis
with a base such as sodium hydroxide, or for example a f-butyl group which may be removed,
for example, by treatment with an acid, for example an organic acid such as trifluoroacetic
acid, or for example a benzyl group which may be removed, for example, by hydrogenation
over a catalyst such as palladium-on-carbon. Resins may also be used as a protecting group.
The protecting groups may be removed at any convenient stage in the synthesis using
conventional techniques well known in the chemical art.
A compound of the invention, or a pharmaceutically-acceptable salt or an in vivo
hydrolysable ester thereof, may be prepared by any process known to be applicable to the
preparation of chemically-related compounds. Such processes, when used to prepare a
compound of the invention, or a pharmaceutically-acceptable salt or an in vivo hydrolysable
ester thereof, are provided as a former feature of the invention and are illustrated by the
following representative examples. Necessary starting materials may be obtained by standard
procedures of organic chemistry (see, for example, Advanced Organic Chemistry
(Wiley-Interscience, 2001), Jerry March or Houben-Weyl, Methoden der Organischen
Chemie), The preparation of such starting materials is described within the accompanying
non-limiting Examples. Alternatively, necessary starting materials are obtainable by
analogous procedures to those illustrated that are within the ordinary skill of an organic
chemist. Information on the preparation of necessary starting materials or related compounds
(which may be adapted to form necessary starting materials) may also be found in the certain
Patent Application Publications, the contents of the relevant process sections of which are
incorporated herein by reference; for example W02004/058144; US2004/0224946;
WO2004/002992.
The skilled organic chemist will be able to use and adapt the information contained
and referenced within the above references, and accompanying Examples therein and also the
Examples herein, to obtain necessary starting materials, and products.
Thus, the present invention also provides that the compounds of the invention and
pharmaceutically-acceptable salts and in vivo hydrolysable esters thereof, can be prepared by
a process (a) to (h); and thereafter if necessary:
i) removing any protecting groups;
ii) forming a pro-drug (for example an in-vivo hydrolysable ester); and/or
iii) forming a pharmaceutically-acceptable salt;
wherein said processes (a) to (h) are as follows (wherein the variables are as defined
above unless otherwise stated):
Thus, the present invention also provides that the compounds of the invention and
pharmaceutically-acceptable salts and in vivo hydrolysable esters thereof, can be prepared by
a process (a) to (h); and thereafter if necessary:
i) removing any protecting groups;
ii) forming a pro-drug (for example an in-vivo hydrolysable ester); and/or
iii) forming a pharmaceutically-acceptable salt;
wherein said processes (a) to (g) are as follows (wherein the variables are as defined
above unless otherwise stated):
a) By modifying a substituent in, or introducing a substituent into another
compound of the invention by using standard chemistry (see for example, Comprehensive
Organic Functional Group Transformations (Pergamon), Katritzky, Meth-Cohn & Rees). For
example:
• a hydroxy group may be converted into a fluoro group, an acyloxy group (for
instance an acetoxy group), an amino group, a heterocycly] group linked through
nitrogen (optionally substituted on a carbon other than a carbon atom adjacent to the
linking nitrogen ring atom—for instance an optionally substituted amino group). The
skilled artisan understands that such reactions of the hydroxy group take place directly
(for instance by acylation or Mitsunobu reaction) or through the intermediacy of one
or more derivatives (for instance a mesylate or an azide);
• an acyloxy group may be converted into a hydroxy group or into the groups
that may be obtained from a hydroxy group (either directly or through the
intermediacy of a hydroxy group); an alkyl halide group may be converted to a
hydroxy group, an amino group, a tliioalkyl group or a heterocyclyl group linked
through nitrogen; a keto group may be reduced to a hydroxy group or an saturated
alkyl group.
b) as depicted in Scheme 1, by alkylation of a suitable bicyclic ring system
containing a NH group in the ring with a suitable alkylating reagent containing a leaving
group (such as an O-mesylate, chloro, bromo or iodo) in the presence of a base. Alkylation
may be followed by functional group manipulations and/or further alkylations or reductive
aminations,
Scheme 1
I.NaH N V-NH
1.HCI
2.3A Mol Sieves, (
P—
O
3. NaBH(OAc)3
c) As depicted in Scheme 2, by reaction of a suitable bicyclic ring system
containing a NH group in the ring with a suitable alcohol under Mitsunobu conditions,
followed by deprotection and reductive amination with an aldehyde. This sequence may be
followed by functional group manipulations and/or further alkylations or reductive
aminations.
NH
Mi
le
Me
Scheme 2
dlisopropylazodicarboxylate,
(Ph)3P
P
[Pb
1.HCI
2. 3A Mol Sieves, °' [I
3. NaBH(OAc)3
d) As depicted in Scheme 3, by alkylation of a suitable bicyclic ring system
containing a NH group in the ring with bromo- or chloroacetic acid or with a derivative
thereof, followed by activation of the acid and amide coupling. The amide coupling reaction
may be followed by functional group manipulations and/or further alkylations or reductive
animations and optional reduction of the amide moiety.
Scheme 3
H
1)BrCH2COOH
2) Peptide coupling with
amine
Me
1.HCI
2. 3A Mol Sieves,
3. NaBH(OAc)3
DIBAL
e) As depicted in Scheme 4, by alkylation of a suitable bicyclic ring system
containing a NH group in the ring with allylbromide, followed by oxidative cleavage of the
double bond with a suitable oxidizing agent, such as ozone or periodate and subsequent
manipulation of the resulting alcohol, e.g., by conversion to a mesylate, followed by
alkylation. The alkylation reaction may be followed by functional group manipulations and/or
further alkylations or reductive animations.
Scheme 4
1)Allylbromide/NaH
2) Nal04
OH
R
1) Mesylchloride/ NEt3
2)
Me
Me
1. HCI
2. 3A Mol Sieves, cr
H
O'
3. Na(BOAc)3H
f) As depicted in Scheme 5, by alkylation of a suitable bicyclic ring system
containing a NH group in the ring with allylbromide, followed hydroboration and subsequent
manipulation of the resulting alcohol, e.g. by conversion to a mesylate, followed by
alkylation. The alkylation reaction may be followed by functional group manipulations and/or
further alkylations or reductive animations.
Scheme 5
H
1)Allylbromide/NaH
2) borane,
1)Mesylchloride/NEt3
Me
Me Me
2. 3A Mol Sieves,
3. NaBH(OAc)3 ^^—•* -og)
Alternatively, as depicted in Scheme 6,the alcohol intermediate in Scheme 5
may be oxidized to the aldehyde, followed by reductive amination to arrive at the same
intermediate.
Scheme 6
H
-OH
-N
I JL/
NaBH(OAc)3
O
v /
Me Me
Me
1.HCI
2. 3A Mol Sieves, C r ] |
3. NaBH(OAc)3 ^sr~~~y -Qh)
using essentially the procedure described under c), by reaction of a suitable
bicyclic ring system containing a NH group in the ring with an alcohol
HO
^\J~ // ~Ny—
0 /-Me
Me
X= 0 or NR (ii) under Mitsunobu conditions; or by alkylation of a suitable
bicyclic ring system containing a NH group with a derivative of (II), where the alcohol moiety
is converted to a leaving group, such as 0-mesylate, followed by deprotection and reductive
ammination with an aldehyde. This sequence may be followed by functional group
manipulations and/or further alleviations or reductive aminations, also using essentially the
procedure described under c).
For example, as depicted in Scheme 7, an 0-mesylate alkylating reagent may be
prepared from the alcohol, by reaction with mesyl chloride, in the presence of a base, such as
a trialkyl amine or an immobilized version thereof on a resin. It is understood, that such an
alkylating reagent is potentially unstable and needs to be prepared fresh under careful,
controlled conditions.
Scheme 7
Me O Me 9 Me
MsCI
NEt3
I I —
triethylamine
50°C
pressure tube
With respect to (a)-(g) and Schemes 1-5 above, the removal of any protecting groups,
formation of pharmaceutically-acceptable salts and/or formation of in-vivo hydrolysablc
esters or amides are within the skill of an ordinary organic chemist using standard techniques.
Furthermore, details regarding these transformations; for example, the preparation of iri-vivo
hydrolysable ester prodrugs has been described in the section above on such esters.
When an optically active form of a compound of the invention is required, it may be
obtained by carrying out one of the above procedures using an optically active starting
material (formed, for example, by asymmetric induction of a suitable reaction step), or by
resolution of a racemic form of the compound or intermediate using a standard procedure, or
by chromatographic separation of diastereoisomcrs (when produced). Enzymatic techniques
may also be useful for the preparation of optically active compounds and/or intermediates.
Similarly, when a pure regioisomer of a compound of the invention is required, it may
be obtained by carrying out one of the above procedures using a pure regioisomer as a starting
material, or by resolution of a mixture of the regioisomers or intermediates using a standard
procedure.
Biological Activity
According to a further feature of the invention there is provided a compound of the
invention, or a pharmaceutically-acceptable salt, or in-vivo hydrolysable ester thereof for use
in a method of treatment of the human or animal body by therapy.
According to a further feature of the present invention there is provided a method for
producing an antibacterial effect in a warm blooded animal, such as man, in need of such
treatment, which comprises administering to said animal an effective amount of a compound
of the present invention, or a pharmaceutically-acceptable salt, or in-vivo hydrolysable ester
thereof.
The ability of the invention compounds disclosed herein to achieve an antibacterial
effect is demonstrated by the following tests.
Enzyme Potency Testing Methods
Supercoiling assay description:
Compounds were tested for inhibition of Escherichia coli DNA supercoiling activity
as follows. Assays were performed in polypropylene multiwell plates in 50 ul reactions
containing 35 mM Tris-HCl (pH 7.5), 24 mM KC1,4 mM MgCl2, 2 mM dithiothreitol, 1.8
mM spermidine, 5% (v/v) glycerol, 200 nM bovine serum albumin, 1.25% (v/v) DMSO, 3
mM ATP, 10 ng/ml relaxed pBR322 plasmid, 0.6 nM DNA gyrase, and test compound.
Reactions were quenched after 1 hour by the addition of 10 (j,l of 30% (w/v) Ficoll-400,10
mM EDTA, and 5% sodium dodecyl sulfate. Twenty-five ul of each sample was loaded onto
a 0.8% (w/v) agarose gel and electrophoresed. The gel and gel buffer contained IX THE
buffer (89 mM Tris base, 89 mM boric acid, and 2 mM EDTA at pH 8.3). After
electrophoresis for 3 hours at 70V, the gel was stained with ethidium bromide and visualized
by excitation with ultraviolet light. The fluorescence intensity of the most supercoiled plasmid
band was used to measure gyrase activity. Compound potency was based ICso measurements
determined from reactions performed with eight 2-fold serial dilutions of each compound and
a control without compound.
Compounds of the Examples generally have an ICso of ATPase assay description:
Compounds were tested for inhibition of GyrB ATPase activity using an ammonium
molybdate/malachite green-based phosphate detection assay (Lanzetta, P. A., L. J. Alvarez, P.
S. Reinach, and O. A. Candia, 1979,100: 95-97). Assays were performed in multiwell plates
in 100 |il reactions containing: 50 mM TRIS buffer pH 7.5, 75 rnM ammonium acetate, 5.5
mM magnesium chloride, 0.5 mM ethylenediaminetetraacetic acid, 5% glycerol, 1 mM 1,4-
dithio-DL-threitol, 200 nM bovine serum albumin, 16 ug/ml sheared salmon sperm DNA, 4
nM E. coli GyrA, 4 nM E. coll GyrB, 250 /M ATP, and compound in dimethylsulfoxide.
Reactions were quenched with 150 //L of ammonium molybdate/malachite green detection
reagent containing 1.2 mM malachite green hydrochloride, 8.5 mM ammonium rnolybdate
tetrahydrate, and 1 M hydrochloric acid. Plates were read in an absorbance plate reader at 625
run and percent inhibition values were calculated using dimethylsulfoxide (2%)-containing
reactions as 0% inhibition and novobiocin-containing (2 /M) reactions as 100% inhibition
controls. Compound potency was based on ICso measurements determined from reactions
performed in the presence of 10 different compound concentrations.
Compounds of the invention generally have an ICso of Bacterial Susceptibility Testing Methods
Compounds were tested for antimicrobial activity by susceptibility testing in liquid
media in a 96 well format. Compounds were dissolved in dimethylsulfoxide and tested in 10
doubling dilutions in the susceptibility assays. The organisms used in the assay were grown
overnight on suitable agar media and then suspended in a liquid medium appropriate for the
growth of the organism. The suspension was a 0.5 McFarland and a further 1 in 10 dilution
was made into the same liquid medium to prepare the final organism suspension in 100 jjL.
Plates were incubated under appropriate conditions at 37 °C for 24 hours prior to reading. The
Minimum Inhibitory Concentration (MIC) was determined as the lowest drug concentration
able to reduce growth by 80% or more.
Compounds were evaluated against a panel of Gram-positive species, including
Staphylococcus aureus, Streptococcuspneumoniae, Streptococcus pyogenes, and
Enterococcus faecium. In addition, compounds were evaluated against a panel of Gramnegative
species including Haemophilus influenzas, Escherichia coli and Moraxella
catarrhalis. Compounds of the present invention have MIC's less than or equal to 8 ug/ml
versus one or more of the organisms named above.
Data for several compounds of the invention are depicted below:
Example
5
66
37
26
49
gyrase ATPase
[microgram/ml]
0.07
0.3
0.008
ND
ND
gyrase supercoiling
[microgram/ ml]
0.051
ND
ND
0.42
3
E. coli MIC
[microgram/
ml]
0.5
4
0.25
1
8
S. pneumo
[microgram/
ml]
0.12
8
0.06
0.25
4
Pharmaceutical Formulations
In another embodiment the present invention provides a pharmaceutical composition
which comprises a compound of formula (I) admixed with a pharmaceutically-acceptable
carrier, diluent, or excipient.
The invention compositions may be in a form suitable for oral use (for example as
tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible
powders or granules, syrups or elixirs), for topical use (for example as creams, ointments,
gels, or aqueous or oily solutions or suspensions), for administration as eye-drops, for
administration by inhalation (for example as a finely divided powder or a liquid aerosol), for
administration by insufflation (for example as a finely divided powder) or for parenteral
administration (for example as a sterile aqueous or oily solution for intravenous,
subcutaneous, sub-lingual, intramuscular or intramuscular dosing or as a suppository for rectal
dosing).
In addition to the compounds of the present invention, the pharmaceutical composition
of this invention may also contain (i.e. through co-formulation) or be co-administered
(simultaneously, sequentially or separately) with one or more known drugs selected from
other clinically useful antibacterial agents (for example, B-lactams, macrolides, quinolones or
aminoglycosides) and/or other anti-infective agents (for example, an antifungal triazole or
amphotericin). These may include carbapenems, for example meropenem or imipenem, to
broaden the therapeutic effectiveness. Compounds of this invention may also be coformulated
or co-administered with bactericidal/permeability-increasing protein (BPI)
products or efflux pump inhibitors to improve activity against gram negative bacteria and
bacteria resistant to antimicrobial agents.
The compositions of the invention may be obtained by conventional procedures using
conventional pharmaceutical diluents, carriers, or excipients, well known in the art. Thus,
compositions intended for oral use may contain, for example, one or more coloring,
sweetening, flavoring and/or preservative agents. A pharmaceutical composition to be dosed
intravenously may contain advantageously (for example to enhance stability) a suitable
bactericide, antioxidant or reducing agent, or a suitable sequestering agent.
Suitable pharmaceutically acceptable excipients for a tablet formulation include, for
example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium
carbonate, granulating and disintegrating agents such as corn starch or algenic acid; binding
agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc;
preservative agents such as ethyl or propyl p_~hydroxybenzoate, and anti-oxidants, such as
ascorbic acid. Tablet formulations may be uncoated or coated either to modify their
disintegration and the subsequent absorption of the active ingredient within the
gastrointestinal tract, or to improve their stability and/or appearance, in either case, using
conventional coating agents and procedures well known in the art.
Compositions for oral use may be in the form of hard gelatin capsules in which the
active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium
phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with
water or an oil such as peanut oil, liquid paraffin, or olive oil.
Aqueous suspensions generally contain the active ingredient in finely powdered form
together with one or more suspending agents, such as sodium carboxymethylcellulosc,
methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum
tragacanth and gum acacia; dispersing or wetting agents such as lecithin or condensation
products of an alkylene oxide with fatty acids (for example polyoxethylene stearate), or
condensation products of ethylene oxide with long chain aliphatic alcohols, for example
heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters
derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or
condensation products of ethylene oxide with long chain aliphatic alcohols, for example
heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters
derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or
condensation products of ethylene oxide with partial esters derived from fatty acids and
hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions
may also contain one or more preservatives (such as ethyl or propyl p_-hydroxybenzoate, antioxidants
(such as ascorbic acid), coloring agents, flavoring agents, and/or sweetening agents
(such as sucrose, saccharine or aspartame).
Oily suspensions may be formulated by suspending the active ingredient in a
vegetable oil (such as arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such
as liquid paraffin). The oily suspensions may also contain a thickening agent such as beeswax,
hard paraffin or cetyl alcohol. Sweetening agents such as those set out above, and flavoring
agents may be added to provide a palatable oral preparation. These compositions may be
preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by
the addition of water generally contain the active ingredient together with a dispersing or
wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting
agents and suspending agents are exemplified by those already mentioned above. Additional
excipients such as sweetening, flavoring and coloring agents, may also be present.
The pharmaceutical compositions of the invention may also be in the form of oil in
water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, or a
mineral oil, such as for example liquid paraffin or a mixture of any of these. Suitable
emulsifying agents may be, for example, naturally-occurring gums such as gum acacia or gum
tragacanth, naturally-occurring phosphatides such as soya bean, lecithin, an esters or partial
esters derived from fatty acids and hexitol anhydrides (for example sorbitan monooleate) and
condensation products of the said partial esters with ethylene oxide such as polyoxyethylene
sorbitan monooleate. The emulsions may also contain sweetening, flavoring and preservative
agents.
Syrups and elixirs may be formulated with sweetening agents such as glycerol,
propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent,
preservative, flavoring and/or coloring agent.
The pharmaceutical compositions may also be in the form of a sterile injectable
aqueous or oily suspension, which may be formulated according to known procedures using
one or more of the appropriate dispersing or wetting agents and suspending agents, which
have been mentioned above. A sterile injectable preparation may also be a sterile injectable
solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example a
solution in 1,3-butanediol. Solubility enhancing agents, for example cyclodcxtrins may be
used.
Compositions for administration by inhalation may be in the form of a conventional
pressurised aerosol arranged to dispense the active ingredient either as an aerosol containing
finely divided solid or liquid droplets. Conventional aerosol propellants such as volatile
fluorinated hydrocarbons or hydrocarbons may be used and the aerosol device is conveniently
arranged to dispense a metered quantity of active ingredient.
For further information on formulation the reader is referred to Chapter 25.2 in
Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial
Board), Pergamon Press 1990.
The amount of active ingredient that is combined with one or more excipients to
produce a single dosage form will necessarily vary depending upon the host treated and the
particular route of administration. A suitable pharmaceutical composition of this invention is
one suitable for oral administration in unit dosage form. For example, a formulation intended
for oral administration to humans will generally contain, for example, a therapeutically
effective amount of active agent compounded with an appropriate and convenient amount of
excipients which may vary from about I to about 98 percent by weight of the total
composition. For further information on Routes of Administration and Dosage Regimes the
reader is referred to Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry
(Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990.
In another aspect a pharmaceutical composition of the invention is one suitable for
intravenous, subcutaneous or intramuscular injection. Each patient may receive, for example,
a daily intravenous, subcutaneous or intramuscular dose of a compound of this invention, the
composition being administered 1 to 4 times per day. The intravenous, subcutaneous and
intramuscular dose may be given by means of a bolus injection. Alternatively, the intravenous
dose may be given by continuous infusion over a period of time. Alternatively, each patient
may receive a daily oral dose which may be approximately equivalent to the daily parenteral
dose, the composition being administered 1 to 4 times per day.
A composition of the present invention is synergistic and exhibits surprising and
unexpected effects. Therefore, the said composition is synergistic in nature.
Examples
The invention will now be illustrated by the following non-limiting examples.
Example 1
l-(2-{4-[(2,3-Dihydro[l,4]dioxino[2^-c]pyridln-7-ylmethyl)amino]piperidin-lyl}
ethyl)-7-methoxyquinolm-2(lJ3)-one
A solution of l-[2-(4-aminopiperidin-l-yl)ethyl]-7-methoxyquinolin-2(l//)-one
(Intermediate 1, crude, 60 mg, 0.20 mmol) and 2,3-dihydro[l,4]dioxino[2,3-c]pyridine-7-
carbaldehyde (WO 2004/058144) (33 mg, 0.20 mmol) in dry chloroform/methanol (5 raL,
1:1) was heated over 3 A molecular sieves at 70°C for 3 hours. The reaction mixture was
cooled to 0°C, and sodium triacetoxy borohydride (127 mg, 0.6 mmol) was added. The
resulting reaction mixture was stirred at room temperature for 30 minutes and then was
filtered through a 0.45 um membrane and concentrated to dryness under reduced pressure.
The residue was taken up in dichloromethane (50 mL) and saturated aqueous sodium
hydrogen carbonate solution (5 mL). The pH of the aqueous phase was adjusted to a pH of 10
with 1M aqueous sodium hydroxide solution. The aqueous phase was back extracted twice
with dichloromethane (2x 20 mL) and the combined organic phases were dried over sodium
sulfate and concentrated under reduced pressure. Chromatography on silica gel with
dichloromethane/ methanol (8:1 to 4:1) gave the free base of the title compound as a colorless
oil. The free base was taken up in dichloromethane (2 mL), ethanol (7 mL) was added,
followed by addition of 1M HC1 in ether (0.3 mL). The colorless precipitate was collected by
filtration and gave 50 mg (48%) of the bis-hydrochloride salt of the product, mp 243°C.
MS (ESV 451.14 (MH*) for QjHsoN-A
fDMSO-d^ 8 (ppm): 2.00-3.80 (m, 1 1H); 3.96 (s, 3H); 4.20-4.45 (m, 6H);
4.68 (m, 2H); 6.45 (d, 1H); 6.93 (d, 1H); 7.18 (s, 1H); 7.30 (s, 1H); 7.68 (d, 1H); 7.88 (d, 1H);
8.25 (s, 1H); 9.74 (brs, 2H); 11.18 (brs, 1H).
Intermediate 1: l-[2-(4-Aminopiperidin-l-vl')ethvn-7-methoxvquinolin-2('lffl-one
A solution of tert-butyl {l-[2-(7-methoxy-2-oxoquinolin-l(2//)-yl)ethyl]piperidin-4-
yl}carbamate (Intermediate 2, 150 mg, 0.37 mmol) in dioxane (4 mL) was treated at room
temperature under vigorous stirring with a solution of HC1 in dioxane (4M, 2 mL). After 18
hours, the reaction mixture was concentrated under reduced pressure. The residue was taken
up in dichloromethane (60 mL) and saturated aqueous sodium hydrogen carbonate solution
(10 mL). The aqueous phase was extracted three times with dichloromethane (3x 50 mL) and
the combined organic phases were dried over sodium sulfate and concentrated under reduced
pressure to give 1 13 mg (100% yield) of the crude product as an oil.
MS (ESV. 302.24 (MH*) for Ci7H23N302
'H-NMR (DMSO-d^ 8: 1.21 (m, 2H); 1.65 (m, 2H); 2.04 (t, 2H); 2.40-2.52 (m, 2H);
2.89 (m, 2H); 3.69 (m, 1H); 3.88 (s, 3H); 4.31 (t, 2H); 6.40 (m, 1H); 6.88 (m, 1H); 6.94 (m,
1H); 7.63 (m, 1H); 7.80 (m, 1H). (The NH2 protons were not observed)
Intermediate 2: te/V-ButvI n-[2z(7-methoxv-2-oxoquinolin-l(2ffl-yI)e(hyl]piperidin-
4-yl} carbamate
A solution of 7-methoxyquinolin-2(l#)-one (Intermediate 3, 340 mg, 2.2 mmol) in
dry dimethylformarnide (DMF) (10 mL) was treated at 0°C with a cooling bath under stirring
with sodium hydride (88 nig, 60% in oil, 2,2 mmol). The cooling bath was removed and the
mixture was stirred for 30 minutes at room temperature. A solution of 2-{4-[(tertbutoxycarbonyl)
amino]piperidin-l-yl} ethyl methanesulfonate in N,N-dimethylformamide
(DMF) (Intermediate 6, 0.58 mmol/ mL, 3.5 mL, 2.03 mmol) was then added and the
resulting mixture was stirred over night at room temperature. Thin Layer Chromatography
(TLC): Rf = 0.1 (hexanes/ acetone, 1:1) (the 0-alkylated product was observed as a minor
product and has a rf value of 0.3). The DMF was removed under reduced pressure, and the
residue was taken up in ethyl acetate (100 mL) and saturated aqueous sodium
hydrogencarbonate solution (30 mL). The aqueous phase was back extracted once with ethyl
acetate (50 mL). The combined organic phases were dried over sodium sulfate and
concentrated under reduced pressure. Chromatography on silica gel with hexanes/acetonc
(1:1) gave!53 mg (20% yield) of the product as a colorless hard foam.
MS (ES): 402.25 (MH+) for CaHajNsCU
'H-NMR (DMSO-d^ 5: 1.30-1.42 (m, 2H); 1.36 (s, 9H); 1.66 (m, 2H); 2.04 (m, 211);
2.45-2.53 (m, 2H); 2.92 (m, 2H); 3.15 (m, 1H); 3.88 (s, 3H); 4.31 (t, 211); 6.39 (m, 1H); 6.76
(m, 1H); 6.88 (m, 1H); 6.93 (m, 1H); 7.62 (d, 1H); 7.80 (d, 1H). (The structure was confirmed
by an HMBC-NMR experiment)
Intermediate 3: 7-Methoxyquinolin-2(lffl-one
A solution of methyl (2£)-3-(2-amino-4-methoxyphenyl)acrylate (Intermediate 4,
500 mg, 2.4 mmol) in acetonitrile (600 mL) was deoxygenated under vacuum, purged with
nitrogen and irradiated at 365 nm with a long wave UV lamp (B-100AP, Blak Ray) for 28
hours. The solvent was removed under reduced pressure and the product was precipitated
from dichloromethane (20 mL) by the addition of hexanes (100 mL) to give 357 mg (76%
yield) of the crude product as a colorless solid, 90 % pure by 'H-NMR (together with 10%
dimer), mp 190°C.
MS (ESV. 176.21 (MH*) for Ci0H9N02
'H-NMR fDMSO-dfil 8: 3.79 (s, 3H); 6.28 (d, 1H); 6.75-6.81 (m, 2H); 7.55 (d, 1H);
7.79 (d, 1H); 11.59 (s, 1H).
Intermediate 4: Methyl f2Jg)-3-f2-amino-4-methoxvphenvl)acrvlate
To a solution of methyl (2JS)-3-(4-methoxy-2-nitrophenyl)acrylate (Intermediate 5,
4.9 g, 20.66 mmol) in acetic acid (150 mL) at room temperature under nitrogen was added
zinc powder (7.7 g, 118 mmol) in portions. After 4 hours, another 5 g of zinc was added and
the resulting reaction mixture was heated at 50°C for two hours. The reaction mixture was
then cooled to room temperature, filtered, and the filtrate was concentrated to dryness under
reduced pressure. The residue was chromatographed on silica gel with hexanes/ethyl acetate
(3:1) to give 1.0 g (23% yield) of product as a yellow solid, mp 149°C.
MS (Eg): 208.17 (MH4" for CnHi3N03
'H-NMR (DMSO-dQ 5: 3.67 (s, 3H); 3.68 (s, 3H); 5.68 (brs, 2H); 6.14 (dd, 1H); 6.21
(d, 1H); 6.23 (s, 1H); 7.40 (d, 1H); 7.82 (d, 1H).
Intermediate 5: (2E)-3 -(4-Methoxv-2-nitrophenvl)acrylate
A solution of 4-iodo-3-nitroanisole (10 g, 36 mmol), methylacrylate (3.87 mL, 43
mmol), tris(4-methylphenyl)phosphine (1.1 g, 3.6 mmol) and triethylamine (6.05 mL, 43
mmol) was degassed and flushed with nitrogen. Palladium(II) acetate (1.2 g, 1.8 mmol) was
added and the mixture was heated at 70°C overnight. It was filtered through a 0.45 urn
membrane and the solvent was removed under reduced pressure. The residue was taken up in
ethyl acetate (300 mL), it was washed with potassium phosphate buffer (1M, pH 7, 2x 300
mL) and dried over sodium sulfate. Chromatography on silica gel with dichloromethane,
followed by precipitation from dichloromethane (50 mL) with hexanes (500 mL) gave 4,96 g
(58% yield) of product as a yellow solid.
MSnBS): 260.20 (MNa*) for CnH,iN05
'H-NMR CDMSO-d^l 5: 3.73 (s, 3H); 3.88 (s, 3H); 6.59 (d, 1H); 7.33 (dd, 1H); 7.57
(d, 1H); 7.78 (d, 1H); 7.94 (d, 1H).
Intermediate 6: 2-(44(ter/-Butoxvcarbonyl)arnino]piperidin-1 -yl)ethyl
methanesulfonate
A mixture of tert-butyl [l-(2-hydroxyethyl)piperidin-4-yl]carbamate (Intermediate 7,
1.7 g, 7 mmol) in dry dichloromethane (20 mL) and triethyl amine (1.4 mL, 9.8 mmol) was
treated at 0°C with methanesulfonyl chloride (0.65 mL, 8.4 mmol). After 45 minutes the
reaction was complete by TLC (chloroform/methanol 6:1, rf 0.54). Potassium phosphate
buffer (pH 7, 1M, 50 mL) was added, dichloromethane was removed under reduced pressure
and it was extracted with ice-cold ethyl acetate (2 x 100 mL) and dried over sodium sulfate.
The solvent was removed under reduced pressure and the crude preparation of the mesylate
was used without delay for the next step,
MS HSS>: 323.18 (MH*) for
Intermediate 7: tert-Butvl [l-('2-hydroxvethyl')piperidin-4-vl1carbamate
A mixture of tert-butyl piperidin-4-ylcarbamate (5 g, 25 mmol), 2-bromoethanol (1.77
mL, 25 mmol) and triethylamine (3.86 mL, 27.5 mmol) in acetonitrile (20 mL) was heated in
a sealed tube at 50°C for 16 hours. The solvent was removed under reduced pressure, and the
residue was taken up in ethyl acetate (300 mL) and washed with saturated aqueous sodium
hydrogen carbonate solution (100 mL). The aqueous phase was back-extracted once with
ethyl acetate (100 mL) and the combined organic phases were dried over sodium sulfate and
concentrated under reduced pressure. Chromatography on silica gel with dichloromethane/
methanol (4:1) gave 4.04 g (66% yield) of product as a colorless solid, mp 66°C.
MS (BS): 245.28 (Mtf) for CuR^Os
'H-NMR fPMSO-dft 5: 1.33 (m, 2H); 1.36 (s, 9H); 1.62 (m, 2H); 1.92 (t, 2H); 2.32 (t,
2H); 2.77 (m, 2H); 3.17 (m, 1H); 3.43 (m, 2H); 4.34 (t, 1H); 6.73 (d, 1H).
Example 2
l-(2-{4-[(23-I>ihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)aminolpiperidin-lyl}
ethyl)-7-methoxyquinolin-4(lfl)-one
A solution of l-[2-(4-aminopiperidin-l-yl)ethyl]-7-methoxyquinolin-4(l//)-onc
(Intermediate 8, 60 mg, 0.20 mmol) and2J3-dihydro[l,4]dioxino[2,3-c]pyridine-7-
carbaldehyde (WO 2004/058144) (33 mg, 0.20 mmol) in dry chloroform/ methanol (5 mL,
1:1) was heated over 3 A molecular sieves at 70°C for 3 hours. The reaction mixture was
cooled to 0°C, and sodium triacetoxyborohydride (127 mg, 0.6 mmol) was added and the
resulting mixture was stirred at room temperature for 30 minutes. The mixture was then
filtered through a 0.45 urn membrane, acidified with cone. HC1 to pll 1 and concentrated to
dryness under reduced pressure. The residue was taken up in dichloromethane (50 mL) and
saturated aqueous sodium hydrogen carbonate solution (5 mL). The pH of the aqueous phase
was adjusted to pHIO with 1M aqueous sodium hydroxide solution. The aqueous phase was
back extracted twice with dichloromethane (2x 20 mL) and the combined organic phases were
dried over sodium sulfate. Chromatography on silica gel with dichloromethane/methanol
(4:1), containing 0.125% ammonium hydroxide, gave the free base of the title compound as a
colorless oil. The free base was taken up in dichloromethane (2 mL), ethanol (7 mL) was
added, followed by addition of 1M HC1 in ether (0.45 mL). The colorless precipitate was
collected by filtration and gave 84 mg (81% yield) of the bis-hydrochloride salt of the
product, mp 260°C.
MS (ESV 451.21 (MH+) for C25H3oN404
'H-NMR fDMSO-d^ 5: 2.00-3.80 (m, 11H); 4.07 (s, 3H); 4.30-4.46 (m, 6H); 5.06 (m,
2H); 6.83 (d, 1H); 7.28 (d, 1H); 7.45-7.58 (m, 2H); 8.22 (d, 1H); 8.37 (s, 1H); 8.61 (d, 1H);
9.94 (brs, 2H); 11.90 (brs, 1H).
Intermediates: l-r2-(4-Arninopiperidin-l-yDethvl]-7-methoxvquinolin-4d/f)-Qne
A mixture of tert-butyl {l-[2-(7-methoxy-4-oxoquinolin-l(4/f)-yl)ethyl]piperidin-4-
yl}carbamate (Intermediate 9, 370 mg, 0.92 mmol) in dioxane (10 mL) was treated at room
temperature under vigorous stirring with a solution of HC1 in dioxane (4M, 4 mL). After 18
hours, the reaction mixture was diluted with isopropanol (10 mL) and with water (4 ml.) and
more HC1 in dioxane (4M, 5 mL) was added. After Ihour, the reaction mixture was
concentrated under reduced pressure to give the hydrochloride of the product as a colorless
solid. The hydrochloride salt was taken up in aqueous sodium hydroxide solution (1M, 10
mL) and extracted with dichloromethane (60 mL). The aqueous phase was extracted three
times with dichloromethane (3x 60 mL) and the combined organic phases were dried over
sodium sulfate to give 278 mg (100% yield) of the crude product as an oil.
MS (ES): 302.24 (MH+) for CnH^NaC^
'H-NMR (DMSO-d^ (data for the hydrochloride salt) 6: 1.80-2.30 (m, 4H); 3.14 (m,
2H); 3.36 (m, 1H); 3.48 (m, 2H); 3.68 (m, 2H); 4.06 (s, 3H); 5.03 (m, 2H); 6.74 (d, 1H); 7.24
(d, 1H); 7.45 (s, 1H); 8.21 (d, 1H); 8.46 (brs, 2H); 8.55 (d, 1H); 8.60 (brs, 1H); 11.95 (brs,
1H).
Intermediate 9: te/V-Butyl ll-[2-C7-methoxy-4-oxoquinolin-ir4//)-vl')ethvl1piperidin-
4-yUcarbamate
A solution of 7-methoxyquinolin-4-ol (Intermediate 10, 500 mg, 2.85 mmol) in dry
DMF (10 mL) was treated at 0°C with a cooling bath under stirring with sodium hydride (114
mg, 60% in oil, 2.85 mmol). The cooling bath was removed and the mixture was stirred for 30
minutes at room temperature. A solution of 2-{4-[(te/-/-butoxycarbonyl)amino]piperidin-] -
yl}ethyl methanesulfonate in DMF (Intermediate 6, 0.58 mmol/ mL, 5 raL, 2.9 mmol) was
added and the resulting solution was stirred over night at room temperature. DMF was
removed under reduced pressure, the residue was taken up in ethyl acetate (100 mL) and
saturated aqueous sodium hydrogen carbonate solution (30 mL) and the aqueous phase was
back extracted three times with ethyl acetate (3x 70 mL). The combined organic phases were
dried over sodium sulfate. Some starting 7-methoxyquinolin-4-ol was precipitated from
dichloromethane (30 mL) with hexanes (20 mL) and removed by filtration. The filtrate was
concentrated to dryness under reduced pressure. Chromatography of the residue on silica gel
with acetonitrile/water (15:1 to 10:1) gave 373 mg (33% yield) of the product as a colorless
solid, mp 207°C.
MS (ES): 402.36(MH+) for C22H3iN304
'H-NMR(DMSO-dg) 5: 1.25-1.37 (m, 2H); 1.35 (s, 9H); 1.63 (m, 2H); 2.02 (m, 2H);
2.60 (t, 2H); 2.82 (m, 2H); 3.16 (m, 1H); 3.89 (s, 3H); 4.28 (t, 2H); 5.92 (d, 1H); 6.75 (d, 1H);
6.96 (dd, 1H); 7.00 (d, 1H); 7.82 (d, 1H); 8.06 (d, 1H).
Intermediate 10; 7-Methoxvquinolin-4-ol
5-{[(3-Methoxyphenyl)amrno]methylene}-2,2-dimethyl-l,3-dioxane-4,6-dione
(Intermediate 11, 43.5 g, 157 mmol) was added in small portions to phenylether (200 mL) at
225-260°C under stirring. The reaction mixture was stirred for an additional 5 minutes, until
the evolution of gas had stopped. The reaction mixture was cooled to room temperature and
the precipitate was collected by filtration and washed with hexanes. Purification by
recrystallization from methanol gave 12.4 g (45% yield) of product as a green solid, mp
210°C.
MS (ES): 176.21 (MM"1) forCi0H9N02
te-NMR rDMSO-d^ 5: 3.83 (s, 3H); 5.93 (d, 1H); 6.85-6.95 (m, 2H); 7.80 (m, 1H);
7.97 (d,!H);l 1.55 (brs, 1H).
Intermediate 11; S-lfG-MethoxyphenvDaminolmethylenel^^-dimethyl-l^-
dioxane-4.6-dione
A mixture of m-anisidine (22 g, 178 mmol), 2,2-dimethyl-l,3-dioxane-4,6-dione
(30.75 g, 214 mmol) and triethylorthoformate (30 mL, 178 mmol) in ethanol (200 mL) was
heated at 85°C for two hours. The mixture was allowed to cool to room temperature and the
precipitate was collected by filtration and washed with ethanol to give 43,7 g (89% yield) of
product as a pale yellow solid, mp 108°C.
MS fESV 276.12 (M-H-) for CwHijNOs
^ 5: 1.66 (s, 6H); 3.78 (s, 3H); 6.81 (d, 1H); 7.09 (d, 1H); 7.19 (ra,
1H); 7.32 (dd, 1H); 8.59 (d, 1H); 11.19 (d, 1H).
Example 3
Methyl l-(2-{4-[(2,3-dihydro[l,4]dioxino[2,3-c]pyridin-7-
ylmethyl)amino]piperidin-l-yl}ethyl)-6-niethoxy-l//-indole-2-carboxylate
A solution of methyl l-[2-(4-aminopiperidin-l-yl)ethyl]-6-methoxy-l//-indole-2-
carboxylate (Intermediate 12, 200 mg, 0.60 mmol) and 2,3-dihydro[l,4]dioxino[2,3-
c]pyridine-7-carbaldehyde (WO 2004/058144) (100 rag, 0.60 mmol) in dry chloroform/
methanol (10 mL, 1:1) was heated over 3 A molecular sieves at 70°C for 3 hours. The reaction
mixture was cooled to 0°C, sodium triacetoxy borohydride (384 mg, 1.8 mmol) was added
and the resulting mixture was stirred at room temperature for 30 minutes. The reaction
mixture was filtered through a 0.45 u,m membrane and concentrated to dryness under reduced
pressure. The residue was taken up in dichloromethane (150 mL) and saturated aqueous
sodium hydrogen carbonate solution (30 mL), the aqueous phase back extracted once with
dichloromethane (70 mL) and the combined organic phases were dried over sodium sulfate.
Chromatography on silica gel with dichloromethane/ methanol (5:1), containing 0.125%
ammonium hydroxide, gave the free base of the title compound, 239 mg (82% yield), as a
colorless solid, mp 130°C.
MS (ESV 481 .15 (MH4) for C^Hb^Os
'H-NMR rDMSO-d^ 5: 1.10-1.25 (m, 2H); 1.70 (m, 2H); 1.96 (t, 2H); 2.12 (m, 1H);
2.30 (m, 2H); 2.79 (m, 2H); 3.62 (s, 2H); 3.80 (s, 3H); 3.82 (s, 3H); 4.22-4.35 (m, 4H); 4.58
(t, 2H); 6.75 (m, 1H); 6.91 (s, 1H); 7.01 (s, 1H); 7.17 (s, 1H); 7.52 (d, 1H); 7.98 (s, 1H).
Intermediate 12: Methyl l-r2-(4-aminopiperidin-l-yl)etlw!]-6-methoxy-l//-indole-2-
carboxylate
A solution of methyl l-(2-{4-[(te/"/-butoxycarbonyl)amino]piperidin-l-yl}ethyl)-6-
methoxy-l/f-indole-2-carboxylate (Intermediate 13, 520 mg, 1.2 mmol) in dioxane (4 mL)
was treated at room temperature under vigorous stirring with a solution of HC1 in dioxane
(4M, 2 mL). After 3 days, the reaction mixture was concentrated under reduced pressure. The
residue was taken up in dichloromethane (60 mL) and saturated aqueous sodium hydrogen
carbonate solution (10 mL), the aqueous phase was extracted three times with
dichloromethane (3x 50 mL) and the combined organic phases were dried over sodium sulfatc
to give 407 mg (100% yield) of the crude product as colorless solid, mp 101°C,
MS (ES\. 332.23 (MH4) for CiglfeNsOa
'H-NMR fDMSO-d^ 5: 1.15 (m, 2H); 1.61 (m, 2H); 1.99 (t, 2H); 2.51 (m, 2H); 2.79
(m, 2H); 3.49 (m, 1H); 3.81 (s, 3H); 3.83 (s, 3H); 4.59 (t, 2H); 6.76 (m, 1H); 7.02 (brs, 1H);
7.18 (s, 1H); 7.53 (d, 1H). (The NH2 protons were not observed)
Intermediate 13: Methyl l-(2-H-[( 6-methoxy-l/jr-indole-2-carboxylate
A solution of methyl 6-methoxy-2-indole-carboxylate (574 mg, 2.8 mmol) in dry
DMF (10 mL) was treated at 0°C with a cooling bath under stirring with sodium hydride (123
mg, 60% in oil, 3.08 mmol). The cooling bath was removed and the mixture was stirred for 30
minutes at room temperature. A solution of 2-{4-[(ter ethyl methanesulfonate in DMF (Intermediate 6, 0.58 mmol/ mL, 3.4 mL, 2.0 mmol) was
added and the resulting mixture was stirred over night at room temperature. The DMF was
removed under reduced pressure, the residue was taken up in ethyl acetate (100 tnL) and
saturated aqueous sodium hydrogencarbonate solution (30 mL) and the aqueous phase was
back extracted once with ethyl acetate (70 mL). The combined organic phases were dried over
sodium sulfate. Chromatography on silica gel with hexanes/ethyl acetate (1:1 to pure ethyl
acetate) gave 523 mg (43% yield) of the product as a colorless solid, mp 158°C.
MS fESV 432.25 (MH+) for CaHtoNaOs
'H-NMR (DMSO-d^ S: 1.23-1.37 (m, 2H); 1.35 (s, 9H); 1.63 (m, 2H); 1.99 (t, 2H);
2.51 (m, 2H); 2.81 (m, 2H); 3.15 (m, 1H); 3.81 (s, 3H); 3.83 (s, 3H); 4.58 (t, 2H); 6.72-6.78
(m, 2H); 7.01 (brs, 1H); 7.17 (s, 1H); 7.53 (d, 1H).
Example 4
6-[({l-[2-(7-Methoxy-2-oxoquinolin-l(2J?)-yl)ethyl]piperidin-4-yl}amino)methyl]-
2#-pyrldo[3,2-A] [1,4] oxazin-3(4#)-one
l-[2-(4-Aim'nopiperidm-l-yl)emyl]-7-methoxyquinolin-2(l//)-one (Intermediate 1,
crude, 60 mg, 0.20 mmol), 3-oxo-3,4-dihydro-2/f-pyrido[3,2-i][l,4]oxazine-6-carbaldehyde
(WO 2004/058144) (43 mg, 0.24 mmol) in dry dichloroethane/methanol (10 mL, 1:1) were
heated over 3 A molecular sieves at reflux for 4 hours. The reaction mixture was cooled to
0°C, and sodium cyanoborohydride (19 mg, 0.30 mmol) was added and it was stirred at room
temperature for 2 hours. The mixture was filtered through a fritted runnel and concentrated to
dryness under reduced pressure. The residue was taken up in ethyl acetate and washed with
saturated sodium bicarbonate followed by saturated sodium chloride. The saturated sodium
bicarbonate was extracted with chloroform, and the chloroform was washed with saturated
sodium chloride. The ethyl acetate and chloroform extracts were combined, dried over sodium
sulfate and concentrated to dryness under reduced pressure. Silica gel chromatography with
dichloromethane/methanol/ammonia ammonia (8:2:0.01) gave title compound as a colorless
oil, 27 mg (30%).
MS fESV 464.34 (MET") for Cis^NsCU
'H-NMRrCDCK-d) 6: 1.93 (m, 4H); 2.94 (m, 3H); 3.38 (m, 2H); 3.48 (s, 2H); 4.02
(m, 6H); 4.64 (s, 2H); 4.66 (m, 1H); 6.51 (d, J = 9.4 Hz, 1H); 6.83 (dd, J = 6.5,2.1 Hz, 1H);
7.22 (d, J - 8.1 Hz, 1H); 7.46 (m, 2H); 7.62 (m, 211).
Example 5
l-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]pipcridin-lyl}
ethyl)-2-oxo-l,2-dihydroquinoline-7-carbonitrile
1 -[2-(4-Aminopiperidin-1 -yl)ethyl]-2-oxo-1,2-dihydroquinoline-7-carbonitrile
(Intermediate 14, 70 mg, 0.24 mmol), 2,3-dihydro[l,4]dioxino[2,3-c]pyridine-7-
carbaldehyde (WO 2004/058144) (40 mg, 0.24 mmol) and sodium triacetoxy borohydride
(150 mg, 0.75 mmol) were reacted as described for Example 1, but the aqueous workup was
omitted. Chromatography on silica gel with dichloromethane/ methanol (6:1) and
crystallization from dichloromethane/ ether/ hexanes gave the monoacetate salt of the product
as a colorless solid, 69 mg (58%), mp 130-135°C.
MS (ES\. 446.24 (MH+) for Cjs^NsOs
'H-NMR (PMSO-d^ 8: 1.19 (m, 2H); 1.73 (m, 2H); 1.89 (s, 3H); 2.00 (t, 2H); 2.34
(m, 1H); 2.51 (m, 2H, under solvent peak); 2.88 (m, 2H); 3.65 (s, 2H); 4.24-4.37 (m, 6H);
6.76 (d, 1H); 6.92 (s, 1H); 7.63 (dd, 1H); 7.90 (d, 1H); 7.97-8.00 (m, 2H); 8.07 (brs, 1H).
Intermediate 14: H2-(4-Ammopiperidin-l-ynethyl1-2-oxo-1.2-dihydroquinoline-7-
carbonitrile
A solution of ter/-butyl {l-[2-(7-cyano-2-oxoquinolin-l(2//)-yl)ethyl]piperidin-4-
yl}carbamate (Intermediate 15) (6.57 g, 16.57 mmol) in dichloromethane (100 :nL) was
treated with trifluoroacetic acid (40 mL) at 0°C for 30 minutes. The solvent was removed
under reduced pressure and the residue codistilled once with dichloromethane, then taken up
in dichloromethane (200 mL) and washed with saturated sodium hydrogencarbonate solution
(50 mL, pH adjusted to 10 with sodium hydroxide). The aqueous phase was back-extracted
three times with dichloromethane (3x 100 mL) and dried over sodium sulfate. The solvent
was removed under reduced pressure to give the product as off-white solid, 5g, mp 138°C.
MS (ES): 296.91 (MH+) for Ci7H2oN40
'H-NMRfDMSO-dO 5: 1.13 (m, 2H); 1.48 (m, 1H); 1.62 (m, 2H); 2.01 (t, 2H); 2.50
(m, 2H, under solvent peak); 2.86 (m, 2H); 4.35 (t, 2H); 6.76 (d, 1H); 7.63 (d, 1H); 7.90 (d,
1H); 7.98 (d, 1H); 8.07 (s, 1H).
Intermediate 15: ter/-Butvl (l-[2-r7-cvano-2-oxoquinolin-U2flr)-vl)ethvnpiperidin-
4-vl}carbamate
A mixture of ter/-butyl {l-[2-(7-bromo-2-oxoquinolin-l(2//)-yl)ethyl]piperidin-4-
yl}carbamate (Intermediate 16) (9.85 g, 21.9 mmol) and potassium cyanide (2.14 g, 32.8
mmol) in dry acetonitrile (60 mL) was degassed and flushed with nitrogen three times.
Tributyltinchloride (0.059 mmol, 1.13 mL of a 51.6 mM solution in heptane) was added,
followed by 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (63 mg, 0.11 mmol) and
tris(dibenzylideneacetone)dipalladium (0) (100 mg, 0.11 mmol) and it was degassed and
flushed with nitrogen like above, The mixture was stirred for 30 minutes at room temperature
and then degassed and flushed with nitrogen again. It was heated at 85°C for 20 hours. The
solvent was removed under reduced pressure and the residue taken up in dichloromethane
(500 mL) and washed with water (200 mL). The aqueous phase was back-extracted once with
dichloromethane (200 mL) and combined organic phases were dried over sodium sulfate.
Solvent was removed under reduced pressure and the residue was crystallized from
acetonitrile ( 60 mL) to give the product as a colorless solid, 6.57g (76%), mp 202°C.
MS (ESI: 397.21 (MH*) for
'H-NMRfDMSO-d.) 5: 1.30 (m, 2H); 1.36 (s, 9H); 1.64 (m, 2H); 2.02 (m, 2H); 2.50
(m, 2H, under solvent peak); 2.90 (m, 2H); 3.15 (m, Hi); 4.34 (t, 2H); 6.74-6.78 (m, 2H);
7.63 (m, 1H); 7.89 (d, 1H); 7.99 (d, 1H); 8.05 (s, 1H).
Intermediate 16: tert-Butvl n-r2-f7-bromo-2-oxoquinolin-l(2fln)-vl')ethvnpiperidin-
4-yl} carbamate
7-Bromoquinolin-2(l//)-°ne (Intermediate 17) (7.4 g, 33 mmol) was deprotonated
with sodium hydride (1.45 g, 60% in oil, 36 mmol) and alkylated with 2-{4-[(tertbutoxycarbonyl)
amino]piperidin-l-yl} ethyl methanesulfonate (Intermediate 6) (40 mmol) as
described for Intermediate 2; Chromatography on silica gel with hexanes/ acetone (5:2) gave
9.87 g (66%) of the product as a colorless solid, mp 155°C.
MS (ES\. 450\452 (MIT1) for CjiEbBrNsOa
'H-NMR (DMSO-d^ 5: 1.32 (m, 2H); 1.36 (s, 9H); 1.65 (m, 2H); 2.01 (t, 2H); 2.46
(m, 2H); 2.90 (m, 2H); 3.19 (m, 1H); 4.29 (t, 2H); 6.61 (d, 1H); 6.75 (d, 1H); 7.41 (d, III);
7.65 (d, 1H); 7.73 (brs, 1H); 7.89 (d, 1H).
Intermediate 17: 7-Bromoquinolin-2(l//)-one
(2£)-W-(3-bromophenyl)-3-phenylacrylamide (Intermediate 18) (16 g, 53 mmol) and
aluminium trichloride (31.8 g, 238 mmol) were heated in chlorobenzene (100 mL) at 90°C
bath temperature for one hour. The reaction mixture was cooled to room temperature and
poured onto ice. It was stirred until the ice was completely melted, the mixture was filtered
and washed with water and ethyl acetate to give the crude product as slightly brown solid in a
mixture with the minor product 5-bromoquinolin-2(l/3f)-one (3:2), 8.8 g (70%). This mixture
could not be separated. The mixture was heated in phosphoroxychloride (50 mL) at 65°C for
one hour. The reaction mixture was cooled to room temperature and poured onto ice. Tt was
carefully neutralized at 0°C with sodium carbonate, extracted into ethyl acetate (300 mL),
washed with brine, dried over sodium sulfate and concentrated to give the crude mixture of 7-
bromo-2-chloroquinoline and 5-bromo-2-chloroquinoline. The mixture was taken up in
dichloromethane (100 mL), treated with silica gel (20 g), filtered and the filter cake was
washed with dichloromethane. Filtrate and wash were combined and concentrated. The
residue was crystallized from toluene/ hexanes (70 mL, 1:1) to provide pure 7-bromo-2-
chloroquinoline, 3.74 g as a colorless solid mp 113 °C.
MS (ES): 242/244/246 (Mtf) for C9H5BrClN
'H-NMRfDMSO-dfi') 5:1.63 (d, J 8.4 Hz, 1H); 7.81 (dd, J 8.4,1.6 Hz, 1H); 8.03 (d, J
8.4 Hz, 1H); 8.18 (d, J 1.6 Hz, 1H); 8.48 (d, J 8.4 Hz, 1H).
7-Bromo-2-chloroquinoline was heated in 5M HC1 (100 mL) and dioxanc (10 mL) for
1 hour at reflux. The Reaction mixture was cooled, filtered and washed with water to give the
title compound, 2.89 g, as a colorless solid, mp 295°C.
MS (ES): 224.13/226.13 (MH*) for C9H6BrNO
'H-NMR(DMSO-dg) 5: 6.51 (d, J 9.6 Hz, 1H); 7.32 (dd, J 8.6,1.6 Hz, 1H); 7.46 (d, J
1.6 Hz, 1H); 7.61 (d, J 8.6 Hz, 1H); 7.88 (d, J 9.6 Hz, 1H); 11.80 (brs, 1H).
Intermediate 18: (2Jg)-JV-(3-BromophenylV3-phcnvlacrylamide
To a solution of 3-broraoaniline (13.1 mL, 120 mmol) in dichloromethane (100 mL)
and 2,6-lutidine (21 mL, 180 mmol) at 0°C was added a solution of cinnamoylchloride (20 g,
120 mmol) in dichloromethane (50 mL) dropwise. The reaction mixture was allowed to reach
room temperature and was stirred for 2 hours. It was quenched with potassium phosphate
buffer (100 mL, 1M, pH 7) and stirred for 15 minutes. Dichloromethane was removed under
reduced pressure. The residue was extracted with ethyl acetate. The organic phase was
washed with phosphate buffer (200 mL), dried over sodium sulfate and concentrated to
dryness. The residue was crystallized from toluene/ hexanes to give the product as colorless
solid (33.4 g, 92%).
MS (BS); 302/304 (MH*) for CisHnBrNO
'H-NMRfDMSQ-dfilS: 6.79 (d, 1H); 7.23-7.70 (m, 9H); 8.07 (s, 1H); 10.38 (s, 1H).
Example 6
2-Oxo-l-[2-(4-{[(3-oxo-3,4-dihydro-2ff-pyrido[3,2-6][l,4]oxazin-6-
yl)methyl]amino}piperidin-l-yl)ethyl]-l,2-dihydroquinoline-7-carbonitrile
l-[2-(4-Aminopiperidin-l-yl)ethyl]-2-oxo-l,2-dihydroquinoline-7-carbonitrile
(Intermediate 14, 70 mg, 0.24 mmol), 3-oxo-3,4-dihydro-2#-pyrido[3,2-Z>][l,4]oxazine-6-
carbaldehyde (WO 2004/058144) (42 mg, 0.24 mmol)and sodium triacetoxy borohydride
(150 mg, 0.75 mmol) were reacted as described for Example 5. Chromatography on silica gel
with dichloromethane/ methanol (6:1) and crystallization from ethyl acetate/ hexanes gave the
product as a colorless solid, 73 mg (67%), mp 212°C.
MS (ES): 459.37 (MH*) for C2sHa6N«03
'H-NMRfDMSO-dgtS: 1.19 (m, 2H); 1.74 (m, 2H); 2.01 (t, 2H); 2.35 (m, 1H); 2.51
(m, 2H, under solvent peak); 2.88 (m, 2H); 3.65 (s, 2H); 4.35 (t, 2H); 4.59 (s, 2H); 6.76 (d,
1H); 7.00 (d, 1H); 7.28 (d, 1H); 7.63 (dd, 1H); 7.89 (d, 1H); 7.99 (d, 1H); 8.06 (bis, 1H);
11.08(brs,
Example 7
6-[({l-[2-(7,8-Difluoro-2-oxoquinolin-l(2fl)-yl)ethylJpiperidin-4-
yl}amino)methyl]-2#-pyrido[3,2-&][l,4]oxazin-3(4#)-one
1 -[2-(4-Aminopiperidin- 1 -yl)ethyl] -7, 8-difluoroquinolin-2( 1 /f)-one (Intermediate
19) (100 mg, 0.325 mmol), 3-oxo-3)4-dihydro-2#-pyrido[3,2-&][l,4]oxazine-6-carbaldehyde
(WO 2004/058144) (58 mg, 0.325 mmol) and sodium triacetoxy borohydride (207 mg, 0.98
mmol) were reacted as described for Example 1, but the aqueous workup was omitted, to give
107 mg of the mono acetate salt of the product after chromatography, as a colorless solid, mp
158-170°C.
MS (ESV. 470.13 (MH4) for CwHasFjNjOs
'H-NMRfDMSO-d^ 5: 1.20 (m, 2H); 1.75 (m, 2H); 1.89 (s, 3H); 2.03 (t, 2H); 2.36
(m, 1H); 2.55 (m, 2H); 2.82 (m, 2H); 3.66 (s, 2H); 4.40 (m, 2H); 4.59 (s, 2H); 6.60 (d, 1H);
7.00 (d, 1H); 7.28 (d, 1H); 7.34 (m, 1H); 7.60 (m, 1H); 7.91 (d, 1H); 11.17 (brs, 1H).
Intermediate 19; l-|'2-(4-Aminopiperidin-l-vl)ethvl1-7,8-difluoroquinolm-2(lflr)-one
The title compound was obtained from tert-buty\ {l-[2-(7,8-difluoro-2-oxoquinolinl(
2//)-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 20) (412 mg, 1.01 mmol) by the
procedure described for Intermediate 1, 316 mg (quantitative yield), as a colorless gum.
MS (ESV 308.29 (MH+) for Ci6H,9F2N3O
'H-NMR rDMSO-d^ 5: US (m, 2H); 1.46 (m, 1H); 1.62 (m, 2H); 2.03 (t, 2H); 2.53
(m, 2H, under solvent peak); 2.79 (m, 2H); 4.39 (m, 2H); 6.60 (d, 1H); 7.34 (m, 1H); 7.59 (m,
1H); 7.91 (d, 1H).
Intermediate 20: tert-Butyl U-r2-(7.8-difluoro-2-oxpquinolin-l(2//)-
yDethyl]piperidin-4-vl } carbamate
7,8-Difluoroquinolin-2(l/f)-one (Intermediate 21) (500 mg, 2.8 mmol) was
deprotonated with sodium hydride (121 mg, 60% in oil, 3.04 mmol) and alkylated with 2-{4-
[(tert-butoxycarbonyl)amino]piperidin-l-yl} ethyl methanesulfonate (Intermediate 6) (3.3
mmol) as described for Intermediate 2. Chromatography on silica gel with hexanes/ acetone
2:1 gave the product as a colorless solid, 414 mg (37%).
MS (ES): 408.30 (MH+) for CaiEfoFzNaOa
'H-NMRfDMSQ-d^ 5: 1.32 (m, 2H); 1.36 (s, 9H); 1.65 (m, 2H); 2.04 (t, 2H); 2.53
(m, 2H); 2.83 (m, 2H); 3.16 (m, 1H); 4.38 (m, 2H); 6.61 (d, 1H); 6.75 (d, 1H); 7.34 (m, 1H);
7.60 (m, 1H); 7.91 (m, 1H).
Intermediate 21: 7.8-Difluoroquinolin-2(l/f)-one
The compound was prepared from {2£)-A'-(2,3-difluorophenyl)-3-phenylacrylaniide
(Intermediate 22) (7.4 g, 28.5 mmol) and aluminium trichloride (19 g, 142 mmol) as
described for Intermediate 17. The crude cyclization product was obtained as a single
regioisomer, which was used without further purification, 2 g light brown solid (37%).
MS fESI: 182.04 (MH+) for C9H5F2NO
'H-NMR(DMSO-d6) 8: 6.51 (d, 1H); 7.22 (m, 1H); 7.52 (m, 1H); 7.91 (m, 1H).
Intermediate 22: (2ff)-N-(2.3-DifluorophenylV3-phenylacrylamide
The compound was prepared from 2,3-difluoroaniline (5 g, 38.7 mmol) and
cinnamoylchloride (6.45 g, 38.7 mmol) in the presence of 2,6-lutidine (6.8 mL, 58 mmol) as
described for Intermediate 18 to give a colorless solid, 7.4 g (74%).
MS (ES1: 260.08 (MH*) for Ci5HnF2NO
'H-NMR (DMSO-d^ 6: 7.05 (d, 1H); 7.14-7.22 (m, 2H); 7.40-7.50 (m, 3H); 7.59-7.64
(m, 3H); 7.89 (m, 1H); 10.16 (brs, 1H).
Example 8
6-[({l-[2-(5,7-Difluoro-2-oxoquinolin-l(2/^-yl)ethyl]piperidin-4-
yl}ammo)methyl]-2#-pyrido[3,2-&][l,41oxazin-3(4#)-one
l-[2-(4-Aminopiperidin-l-yl)ethyl]-5,7-difluoroquinolin-2(l//)-one (Intermediate
23) (100 mg, 0.325 mmol), 3-oxo-3,4-dihydro-2#-pyrido[3,2-Z>][l,4]oxazine-6-carbaldehyde
(WO 2004/058144) (58 mg, 0.325 mmol) and sodium triacetoxy borohydride (207 mg, 0.98
mmol) were reacted as described for Example 6, to give 114 mg of the mono acetate salt of
the product as a colorless solid, mp 170-180°C.
MS (ES): 470.32 (MH*) for Ca^sFzNsOa
'H-NMRflDMSQ-dj) 5: 1.20 (m, 2H); 1.74 (m, 2H); 1.89 (s, 3H); 2.00 (t, 2H); 2.36
(m, 1H); 2.48 (m, 2H); 2.88 (m, 2H); 3.66 (s, 2H);.4.29 (t, 2H); 4.59 (s, 2H); 6.61 (d, 1H);
7.00 (d, 1H); 7.18-7.33 (m, 3H); 7.96 (d, 1H); 11.16 (brs, 1H).
Intermediate 23; l-[2-(4-Aminopiperidin-l-vl')ethvl1-5.7-difluoroquinolin-2(lJ:D-one
The title compound was obtained from tert-butyl {l-[2-(5,7-difluoro-2-oxoquinolinl(
2#)-yl)ethyl]piperidin~4-yl}carbamate (Intermediate 24) (637 mg, 1.01 mmol) by the
procedure described for Intermediate 1, 483 mg (quantitative), as a colorless solid.
MS (ES): 308.27 (MM") for Ci6Hi9F2N30 y
'H-NMRfDMSQ-dg") 5: 1.15 (m, 2H); 1.46-1.64 (m, 3H); 2.00 (t, 2H); 2.46 (m, 2H,
under solvent peak); 2.85 (m, 2H); 4.28 (t, 2H); 6.61 (d, 1H); 7.21 (m, 1H); 7.30 (d, 1H); 7.95
(d, 1H).
Intermediate 24: fe/7-Butyr(l-[2-(5.7-difluoro-2-oxoquinolin-l(2/jr)-
vr)ethyl]piperidin-4-yl) carbamate
5,7-Difiuoroquinolin-2(l.H)-one (Intermediate 25) (500 mg, 2.8 mmol) was
deprotonated with sodium hydride (121 mg, 60% in oil, 3.04 mmol) and alkylated with 2-{4-
[(ter/-butoxycarbonyl)amino]piperidin-l-yl}ethyl methanesulfonate (Intermediate 6) (3.3
mmol) as described for Intermediate 20. Colorless solid, 637 mg (57%).
MS (ES): 408.30 (MH+) for C2iH27F2N3O3
:H-NMR fDMSO-d^ 5: 1.32 (m, 2H); 1.36 (s, 9H); 1.64 (m, 2H); 2.01 (t, 2H); 2.48
(m, 2H); 2.88 (m, 2H); 3.18 (m, 1H); 4.28 (m, 2H); 6.61 (d, 1H); 6.75 (d, 1H); 7.21 (m, 1H);
7.30 (d, 1H); 7.95 (m, 1H).
Intermediate 25: 5.7-Difluoroquinolin-2(l/f)-one
The compound was prepared from (2£)-A^-(3,5-difluorophenyl)-3-phenylacrylamide
(Intermediate 26) (8.1 g, 31.2 mmol) and aluminium trichloride (21 g, 156 mmol) in a
similar way as described for Intermediate 21. 3.47 g light brown solid (61%), mp 292-318°C.
MS (ES): 181.98 (Ml-f) for C9H5F2NO
'H-MMR (PMSO-d^ S: 6.51 (d, 1H); 6.90 (m, 1H); 7.10 (ddd, 1H); 7.93 (d, Hi);
12.05 (brs, 1H).
Intermediate 26: (2Jg)-Ar-f3.S-Difluoronhenvl)-3-phenvlacrylamide
The compound was prepared from 3,5-difluoroaniline (5 g, 38.7 mmol) and
cinnamoylchloride (6.45 g, 38.7 mmol) in the presence of 2,6-lutidine (6.8 mL, 58 ramol) as
described for Intermediate 18 to give a colorless solid, 8.1 g (81%).
MS HBSV 260.10 (MH4) for CijHiiF2NO
'H-NMR fDMSO-da 8: 6.76 (d, 1H); 6.92 (m, 1H); 7.35-7.49 (m, 5H); 7.60-7.65 (m,
3H); 10.59 (s, 1H).
Example 9
6-[({l-[2-(7-Fluoro-2-oxoquinolin-l(2fif)-yl)ethyl]piperidin-4-yl}amino)metliyl]-
2J7-pyrido [3,2-6] [1,4] oxazin-3(4fl)-one
l-[2-(4-Aminopiperidin-l-yl)ethyl]-7-fluoroquinolin-2(l//)-one (Intermediate 27)
(100 mg, 0.346 mmol), 3-oxo-3,4-dihydro-2#-pyrido[3,2-6][l,4]oxazine-6-carbaldehyde
(WO 2004/058144) (62 mg, 0.346 mmol) and sodium triacetoxy borohydride (220 mg, 1.04
mmol) were reacted as described for Example 7 to give 115 mg (74%) of the monoacetatc
salt of the product as a colorless solid, mp 150-155°C,
MS fES): 452.22 (MH4) for C24H26FN503
'H-NMR CDMSO-d^ 6: 1.22 (m, 2H); 1.75 (m, 2H); 1.89 (s, 3H); 2.01 (t, 2H); 2.37
(m, 1H); 2.48 (m, 2H); 2.89 (m, 2H); 3.67 (s, 2H); 4.29 (t, 2H); 4.59 (s, 2H); 6.55 (d, 1H);
7.00 (d, 1H); 7.12 (ddd, 1H); 7.28 (d, 1H); 7.38 (dd, 1H); 7.78 (dd, 1H); 7.90 (d, 1H); 11.16
(brs, 1H).
Intermediate 27; 1 -f 2-f 4-Aminopiperidin-1 -vl)ethvl1-7-fluoroquinolin-2f Iffl-one
The title compound was obtained from tert-butyl {l-[2-(7-fluoro-2-oxoquinolinl(
2H)-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 28) (565 mg, 1.45 mmol) by the
procedure described for Intermediate 1,425 mg (quantitative), as a colorless solid.
MS (ESY. 290.19 (MH+) for Ci6H2oFN30
'H-NMR (DMSQ-d^ S: 1.16 (m, 2H); 1.62 (m, 2H); 2.00 (t, 2H); 2.46 (m, 2H, under
solvent peak); 2.85 (m, 2H); 3.46 (m, 1H); 4.28 (t, 2H); 6.54 (d, 1H); 7.12 (ddd, 1H); 7.36
(dd, 1H); 7.76 (dd, 1H); 7.89 (d, 1H).
Intermediate 28: tert-Butvl n-[2-r7-fluoro-2-oxoquinolin4(2/f)-vlWhvl1piperidin-
4-yl} carbamate
7-Fluoroquinolin-2(l//)-one (Intermediate 29) (500 mg, 3.06 mmol) was
deprotonated with sodium hydride (135 mg, 60% in oil, 3.37 mmol) and alkylated with 2-{4-
[(tert-butoxycarbonyl)amino]piperidin-l-yl} ethyl methauesulfonate (Intermediate 6) (3.7
mmol) as described for Intermediate 20. Colorless solid, 570 mg (48%).
MS (ESY. 390.21 (MH+) for C2iH28FN3O3
'H-NMR (DMSO-(V)S: 1.32 (m, 2H); 1.36 (s, 9H); 1.64 (m, 2H); 2.02 (t, 2H); 2.48
(m, 2H); 2.90 (m, 2H); 3.19 (m, 1H); 4.28 (m, 2H); 6.54 (d, 1H); 6.75 (d, 1H); 7.12 (m, 1H);
7.38 (m, 1H); 7.78 (dd, 1H); 7.90 (d, 1H).
Intermediate 29: 7-Fluoroquinolin-2('l//Vone
The compound was prepared from {2/^-Af-(3-fluorophenyl)-3-phenylacrylamide
(Intermediate 30) (13.8 g, 57.2 mmol) and aluminium trichloride (30.5 g, 229 mmol) in a
similar way as described for Intermediate 21 to give a mixture of the title compound together
with the corresponding 5-fluoro regioisomer in a ratio of 3:1. This mixture was vigorously
stirred in dichloromethane (100 mL) for 3 hours at room temperature and then filtered. The
solid obtained was resuspended in diethyl ether (200 mL) and stirred like above and filtered to
give 3.63 g (34%) of the crude product containing 12% of the 5-fluoro regioisomer. This was
used without further purification for the next step.
MS (ESV 164.02 (MH+) for C9H6FNO
'H-NMR (CPCy MeOD) S: 6.31 (d, IH); 6.73 (ddd); 6.79 (dd, 1H); 7.35 (dd, III);
7.60 (d, 1H).
Intermediate 30: (2ffi-W3-Fluorophenvn-3-phenylacrvlamide
The compound was prepared from 3-fluoroaniline (5.8 mL, 60 mmol) and
cinnamoylchloride (10 g, 60 mmol) in the presence of 2,6-lutidine (10.5 mL, 90 mmol) as
described for Intermediate 18 to give a colorless solid, 13.9 g (96%), mp 110°C.
MS (ES\. 242.20 (MH4) for C,5Hi2FNO
'H-NMR (DMSO-d^ 5: 6.80 (d, 1H); 6.89 (m, 1H); 7.31-7.48 (m, 5H); 7.58-7.65 (m,
3H); 7.73 (m, 1H); 10.43 (s, 1H).
Example 10
l-(2.{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-lyI}
ethyl)~7-fluoroquinolin-2(lH)-one
l-[2-(4-Aminopiperidin-l-yl)ethyl]-7-fluoroquinolin-2(l//)-one (Intermediate 27)
(100 mg, 0.346 mmol), 2)3-dihydro[l,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO
2004/058144) (57 mg, 0.346 mmol) and sodium triacetoxy borohydride (220 mg, 1.04 mmol)
were reacted as described for Example 7. The free base obtained after chromatography was
dissolved in dichloromethane/ ether (10 mL, 1:1) and HC1 in ether (1M, 1 mL) was added
under vigorous stirring. It was evaporated to dryness under reduced pressure and the residue
was taken up as a suspension in dichloromethane/ hexanes ( 10 mL, 1:1). It was filtered and
dried to give 1 18 mg (78%) of the bis HC1 salt of the product as a colorless solid, mp >275°C
(decomposed).
MS (ESV. 439.23 (MH+) for CM^R^OS
'H-NMR (PMSO-d,;) 5: 2.10 (m, 2H); 2.37 (m, 2H); 3.10 (m, 2H); 3.20-3.38 (m, 311);
3.78 (m, 2H); 4.27 (m, 2H); 4.37 (m, 2H); 4.43 (m, 2H); 4.62 (t, 2H); 6.60 (d, 1H); 7.19 (ddd,
1H); 7.41 (s, 1H); 7.78 (dd, 1H); 7.84 (dd, 1H); 7.98 (d, 1H); 8.31 (s, 1H); 9.91 (brs, 2H);
11.04(brs,
Example 11
6-[({l-[2-(7-Methoxy-2-oxo-3,4-dihydroquinolin-l(2jH)-yl)ethyl]piperidin-4-
yl}amino)methyl]-2/f-pyrido[3,2-£][l,4]oxazin-3(4/f)-one
l-[2-(4-Aminopiperidin-l-yl)ethyl]-7-methoxy-3,4-dihydroquinolin-2(l/f)-one
(Intermediate 31) (110 mg, 0.36 mmol), 3-oxo-3,4-dihydro-2//-pyrido[3,2-
6][l,4]oxazine-6-carbaldehyde (WO 2004/058144) (65 mg, 0.325 mmol) and sodium
triacetoxy borohydride (220 mg, 1.04 mmol) were reacted as described for Example 1, but
the aqueous workup was omitted. Chromatography on a Phenomenex Synergy Polar-RP4um
column, eluent: 30-60% acetonitrile, 10 mM ammonium acetate pH8, followed by
chromatography on silica gel with dichloromethane/ methanol (7:1). The bis HC1 salt of the
product was prepared as described for Example 10 to give 46 mg (24%) as a colorless solid,
mp >285°C (dec).
MS (BS): 466.21 (MH*) for C25H3iN504
'H-NMR fDMSO-d^ 8: 2.10 (m, 2H); 2.36 (m, 2H); 2.53 (t, 211); 2.86 (t, 2H); 3.10
(m, 2H); 3.16 (m, 2H); 3.36 (m, 1H); 3.70 (m, 2H); 3.73 (s, 3H); 4.16 (m, 2H); 4.28 (m, 2H);
4.70 (s, 2H); 6.80 (m, 1H); 6.86 (s, 1H); 7.23-7.28 (m, 2H); 7.45 (d, 1H); 9.70 (brs, 211);
11.07 (brs, 1H); 11.37 (s, 1H).
Intermediate 31; l-f2-f4-Aminopiperidin-l-ynethvri-7-methoxv-3,4-
dihydroquinolin-2(l/:f)-one
The title compound was obtained from ter/-butyl {l-[2-(7-methoxy-2-oxo-3,4-
dihydroquinolin-l(2//)-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 32) (550 mg, 1.36
mmol) by the procedure described for Intermediate 1, 338 mg (82%), as a colorless oil.
MS (ESV 304.23 (MH+) for CnlfoNaCU
'H-NMR (DMSO-d^ 8: 1.19 (m, 2H); 1.62 (m, 2H); 1.96 (t, 2H); 2.36 (t, 2H); 2.46
(m, 2H); 2.73-2.80 (m, 5H); 3.71 (s, 3H); 3.91 (m, 2H); 6.77-6.84 (m, 2H); 7.04 (m, 1H).
Intermediate 32: tert-Butvl U-f2-f7-memoxy-2-oxo-3.4-dihydroquinolin-l(2//)-
yl)ethyl]piperidin-4-yllcarbamate
7-Methoxy-3,4-dihydroquinolin-2(l//)-one (Intermediate 33) (300 mg, 1.78 mmol)
was deprotonated with sodium hydride (75 mg, 60% in oil, 1.86 mmol) and alkylated with 2-
{4-[(/er/-butoxycarbonyl)amino]piperidin-l-yl} ethyl methanesulfonate (Intermediate 6)
(2.03 mmol) as described for Intermediate 2. Chromatography on silica gel eluting with ethyl
acetate and then acetone/ dichloromethane (4:1) gave the product as a colorless oil, 559 mg
(82%).
MS (ES): 404.21 (MH4^ for C22H33N304
'H-NMR fDMSO-df,1 8: 1.32 (m, 2H); 1.36 (s, 9H); 1.64 (m, 2H); 1.93-2.00 (m, 411);
2.37 (m, 2H); 2.47 (m, 2H); 2.78 (m, 2H); 3.16 (m, 1H); 3.71 (s, 3H); 3.91 (t, 2H); 6.72-6.82
(m, 3H); 7.05 (d, 1H).
Intermediate 33: 7-Methoxy-3.4-dihydroquinolin-2(l//)-one
A mixture of 7-hydroxy-3,4-dihydroquinolin-2(l/7)-one (3.0 g, 17 mmol) and triethyl
amine (3.14 mL, 22 mmol) in dichloromethane/ methanol/ acetonitrile (10:1:10, 168 mL) was
treated with (trimethylsilyl)diazomethane (2M solution in hexanes, 10.25 mL, 20.5 mmol). It
was stirred over night at room temperature, the.solvcnt was removed under reduced pressure
and chromatography on silica gel with hexanes/ acetone (1:1) gave 2.2 g (67%) of the product
as a colorless solid.
MS (ES\. 178.16 (MH*) for Ci0HuN02
'H-NMRfDMSQ-d^ 8: 2.38 (t, 2H); 2.81 (t, 2H); 3.68 (s, 3H); 6.68-6.78 (m, 311);
9.90 (brs, 1H).
Example 12
(35,4fi)-l-[2-(S,7-Difluoro-2-oxoquinolin-l(2JH)-yl)ethyl]-4-[(2,3-
dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidine-3-carboxylic acid
A solution of methyl (35l,4/?)-l-[2-(5,7-difluoro-2-oxoquinolin-l(2H)-yl)ethyl]-4-
[(2,3-dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidine-3-carboxylate
(Example 13) (120 mg, 0.233 mmol) in tetrahydrofuran/ water (1:1,10 mL) was treated with
sodium hydroxide (15% aqueous, 0.2 mL) at room temperature for 3 hours. It was quenched
with glacial acetic acid (1 mL) and concentrated to dryness under reduced pressure.
Chromatography on a CIS cartridge (RediSep, ISCO) with 0-25 % acetonitrile in water,
containing 0.1% acetic acid and treatment with HC1 as described for Example 10 gave 113
mg (90%) of the mono hydrochloride salt of the product as a colorless solid, mp 100-180°C.
MSfESV 501.03 (MH") for CzsHafiFjN^s
1H-NMR nPMSQ-d^ 8: 2.02 (m, 2H); 2.60 (m, 2H); 3.15-3.51 (m, 8H); 4.18 (m, 2H);
4.33 (m, 2H); 4.37 (m, 2H); 4.50 (m, 1H); 6.62 (d, 1H); 7.12 (s, 1H); 7.24 (m, 1H); 7.41 (m,
1H); 7.98 (d, 1H); 8.15 (s, 1H).
Example 13
(35,4/?)-l-[2-(5,7-Difluoro-2-oxoquinoHn-l(2flf)-yl)ethyl]-4-{[(2£)-3-(2,Sdifluorophenyl)
prop-2-en-l-yl]amino}piperidine-3-carboxylic acid
Methyl (3S,4^)-l-[2-(5,7-difluoro-2-oxoquinolin-l(2J:0-yl)ethyl]-4-{[(27?)-3-(2,5-
difluorophenyl)prop-2-en-l-yl]amino}piperidine-3-carboxylate (Example 15) (80 mg, 0.155
mmol) was treated with sodium hydroxide as described for Example 12 to give 51 mg (61 %)
of the mono hydrochloride salt of the product as a colorless solid, mp 150-180°C.
MS (ESV. 504.19 (MH+) for 026^4^03
'H-NMRfDMSO-d/Q 5: 2.10 (m, 2H); 2.75-3.75 (m, 8H); 3.86 (m, 2H); 4.33 (m, 1H);
4.54 (m, 1H); 6.50 (m, 1H); 6.64 (d, 1H); 6.91 (d, 1H); 7.19-7.34 (m, 3H); 7.48 (m, 2H); 8.00
(s, 1H); 9.19 (brs, 1H).
Example 14
•Methyl (3J,4J?)-l-[2-(5,7-dinuoro-2-oxoquinolin-l(2//)-yl)ethyl]-4-[(2,3-
dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)ainino]piperidine-3-carboxylate
Methyl (35,4/Z)-4-amino-1 -[2-(5,7-difluoro-2-oxoquinolin-1 (2#)-yl)ethyl]piperidine-
3-carboxylate (Intermediate 34) (120 mg, 0.328 ramol), 2,3-dihydro[l,4]dioxino[2,3-
c]pyridine-7-carbaldehyde (WO 2004/058144) (54 mg, 0.328 mmol) and sodium triacetoxy
borohydride (209 mg, 0.98 mmol) were reacted as described for Example 6. Chromatography
on silica gel with dichloromethane/ methanol (20:1) gave 130 mg (77%) of product as a
colorless hard foam.
MS (ESV. 515.03 (MH+) for QwHaiFzN^s
'H-NMR (PMSO-d^ 5: 1.52 (m, 1H); 1.75 (m, 1H); 2.43 (m, 1H); 2.50 (m, 1H); 2.54
(m, 2H); 2.60-2.73 (m, 3H); 2.87 (m, 1H); 3.51 (s, 3H); 3.53 (d, 1H); 3.69 (d, 1H); 4.22-4.34
(m, 6H); 6.61 (d, 1H); 6.86 (s, 1H); 7.21 (m, 1H); 7.30 (m, 1H); 7.95 (d, 1H); 7.97 (s, 1H).
Example IS
Methyl (35J4^)-l-[2-(5,7-difluoro-2-oxoquinolin-l(2fl)-yl)cthyI]-4-{[(2£)-3-(2,5-
difluorophenyl)prop-2-en-l-yl]amino}piperidine-3-carboxylate
Methyl (35,4/?)-4-amino-l-[2-(5,7-difluoro-2-oxoquinolin-l(2/f)-yl)ethyl]piperidinc-
3-carboxylate (Intermediate 34) (120 mg, 0.328 mmol), (2£)-3-(2,5-
difluorophenyl)acrylaldehyde (FR 2872164) (54 mg, 0.328 mmol) and sodium triacetoxy
borohydride (209 mg, 0.98 mmol) were reacted as described for Example 6. Chromatography
on silica gel with dichloromethane/ N,N-dimethylformamide (30:1) gave 83 mg (49%) of
product as a colorless hard foam.
MS (ESV 518.10 (MH4) for CwHWWA
'H-NMRfDMSO-d^S: 1.56 (m, 1H); 1.75 (m, 1H); 1.90 (m, 1H); 2.41 (m, 1H); 2.51-
2.72 (m, 5H); 2.90 (m, 1H); 3.25 (dd, III); 3.39 (dd, 1H); 3.51 (s, 3H); 4.29 (m, 211); 6.42 (m,
1H); 6.57 (d, 1H); 6.61 (d, 1H); 7.09 (m, 1H); 7.17-7.24 (m, 2H); 7.30 (m, 1H); 7.43 (m, III);
7.95 (d, 1H).
Intermediate 34: Methyl f3^.4J?)-4-amino-1-[2-(5.7-difluoro-2-oxoquin.olin-l('2//)-
ynethyl]piperidine-3-carboxylate
A solution of methyl (35,4/?)-4-{[(benzyloxy)carbonyl]amino}-1 -[2-(5,7-difluoro-2-
oxoquinolin-l(2#)-yl)ethyl]piperidine-3-carboxylate (Intermediate 35) (595 mg, 1.19 mmol)
in methanol (10 mL) was hydrogenated over palladium on carbon (10%, wet) at normal
pressure and room temperature for 30 minutes. It was filtered through a 0.45 um membrane,
washed with methanol and the wash and filtrate were concentrated under reduced pressure to
give 395 rag (91%) of the product as a colorless hard foam.
MS (ESV. 365.98 (MH+) for QsIfciF^Os
'H-NMR fDMSO-dg') 8: 1.58 (m, 2H); 2.37-2.69 (m, 7H); 3.14 (m, 1H); 3.53 (s, 3H);
4.28 (m, 2H); 6.60 (d, 1H); 7.21 (m, 1H); 7.30 (m, 1H); 7.95 (d, 1H).
Intermediate 35: Methvl difluoro-2-oxoquinolin- 1 (2/A-yl)ethyl]piperidine-3-carboxylate
5,7-Difluoroquinolin-2(l/f)-one (Intermediate 25) (350 mg, 1.93 mmol) was
deprotonated with sodium hydride (85 rng, 60% in oil, 2.13 mmol) and alkylated with methyl
(3S',47?)-4-{[(benzyloxy)carbonyl]amino}-l-(2-chloroethyl)piperidine-3-carboxylate
(Intermediate 36) ( 1.93 mmol) as described for Intermediate 20. Colorless hard foam, 604
mg (63%).
MS fBS); 500.05 (MH+) for C26H27F2N305
'H-NMR(60°a rDMSO-dfi) 5: 1.64 (m, 1H); 1.72 (m, 1H); 2.44 (m, 1H); 2.59 (t,
2H); 2.61-2.76 (m, 3H); 2.85 (dd, 1H); 3.49 (s, 3H); 3.93 (m, 1H); 4.28 (m, 2H); 4.99 (d, 1H);
5.03 (d, 1H); 6.60 (d, 1H); 6.90 (m, 1H); 7.13 (m, 1H); 7.24-7.37 (m, 6H); 7.93 (d, 1H).
Intermediate 36: Methyl (3tSl.4J?)-4-ir(benzvloxv)carbonvl]amino)-l-(2-
chloroethyl)piperidine-3-carboxylate
Methyl (35',4/?)-4-{[(benzyloxy)carbonyl]amino}-l-(2-hydroxyethyl)piperidine-3-
carboxylate (Intermediate 37) (650 mg, 1 .93 mmol) was reacted with methanesulfonyl
chloride (0.18 mL, 2.32 mmol) in the presence of triethylamine (0.38 mL, 2.7 mrnol) as
described for Intermediate 6. The crude chloride was used without delay for the next step.
MS (ES^ 355/357 (MIT1) for
Intermediate 37: Methyl f3£4#V4-(rO?enzyloxv')carbonvl1amino}-l-(2-
hydroxyethvl)piperidine-3-carboxylate
A mixture of methyl (3S,4^)-4-{[(benzyloxy)carbonyl]amino}piperidine-3-
carboxylate (WO 2005/066176) (2.29 g, 7.83 mmol), N,N-diisopropylethylamine (2.05 mL,
1 1.75 mmol and 2-bromoethanol (0.722 mL, 10.18 mmol) in dry acetonitrile (17 mL) was
heated in the microwave at 70°C for 4.5 hours. The solvent was removed under reduced
pressure and the residue taken up in ethyl acetate (200 raL) and washed with saturated
aqueous sodium hydrogencarbonate solution (100 mL). The aqueous phase was back
extracted once with ethyl acetate (100 mL) and the combined organic phases were dried over
sodium sulfate. Chromatography on silica gel with dichloromethane/ methanol (12:1) gave 2.0
g(76%),mp73°C.
MS (ES): 337.16 (MH4) for Ci7H24N2Os
'H-NMRfDMSQ-d^ 5: 1.66 (m, 2H); 2.34-2.55 (m, 5H); 2.67-2.79 (m, 2H); 3.44 (dt,
2H); 3.51 (s, 3H); 3.95 (m, 1H); 4.31 (t, 1H); 4.97 (d, 1H); 5.02 (d, 1H); 7.21 (d, 1H); 7.25-
7.38 (m, 5H).
Example 16
(3IZ,4JR)-l-[2-(5,7-Difluoro-2-oxoquinolin-l(2J!ir)-yl)ethyl)-4-[(2,3-
dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidine-3~carboxyIic acid
Methyl (3/?,4J?)-l-[2-(5,7-difluoro-2-oxoquinolin-l(2F)-yl)ethyl]-4-[(2J3-
dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidine-3-carboxylate (Example 18)
(201 mg, 0.4 mmol) was saponified and converted into the bis hydrochloride salt as described
for Example 12, 194 mg (87%), colorless solid, mp > 190°C.
MS fESV 501.22 (MH+) for €25^2^05
'H-NMR (DMSO-d^ 5: 2.24 (m, 1H); 2.46 (m, 1H); 3.12 (m, 1H); 3.34 (m, 4H); 3.58
(m, 1H); 3.83 (m, 1H); 3.93 (m, 1H); 4.24 (d, 1H); 4.31-4.44 (m, 5H); 4.63 (m, 211); 6.66 (d,
1H); 7.26-7.31 (m, 2H); 7.69 (d, 1H); 8.02 (d, 1H); 8.25 (s, 1H); 11.51 (bs, 1H).
Example 17
(37Z,4/?)-l.[2-(5,7-Difluoro-2-oxoquinolin-l(2«)-yl)cthyl]-4-{l(2JE)-3-(2,5-
difluorophenyl)prop-2-en-l-yl]amino}piperidine-3-carboxylic acid
Methyl (3£,4fl)-1 -[2-(5,7-difluoro-2-oxoquinolin-1 (2/f)-yl)ethyl]-4- {[(2£>3-(2,5-
difluorophenyl)prop-2-en-l-yl]amino}piperidine-3-carboxylate (Example 19) (106 mg, 0.2
mmol) was treated with sodium hydroxide as described for Example 12 to give 82 mg (69 %)
of the bis hydrochloride salt of the product as a colorless vsolid, mp > 205°C.
MS (ES): 504.23 (MH"*) for
'H-NMRfDMSO-dgl 6: 2.15 (m, 1H); 2.40 (m, 1H); 3.01-3.98 (m, 10H); 4.60 (m,
2H); 6.50 (m, 1H); 6.67 (d, 1H); 6.95 (d, 1H); 7.20-7.35 (m, 3H); 7.47 (m, 1H); 7.62 (m, 1H);
8.02 (d, 1H).
Example 18
Methyl (3JR,4JZ)-l-[2-(5,7-difluoro-2-oxoquinolin-l(2H)-yl)ethyl]-4-[(2,3-
dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidine-3-carboxylatc
Methyl (3^,4J?)-4-amino-l-[2-(5,7-difluoro-2-oxoquinolin-l(2//)-yI)ethyl]piperidine-
3-carboxylate (Intermediate 38) (195 mg, 0.53 mmol), 2,3-dihydro[l,4]dioxino[2,3-
c]pyridine-7-carbaldehyde (WO 2004/058144) (88 rag, 0.53 mmol) and sodium triacetoxy
borohydride (339 mg, 1.6 mmol) were reacted as described for Example 14 to give 216 mg
(79%) of product as a colorless hard foam.
MS fESV. 515.23 (MH*) for CwHajFj^Os
'H-NMROJMSO-d^S; 1.18 (m, 1H); 1.92 (m, 1H); 2.05 (ddd, 1H); 2.14 (dd, 1H);
2.34 (ddd, 1H); 2.52 (t, 2H); 2.57 (m, 1H); 2.88 (m, 1H); 3.03 (m, 1H); 3.57 (d, 1H); 3.58 (s,
3H); 3.69 (d, 1H); 4.24-4.33 (m, 6H); 6.61 (d, 1H); 6.87 (s, 1H); 7.21 (ddd, 1H); 7.33 (m,
1H); 7.93-7.96 (m, 2H).
Example 19
Methyl (3/Z,4^)-l-[2-(S,7-dinuoro-2-oxoquinolin-l(2fl)-yl)ethyl]-4-{[(2£)-3-(2,5-
difluorophenyl)prop-2-en-l-yl]amino}piperidine-3-carboxylate
Methyl (3^,4^)-4-amino-l-[2-(5,7-difluoro-2-oxoquinolin-l(2//)-yl)ethyl]piperidine-
3-carboxylate (Intermediate 38) (195 mg, 0.53 mmol), (2E)-3-(2,5-
difluorophenyl)acrylaldehyde (FR 2872164) (90 mg, 0.53 mmol) and sodium triacetoxy
borohydride (339 mg, 1.6 mmol) were reacted as described for Example 6. Chromatography
on silica gel with dichloromethane/N,N-dimethylformamide (25:1 to 15:1) gave 119 nig
(43%) of product as a colorless oil.
MS (ESI: 518.25 (MH*) for C^t^NjOa
'H-NMRfDMSO-dfil 5:1.20 (m, 1H); 1.94 (m, 1H); 2.08 (ddd, 1H); 2.16 (dd, 1H);
2.34 (ddd, 1H); 2.53 (t, 2H); 2.61 (ddd, 1H); 2.90 (m, 1H); 3.04 (m, 1H); 3.24 (dd, 1H); 3.39
(dd, 1H); 3.58 (s, 3H); 4.28 (m, 2H); 6.40 (m, 1H); 6.55-6.62 (m, 2H); 7.05-7.25 (m, 3H);
7.32 (d, 1H); 7.42 (m, 1H); 7.95 (d, 1H).
Intermediate 38; Methyl (37?.4/;V4-amino-l-r2-('5.7-difluoro-2-oxoquinolin-l('2//)-
vDethvl]piperjdine-3-carboxylate
Methyl (3/2,4/?)-4-{[(benzyloxy)carbonyl]amino}-l-[2-(5,7-difluoro-2-oxoquinolinl(
2/0-yl)ethyl]piperidine-3-carboxylate (Intermediate 39) (535 mg, 1.07 mmol) was
hydrogenated as described for Intermediate 34 to give 391 mg (quantitative) of the product
as a colorless hard foam.
MS (ESI: 366 (MH+) for
Intermediate 39: Methl
difluoro-2-oxoquinolin- 1 (2/j)-vl)ethvnpiperidine-3-carboxylate
5,7-Difluoroquinolin-2(l#)-one (Intermediate 25) (350 mg, 1.93 mmol) was
deprotonated with sodium hydride (85 mg, 60% in oil, 2.13 mmol) and alkylated with methyl
(3/?,4/?)-4-{[(benzyloxy)carbonyl]amino}-l-{2-[(methylsulfonyl)oxy]ethyl}piperidine-3-
carboxylate (Intermediate 40) (1.93 mmol) as described for Intermediate 20 to give the
product as a colorless hard foam, 538 mg (56%).
MS (ES): 500.38 (MH+) for C26H27F2N3O5
'H-NMR (60°O (DMSO-dg) 8: 1.40 (dddd, 1H); 1.70 (m, 1H); 2.10-1.45 (m, 2H);
2.44 (ddd, 1H); 2.54 (t, 2H); 2.89 (m, 1H); 3.07 (m, 1H); 3.49 (s, 3H); 3.54 (m, 1H); 4.28 (m,
2H); 4.95 (d, IH); 4.99 (d, 1H); 6.61 (d, 1H); 7.21 (ddd, 1H); 7.29-7.37 (m, 711); 7.95 (d, 1H).
Intermediate 40: Methyl (3J?.4J?)-4-|f(benzyloxv)carbonyl1ammo}-l-(2-
f(methylsulfonyl)oxv1ethvUpiperidine-3-carboxylate
Methyl (3Rt4R)-4- {[(benzyloxy)carbonyl]amino) -1 -(2-hydroxyethyI)piperidinc-3-
carboxylate (Intermediate 41) (650 mg, 1.93 mmol) was reacted with methanesulfonyl
chloride (0.18 mL, 2.32 mmol) in the presence of triethylamine (0.38 mL, 2.7 mmol) as
described for Intermediate 6. The crude product was used without delay for the next step.
MS (ESI: 415.3 (MH+
Intermediate 41: Methyl (3^.4J?)-4-{r(benzyloxv')carbonvl]amino}-l-(2-
hydroxyethyl')piperidine-3-carboxylate
Methyl (3iSr,4J?)-4-{[(benzyloxy)carbonyl]amino}piperidine-3-carboxylate (WO
2005/066176) (2.0 g, 6.84 mmol), N.N-diisopropylethylamine (1.8 ml., 10.26 mmol) and 2-
bromoethanol (0.63 mL, 8.9 mmol) were reacted as described for Intermediate 37 to give
1.38 g (60%) of the product as a colorless oil.
MS (BS); 337.36 (MH+) for CI7H24N205
'H-NMR rDMSO-dfi-) 5: 1.43 (dddd, 1H); 1.70 (m, 1H); 1.97-2.14 (m, 2H); 2.37 (t,
2H); 2.49 (m, 1H); 2.80 (m, 1H); 2.94 (m, 1H); 3.44 (dt, 2H); 3.50 (s, 3H); 3.54 (m, 1H); 4.39
(t, 1H); 4.95 (d, 1H); 5.00 (d, 1H); 7.27-7.38 (m, 6H).
Example 20
CIs(±)6-[({l-[2-(5,7-difluoro-2-oxoquinolin-l(2fl)-yl)ethyl]-3-hydroxypiperidin-4-
yl}amino)methyl]-2/f-pyrido[3,2-Z»][l,4]oxazin-3(4jy)-one
Cis(±)l-{2-[4-amino-3-hydroxypiperidin-l-yl]ethyl}-5,7-difluoroquinolin-2(l/f)-one
(175 rag, 0.54 mmol), 3-oxo-3,4-dihyciro-2tf-pyrido[3,2-&][l,4]oxazine-6-carbaldehyde (WO
2004/058144) (96 mg, 0.54 mmol) and sodium triacetoxy borohydride (344 mg, 1.6 mmol)
were reacted as described for Example 1 to give 186 mg (71%) of the free base of the product
as a colorless oil.
MS fBSV 486.24 (MH+) for C24H25F2N5O5
'H-NMRYMeOD^ 8: 1.-67-1.78 (m, 2H); 2.22 (m, 1H); 2.33 (d, 1H); 2.55-2.69 (m,
311); 2.90 (m, 1H); 3.06 (m, 1H); 3.75 (d, 1H); 3.79 (d, 1H); 3.91 (m, 1H); 4.30-4.46 (m, 2H);
4.59 (s, 2H); 6.61 (d, 1H); 6.93 (ddd, 1H); 6.95 (d, 1H); 7.21 (d, 1H); 7.27 (m, 1H); 7.96 (d,
1H).
Intermediate 42; CisMl-{2-[4-ammo-3-hvdroxvpiperidin-l-vl]ethyl}-5.7-
difluoroquinolin-2(lffl-orie
Cis(±)l-{2-[4-azido-3-hydroxypiperidin-l-yl]ethyl}-5,7-difluoroquinolm-2(l/;/)-one
(Intermediate 43) (190 mg, 0.54 mmol) was hydrogenated as described for Intermediate 34,
for 3 hours, to give the product as a colorless oil, 175 mg (quantitative).
MS (BS); 324.02 (MH+) for C16H19F2N302
'H-NMR (CDCl^ 5: 1.82 (m, 2H); 2.25 (ddd, 1H); 2.39 (d, 1H); 2.62-2.73 (m, 3H);
2.90 (m, 1H); 2.98 (m, 1H); 3.13 (m, 1H); 3.92 (m, 1H); 4.23 (ddd, 1H); 4.44 (ddd, 1H); 6.63
(d, 1HJ; 6.70 (ddd, 1H); 6.91 (d, 1H); 7.85 (d, 1H).
Intermediate 43: Cis(±)l - {2-[4-azido-3-hvdroxvpiperidin-1 -yllethvl) -5.7-
difluoroquinolin-2fj/:n-one
5,7-Difluoroquinolin-2(l,#)-one (Intermediate 25) (389 mg, 2.15 mmol) was
deprotonated with sodium hydride (95 mg, 60% in oil, 2.36 mmol) and alkylated with cis(±)
2-(4-azido-3-hydroxypiperidin-l~yl)ethyl methanesulfonate (Intermediate 44) (2.15 mmol)
as described for Intermediate 20, except after 24 hours, potassium carbonate (100 mg, 0.72
mmol) was added and the resulting mixture was stirred for another 24 hours at room
temperature to give the product as a colorless hard foam, 195 mg (26%).
MS (ESy- 350.15 (MH*) for CwHwFaNsCfc
'H-NMR (DMSO-d^ S: 1.56 (m, IH); 1.71 (m, 1H); 2.32 (m, 1H); 2.40 (m, 1H); 2.48
(m, 1H); 2.53 (dd, 2H); 2.59 (m, 1H); 3.61-3.71 (m, 2H); 4.29 (dd, 2H); 5.05 (d, 1H); 6.61 (d,
1H); 7.21 (ddd, 1H); 7.32 (d, 1H); 7.95 (d, 1H).
Intermediate 44: Cis(±)2-(4-a2ido-3-hydroxyrjiperidin-l-vl)gthvlmethapesulfonatc
A solution of cis(±)4-azido-l-(2-hydroxyethyl)piperidin-3-ol (Intermediate 45) (0.4
g, 2.15 mmol) in dry dichloromethane (15 mL) and 2,6-lutidine (0.325 mL, 2.8 mmol) was
treated at-20°C dropwise with a solution of methanesulfonyl chloride (0.175 mL, 2.26 mmol)
in dichloromethane (5 mL). The temperature was allowed to reach 0°C and kept at 0°C for 10
hours. The resulting reaction mixture was diluted with dichloromethane (50 mL) and washed
with saturated aqueous sodium hydrogen carbonate solution (10 mL). The aqueous phase was
back extracted with dichloromethane (20 mL) and the combined organic phases were dried
over sodium sulfate. The solvent was removed under reduced pressure, and the residue was
codistilled with dry DMF (10 mL) without heating. This crude preparation of the mesylatc
was used without further purification directly for the next step.
MS fES): 265.02 (MH4) for C8H]6N404S
Intermediate 45: CisM4-azido-l -(2-hydroxyethyDpiperidin-3-ol
Cis(±)4-azidopiperidin-3-ol (prepared following the procedure described in WO
2005/066176 for the chiral material) (0.945 g, 6.65 mmol), N,N-diisopropylethylamine (1.7
mL, 10 mmol) and 2-bromoethanol (0.61 mL, 8.64 mmol) were reacted as described for
Intermediate 37, except heating for one hour. The solvent was removed under reduced
pressure. The residue was taken up in dichloromethane (100 mL), washed with 1M sodium
hydroxide solution (30 mL) and the aqueous phase was back extracted five times with
dichloromethane (5x 100 mL). The combined organic phases were dried over sodium sulfate.
Chromatography on silica gel with dichloromethane/ methanol 3:1 gave 1.15 g (93%) of the
product as a colorless oil.
MS (ES\. 187.24 (MH4) for C7H,4N402
'H-NMR fDMSO-dfi) 8: 1.61 (m, 1H); 1.72 (m, 1H); 2.28-2.38 (m, 5H); 2.45 (m, 1H);
3.43 (ddd, 2H); 3.57 (m, 1H); 3.73 (m, 1H); 4.33 (dd, 1H); 5.01 (d, 1H).
Example 21
4-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-yImethyl)aminoJpipcridin-lyl}
ethyl)-6-methoxy-2#-l,4-benzoxazin-3(4jfiO-one
A mixture of 4-[2-(4-aminopiperidin- 1 -yl)ethyl]-6-methoxy-2//- 1 ,4-benzoxazin-
3(4//)-one trifluoroacetate (Intermediate 46) ( 0.4 mmol), N.N-diisopropylethylamine (1 mL)
and2,3-dihydro[l,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO 2004/058144) (74 mg, 0.45
mmol) in dichloroethane/methanol (1:1, 10 mL) was reacted and reduced with sodium
cyanoborohydride (50 mg, 0.74 mmol) as described for Example 4. Reverse phase
chromatography with water/acetonitrile/trifluoroacetic acid gave the product as the
trifluoroacetic acid salt. The salt was dissolved in water and chloroform and basified with
saturated sodium carbonate. The layers were separated and the aqueous was extracted with
chloroform. The organic extracts were dried over magnesium sulfate and evaporated to
dryness to give the free base of the title compound as a gum, 54 mg (32%).
MS (ESI: 455.33 (MH+) for C^iMOs
'H-NMRfCDCU-dl 5: 1.46 (m, 2H); 1.88 (m, 2H); 2.14 (m, 2H); 2.54 (m, 1H); 2.58
(t, J = 7.3 Hz, 2H); 2.95 (m, 2H); 3.78 (s, 3H); 3.79 (s, 2H); 4.01 (t, J = 7.4 Hz, 2H); 4.29 (m,
4H); 4.52 (s, 2H); 6.50 (dd, J = 6.2, 2.7 Hz, 1H); 6.67 (d, J = 2.7 Hz, 111); 6.81 (s, 1H); 6.89
(d,J = 8.7Hz, lH);8.08(s,
Intermediate 46 : 4-|"2-(4-Aminopiperidin- 1 -vl)ethvl1-6-methoxy-2//- 1 ,4-benzoxaxin
3r4ffl-one
terf-Butyl { 1 -[2-(6-methoxy-3-oxo-2,3-dihydro-4//-l ,4-benzoxazin-4-
yl)ethyl]piperidine-4-yl}carbamate (Intermediate 47) (510 mg, 1.26 mmol) was reacted as
described for Intermediate 14. The crude trifluoro acetate of the title compound was used
without further purification for the next step (quantitative yield).
MS (ESV 306 (MH+)
Intermediate 47; tert-Butvl (l-[2-f6-methoxv-3-oxo-2,3-dihydro-4J/-1.4-benzoxa?:in-
4-yl)ethyl]piperidine-4-vllcarbamate
6-Methoxy-2/:M,4-benzoxazin-3(4/;/)-one (Intermediate 48) (380 mg, 2.1 mmol) was
deprotonated with sodium hydride (100 mg, 60% in oil, 2.5 mmol) and alkylated with 2-{4-
[(te^butoxycarbonyl)arnino]piperidin-l-yl} ethyl methanesulfonate (Intermediate 6) (2.3
mmol) as described for Intermediate 2. Chrornatography on silica gel with hexanes/ ethyl
acetate (1:1) afforded 510 mg (60%) of the product.
MS (ES): 406.49 (MH+) for C2iH3iN305
'H-NMR CCDCh-d) 6: 1.34 (m, 2H); 1.36 (m, 2H); 1.62 (m, 2H); 1.98 (m, 2H); 2.43
(m, 2H); 2.84 (m, 2H); 3.20 (m, 1H); 3,73 (s, 3H); 3.96 (m, 2H); 4.53 (s, 2H); 6.56 (m, 1H);
6.76 (m, 1H); 6.92 (m, 1H).
Intermediate 48: 6-Methoxv-2//-1.4-benzoxazin-3(4f/)-one
To a solution of ethyl (4-methoxy-2-nitrophenoxy)acetate (Intermediate 49) (1,8 g,
7.1 mmol) in acetic acid (20 mL) was added iron powder (1.1 g, 19.9 mmol). The reaction
was heated at 90°C for 3 hours. It was cooled to room temperature, diluted with ethyl acetate,
filtered through celite, and concentrated to dryness under reduced pressure. Silica gel
chromatography with hexanes/ ethyl acetate (7:3) afforded product, 1 g (79%).
MS (ES): 180.15 (MH*) for C9H9N03
'H-NMRfCDCK-d) 5: 3.75 (s, 3H); 4.55 (s, 211); 6.40 (d, 1H); 6.50 (dd, 1H); 6.89 (d,
1H); 8.85 (bs, 1H).
Intermediate 49; Ethyl (r4-methoxv-2-nitrophenoxv)acetate
A mixture of 4-methoxy-2-nitrophenol (2 g, 11.8 mmol), cesium carbonate (7.7 g,
23.6 mmol) and 2-bromo ethyl acetate (1,31 mL, 11.8 mmol) in acetone (50 mL) was heated
at 50°C overnight. The mixture was heated at 55°C for an additional 1 hour, then filtered and
concentrated to dryness under reduced pressure. Silica gel chromatography with hexanes/
ethyl acetate (4:1) afforded product, 1.8 g (60%).
MS rES): 256.26 (MR") for CnHnNOe
'H-NMR(CDCh-d) 5: 1.28 (t, 3H); 3.81 (s, 3H); 4.25 (q, 2H); 4.70 (s, 211); 7.04 (m,
2H); 7.39 (d, 1H).
Example 22
6-[({l-{2-(6-Methoxy-3-oxo-2,3-dihydro-4JH-l,4-benzoxazin-4-yl)ethyI]piperidin-
4-yl}amino)methyI]-2#~pyrido[3,2-fiI[l,4]oxazin-3(4//)-one
4-[2-(4-aminopiperidin-1 -yl)ethyl]-6-methoxy-2/f-1,4-benzoxazin-3 (4H)-on&
trifluoroacetate (Intermediate 46) (0.4 mmol), 3-oxo-3,4-dihydro-2/7-pyrido[3,2-
6][l,4]oxazine-6-carbaldehyde (WO 2004/058144) (80 mg, 0.44 mmol) and sodium
cyanoborohydride were reacted as described under Example 21, but, the reaction was stirred
at room temperature overnight after sodium cyanoborohydride addition to give the title
compound as a free base, 30 mg (17%).
MS (ES\. 468.27 (MH+) for C24H29N5O5
'H-NMRtCDCh-d) 5: 1.56 (m, 2H); 1.96 (m, 2H); 2.18 (m, 3H); 2.62 (m, 3H); 3.01
(m, 2H); 3.79 (s, 3H); 3.84 (s, 2H); 4.06 (m, 2H); 4.51 (s, 2H); 4,63 (s, 2H); 6.51 (1H); 6.67
(s, 1H); 6.89 (1H); 6.95 (1H); 7.20 (1H).
Example 23
6-[({l-[2-(6-Methoxy-3-oxo-2,3-dihydro-4/f-l,4-benzothiazin-4-yl)ethyl]piperidin-
4-yl}amino)methyl]-2jy-pyrido[3,2-61[l,4]oxazin-3(4#)-one
4-[2-(4-Aminopiperidin-l-yl)ethyl]-6-methoxy-2//'-l,4-benzothiazm-3(4/ir)-one
(Intermediate 50) (0.9 mmol), 3-oxo-3,4-dihydro-2#-pyrido[3,2-£][l,4]oxazine-6-
carbaldehyde (WO 2004/058144) (190 mg, 1.1 mmol) and sodium cyanoborohydride (110
mg, 1,77 mmol) were reacted as described under Example 21, with stirring for 2.5 hours at
room temperature after sodium cyanoborohydride addition. The title compound was obtained
as a solid, 52 mg (12%).
MS (ES): 484.26 (MH+) for €241^5048
'H-NMRfCDCh-d) 6: 1.49 (m, 2H); 1.91 (m, 3H); 2.16 (m, 2H); 2.54 (m, 1H); 2.61
(m, 2H); 2.96 (m, 2H); 3.33 (s, 2H); 3.81 (s, 5H); 4.09 (ra, 2H); 4.63 (s, 2H); 6.58 (dd, 1H);
6.87 (d, 1H); 6.93 (d, 1H); 7,20 (d, 1H); 7.24 (d, 1H).
Intermediate SO; 4-r2-f4-Aminopiperidin-l-yl)ethyl1-6-methoxv-2^'-l,4-
benzothiazin-3 f 4//)-one
tert-Butyl {l-[2-(6-methoxy-3-oxo-2,3-dihydro-4//-l54-benzothiazin-4-
yl)ethyl]piperidin-4-yl}carbamate (Intermediate 51) (750 mg, 1.78 mmol) was reacted as
1—
described for Intermediate 14. The crude trifluoro acetate of the title compound was used
without further purification for the next step (quantitative yield).
MS (ES): 322 (MH+) for C,6H23N302S
Intermediate 51; te/V-Butyl (l-[2-f6-methoxv-3-oxo-2,3-dihvdro-4//-1.4-
benzothiazin-4-yl)ethvl1piperidin-4-vllcarbamate
6-Methoxy-2//-l,4-benzothiazin-3(4/:0-one (Intermediate 52) (410 mg, 2.1 mmol)
was deprotonated with sodium hydride (100 mg, 60% in oil, 2.5 mmol) and alkylated with 2-
{4-[(tert-butoxycarbonyl)amino]piperidin-l-yl}ethyl methanesulfonate (Intermediate 6) (2.3
mmol) as described for Intermediate 2. Chromatography on silica gel with hexanes/ethyl
acetate (1:3) afforded 750 mg (85%) of the product,
MS (ESI: 422.24 (MH4) for CziHsiNaC^S
1H-NMRfCDCK-d') 6: 1.40 (m, 2H); 1.45 (s, 9H); 1.92 (m, 2H); 2.22 (m, 2H); 2.62 (t,
2H); 2.88 (m, 2H); 3.35 (s, 2H); 3.49 (m, 1H); 3.82 (s, 3H); 4.08 (t,-2H); 4.43 (m, 1H); 6.61
(dd, 1H); 6.86 (d, 1H); 7.28 (s, 1H).
Intermediate52: 6-MethQxy-2//-1.4-benzothiazin-3(4/-ir)-one
Prepared from ethyl [(4-methoxy-2-nitrophenyl)thio]acetate (Intermediate S3, 3 g, 11
mmol) according to procedure described for preparation of Intermediate 48. Silica gel
chromatography with hexanes/ ethyl acetate (3:2) afforded desired product, 2 g (93%).
MS (ES): 196.12 (MH^ for C9H9NO2S
'H-NMR (CDClr 1H); 8.63 (bs, 1H).
Intermediate S3: Ethyl [C4-methoxy-2-nitrophenvl')thio1acetate
Ethyl mercaptoacetate (2.3 niL, 21.5 mmol) was dissolved in DMF (20 mL) and
cooled to 0°C. Sodium hydride (1 g, 60% in oil, 25.8 mmol) was added and the reaction was
stirred for 1 hour. Then a solution of l-bromo-4-methoxy-2-nitrobenzene (5 g, 21.5 mmol) in
DMF (20 mL) was added at 0°C. The reaction mixture was allowed to warm to room
temperature and stirred overnight. It was diluted with ethyl acetate, washed with water (four
times) and with brine and then dried over magnesium sulfate. Silica gel chromatography with
hexanes/ ethyl acetate (4:1) afforded the product, 3 g (52%).
MS fES"): 272.14 (MH+) for CnHi3NO5S
'H-NMRfCDCh-fl 5: 1.24 (t, 3H); 3.68 (s, 2H); 3,86 (s, 3H); 4.18 (q, 2H); 7.15 (dd,
1H); 7.47 (d, 1H); 7.65 (d, 1H).
Example 24
4-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]pipcridin-lyI}
ethyI)-6-methoxy-2fir-l,4-benzothiazin-3(4J?)-one
4-[2-(4-Aminopiperidin-l-yl)emyl]-6-methoxy-2//-l,4-benzothiazin-3(4#)-one
(Intermediate 50) (0.9 mmol), 2,3-dihydro[l,4]dioxino[2>3-c]pyridine-7-carbaldehyde (WO
2004/058144) (180 mg, 1.1 ramol), and sodium cyanoborohydride (110 rng, 1.76 mmol) were
reacted as described under Example 21 to give 55 mg (13%) product as a dry film.
MS fES): 471.26 (MH+) for C24H3oN404S
'H-NMR(CDClrdl 5: 1.47 (m, 2H); 1.91 (m, 2H); 2.15 (ra, 2H); 2.54 (m, 1H); 2.60
(t, J - 6.4 Hz, 2H); 2.94 (m, 2H); 3.33 (s, 2H); 3.47 (s, 2H); 3.80 (s, 5H); 4.08 (t, 2H); 4.29
(m, 4H); 6.58 (dd, 1H); 6.80 (s, 1H); 6.88 (d, 1H); 7.23 (d, 1H); 8.08 (s, 1H).
Example 25
6-[({l-[2-(6-Fluoro-3-oxo-2,3-dihydro-4H-l,4-benzoxazin-4-yl)ethyl]piperidin-4-
yl}amino)methyl]-2/f-pyrido[3,2-6] [1,4] oxazin-3(4fO-one
4-[2-(4-Aminopiperidin-l-yl)ethyl]-6-fluoro-2/:/-l)4-benzoxazin-3(4//)-one
(Intermediate 54), (0.7 mmol), 3-oxo-3,4-dihydro-2#-pyrido[3,2-6][l,4]oxazine-6-
carbaldehyde (WO 2004/058144) (150 rag, 0.84 mmol) and sodium cyanoborohydride (90
mg, 1.4 mmol) were reacted as described under Example 21 to give 51 mg (16%) product as
a solid.
MS (ES): 456.24 (MH4) for C23H26FN5O4
'H-NMR fCDClrd) 5: 1.52 (m, 2H); 1.94 (m, 2H); 2.15 (m, 2H); 2.57 (m, 1H); 2.59
(t, J - 7.1 Hz, 2H); 2.97 (m, 2H); 3.84 (s, 2H); 4.01 (t, J = 7.1 Hz, 2H); 4.54 (s, 2H); 4.62 (s,
2H); 6.68 (m, 1H); 6.86 (m, 1H); 6.89 (m, 1H); 6.95 (d, J = 8.1 Hz, 1H); 7.20 (d, J = 8.1 Hz,
1H).
Intermediate 54: 4-r2-(4-AminQpiperidin-l-yDethvl]-6-fluoro-2/jr-l,4-benzoxazin;
3(4/f>-one
tert-B\tfyl {1 -[2-(6-fluoro-3-oxo-2,3-dihydro-4flr-l,4-benzoxazin-4-yl)ethyl]piperidhi-
4-yl}carbamate (Intermediate 55) (640 mg, 1.56 mmol) was reacted as described for
Intermediate 14. The crude trifluoro acetate of the title compound was used without further
purification for the next step (quantitative yield).
MS (ES\. 294 (MH+) for Ci
Intermediate 55: fert-Butvl (l-[2-(6-fluoro-3-oxo-2.3-dihvdro-4Jjr-1.4-ben7.oxazin-4-
yl)ethyl]piperidin-4-yUcarbamate
Commercially available 6-fluoro-2#-l,4-benzoxazin-3(4#)-one (350 mg, 2.1 mmol)
was deprotonated with sodium hydride and alkylated with 2-{4-[(tertbutoxycarbonyl)
amino]piperidin-l-yl} ethyl methanesulfonate (Intermediate 6) (2.3 mniol)
as described for Intermediate 2. Chromatography on silica gel with hexanes/ ethyl acetate
(1:1) gave 550 mg (67%) product.
MS (ES\. 394.26 (MH+) for C2oH28FN3O4
'H-NMR f CDCl?-d) 8: 1.39 (m, 2H); 1.43 (s, 9H); 1.92 (m, 2H); 2.20 (m, 211); 2.58 (t,
2H); 2.88 (m, 2H); 3.45 (m, 1H); 3.98 (t, 2H); 4.41 (m, 1H); 4.55 (s, 2H); 6.68 (m, 1H); 6.85
(m, 1H); 6.91 (m, 1H).
Example 26
4-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-
yl}ethyl)-6-fluoro-2/y-l,4-benzoxazin-3(4.£0-one
4-[2-(4-Aminopiperidin-l-yl)ethyl]-6-fluoro-2//-l,4-benzoxazin-3(4//)-one
(Intermediate 54) (0.7 mmol), 2,3-dihydro[l,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO
2004/058144) (140 mg, 0.84 mmol), and sodium cyanoborohydride (90 mg, 1.4 mmol) were
reacted as described under Example 21 to give 100 mg (32%) product.
MS HBS): 443.24 (MH4) for C23H27FN4O4
'H-NMR (CDCh-d) 8: 1.46 (m, 2H); 1.90 (m, 2H); 2.13 (m, 2H); 2.53 (m, 1H); 2.57
(t, 2H); 2.93 (m, 2H); 3.80 (s, 2H); 3.99 (t, 2H); 4.29 (m, 4H); 4.54 (s, 2H); 6.67 (td, 1H);
6.81 (s, 1H); 6.86 (dd, 1H); 6.90 (dd, 1H); 8.09 (s, 1H).
Example 27
64({l-[2-(6-Chloro-3-oxo-2,3-dihydro-4/M,4-benzoxazin-4-yl)ethyl]piperidin-4-
yl}ammo)methyl]-2//-pyrido[3,2-A][l,4]oxazin-3(4#)-one
4-[2-(4-Aminopiperidin-l-yl)ethyl]-6-chloro-2//-l,4-benzoxasiin-3(4/f)-one
(Intermediate 56) (0.8 mmol), 3-oxo-3,4-dihydro-2#-pyrido[3,2-&][l,4]oxazine-6-
carbaldehyde (WO 2004/058144) (150 mg, 0.84 mmol) and sodium cyanoborohydride (90
mg, 1.4 mmol) were reacted as described under Example 21 to give 78 mg (21%) product as
a solid.
MS rES): 472.24 (MH+) for C23H26C1N5O4
dl 8: 1.50 (m, 2H); 1.93 (m, 3H); 2.15 (m, 2H); 2.56 (m, 1H); 2.59
(t, 2H); 2.96 (m, 2H); 3.82 (s, 2H); 4.01 (t, 2H); 4.56 (s, 2H); 4.63 (s, 2H); 6.92 (m, 3H); 7.12
(d, 1H); 7.20 (d, 1H).
Intermediate 56; 4-r2-f4-AmiDOpiperidin-l-vl)ethyn-6-chloro-2/j'-1.4-1benzoxazin-
3(4#Vone
/erf-Butyl { 1 -[2-(6-chloro-3-oxo-2,3-dihydro-4/f-l ,4-benzoxazin-4-yl)ethyl]piperidin-
4-yl}carbamate (Intermediate 57) (640 mg, 1.56 mmol) was reacted as described for
Intermediate 14. The crude trifluoro acetate of the title compound was used without further
purification for the next step (quantitative yield).
MS fBS"): 310 (MH4) for ds^oClNsOz
Intermediate 57: ter/-Butvl ll-r2-f6-chloro-3-oxo-2.3-dihYdTo-4J/-l,4-benzoxagin-4-
vr)ethvl]piperidin-4-yl } carbamate
Commercially available 6-chloro-2//-l,4-benzoxazin-3(4//)-one (380 mg, 2.1 mmol)
was deprotonated with sodium hydride and alkylated with 2-{4-[(tertbutoxycarbonyl)
amino]piperidin-l-yl} ethyl methanesulfonate (Intermediate 6) (2.3 mmol)
as described for Intermediate 2. Chromatography on silica gel with hexanes/ ethyl acetate
(1:1) gave 640 mg (74%) product.
MS (ESI: 410.22 (MH*) for CzoHzgClNjC^
'H-NMRfCDCh-d) 6: 1.43 (m, 2H); 1.43 (s, 9H); 1.92 (m, 2H); 2.21 (m, 2H); 2.58
(m, 2H); 2.88 (m, 2H); 3.45 (m, 1H); 3.99 (m, 2H); 4.41 (m, 1H); 4.56 (s, 2H); 6.91 (m, 2H);
7.13 (s, 1H).
Example 28
6-[({l-[2-(6-Methoxy-3-oxo-2,3-dihydro-4/f-l,4-benzoxazin-4-yl)ethyl]piperidin-
4-yI}amino)methyl]-2flr-pyrido[3,2-6][l,4]thiazin-3(4fl)-one
4-[2-(4-aminopiperidin- 1 -yl)ethyl] -6-methoxy-2//- 1 ,4-benzoxazin-3 (4//)-oue
(Intermediate 46) (0.2 mmol), 3-oxo-3,4-dihydro-2//-pyrido[3,2-6][l,4]thiazine-6-
carbaldehyde (WO 2004/058144) (42 mg, 0.22 nimol) and sodium cyanoborohydride (23 mg,
0.36 mmol) were reacted as described under Example 21 to give 28 mg (32%) of product as a
dry film.
MS (TBS); 484.27 (MH*) for Cz^NsCHS
'H-NMRfCDCh-d-) 6: 1.50 (m, 2H); 1.92 (m, 2H); 2.17 (m, 3H); 2.55 (m, 1H); 2.61
(m, 2H); 2.98 (m, 2H); 3.46 (s, 2H); 3.78 (s, 3H); 3.84 (s, 2H); 4.04 (m, 2H); 4.51 (s, 2H);
6.50 (dd, 1H); 6.67 (d, 1H); 6.89 (d, 1H); 6.98 (d, 1H); 7.57 (d, 1H).
Example 29
3-Oxo-4-[2-(4-{[(3-oxo-3,4-dihydro-2fl-pyrido[3,2-6][l,41oxazin-6-
yl)methyl]amino}piperidin-l-yl)ethyl]-3,4-dihydro-2F-l,4-benzoxazine-6-carbonitrile
4-[2-(4-aminopiperidin-1 -yl)ethyl]-3-oxo-3,4-dihydro-2#-1,4-benzoxazine-6-
carbonitrile (Intermediate 58) (0.8 romol), 3-oxo-3,4-dihydro-2//-pyrido[3,2-6][l,4]oxa/inc-
6-carbaldehyde (WO 2004/058144) (140 mg, 0.79 mmol) and sodium cyanoborohydride (83
mg, 1.32 mmol) were reacted as described under Example 21 to give 60 mg (19%) product as
a solid.
MS (ES): 463.32 (MH+) for C24H26N6O4
'H-NMR (CDCh-J) 6: 1.49 (m, 2H); 1.94 (m, 2H); 2.14 (m, 2H); 2.56 (m, 1H); 2.59
(t, J = 6.7 Hz, 2H); 2.94 (m, 2H); 3.84 (s, 2H); 4.03 (t, 211); 4.62 (s, 2H); 4.67 (s, 2H); 6.94 (d,
1H); 7.03 (d, 1H); 7.19 (d, 1H); 7.30 (dd, 1H); 7.46 (d, 1H).
Intermediate 58: 4-r2-(4-Aminopiperidin-l-vl)ethyl]-3-oxQ-3,4-dihydror2//-1.4-
ben2oxazine-6-carbonitrile trifluoroacetate
terf-Butyl {1 -[2-(6-cyano-3-oxo-2,3-dihydro-4/?-1,4-benzoxazin-4-yl)ethyl]pipcridin-
4-yl}carbamate (Intermediate 59) (610 mg, 1.52 mmol) was reacted as described for
Intermediate 14. The crude trifluoro acetate of the title compound was used without further
purification for the next step (quantitative, yield).
MS flES): 301 (MH+) for Ci6H2oN4O2
Intermediate 59: /grt-Butyl n-r2-(6-cvano-3-oxo-2.3-dihydro-4/f-1.4-bcnzQxazin-4-
vltethyripiperidin-4-yn carbamate
3-oxo-3,4-dihydro-2/f-l,4-benzoxazine-6-carbonitrile (Intermediate 60) (350 mg, 2.0
mmol) was deprotonated with sodium hydride and alkylated with 2-{4-[(tertbutoxycarbonyl)
amino]piperidin-l-yl} ethyl methanesulfonate (Intermediate 6) (2.2 mmol)
as described for Intermediate 2. Chromatography on silica gel with hexanes/ethyl acetate
(1:3) afforded 610 mg (76%) of the product.
MS (ES): 401.27 (MH4) for C2iH28N404
'H-NMR rCDClr-dl 8: 1.41 (m, 2H); 1.42 (s, 9H); 1.93 (m, 2H); 2.21 (m, 2H); 2.58
(m, 2H); 2.87 (m, 2H); 3.45 (m, 1H); 4.02 (m, 2H); 4.43 (m, 1H); 4.67 (s, 2H); 7.03 (d, 1H);
7.30 (m, 1H); 7.47 (s, 1H).
Intermediate 60: 3-Oxo-3.4-dihvdro-2//-l .4-benzoxazine-6-carbonitrile
The title compound was prepared similarly to literature procedure (Caliendo, G; et. al.;
Bioorg, Med. Chem. Lett., 2002, 10. 2663), but in one step. Commercially available 3-amino-
4-hydroxybenzonitrile (2.5 g, 18.6 mmol) was dissolved in chloroform (300 mL) and
saturated sodium bicarbonate (90 mL). The biphasic reaction mixture was cooled to 0°C and
bromoacetyl bromide (2.4 mL, 28 mmol) was added dropwise. The reaction was stirred
overnight at room temperature. The layers were separated and the aqueous layer was filtered
to yield the desired product as a tan solid, 2.3 g (69%).
MS fESV 175.11 (MH+) for CgHeNaOz
'H-NMR CPMSO-d^ 8: 4.70 (s, 2H); 7.11 (d, 1H); 7.19 (d, 1H); 7.40 (m, 1H); 10.98
(bs, 1H).
Example 30
yl]ethyl}piperidin-4-yl)amino]methyl}-2Jyr-pyrido[3,2-Z>][l,4]oxazin-3(4//)-onc
4-[2-(4-Aminopiperidin-l-yl)ethyl]-6-(trifluoromethoxy)-2//'-l,4-benzoxazin-3(4//)-
one (Intermediate 61) (0.55 mmol), 3-oxo-3,4-dihydro-2tf-pyrido[3,2-&][l,4]oxazine-6-
carbaldehyde (WO 2004/058144) (120 mg, 0.66 mmol) and sodium cyanoborohydride (69
mg, 1.1 mmol) were reacted as described under Example 21 to give 44 mg (15%) product as
a solid.
MS (ES): 522.25 (MH+) for Cj^FjNsOs
'H-NMR fCDCh-d") S: 1 .53 (m, 2H); 1.95 (m, 2H); 2.14 (m, 2H); 2.59 (t, 2H); 2.59
(m, 1H); 2.96 (m, 2H); 3.85 (s, 2H); 4.02 (t, 2H); 4.59 (s, 2H); 4.63 (s, 2H); 6.85 (d, 1H); 6.96
(d, 3H); 6.97 (d, 1H); 7.20 (d, 1H).
Intermediate 61: 4-r2-(4-Aminopiperidin-l-vnethvn-6-Ctrifluoromethoxy)-2//-l,4-
benzoxazin-3f4flVone
tert-Butyl(l-{2-[3-oxo-6-(trifluoromethoxy)-2,3-dihydro-4/:r-l,4-benzoxazin-4-
yl]ethyl}piperidin-4-yl)carbamate (Intermediate 62) (790 mg, 1.72 mmol) was reacted as
described for lotermediate 14. The crude trifluoro acetate of the title compound was used
without further purification for the next step (quantitative yield).
MS (ES): 360 (MH+) for Ci6H2oF3N303
Intermediate 62: tert-Butvl n-{2-[3-oxo-6-ftrifluoromethoxv)-2,3-dihydro-4/f-L4-
benzoxazin-4-ynethyllpiperidin-4-vl)carbamate
6-(Trifluorornethoxy)-2//-l)4-benzoxazin-3(4//)-one (Intermediate 63) (490 mg, 2.0
mmol) was deprotonated with sodium hydride and alkylated with 2-{4-[(/er/-
butoxycarbonyl)amino]piperidin-l-yl}ethyl methanesulfonate (Intermediate 6) (2.2 mmol)
as described for Intermediate 2. Chromatography on silica gel with hexanes/ethyl acetate
(2:3) afforded 790 mg (86%) of the product,
MS fES); 460.26 (MH+) for C21H28F3N305
'H-NMRfCDCh-d) 5: 1.38 (m, 2H); 1.43 (s, 9H); 1.92 (m, 2H); 2.20 (m, 213); 2.57
(m, 2H); 2.87 (m, 2H); 3.45 (m, 1H); 4.00 (m, 2H); 4.41 (m, 1H); 4.58 (s, 2H); 6.85 (m, 1H);
6.95 (s, 1H); 6.99 (m, 1H).
Intermediate 63; 6-(Trifluoromethoxv)-2//-1.4-benzoxaziTi-3(4J:f)-onc
Ethyl [2-nitro-4-(trifluoromethoxy)phenoxy]acetate (Intermediate 64) (1,14 g, 3.7
mmol) and iron powder (510 mg, 9.2 mmol) were reacted according to procedure for
Intermediate 48, but heating for only one hour. Silica gel chromatography with
hexanes/ethyl acetate (4:1) afforded product, 770 mg (90%).
MS (ES): 234.16 (MH+) for C9H6F3N03
'H-NMR fCDCl?- (bs, 1H).
Intermediate 64; Ethyl [2-nifro-4-(trifluorornethoxy)pbenoxv1 acetate
Prepared from 2-nitro-4-(trifluoromethoxy)phenol (2 g, 8.9 mmol) according to
procedure for Intermediate 49. Silica gel chromatography with hexanes/ethyl acetate (4:1)
afforded product, 1.14 g (41%).
MS (ES): 310.12 (MH4) for CnH|0F3N06
1H-NMRfCDCU-d>) 6: 1.28 (t, 3H); 4.26 (q, 2H); 4.78 (s, 2H); 7.03 (d, 1H); 7.40 (m,
1H); 7.78 (d, 1H).
Example 31
6-[({l-[2-(6-Fluoro-3-oxo-2,3-dihydro-4flr-l,4-benzoxazin-4-yl)ethyl]piperidin-4-
yl}amino)methyl]-2fl'-pyrido[3,2-Z>][l,4]thiazin-3(4//)-one
4-[2-(4-Aminopiperidin-1 -yl)ethyl] -6-fiuoro-2//-1,4-benzoxazin-3 (4#)-one
(Intermediate 54) (0.7 mmol), 3-oxo-3,4-dihydro-2#-pyrido[3,2-6][l,4]thiazine-6-
carbaldehyde (WO 2004/058144) (160 mg, 0.82 mmol) and sodium cyanoborohydride (90
mg, 1.4 mmol) were reacted as described under Example 21, (but the reaction mixture was
refluxed overnight before reduction with sodium cyanoborohydride at room temperature for 2
hours) to give 76 mg (23%) of product.
MS fESV 472.25 (MH+) for CxsHaeFNsOaS
'H-NMRfCDCh-d") 8: 1.48 (m, 2H); 1.92 (m, 2H); 2.15 (m, 2H); 2.55 (m, 1H); 2.59
(t, 2H); 2.96 (m, 2H); 3.46 (s, 2H); 3.84 (s, 2H); 4.00 (t, 2H); 4.55 (s, 2H); 6.68 (td, 1H); 6.86
(dd, 1H); 6.91 (dd, 1H); 6.98 (d, 1H); 7.57 (d, 1H).
Example 32
4.(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)aminoJpiperidin-lyl}
ethyl)-3-oxo-3,4-dihydro-2Jy-l,4-benzoxazine-6-carbonitrile
4-[2-(4-Aminopiperidin-l-yl)ethyl]-3-oxo-3,4-dihydro-2J!/-l,4-benzoxazine-6-
carbonitrile (Intermediate 58) (2.8 mmol), 2,3-dinydro[l,4]dioxino[2,3-c]pyridine-7-
carbaldehyde (WO 2004/058144) (550 mg, 3.36 mmol), and sodium cyanoborohydride (350
mg, 5.6 mmol) were reacted as described under Example 21 to give the crude free base. The
product was precipitated from chloroform by addition of 2M HC1 in ether. 1'he precipitate was
collected by filtration to give title compound as the bis HC1 salt, 420 mg.
MS (ESI: 450.21 (MH+) for CwHfoNsC^
1H-NMR(CDClrd>) 6: 1.43 (m, 2H); 1.89 (m, 2H); 2.12 (m, 2H); 2.48 (bs, III); 2.53
(m, 1H); 2.56 (t, 2H); 2.90 (m, 2H); 3.79 (s, 2H); 4.02 (t, 2H); 4.29 (m, 4H); 4.66 (s, 2H);
6.81 (s, 1H); 7.02 (d, 1H); 7.29 (dd, 1H); 7.37 (d, 1H); 4.66 (s, 1H).
Example 33
6-[({l-[2-(6-Bromo-3-oxo-2,3-dihydro-4JH-l,4-benzoxazin-4-yl)ethyl]piperidin-4-
yI}amino)methyl]-2Jy-pyrido[3,2-ft][l,4]oxazin-3(4fl)-one
4-[2-(4-Aminopiperidin-l-yl)ethyl]-6-bromo-2/:ir-l)4-benzoxazin-3(4/i)-one
(Intermediate 65) (0.57 mmol), 3-oxo-3,4-dihydro-2#-pyrido[3,2-&][l,4]oxazine-6-
carbaldehyde (WO 2004/058144) (120 mg, 0.67 mmol) and sodium cyanoborohydride (72
mg, 1.14 mmol) were reacted as described under Example 21 to give 65 mg (22%) product as
a solid.
MS (ESV. 516.22 (MH*) for C23H26BrN5O4
'H-NMRCCDCh-d) 5: 1.51 (m, 2H); 1.93 (m, 2H); 2.14 (m, 2H); 2.57 (m, 1H); 2.59
(t, 2H); 2.96 (m, 2H); 3.83 (s, 2H); 4.00 (t, 2H); 4.56 (a, 2H); 4.63 (s, 2H); 6.84 (d, 1H); 6.95
(d, 1H); 7.08 (dd, 1H); 7.20 (d, 1H); 7.27 (d, 1H).
Intermediate 65: 4-[2-(4-Aminopiperidin-l-yl')ethyl]-6-bromo-2//-l,4-ben/oxazin-
3f4flV-one
tert-Butyl {l-[2-(6-bromo-3-oxo-2,3-dihydro-47M,4-benzoxazin-4-yl)ethyl]piperidiri-
4-yl}carbamate (Intermediate 66) (261 mg, 0.57 mmol) was reacted as described for
Intermediate 14. The crude trifluoro acetate of the title compound was used without further
purification for the next step (quantitative, yield).
MS (ESI: 354 (MH*) for Ci5H2oBrN302
Intermediate 66; tert-Butvl (l-r2-(6-bromo-3-oxo-2.3-dihvdro-4//-1.4-benzoxazin-4-
vl)ethyl]piperidin-4-yl) carbamate
6-Bromo-2//-l,4-benzoxazin-3(4//)-one (Intermediate 67) (200 mg, 0.87 mmol) was
deprotonated with sodium hydride and alkylated with 2-{4-[(/ertbutoxycarbonyl)
amino]piperidin-l-yl}ethyl methanesulfonate (Intermediate 6) (0.96 mmol)
as described for Intermediate 2. Chromatography on silica gel with hexanes/ethyl acetate
(1:3) afforded 261 mg (67%) product.
Intermediate 67: 6-Bromo-2J/-l,4-benzoxazin-3(4/jr)-one
2-Amino-4-bromophenol (2.1 g, 11 mmol) and bromo acetyl bromide (1.4 mL, 16.5
mmol) were reacted according to the procedure for Intermediate 60 to afford product as a
solid, 2. I g (85%).
MS (ESI: 228 (MH+) for CgH6BrNO2
'H-NMR (DMSO-d^ 5: 4,58 (s, 2H); 6.90 (d, 1H); 7.00 (d, 1H); 7.06 (dd, 1H); 10.9
(bs, 1H).
Example 34
6-[({l-[2-(6-Hydroxy-3-oxo-2,3-dihydro-4fi-l,4-benzoxazin-4-yl)ethyl]piperidin-
4-yl}amino)methyl]-2#-pyrido[3,2-£][l,4]oxazin-3(4#)-one
A solution of 6-[({1 -[2-(6-methoxy-3-oxo-2,3-dihydro-4//-1,4-benzoxazin-4-
yl)ethyl]piperidin-4-yl} amino)rnethyl]-2//-pyrido[3,2-6] [ 1,4]oxazin-3(4//)-one (Example 22)
(100 mg, 0.21 mmol) in dichloromethane was cooled to -78°C and treated with 1M boron
tribromide (0.63 mL, 0.63 mmol) dropwise. The reaction mixture was stirred at room
temperature overnight. The reaction mixture was cooled to -78°C and an additional 1
equivalent of 1M boron tribromide was added. The reaction was stirred for 4 hours at room
temperature, and then quenched with saturated sodium bicarbonate. The organic layer was
separated and the aqueous phase was extracted three times with dichloromethane. The
combined organic extracts were dried over magnesium sulfate and concentrated to dryness
under reduced pressure to afford crude product, 11 mg (11%), as a solid.
MS (ES): 454.35 (MH*) for CzjHavNsOs
'H-NMR (DMSO-d^ 5: 1.47 (m, 2H); 1.98 (m, 4H); 2.94 (m, 3H); 3.94 (m, 4H); 4.49
(s, 2H); 4.66 (s, 2H); 6.38 (dd, J = 6.0, 2.5 Hz, 1H); 6.60 (d, J = 2.2 Hz, 1H); 6.80 (d, J= 8.7
Hz, 1H); 7.12 (d, J- 8.1 Hz, 1H); 7.40 (d, J = 8.3 Hz, 1H); 9.33 (s, 1H); 11.29 (s, 1H).
Example 35
4-{2-[4-({[2-(2,5-Difluorophenyl)cyclopropyl]methyl}amino)piperidin-l-yl]cthyl}-
3-oxo-3,4-dihydro-2//-l,4-benzoxazine-6-carbonitrile
4-[2-(4-Ammopiperidin-l-yl)ethyl]-3-oxo-3)4-dihydro-2//-l,4-benzoxazine-6-
carbonitrile (Intermediate 58) (1 mmol), 2-(2,5-difluorophenyl)cyclopropanecarbaldehyde
(Intermediate 68) (200 mg, 1.1 mmol) and sodium cyanoborohydride (125 mg, 2 mmol)
were reacted as described under Example 21 to give 196 mg (42%) product as a gum.
MS (ES): 506.35 (MH+) for C26H28F2N402
'H-NMR (CDCU-d) 8: 0.94 (m, 2H); 1.31 (m, 1H); 1.41 (m, 2H); 1.89 (m, 3H); 2.13
(m, 2H); 2.55 (m, 1H); 2.57 (t, 2H); 2.70 (d, 2H); 2.92 (m, 2H); 4.03 (t, 2H); 4.67 (s, 2H);
6.55 (m, 1H); 6.77 (m, 1H); 6.93 (m, 1H); 7.03 (d, 1H); 7.30 (dd, 1H); 7.38 (d, 1H).
Intermediate 68:2-(2.S-DifluorQphenvl)cvcloprQpanecarbaldehvde
To a solution of oxalyl chloride (1.2 mL, 13.5 mmol) in dichloromethane at -78°C was
added dimethyl sulfoxide (1.9 mL, 27 mmol) dropwise and it was stirred at -78°C for 30
minutes. A solution of [2-(2,5-difluorophenyl)cyclopropyl]methanol (Intermediate 69) (830
mg, 4.5 mmol) in dichloromethane was added dropwise. The reaction mixture was stirred at -
78°C for 30 minutes. Triethylamine (6.3 mL, 45 mmol) was added and the reaction mixture
was stirred at room temperature for 2 hours. The solvent was removed under reduced
pressure. Silica gel chromatography with hexanes/ ethyl acetate (9:1) afforded the desired
product, 546 mg (66%).
GC/MS: 182 (M+) for Ci0H8F20
'H-MMR (CDClrd^ 5: 1.52 (m, 1H); 1.73 (m, 1H); 2.17 (m, 1H); 2.73 (m, 1H); 6.65
(m, 1H); 6.87 (m, 1H); 6.98 (m, 1H); 9.36 (d, 1H).
Intermediate 69; [2-(2.S4)ifluorophenyl')cvclopropvl1methanol
To a solution of (2^-3-(2,5-difluorophenyl)prop-2-en-l-ol (Intermediate 70) (2.12 g,
12.5 mmol) in dichloromethane at -10°C was added dropwise diethyl zinc (1M, 75 mL, 75
mmol) over 20 minutes. Diiodomethane (6 mL, 75 mmol) was added and the reaction mixture
was stirred at room temperature overnight. Saturated ammonium chloride was added carefully
to quench the reaction. The reaction mixture was diluted with diethyl ether and the layers
were separated. The organic phase was washed with 10% aqueous hydrochloric acid,
saturated sodium bicarbonate and brine, then dried over magnesium sulfate and concentrated
to dryness under reduced pressure. Silica gel chromatography with hexanes/ ethyl acetate
(4:1) afforded the product, 940 mg (41%).
GC/MS: 184 (M+) for C,0HioF20
'H-NMR (DMSO-d^ 5: 0.92 (m, 2H); 1.36 (m, 1H); 1.91 (m, 1H); 3.43 (m, 2H); 4.64
(t, 1H); 6.82 (m, 1H); 6.97 (m, 1H); 7.15 (m, 1H).
Intermediate 70; (2jg)-3-f2.S-Difluorophenvnprop-2-en-l-Ql
A mixture of (2£)-3-(2,5-difluorophenyl)acrylic acid (1 g, 5.43 mmol) and N,Ndiisopropylethylamine
(1.7 mL, 9.8 mmol) in tetrahydrofuran (THF) was treated with isobutyJ
chloroformate (1.4 mL, 10.8 mmol) at room temperature, The reaction mixture was stirred for
30 minutes, and then filtered. The filtrate was cooled to 0°C and 2M lithium borohydride (4.1
mL, 8.2 mmol) was added dropwise. The reaction mixture was stirred at 0°C for 30 minutes
then at room temperature for 30 minutes. Ice and IN hydrochloric acid were added to the
reaction mixture to adjust the pH to 7. The aqueous layer was extracted with ethyl acetate
twice. The combined organic extracts were dried over sodium sulfate and concentrated to
dryness under reduced pressure. Silica gel chromatography with hexanes/ethyl acetate (3:2)
afforded desired product, 750 mg (82%).
GC/MS: 170 (M*) for C9H8F2O
'H-NMRflPMSO-djQ 6:4.15 (t, 2H); 5.01 (t, 1H); 6.61 (m, 2H); 7.10 (m, 1H); 7.23
(m, 1H); 7.48 (m, 1H).
Example 36
6-t({l-[2-(6,8-Difluoro-3-oxo-2,3-dihydro-4flr-l,4-benzoxazin-4-yl)ethyl]piperidin-
4-yl}amino)methyl]-2#-pyrido[3,2-A][l,4]oxazin-3(4#)-one
4-[2-(4-Aminopiperidin-l -yl)ethyl]-6,8-difluoro-2//'-1,4-benzoxazin-3 (4//)-onc
(Intermediate 71) (1 rnmol), 3-oxo-3,4-dihydro-2//'-pyrido[3,2-&][l,4]oxazine-6-
carbaldehyde (WO 2004/058144) (220 mg, 1.24 mmol) and sodium cyanoborohydride (130
mg, 2.1 mmol) were reacted as described for Example 21 to give 41 mg (8%) product as a
dry film.
MS (ES): 474.26 (MH+) for CzjIfeFaNsC^
'H-NMR (DMSO-d^ 8: 1.19 (m, 2H); 1.74 (m, 2H); 1.96 (m, 3H); 2.34 (m, 1H); 2.42
(m, 2H); 2.82 (m, 2H); 3.65 (s, 2H); 3.97 (m, 2H); 4.59 (s, 2H); 4.70 (s, 2H); 7.00 (d, 1H);
7.09 (m, 2H); 7.28 (d, 1H); 11,16 (s, 1H).
Intermediate 71.'4-[2-f4-Aminopiperidin-l-yl')ethyl1-6.8-difluoro-2/f-l14-
benzoxazin-3 (4/f)-one
ter/-Butyl {l-[2-(6,8-difluoro-3-oxo-2,3-dihydro-4//-l,4-benzoxazin-4-
yl)ethyl]piperidin-4-yl}carbamate (Intermediate 72) (423 mg, 1 mmol) was reacted as
described for Intermediate 14. The crude trifluoro acetate of the title compound was used
without further purification for the next step (quantitative yield).
MS fES^ 312 (MH+)
Intermediate 72; tert-Butvl {l-[2-f6.8-difluoro-3-oxo-2.3-dihvdro-4/y-1.4-
benzoxazin-4-yr)ethyl]piperidin-4-vUcarbamate
6,8-difluoro-2#"-l,4-benzoxazin-3(4//)-one (Intermediate 73) (205 mg, 1.11 mmol)
was deprotonated with sodium hydride and alkylated with 2~{4-[(tertbutoxycarbonyl)
amino]piperidin-l-yl} ethyl methanesulfonate (Intermediate 6) (1.2 mmol)
as described for Intermediate 2. Chromatography on silica gel with hexanes/ethyl acetate
(1 :3) afforded 423 mg (92%) product.
MS (ES): 412.36 (MH+) for
Intermediate 73; 6,8-Difluoro-2#'-K4-benzoxazin-3(4/f)-one
Commercially available 2-amino-4,6-difluorophenol (1 g, 6.9 mmol) and bromo acetyl
bromide (0.9 rnL, 10.3 mmol) were reacted according to the procedure for Intermediate 60 to
afford the product as a solid, 208 mg (16%).
MS (ESI: 184.34 (M-HT) for CsHsFaNC^
1H-NMR(DMSO-dfi') 5: 4.64 (s, 2H); 6.55 (m, 1H); 6.94 (m, 1H); 10.99 (bs, III).
Example 37
4-[2-(4-{[(2£)-3-(255-Difluorophenyl)prop-2-en-l-yl]amino}piperidin-l-yl)ethyll-
3-oxo-3,4-dihydro-2//-l,4-benzoxazine-6-carbonitrile
4-[2-(4-Aminopiperidin- 1 -yl)ethyl]-3-oxo-3 ,4-dihydro-2//- 1 ,4-benzoxazine-6-
carbonitrile (Intermediate 58) (1.5 mmol), (2£)-3-(2,5-difluorophenyl)acrylaldehyde
(202mg, 1.2 mmol) (FR 2872164) (200 mg, 1.1 mmol) and sodium cyanoborohydride were
reacted as described under Example 21. Chromatography on silica gel with dichloromcthane/
methanol gave 168 mg (25%) product
MS ffiS): 453 (MH+) for C25H26N4O2
'H-NMRrCDCIV) 5: 1.43 (q, 2H); 1.93 (d, 2H); 2.15 (t, 2H); 2.58 (t, 3H); 2.93 (d,
2H); 3.48 (d, 2H); 4.03 (t, 2H); 4.67 (s, 2H); 6.35 (dt, 1H); 6.65 (d, 1H); 6.88 (m, IH); 6.96
(m, IH); 7.03 (d, IH); 7.12 (m, IH); 7.30 (dd, IH); 7.40 (d, IH).
Example 38
6-[({/ra/is-4-[2-(6-Methoxy-3-oxo-2,3-dihydro-4fl-l,4-benzoxazin-4-
yl)ethyI]cyclohexyl}amino)methyl]-2J:f-pyrido[3,2-*][l,4]oxazin-3(4JH)-one
4-[2-(7>fl77j-4-aminocyclohexyl)ethyl]-6-methoxy-2//-l,4-benzoxazin-3(4/i)-one
(Intermediate 74) (310mg, 1.73 mmol), 3-oxo-3,4-dihydro-2#-pyrido[3,2-&][l,4]oxazine-6-
carbaldehyde (WO 2004/058144) (1.73 mmol) and sodium cyanoborohydride were reacted as
described under Example 21 to give 110 mg (24%) product.
MS (ES1: 467 (MH+) for C25H3oN4O5
'H-NMR fCDCM 5: 1.05 (q, 2H); 1.19 (d, 2H); 1.35 (m, 1H); 1.53 (q, 2H); 1.86 (d,
2H); 2.00 (d, 2H); 2.47 (m, 1H); 3.77 (s, 3H); 3.84-3.91 (m, 4H); 4.50 (s, 2H); 4.61 (s, 2H);
6.47 (m, 2H); 6.90 (t, 2H); 7.18 (d, 2H).
Intermediate 74: 4-[2-f/ra«j-4-Amipocvclohexvl)ethvl'|-6-methoxv-2H-1.4-
benzoxazin-3(4/f)-one
terf-Butyl {fra«.y-4-[2-(6-methoxy-3-oxo-2,3-dihydro-4/:/-1,4-benzoxazin-4-
yl)ethyl]cyclohexyl}carbamate (Intermediate 75) was reacted as described for Intermediate
14. The crude trifluoro acetate of the title compound was used without further purification for
the next step (quantitative yield).
MS ffiS"): 305 (MH+) for CI7HnN2O3
tt
Intermediate 75; tert-Butyl lfrara-4-f2-r6-methoxv-3-oxo-2,3-dihvdro-4//-1.4-
benzoxazin^-ynethyllcyclohexyllcarbamate
6-Methoxy-2/f-l,4-benzoxazin-3(4F)-one (Intermediate 48) (310 mg, 1.73 mmol)
was deprotonated with sodium hydride and alkylated with 2-{trans-4-[(tert
butoxycarbonyl)amino]cyclohexyl}ethyl methanesulfonate (Intermediate 76) (2 mmol) as
described for Intermediate 2. Chromatography on silica gel with dichloromethane/ methanol
(20:1) afforded the product as a solid (58%).
MS (ESI: 405 (MH+) for CzzI^NzOj
Intermediate 76; 2-{trans-4-\(tert Butoxvcarbonylkminolcvclohexvnethvl
methanesulfonate
Commercially available tert-butyl [*ran^4-(2-hydroxyethyl)cyclohexyl]carbarnate
(SOOmg, 2.05 mmol) was reacted according to the procedure described for Intermediate 6 to
give the product as a white solid (yield 92%).
'H-NMRCCDCM 8: 1.0? (m, 4H); 1.42 (m, 9H); 1.62 (m, 3H); 1.79 (m, 3H); 1.98 (ra,
1H); 2.99 (s, 3H); 3.35 (s, br, 1H); 4.24 (t, 2H); 4.35 (s, 1H).
Example 39
3-Oxo-4-[2-( yl)methyl]amino}cyclohexyl)ethyl]-3,4-diliydro-2/M,4-benzoxazine-6-carbonitrile
4-[2-(7Va7tt-4-aminocyclohexyl)emyl]-3-oxo-3,4-dihydro-2#-l,4-benzoxazine-6-
carbonitrile (Intermediate 77), 3-oxo-3,4-dihydro-2f/-pyrido[3,2-6][l,4]oxazine-6-
carbaldehyde (WO 2004/058144) (1.73 mmol) and sodium cyanoborohydride were reacted
following the procedure described for Example 21 to give the product in 7% yield, as an offwhite
solid.
MS (ESI: 462 (MH+) for CjsHwNsCU
'H-NMRfCDCl-Q 8: 1.05 (q, 2H); 1.45 (m, 5H); 1.88 (d, 2H); 2.07 (d, 2H); 2.65 (t,
1H); 3.90 (m, 2H); 3.95 (s, 2H); 4.61 (s, 2H); 4.66 (s, 2H); 6.97 (d, 1H); 7.04 (d, 1H); 7.17 (d,
1H); 7.20 (d, 1H); 7.31 (dd, 1H).
Intermediate 77: 4-[2-Om«J-4-Aminocyclohexyl')ethyl1-3-oxo-3.4-dihydro-2//-l,4-
benzoxazine-6-carbonitrile
tert-Butyl {fra/7S-4-[2-(6-cyano-3-oxo-2,3-dihydro-4//-l,4-benzoxa;dn-4-
yl)ethyl]cyclohexyl}carbamate (Intermediate 78) was reacted as described for Intermediate
14. The crude trifluoro acetate of the title compound was used without further purification for
the next step (quantitative yield).
MS fES): 300 (MH+) for
Intermediate 78: tert-Butyl ^r?-gK.y-4-[2-(6-cvano-3-oxo-2.3-dihydro-4/jr-l,4-
benzoxazrn-4-yr)ethyl]cyclohexvUcarbamate
3-Oxo-3,4-dihydro-2#-l,4-benzoxazine-6-carbonitrile (Intermediate 60) (350 mg,
2.0 mmol) was deprotonated with sodium hydride and alkylated with 2-{trans-4-[(tert
butoxycarbonyl)amino]cyclohexyl} ethyl methanesulfonate (Intermediate 76) as described
for Intermediate 2. Chromatography on silica gel with dichloromethane/ methanol (20: 1)
afforded the product as a solid (50%).
MS (ES) 400 (MH*) for C22H29N304
Example 40
6-Bromo-4-[2-(4-{[(3-oxo-3,4-dihydro-2flr-pyrido[3,2-6][l,4]oxazin-6-
yI)methyl]amino}piperidin-l-yl)ethyl]-2^-pyrido[3,2-6][l,4]oxazin-3(4JHr)-one
4-[2-(4-Aminopiperidin-l -yl)ethyl]-6-bromo-2#-pyrido[3 ,2-b] [ 1 ,4]oxazin-3(4#)-one
(Intermediate 79), 3-oxo-3,4-dihydro-2//-pyrido[3,2-&][ 1 ,4]oxazine-6-carbaldehyde
(WO 2004/058144) and sodium cyanoborohydride were reacted as described under Example
21 to give the product as an off-white solid in 64% yield.
MS fES): 517, 519(MH*) for C22H25BrN604
'H-NMRfDMSO-d.1 5: 1.25 (q, 2H); 1.81 (d, 5H); 1.98 (t, 2H); 2.6 (s, 2H); 2.89 (m,
2H); 3.15 (s, 1H); 3.83 (s, 2H); 4.05 (t, 2H); 4.62 (s, 2H); 4.76 (s, 2H); 6.97 (d, 1H); 7.04 (d,
1H); 7.23 (d, 1H); 7.34 (dd, 2H); 11.23 (s, br, 1H)
Intermediate 79: 4-[2-(4-Aminopiperidin-l-yl')ethyl]-6-brQmo-2//-pyridQf3.2-
b] f 1 .4]oxazin-3(4//Vone
tert-Butyl {l-[2-(6-bromo-3-oxo-2,3-dihydro-4//-pyrido[3,2-Z)][l,4]oxazin-4-
yl)ethyl]piperidin-4-yl}carbamate (Intermediate 80) was reacted as described for
Intermediate 14. The crude trifluoro acetate of the title compound was used without further
purification for the next step (quantitative yield).
MS (ES^: 3557 357 (MH4) for
Intermediate 80: tert-Butvl {l-[2-(r6-bromo-3-oxo-2.3-dihvdro-4//-pvridor3.2-
b] f 1 .4]oxazin-4-yDethyl]piperidin-4-yl} carbamate
6-Bromo-2/f-pyrido[3,2-6][l,4]oxazin-3(4^-one (WO 2004/058144) (935 mg, 4.08
rnmol) was deprotonated with sodium hydride and alkylated with 2-{4-[(tertbutoxycarbonyl)
amino]piperidin-l-yl} ethyl methanesulfonate (Intermediate 6) (5.6 mmol)
as described for Intermediate 2, but chromatography was omitted, to give the product as a
solid in 92% yield.
MS (BS); 455, 457 (MH4) for Ci9H27BrN4O4
Example 41
6-[({l-[2-(6-Nitro-3-oxo-2,3-dihydro-4flr-l,4-benzoxazin-4-yl)ethyl]piperidin-4-
yl}amino)methyl]-2J3r-pyrido[3,2-A][l,4]oxazin-3(4J5r)-one
4-[2-(4-Aminopiperidin- 1 -yl)ethyl]-6-nitro-2.#- 1 ,4-benzoxazin-3 (4//)-one
(Intermediate 81), 3-oxo-3,4-dihydro-2#-pyrido[3,2-&][l,4]oxazine-6-carbaldehyde (WO
2004/058144) and sodium cyanoborohydride were reacted as described under Example 21 to
give the product as an off-white solid in 7% yield,
MS fESV 483(MH+) for C23H26N606
'H-NMRCCDCl^ 8: 1.55 (q, 2H); 1.92 (d, 2H); 2.15 (t, 2H); 2.64 (t, 3H); 2.95 (d,
2H); 3.86 (s, 2H); 4.08 (t, 2H); 4.62 (s, 2H); 4.71 (s, 2H); 6.93 (d, 1H); 7.03 (d, 1H); 7.17 (d,
1H); 7.90 (dd, 1H); 8.13 (d, 1H).
Intermediate 81: 4-[2-(4-Ammopiperidin-l-ynethvl]-6-nitro-2//-1.4-benzoxazin-
3(4ff)-one
tert-Butyl { 1 -[2-(6-nitro-3-oxo-2,3-dihydro-4//- 1 ,4-benzoxazin-4-yl)ethyl]piperidin-
4-yl}carbamate (Intermediate 82) was reacted as described for Intermediate 14. The crude
trifluoro acetate of the title compound was used without further purification for the next step
(quantitative yield).
MS (ESI: 32 1 (MH4)
Intermediate 82; tert-Butyl n42-f6-nitro-3-oxo-2.3-dihydro-4#-1.4-benzoxazin-4-
yr)ethyl]piperidin-4-vn carbamate
6-Nitro-2//-l,4-benzoxazin-3(4/;0-one (Intermediate 83) (776 mg, 4 mmol) was
deprotonated with sodium hydride and alkylated with 2-{4-[(tertbutoxycarbonyl)
amino]piperidin-l-yl}ethyl methanesulfonate (Intermediate 6) (5.6 mmol)
as described for Intermediate 2. The product precipitated upon quenching of the reaction
mixture with water and was isolated by filtration in 98% yield, yellow solid.
MS fES): 421 (MH4) for
Intermediate 83; 6-Nitro-2//-1.4-benzoxazin-3(4J:n-one
The title compound was prepared according to the procedure described for
Intermediate 60, in 28% yield, yellow solid.
MS raS"): 193(M-H-)forC8H6N204
'H-NMRfDMSO-d^S: 4.80 (s, 2H); 7.18 (d, 1H); 7.75 (s, 1H); 7.85 (d, 1H); 11.10
Example 42
3-Oxo-4-[2-(4-{[(3-oxo-3,4-dihydro-2//-pyrido[3,2-6][l,4]oxazin-6-
yI)methyl]amino}piperidin-l-yl)ethyl]-3,4-dihydro-2JHr-pyrido[3,2-6][l,4]oxazinc-6-
carbonitrile
and
Example 43
3-Oxo-4-[2-(4-{[(3-oxo-3,4-dihydro-2jHr-pyrido[3,2-A][l,4]oxazin-6-
yl)methyl]amino}piperidin-l-yl)ethyI]-3,4-dihydro-2J7-pyrido[3,2-6][l,4]oxazine-6-
carboxamlde
A mixture of 6-bromo-4-[2-(4- {[(3-oxo-3,4~dihydro-2//-pyrido[3,2-b] [ 1,4]oxazin-6-
yl)methyl]amino}piperidin-1 -yl)ethyl]-2//-pyrido[3,2-6] [ 1,4]oxazin-3(4/?)-one (Example 40)
(200 mg, 0,387 mmol), zinc cyanide (135 rag, 1.14mmol) and tetrakis(triphenylphosphine)
palladium(O) (50 mg, 0.043mmol) in anhydrous DMF (3 mL) over molecular sieves 3A was
vortexed and then heated in the microwave at 200 °C for one hour. Reverse phase
chromatography and generation of the free base as described for Example 21 gave 27 mg
(15%) of Example 42 and 23 mg (12%) of Example 43, both off-white solids.
Example 42:
MS (ES): 464(MH+) for Cz^^O*
'H-NMRfDMSO-d*") 5: 1.17 (q, 2H); 1.77 (d, 2H); 20.1 (t, 2H); 2.86 (d, 2H); 3.75 (s,
2H); 4.09 (t, 2H); 4.61 (s, 2H); 4.88 (s, 2H); 7.00 (d, 1H); 7.30 (d, 1H); 7.53 (d, 1H); 7.69 (d,
lH);11.20(s,br, 1H).
Example 43:
MS (ESV. 482(MH+) for CzsI^NvOs
'H-NMRfDMSO-d^ 5: 1.09 (q, 2H); 1.66 (d, 2H); 1.91 (t, 2H); 2.31 (m, 1H); 2.43
(m, 2H); 2.83 (d, 2H); 3.04 (s, 2H); 3.63 (s, 2H) 4.28 (t, 2H); 4.59 (s, 2H); 4.80 (s, 2H); 6.96
(d, 1H); 7.26 (d, 1H); 7.45 (d, 1H); 7.57 (s, 1H); 7.64 (d, 1H); 7.90 (s, 1H); 11.30 (s, br, 1H).
Example 44
Methyl 3-oxo-4-[2-(4-{[(3-oxo-3,4-dihydro-2flr-pyrido[3,2-A][l,4]oxazin-6-
yl)methyl]amino}piperidin-l-yl)ethyl]-3,4-dihydro-2ZT-l,4-benzoxazine-6-carboxylate
Methyl 4-[2-(4-aminopiperidin-1 -yl)ethyrj-3-oxo-3,4-dihydro-2//-1,4-benzoxazine-6-
carboxylate (Intermediate 84), 3-oxo-3,4-dihydro-2//-pyrido[3,2-&][l,4]oxazine-6-
carbaldehyde (WO 2004/058144) and sodium cyanoborohydride were reacted as described
under Example 21 to give the product as an off-white solid in 13% yield.
MS fESy 496CMH+) for CzsHfoNsO,;
'H-NMR fCDCh) 5: 1.53 (m, 3H); 2.16 (m, 3H); 2,49 (m, 2H); 2.62 (m, 3H); 3.00 (d,
2H); 3.87 (s, 2H); 3.90 (s, 3H); 4.09 (t, 2H); 4.62 (a, 2H); 4.64 (s, 2H); 6.95 (d, 1H); 6.98 (d,
1H); 7.19 (d, 1H); 7.19 (d, 1H); 7.69 (d, 1H); 7.78 (d, 1H).
Intermediate 84: Methyl 4-r2-C4-aminopiperidin-l-ynethyl1-3-oxo-3.4-dihvdro-27/-
1.4-benzoxazine-6-carboxvlate
Methyl 4-(2- {4-[(/er/-butoxycarbonyl)amino]piperidin-1 -yl} ethyl)-3-oxo-3,4-dihydro-
2//-l,4-benzoxazine-6-carboxylate (Intermediate 85) was reacted as described for
Intermediate 14. The crude trifluoro acetate of the title compound was used without further
purification for the next step (quantitative yield).
MSfES): 334(MH+) for CnlWCU
Intermediate 85; Methyl 4-f2-l4-[(/e;'/-butoxvcarbonyl')amino]pipcridin-l-vUethvl)-
3-oxo-3.4-dihydro-2ff-1.4-benzoxazine-6-carboxylate
Methyl 3-oxo-3,4-dihydro-2//-l,4-benzoxazine-6-carboxylate (Intermediate 86) (330
mg, 1.59 mmol) was deprotonated with sodium hydride and alkylated with 2-{4-[(tertbutoxycarbonyl)
amino]piperidin-l-yl}ethyl methanesulfonate (Intermediate 6) (5.6 mmol)
as described for Intermediate 2. Chromatography on silica gel with dichloromethane/
methanol (20:1) gave the product in 85% yield as a yellow solid.
MS (ES^: 434 (MH*) for C22H3iN3O6
Intermediate 86: Methyl 3-oxo-3.4-dihvdro-2/:/-1.4-benzoxazine-6-carboxvlate
3-Oxo-3,4-dihydro-2/f-l,4-benzoxazine-6-carbonitrile (Intermediate 60) was heated
with chlorotrimethylsilane in methanol according to literature procedure (Fen-tair Luo et al.
Tetrahedron Letters, 39, 1998, page 9455-9456). After removal of volatiles, the product was
purified by chromatography on silica gel with methanol/dichloromethane (1 :20) and obtained
as off white solid, 40% yield.
MS (ES): 208 (MH+) for C,oH9NO4
'H-NMR fPMSO-d^ S: 3.80 (s, 3H); 4.67 (s, 2H); 7.03 (d, 1H); 7.50 (d, 1H); 7.55
(dd, 1H); 10.99 (s, 1H).
Example 45
6-[({l-[2-(6-Acetyl-3-oxo-2,3-dihydro-4J5/-l,4-benzoxazin-4-yl)ethyl]piperidin-4-
yl}amino)methyI]-2H-pyrido[3,2-6][l,4]oxazin-3(4jH)-one
6-Acetyl-4-[2-(4-aminopiperidin-l-yl)ethyl]-2/r-l,4-benzoxazin-3(4//)-one
(Intermediate 87), 3-oxo-3)4-dihydro-2//-pyrido[3,2-6][l,4]oxazine-6-carbaldehyde (WO
2004/058144) and sodium cyanoborohydride were reacted as described under Example 21 to
give the product as an off-white solid in 7% yield.
MS (ESI: 480(MH+) for €251*29^05
'H-NMR (CDCM 8: 1.49 (m, 2H); 1.98 (d, 2H); 2.13 (t, 2H); 2.57 (s, 3H); 2.60 (m,
3H); 2.94 (d, 2H); 3.82 (s, 2H); 4.09 (t, 2H); 4.60 (s, 2H); 4.64 (s, 2H); 6.90 (d, 1H); 7.01 (d,
1H); 7.16 (d, 1H); 7.58 (d, 1H); 7.74 (s, 1H).
Intermediate 87 ; 6-Acetvl-4-r2-(4-aminopiperidin- 1 -yl)ethvl1-2/7- 1 .4-benzoxa?,in-
/ert-Butyl {l-[2-(6-acetyl-3-oxo-2,3-dihydro-4#-l,4-benzoxazin-4-yl)ethyl]piperidin-
4-yl}carbamate (Intermediate 88) was reacted as described for Intermediate 14. The crude
trifluoro acetate of the title compound was obtained as a colorless solid and used without
further purification for the next step (quantitative yield).
MS (ES): 318 (MH4)
Intermediate 88: tert-Butyl {l-r2-(6-acetvl-3-oxp-2,3-dihydro-4//-1.4-benzoxa7in-4-
yl')ethyl]piperidin-4-vU carbamate
6-Acetyl-2#-l,4-benzoxazin-3(4#)-one (Intermediate 89) (382 mg, 2.0 mmol) was
deprotonated with sodium hydride and alkylated with 2-{4-[(tertbutoxycarbonyl)
amino]piperidin-l-yl} ethyl methanesulfonate (Intermediate 6) (2.2 mmol)
as described for Intermediate 2. Chromatography on silica gel with hexanes/ ethyl acetate
(1:1) gave the product in 94% yield as a colorless solid.
MS fESV 418 (MH*) for C22H3iN3Oj
Intermediate 89: 6-Acetvl-2/:f-1.4-benzoxazin-3f4/fi-one
Ethyl (4-acetyl-2-nitrophenoxy)acetate (Intermediate 90) was reacted with iron in
acetic acid as described for Intermediate 48. The crude product was obtained as an off white
solid after work up. Recrystallization with ethyl acetate / methanol afforded the product as a
colorless solid in 51 % yield.
MS fESV. 192 (MH1) for C,0H9NO3
'H-NMRfDMSO-d^ 8:2.50 (s, 3H); 4.68 (s, 2H); 7.06 (d, 1H); 7.47 (d, 1H); 7.60
(dd, 1H); 10.88 (s, 1H).
Intermediate 90: Ethyl (4-aoetvI-2-m'trophenoxy)acetate
l-(4-hydroxy-3-nitrophenyl)ethanone was reacted with cesium carbonate and 2-bromo
ethyl acetate as described for Intermediate 49. Chromatography on silica gel with hexanes/
ethyl acetate (1:1) gave the product in 69% yield as a pink solid
MS fESV 268 (MR") for Ci2H13NO6
'H-NMRfCDClr) 8: 1.30 (t, 3H); 2.60 (s, 3H); 4.30 (q, 2H); 4.86 (s, 2H); 7.00 (d,
1H); 8.20 (d, 1H); 8.50 (s, 1H).
Example 46
6-Acetyl-4-(2-{4-[(2,3-dihydro[l,4]dioxino[2,3-c]pyridin-7-
ylmethyl)amino]piperidin-l-yl}ethyl)-2J?-l,4-benzoxazin-3(4£0-one
6-Acetyl-4-[2-(4-aniinopiperidm-l-yl)ethyl]-2H-l)4-benzoxazin-3(4//)-one
(Intermediate 87), 2J3-dihydro[l)4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO
2004/058144) and sodium cyanoborohydride were reacted as described for Example 21. The
was converted to the free base was treated with HC1 in dioxane (2M, excess) and the excess
HC1 and dioxane were removed under reduced pressure to give the bis hydrochloride salt of
the product, 25 mg (9%), as an off-white solid.
MS fESV 467CMH4") for C23H27N705
'H-NMR fDMSO-d^ 5:2.10 (m, 2H); 2.32 (d, 1H); 2.65 (s, 3H); 3.07 (m, 2H); 3.27
(s, 3H) 3.57 (s, 1H); 3.77 (d, 2H); 4.19 (s, 2H); 4.35 (dd, 4H); 4.46 (t, 2H); 4.81 (s, 2H); 7.12
(d, 1H); 7.24 (s, 1H); 7.66 (d, 1H); 7.76 (s, 1H); 8.18 (s, 1H); 9.73 (brs, 2IT); 11.06 (brs, 1H).
Example 47
4-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-lyI}
ethyl)-6-methyl-2jHr-l,4-benzoxazin-3(4ff)-one
4-[2-(4-Aminopiperidin-1 -yl)ethyl]-6-methyl-2//-1,4-benzoxazin-3(4.fr)-one
(Intermediate 91), 2,3-dihydro[l,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO
2004/058144) and sodium cyanoborohydride were reacted as described for Example 21 to
give the product as an oil, 4.7 mg (2%).
MS (ES\. 439 (MET*) for C24H3oN4O4
'H-NMR (CDCIV) 8: 2.13 (m, 2H); 2.25 (s, 2H); 2.31 (s, 3H); 2.61 (s, 2H); 3.06 (m,
2H) 3.33 (m, 1H); 3.51 (m, 2H); 4.14 (s, 2H); 4.20-4.40 (m, 6H); 4.53 (s, 2H); 6.70-6.95 (m,
4H); 8.09 (s, 1H).
Intermediate 91; 4-r2-(4-Aminopiperidin-1 -yl)ethvl]-6-methvl-2f/-1.4-benzoxazin-
3(4flVone
tert-Butyl {1 -[2-(6-methyl-3 -oxo-2,3-dihydro-4jf/-1,4-benzoxazin-4-
yl)ethyl]piperidin-4-yl}carbarnate (Intermediate 92) was reacted as described for
Intermediate 14. The crude trifluoro acetate of the title compound was obtained as a
colorless solid and used without further purification for the next step (quantitative yield).
MS (E$): 290 (MH+) for QeHasNaOz
Intermediate 92; tert-Butvl |l-T2-(6-methyl-3-oxo-2.3-dihvdro-4ff-1.4-benzoxazin-
4-yr)ethyl]piperidin-4-yl} carbamatg
Commercially available 6-methyl-2//-l,4-benzoxazin-3(4J:0-one (326mg, 2.0 mmol)
was deprotonated with sodium hydride and alkylated with 2-{4~[(tertbutoxycarbonyl)
amino]piperidiu-l-yl} ethyl methanesulfonate (Intermediate 6) (2.2 mmol)
as described for Intermediate 2. Chromatography on silica gel with dichloromethane/
methanol (20:1) gave the product in 66% yield as a colorless solid.
MS (ES): 390 (MH*) for C2iH3iN304
Example 48
3-Oxo-4-[2-(6-{[(3-oxo-3,4-dihydro-2/r-pyrido[3,2-A][l,4]oxazin-6-
yl)methyl]amino}-3-azabicyclo[3.1.0]hex-3-yl)ethyI)-3,4-dihydro-2/M,4-ben/oxa/inc-6-
carbonitrile
4-[2-(6-Amino-3-azabicyclo[3,1.0]hex-3-yl)ethyl]-3-oxo-3,4-dihydro-2//-l,4-
benzoxazine-6-carbonitrile (Intermediate 93), 3-oxo-3,4-dihydro-2//-pyrido[3,2-
6][l,4]oxazine-6-carbaldehyde (WO 2004/058144) and sodium cyanoborohydride were
reacted as described under Example 21 to give the product as an off-white solid in 6% yield.
MS (BS); 461(MH+) for CwHwNeC^
'H-NMRfCDCIO 8: 2.46 (m, 4H); 2.66 (t, 2H); 3.01 (d, 2H); 3.83 (s, 2H); 3.98 (m,
3H) 4.63 (s, 2H); 4.64 (s, 2H); 6.89 (d, 1H); 7.02 (d, 1H); 7.18 (d, 1H); 7.31 (m, 2H).
Intermediate 93: 4-[2-(6-Amino-3-a^abicyclo[3.L01hex-3-vl')ethvl1-3-oxo-3.4-
dihvdro-2.//-1.4-ben20xazine-6-carbonitrile
tert-Butyl {3-[2-(6-cyano-3-oxo-2,3-dihydro-4//-l,4-benzoxazin-4-yl)ethyl]-3-
azabicyclo[3.1.0]hex-6-yl}carbamate (Intermediate 94) was reacted as described for
Intermediate 14. The crude trifluoro acetate of the title compound was obtained as a
colorless solid and used without further purification for the next step (quantitative yield).
MS (ES): 299 (MH4) for C16HigN402.
Intermediate 94: tert-Butyl l3-[2-f6-cvano-3-oxo-2.3-dihydro-4/7-1.4-bcnzoxazin-4-
vnethvl]-3-azabicvclo[3.1.0]hex-6-yncarbamate
3-Oxo-3,4-dihydro-2//-l,4-benzoxazine-6-carbonitrile (Intermediate 60) (231 mg,
1.5 mmol) was deprotonated with sodium hydride and alkylated with 2-{6-[(tertbutoxycarbonyl)
amino]-3-azabicyclo[3.1.0]hex-3-yl}ethyl methanesulfonate (Intermediate
95) (1.55 mmol) as described for Intermediate 2. Chromatography on silica gel with
dichloromethane/ methanol (20:1) gave 442 mg (94%) product as a yellow gum.
MS (ES); 399 (MH4) for C21H26N4O4
Intermediate 95: 2-{6-[f?e^-ButoxvcarbonvDamino]-3-azabicyclor3.1.01hex-3-
yl} ethyl metfaanesulfonate
To a mixture of ter/-butyl [3-(2-hydroxyethyl)-3-azabicyclo[3.1.0]hex-6-yl]carbamate
(Intermediate 96) (376 mg, 1.55 mmol) and triethyl amine (0.283 mL, 3 mmol) in anhydrous
chloroform (15 mL) was added at O°C methanesulfonyl chloride (228 mg, 3 mmol) via
syringe. The reaction was allowed to warm to room temperature over 1 hr and worked up as
described for Intermediate 6. The crude mesylate was used for the next step without delay.
Intermediate 96: tert-Butyl r3-(2-hvdroxvethvl)-3-azabicvclo[3.1.01hex-6-
vl]carbamate
A mixture of tert-butyl 3-azabicyclo[3.1.0]hex-6-ylcarbamate (T. F. Braish et al.
Synlett, 1996, page 1100 and T. Norris et al. J. Chem. Soc. Perkin I, 2000, page 1615-1622),
2-bromoethanol (669 mg, 3.36 mmol) and N,N-ethyldiisopropyl amine (0.087 mL) in
acetonitrile (9 mL) was heated in the microwave at 70°C for 30 minutes. Chromatography on
silica gel with chloroform/ methanol (20:1) gave 376 mg (46%) of the product.
MS(EI) 242 for Ci2H22N203
Example 49
4-(2-{4-[(2,3-Dihydro[l,4]dioxinof2,3-c]pyridin-7-ylmethyl)amino]pipcridin-lyl}
ethyl)-2/y-l,4-benzoxazin-3(4.flr)-one
4-[2-(4-Aminopiperidin-l-yl)ethyl]-2//-l ,4-benzoxazin-3(4//)-one (Intermediate 97),
2,3-dihydro[l,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO 2004/058144) and sodium
cyanoborohydride were reacted as described for Example 21 to give the product as a offwhite
solid, 81 mg (16%).
MS (BS); 425(MH+) for C23H28N404.2HC1
'H-NMRCDMSO-d^ 8: 2.2-3.8 (m, 14H); 3.87 (s, IH); 4.42 (m, 4H); 4.75 (s, 2H);
7.11 (m, 3H); 7.40-7.60 (m, 2H); 8.29 (s, IH); 10.01 (s, 2H); 10.01 (s, 211); 11.35 (brs, III).
Intermediate 97: 4-[2-C4-Aminopiperidin-1 -yl)ethyl1-2//-1,4-benzoxazin-3(4/./)-one
/ert-Butyl {l-[2-(3-oxo-2,3-dihydro-4/7-l,4-benzoxazin-4-yl)ethyl]piperidin-4-
yl}carbamate (Intermediate 98) was reacted as described for Intermediate 14. The crude
trifluoro acetate of the title compound was obtained as a colorless solid and used without
further purification for the next step (quantitative yield).
MS (ES): 276 (MH+) for C15H2iN3O2
Intermediate 98; tert-Butvl
vDethyl]piperidin-4-yl \ carbamate
2//-l,4-Benzoxazin-3(4ff)-one (298 mg, 2.0 mmol) was deprotonated with sodium
hydride and alkylated with 2-{4-[(tert-butoxycarbonyl)amino]piperidin-l-yl}ethyl
methanesulfonate (Intermediate 6) (2.0 mmol) as described for Intermediate 2.
Chromatography on silica gel with dichloromethane/ methanol (20: 1) gave the product in
63% yield as a yellow gum.
MS (ES): 376 (MH+) for C2oH29N3O4
Example 50
6-{[(l-{2-[6-(l-Hydroxyethyl)-3-oxo-2,3-dmydro-4#-l,4-benzoxazin-4-
yl]ethyl}piperidin-4-yl)amino]methyl}-2//-pyrido [3,2-6] [1,4] oxa7in-3(4//)-one
6-[({l-[2-(6-Acetyl-3-oxo-2,3-dihydro-4/M,4-benzoxazin-4-yl)ethyl]piperidin-4-
yl}anuno)methyl]-2//-pyrido[3,2-&][l,4]oxazin-3(4fl>one (Example 45) ( 309 mg, 0.645
mmol) was reduced with sodium borohydride (47 mg, 2 equivalents) in methanol (12 mL) at 0
°C. After quenching the reaction with water, the reaction mixture was concentrated under
reduced pressure and extracted with chloroform. The chloroform layer was washed with brine
and dried over magnesium sulfate and concentrated to dryness to give the as an off-white
solid, 202 mg (95%).
MS (ESV. 482(MH4) for CwHsiNjOs
'H-NMRfCDC10 5: 1.47 (d, 3H); 1.50 (q, 2H); 1.89 (d, 2H); 2.18 (m, 2H); 2.62 (m,
1H) 2.65 (t, 2H); 3.00 (d, 2H); 3.82 (s, 2H); 4.09 (t, 2H); 4.55 (s, 2H); 4.61 (s, 2H); 4.86 (q,
1H) 6,91 (m, 3H); 7.18 (d, 1H); 7.26 (s, 1H).
Example 51
Ethyl Ar-{l-[2-(6-cyano-3-oxo-2,3-dihydro-4fir-l,4-benzoxazin-4-
yl)ethyI]piperidin-4-yl}-7V-[(2£)-3-(2,5-difluorophenyl)prop-2-en-l-yI]glycinate
To a mixture of 4-[2-(4-{[(2£)-3-(2,5-difluorophenyl)prop-2-en-l-yl]amino}piperidinl-
yl)ethyl]-3-oxo-3,4-dihydro-2//-l,4-benzoxazine-6-carbonitrile (Example 37) (120 mg,
0.265 mmol) and ethyl diazoacetate (0.09 mL) in dichloromethane (5 ml) was added
rhodium(II) acetate (4 mg, 0.009 mmol) at room temperature. After 72 hrs, the product was
concentrated and purified by preparative TLC to give 6.7 mg of product (5%).
MS fESI: 539 (MH4)
'H-NMRCCDCM 8: 1.22 (t, 3H); 1.25 (m, 2H); 1.62 (m, 4H); 1.84 (d, 2H); 2.16 (bs,
2H) 2.60 (m, 2H); 2.70 (m, 1H); 3.03 (m, 2H); 3.37 (s, 2H); 3.45 (d, 2H); 4.07 (m, 2H); 4.11
(q, 2H); 4.68 (s, 2H); 6.32 (dt, 1H); 6.67 (d, 1H); 6.86 (m, 1H); 6.97 (dm, 1H); 7.02 (d, 1H);
7.13 (m, 1H); 7.30 (dd, 1H); 7.45 (s, 1H).
Example 52
6-{[(l-{2-[6-(Methylsulfonyl)-3-oxo-2,3-dihydro-4JHr-l,4-benzoxazin-4-
yl]ethyI}piperidin-4-yl)amino]methyl}-2J3r-pyrido(3,2-A][l,4]oxazin-3(4JH)-one
4-[2-(4-Aminopiperidin-l-yl)ethyl]-6-(methylsulfonyl)-2/T-l,4-benzoxazin-3(4//)-one
(Intermediate 99), 3-oxo-3,4-dihydro-2#-pyrido[3,2-&][l,4]oxazine-6-carbaldehyde (WO
2004/058144) and sodium cyanoborohydride were reacted as described under Example 21 to
give the product as an off-white solid in 8% yield.
MS (ES): 516 (MH+) for Ca-jKfoNsOeS
'H-NMRrCDChl 8: 1.53 (m, 2H); 1.87 (d, 2H); 2.13 (t, 4H); 2.54 (m, 1H); 2.60 (t,
2H) 2.93 (d, 2H); 3.05 (s, 3H); 3.82 (s, 2H); 4.08 (t, 2H); 4.60 (s, 2H); 4.66 (s, 211); 6.90 (d,
1H); 7.10 (d, 1H); 7.16 (d, 1H); 7.56 (d, 1H); 7.72 (s, 1H).
Intermediate 99: 4-[2-(4-Aminopiperidin-l-vl')ethvl]-6-(methvlsulfonyl')-2/jr-1.4-
benzox.azin-3(4/f)-one
ter/-Butyl (1 - {2-[6-(methylsulfonyl)-3-oxo-2,3-dihydro-4//-1,4-benzoxazin-4-
yl]ethyl}piperidin-4-yl)carbamate (Intermediate 100) was reacted as described for
Intermediate 14. The crude trifluoro acetate of the title compound was obtained as a
colorless solid and used without further purification for the next step (quantitative yield).
MS (ES): 353 (MH*) for C,6H23N304S
Intermediate 100: tert-Butyl (l-{2-[6-(methvlsulfonvn-3-oxo-2.3-dihvdro-4//-1.4-
benzoxazin-4-vl]ethyl}piperidin-4-vl)carbamate
6-(Methylsulfonyl)-2Jc/-l,4-benzoxazin-3(4//)-one (Intermediate 101) (280 mg, 1.23
mmol) was deprotonated with sodium hydride and alkylated with 2-{4-[(tertbutoxycarbonyl)
amino]piperidin-l-yl} ethyl methanesulfonate (Intermediate 6) (1.62 mmol)
as described for Intermediate 2. Chromatography on silica gel with dichloromethane/
methanol (20:1) gave the product in 66% yield as a yellow gum.
MS (BS): 454 (MH+) for C2iH3,N3Or,S
Intermediate 101: 6-(Methvlsulfonvl')-2//-l A-benzoxazin~3(4f-r>-ane
4-Methylsulfonyl-2-aminophenol (Intermediate 102) (690 mg, 3.68 mmol) was
dissolved in chloroform (30 mL) and saturated sodium bicarbonate (20 mL). The biphasic
reaction mixture was cooled to 0°C and bromoacetyl bromide (889 mg, 4.42 mrnol) was
added dropwise. The reaction was stirred overnight at room temperature. The layers were
separated and the aqueous layer was filtered to yield the desired product as a solid, 280 mg
(33%).
MS (ES): 228(MH+) for C9H9N04S
'H-NMR (DMSO-d^ 8: 3.16 (s, 3H); 4.73 (s, 2H); 7.15 (d, 1H); 7.41 (s, 1H); 7.50 (d,
Intermediate 1Q2 4-Methvlsulfonvl-2-aminophenol
The title compound was prepared by reacting 2-methoxy-5-methylsulfonyl aniline
(5.0g, 24.8 mmol) with boron tribromide (26 mmol, 26 mL, 1M in dichloromethane) in
chloroform (30 m L) at 0 C°. After 20 minutes, the reaction was quenched with sodium
bicarbonate and the ph of the aqueous phase was adjusted to pH 7 and extracted with ethyl
acetate. Concentration under reduced pressure gave 690 mg of product as an orange solid
(15%).
MS (ES); 188(MH*) for C7H9N03S
Example 53
6-{[(l-{2-[6-(EthyIsulfonyl)-3-oxo-2,3-dihydro-4fl-l,4-benzoxazln-4-
yI]ethyl}piperidin-4-yl)amino]methyl}-2Jflr-pyrido[3,2-*][l,4]oxazin-3(4fl)-one
4.[2-(4-Aminopiperidin- 1 -yl)ethyl]-6-(methylsulfonyl)-2//- 1 ,4-benzoxazin-3(4//)-one
(Intermediate 103), 3-oxo-3,4-dmydro-2#-pyrido[3,2-6][l,4]oxazine-6-carbaldehyde (WO
2004/058144) and sodium cyanoborohydride were reacted as described under Example 21 to
give the product as an off-white solid in 19% yield.
MS (ES): 530(MH+) for C25H3iN5O6S
'H-NMR rDMSO-d.1 5: 1,11 (t, 3H); 1.30 (q, 2H); 1.74 (d, 2H); 2.00 (t, 2H); 2.40 (m,
3H) 2.82 (d, 2H); 3.32 (m, 4H); 3.67 (s, 2H); 4.05 (t, 2H); 4,60 (s, 2H); 4.78 (s, 2H); 7.01 (d,
1H); 7.28 (d, 1H); 7.30 (d, 1H); 7.50 (d, 1H); 7.68 (s, 1H); 11.18 (bis, 1H).
Intermediate 103: 4-r2-f4-Aminopiperidin-l-vl')ethvl1-6-rinethvlsulfonvlV2^'-l,4-
benzoxazin-3f4/f>-one
tert-Butyl (1 - {2-[6-(ethylsulfonyl)-3-oxo-2,3-dihydro-4//- 1 ,4-benzoxazin-4-
yl]ethyl}piperidin-4-yI)carbamate (Intermediate 104) was reacted as described for
Intermediate 14. The crude trifluoro acetate of the title compound was obtained as a
colorless solid and used without further purification for the next step (quantitative yield).
MS (ESV. 368 (MH4)
Intermediate 104; tert-Butyl (l-(2-[6-rethvlsulfonvlV3-oxo-2.3-dihydro-4#-l,4-
benzoxazin-4-vnethyllpiperidin-4-yr)carbamate
6-(Ethylsulfonyl)-2#-l,4-benzoxazin-3(4#)-ane (Intermediate 105) (482 mg, 2
rnmol) was deprotonated with sodium hydride and alkylated with 2-{4-[(tertbutoxycarbonyl)
amino]piperidin-l-yl} ethyl methanesulfonate (Intermediate 6) (2.2 mmol)
as described for Intermediate 2. Chromatography on silica gel with hexanes/ ethyl acetate
gave the product in 81% yield as a yellow gum.
MS (ES\. 468 (MHf) for
Intermediate 105: 6-fEthvlsulfonvlV2#-1.4-benzoxazin-3(4//)-one
Commercially available 4-ethylsulfonyl-2-aminophenol (4.02 g, 20 mmol) was
dissolved in DMF (30 mL) and mixed with cesium carbonate (6.5g, 20 mmol). The reaction
mixture was cooled to 0°C and bromoacetyl bromide (4.0 g, 20 mmol) in DMF (5 mL) was
added dropwise. The reaction was stirred overnight at room temperature. After aqueous work
up, the product was purified by silica gel Chromatography with methanol/ dichloromethane to
give the product as an orange solid, 1.7 g (35%).
MS CES\. 242(MH*) for C10HuNO4S
'H-NMRCDMSO-d^ 5: 1.09 (t, 3H); 3.24 (q, 2H); 4.72 (s, 211); 7.16 (d, 1H); 7.37 (s,
lH);7.41(d,
Example 54
6-[({l-[2-(7-Methoxy-2-oxo-2flr-3,l-benzoxazin-l(4/T)-yOethyl]piperidin-4-
yl}amino)methyl]-2#-pyrido [3,2-6] [1,4] oxazin-3(4fl)-one
1 -[2-(4-Aminopiperidin- 1 -yl)ethyl]-7-methoxy- 1 ,4-dihydro-2/f-3 , 1 -benzoxazin-2-one
trifluoro acetate (Intermediate 106) (324 mg, 0.78 mmol) was converted to the free base
using W,.W-diisopropylethylamine for 30 minutes and reacted with 3-oxo-3,4-dihydro-2//-
pyrido[3,2-fc][l,4]oxazine-6-carbaldehyde (WO 2004/058144) (153 mg, 0.86 mmol) and
sodium cyanoborohydride (98 mg, 1.56 mmol) as described under Example 21. The reaction
mixture was filtered through a 0.45 urn membrane and concentrated to dryness under reduced
pressure. Chromatography on silica gel with dichloromethane/ methanol (9:1) gave the free
base of the title compound as a colorless foam. The free base was taken up in 1,4 dioxane (2
mL), followed by addition of 4M HC1 in 1,4-dioxane (0.30 mL). The resulting precipitate was
collected by filtration and gave 75 mg (48%) of the bis-hydrochloride salt of the product.
MS (ES\ 468.17 (MH4) for C24H29N505
'H NMR fDMSO-dft 8 2.09 (m, 2H); 2.31 - 2.44 (m, 2H); 3.00 - 3.15 (m, 2H); 3.66 -
3.78 (m, 2H); 3.82 (s, 3H); 4.13 - 4.22 (m, 2H); 4.22 - 4.35 (m, 2H); 4.69 (s, 2H); 5.25 (s,
2H); 6.70 (d, 1H); 6.85 (s, 1H); 7.20 (dd, 2H); 7.45 (d, 1H); 9.56 - 9.71 (m, 2H); 11.05 - 11.19
(m, 1H); 11.37 (s, 1H).
Intermediate 106: l-[2-(4-Aminopiperidin-l-yl')ethvl]-7-methoxy-l ,4-dihydro-2//-
3 . 1 -bepzoxazin-2-one
A solution of ter/-butyl {l-[2-(7-methoxy-2-oxo-2//-3,l-benzoxazin-l(4//)-
yl)ethyl]piperidin-4-yl}carbamate (Intermediate 107) (319 mg, 0.78 mmol) in
dichloromethane (8 mL) was treated at room temperature under vigorous stirring with a
trifluoroacetic acid (0.75 mL, 10 mmol). After 2 hours, the reaction mixture was concentrated
under reduced pressure to give 324 mg (quantitative) of product as a brown oil.
MS (BS); 302.24 (MH+) for
Intermediate 107: tert-Butyl ll-r2-('7-methoxy-2-oxo-2//'-3.1-benzoxay,in-l(4//)-
vl)ethyl]piperidin-4-vncarbamate
A solution of 7-methoxyquinolin-2(l//)-one (Intermediate 108, 310 mg, 1.8 mmol)
in dry N,N-dimethylformamide (5 rnL) was treated at 0°C under stirring with lithium
bis(trimethylsilyl)amide (1M in tetrahydrofuran, 1.9 mL, 1.9 mmol). The mixture was then
stirred for 30 minutes at room temperature and alkylated with 2-{4~[(tertbutoxycarbonyl)
amino]piperidin-l-yl} ethyl methanesulfonate (Intermediate 6, 2.03 mmol)
as described for Intermediate 2. Chromatography on silica gel with dichloromethane/
methanol (95:5) gave 333 mg (47%) of the product as a colorless solid.
MS (ES); 406 (MII+) for
'H-NMRfCDCM 5: 1.34-1.46 (m, 11H); 1.86 (d, 2H); 2.12-2.25 (m, 2H); 2.60-2.64
(ra, 2H); 2.60-2.64 (m, 2H); 2.81-2.90 (m, 2H); 3.38-3.45 (m, 1H); 3.76 (s, 3H); 3.97 - 3.91
(m, 2H); 4.32- 4.42 (m, 1H); 5.05 (s, 2H); 6.49-6.56 (m, 2H); 6.94 (d, 1H).
Intermediate 108: 7-Methoxvauinolin-2('l/f)-one
A solution of (2-amino-4-methoxyphenyl)methanol (Intermediate 109,744 mg, 4.85
mmol) in toluene (25 mL) was treated with triethylamine (1.36 raL, 9.7 mmol) and
triphosgene (1.58 g, 5.34 mL). The reaction was stirred at room temperature for 1.5 hours and
then was heated to 110 °C for an additional 2 hours. The reaction was cooled to room
temperature, diluted with water (25 mL), filtered, extracted aqueous layer with toluene (3x 30
mL) and ethyl acetate (2x 20 mL). The combined organic layers were washed with brine,
dried over sodium sulfate, and concentrated under reduced pressure. Chromatography on
silica gel with hexanes/ ethyl acetate (3:2) gave 314 mg (36%) of the product as a colorless
solid.
'H-NMRfDMSO-dg) 8: 3.78 (s, 3H); 5.26 (s, 2H); 6.38 (d, 1H); 6.59 (d, 1H); 6.98 (d,
1H); 8.36 (brs, 1H).
Intermediate 109: (2-Amino-4-methoxyphenvl)methanQl
To a solution of commercially available 4-methoxy-2-nitrobenzoic acid (4.0 g, 20.66
mmol) in tetrahydrofuran (20 mL) at -15 °C under nitrogen was added N-methylmorphorine
(2.2 ml, 20 mmol) followed by isobutyl chloroformate (2.6 mL, 20 mmol) in portions. After 5
rain, the reaction was filtered and the solid was rinsed with tetrahydrofuran (20 mL). The
filtrate was cooled to -15 °C and a solution of sodium borohydride in water (3 M, 10 mL) was
added to the filtrate, The reaction was stirred for 5 min. The reaction mixture was partitioned
between water and dichloromethane, and extracted aqueous layer with dichloromethane (3 x
100 mL). The combined organic layers were washed with brine, dried over magnesium
sulfate, and concentrated under reduced pressure. The residue was redissolved in
tetrahydrofuran (35 mL) and added palladium (10% on carbon, 400 mg) and stirred under
hydrogen gas for 18 hours. The reaction mixture was then filtered through celite and
concentrated under reduced pressure. The residue was chromatographed on silica gel with
hexanes/ethyl acetate (3:2) gave 744 mg (24% yield) of product as a yellow solid.
'H-NMR(DMSO-dg) 5 3.63 (s, 3H); 4.30 (s, 2H); 4.84 - 4.96 (m, 2H); 6.08 (dd, 1H);
6.20 (d, lH);6.90(d, 1H).
Example 55
7-Methoxy-3-methyl-l-[2-(4-{[(3-oxo-3,4-dihydro-2/f-pyrido[3,2-6][l,4]oxazin-6-
yl)methyl]amino}piperidin-l-yl)ethyl]quinazoline-2,4(lfir,3J:0-dione
l-[2-(4-Aminopiperidin-l-yl)ethyl]-7-methoxyquinazoline-2,4(l/f,3//)-dione
(Intermediate 110, crude, 1 53 mg, 0.46 mmol) was converted to the free base with N,Ndiisopropylethylamine
for 30 min and reacted with 3-oxo-3,4-dihydro-27/-pyrido[3,2-
6][l,4]oxazine-6-carbaldehyde (WO 2004/058144) (90 mg, 0,51 mmol) as described under
Example 21. The reaction mixture was cooled to 0°C, and sodium triacetoxy borohydride
(194 mg, 0.92 mmol) was added. The resulting reaction mixture was stirred at room
temperature for 18 hours and then worked up as described for Example 54 to give the bishydrochloride
salt of the product, 12.5 mg (25%), as a colorless solid.
MS ffiS); 495 (MH+) for C2jH3oN605
'HNMRCDMSO-D6^ 6 1.85-2.32 (m, 1H); 3.68-3.88 (m, 3H); 3.89-4.08 (m, 3H);
4.10-4.43 (m, 5H); 4.50-4.78 (m, 5H); 6.91-7.44 (m, 5H); 7.99 (bs, 1H); 9.74 (br s, 211);
1 1. 16-11. 38 (m,2H).
Intermediate 110: l-r2-f4-Amino-2-oxopiperidin-l-yl)ethyl]-7-methoxv-3-
methylquinazoline-2.4(l.//.3/D-dione
tert-Butyl {l-[2-(7-methoxy-3-methyl-2,4-dioxo-3,4-dihyaroquinazolin-l(2W)-
yl)ethyl]piperidin-4-yl}carbamate (Intermediate 111, 350 mg, 0.83 mmol) was reacted as
described for Intermediate 106. The crude trifluoro acetate of the title compound was
obtained as a black oil, 395 mg (quantitative), and used without further purification for the
next step.
MS (ESV. 319 (MH4) for
Intermediate 111: tert-Butyl (l-[2-(7-methoxv-3-methvl-2.4-dioxo-3,4-
dihvdroquinazolin- 1 (2/f)-vDethvl]piperidin-4-yl} carbamate
7-Methoxy-3-methylquinazoline-2,4(l#,3/:/)-dione (Intermediate 112, 523 rag, 2.5
mmol) was deprotonated with lithium bis(trimethylsilyl)amide (IM in tetrahydrofuran, 1.9
mL, 1.9 mmol) and alkylated with 2-{4-[(te7-/-butoxycarbonyl)amino]piperidin-l-yl}ethyl
methanesulfonate (Intermediate 6, 3.4 mmol) as described for Intermediate 2.
Chromatography on silica gel with dichloromethane/ methanol (95:5) gave 200 mg (18%) of
the product as a colorless solid.
MS rES1: 433 (MH+) for C22H32N405.
'HNMRCCDC105 1.16-1.28 (m, 1H); 1.14-1.43 (m, 11H); 1.89-2.04 (m, 3H); 2.25-
2.47 (m, 2H); 2.80 (d, 3H); 2.94-3.14 (m, 2H); 3.77 (s, 3H); 4.22-4.36 (m, 1H); 4.40-4.56 (m,
1H); 4.99-5.09 (m, 1H); 7.02-7.03 (m, 1H); 7.31-7.47 (m, 2H).
Intermediate 112: 7-Methoxv-3-methylquinazoline-2.4(ll//.3//)-dione
2-Araino-4-methoxybenzoic acid (Intermediate 113, 950 mg, 6.2 mmol) and 1,3-
diraethyl urea (5.4 g, 62 mmol) were heated at 150 °C for 16 hours. The reaction was cooled
to 100 °C and diluted with water. The mixture was partitioned between ethyl acetate and
water, the aqueous phase extracted with ethyl acetate (3 x 20 mL) and then chloroform/2-
propanol (3:1,2x 20 mL). The combined organic layers were washed with brine, dried over
sodium sulfate, and concentrated under reduced pressure. Chromatography on silica gel with
hexanes/ ethyl acetate (1:2) to give a 350 mg (27%) product as an orange oil.
MS fES): 205 (MH4) for Ci0H10N2O3.
'H-NMR fDMSO-oV) 5: 2.60 (d, 3H); 3.68 (s, 3H); 5.95 (d, 1H); 6.45 (dd, 1H); 6.86
(dd, 1H); 8.47 (s, 1H).
Intermediate 113: 2-Amino-4-methoxvbenzoic acid
4-Methoxy-2-nitrobenzoic acid (3 g, 16.4 mmol) was hydrogenated over palladium on
carbon (10%, 300 mg) in methanol (80 mL) at room temperature and normal pressure for 18
hours. The reaction mixture was filtered through celite and concentrated to dryness under
reduce pressure to give 2.50 g (100%) of the product as a colorless solid.
'HNMRrPMSO-d^ 5 3.70 (s, 3H); 6.09 (dd, 1H); 6.23 (d, 1H); 7.59 (d, 1H).
Example 56
4-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-2-
oxopiperidin-l-yI}ethyl)-6-methoxy-2#-l,4-benzoxazin-3(4#)-onc
4-[2-(4-Amino-2-oxopiperidin-l-yl)ethyl]-6-methoxy-2//-l,4-benzoxazin-3(4//)-one
trifluoroacetate (Intermediate 114, crude, 390 mg, 0.83 mmol) was converted to the free base
with A^A^-diisopropylethylamine and reacted with 2,3-dihydro[l,4]dioxmo[2,3-c]pyridine-7-
carbaldehyde (WO 2004/058144) (150 mg, 0.91 mmol) and sodium triacetoxy borohydride
(360 mg, 1.7 mmol) as described for Example 55 to give the bis hydrochloride salt of the
product as a colorless solid, 89 mg (63%).
MS fES): 469.19 (MH4) for
lHNMR(DMSO-dg) 6 1.84 (dd, 1H); 2.26 (d, 1H); 2.37 - 2.46 (m, 1H); 2.68 - 2.77
(m, 1H); 3.29 - 3.49 (m, 5H); 3.75 (s, 3H); 4.32-4.42 (m, 4H); 4.52 (s, 2H); 6.56 (dd, 1H);
6.91-6.98 (m, 2H); 7.22 (s, 1H); 8.23 (s, 1H); 9.52 (bs, 2H).
Intermediate 114: 4-[2-(4-Amino-2-oxopiperidin-l -vnethvn-6-methoxy-2//- 1 .4-
benzoxazin-3 ( 4H)-on&
tert-Butyl {l-[2-(6-methoxy-3-oxo-2,3-dihydro-4#-l,4-benzoxazin-4-yl)ethyl]-2-
oxopiperidin-4-yl}carbamate (Intermediate 115, 350 mg, 0.83 mmol) was reacted as
described for Intermediate 106. The crude trifluoro acetate of the title compound was
obtained as a black oil, 395 mg (quantitative), and used without further purification for the
next step.
MS (ESI: 320 (MH*) for Ci6H2iN3O4.
Intermediate 115: tert-Butvl U-r2-f6-methoxv-3-oxo-2.3-dihvdro-4//-1.4-
bertzoxazm-4-vr)ethvn-2-oxopiperidin-4-yllcarbamate
A mixture of to-/-butyl {l-[2-(6-methoxy-3-oxo-2,3-dihydro-4//-l,4-benzoxazin-4-
yl)ethyl]piperidin-4-yl}carbamate (Intermediate 47, 1.39 g, 3.4 mmol) in water/ ethyl acetate
(40 mL, 4:1) was treated with sodium periodate (2.8 g, 21.4 mmol) and ruthenium (IV) oxide
hydrate (50 mg, .34 mmol) at room temperature. After 53 hours, the reaction was diluted with
ethyl acetate, the aqueous phase was extracted with ethyl acetate (6 x 25 mL), and the
combined organic layers were mixed with 2-propanol (20 mL) and stirred for 2 hours at room
temperature. The reaction mixture was then filtered through celite, dried over sodium sulfate,
and concentrated in vacuo. Chromatography on silica gel with dichloromethane/ methanol
(95:5) gave 350 mg (25%) of the product as a colorless solid.
MS test: 415 (MH"1) for C29H26N306
^ 8: 1.37 (s, 9H); 1.51-1.56 (m, 1H); 1.81 -1.94 (m, 1H); 2.02-
2.11 (m, 1H); 2.33-2.41 (dd, 1H); 3.06-3.12 (m, 1H); 3.27-3.31 (m, 2H); 3.40-3.45 (m,
2H); 3.55-3.65 (m, 1H); 3.75 (s, 3H); 3.99 (t, 2H); 4.52 (s, 2H); 6.57 (dd, Hi); 6.90-6.98 (m,
3H).
Example 57
6-[({l-[2-(6-Methoxy-3-oxo-2,3-dihydro-4jy-l,4-benzoxazin-4-yI)ethyl]-2-
oxopiperidin-4-yl}amino)methyl]-2JHr-pyrido[3,2-6][l,4]oxazin-3(4//)-one
4-[2-(4-amino-2-oxopiperidin-l-yl)ethyl]-6-methoxy-2//-l,4-benzoxazin-3(4^)-one
trifluoroacetate (Intermediate 114, crude, 335 mg, 1.05 mmol) was converted to the free base
with W,7/-diisopropylethylamine and reacted with 3-oxo-3,4-dihydro-2H-pyrido[3,2-
b][l,4]oxazine-6-carbaldehyde (WO 2004/058144) (205 mg, 1.15 mmol)and sodium
triacetoxy borohydride (132 mg, 2.10 mmol) as described for Example 55 to give the bis
hydrochloride salt of the product as a colorless solid, 36 mg (46%).
MS CESV 482.15 (MH4) for C24H27N506
• 'H NMR (DMSO-d^ 8: 1.75-1.95 (m, 1H); 2.20-2.41 (m, 1H); 2.74 (dd, 1H); 3.76 (s,
3H); 3.92-4.07 (m, 2H); 4.12-4.23 (m, 1H); 4.53-4.62 (m, 2H); 4.69 (s, 2H); 6.57 (dd, 2.26,
1H); 6.90-6.99 (m, 2H); 7.20 (d, 1H); 7.43 (d, 1H); 9.39 (bs, 1H); 11.35 (s, 1H).
Example 58
3-Oxo-4-[2-(2-oxo-4-{[(3-oxo-3,4-dihydro-2Jfir-pyrido[3,2-6][l,4]oxazin-6-
yl)methyl]amlno}piperidin-l-yl)ethyl]-3,4-dihydro-2^-l,4-benzoxazine-6-carbonitrile
4-[2-(4-Amino-2-oxopiperidin-l-yl)ethyl]-3-oxo-3,4-dihydro-2//-l,4-benzoxazinc-6-
carbonitrile trifluoroacetate (Intermediate 116, crude, 232 mg, 0.54 mmol) was converted to
the free base with W,./V-diisopropylethylamine and reacted with 3-oxo-3,4-dihydro-2Hpyrido[
3,2-b][l,4]oxazine-6-carbaldehyde (WO 2004/058144) (110 mg, 0.60 mmol) and
sodium triacetoxy borohydride (240 mg, 1.10 mmol) as described for Example 55 to give the
bis hydrochloride salt of the product as a colorless solid, 65 mg (49%).
MS flSS~>: 477.35 (MH+) for C24H24N605
'HNMRfDMSQ-d^ 5 1.79-1.84 (m, 1H); 2.28-2.42 (m, 2H); 2.70-2.77 (m, 1H);
3.51-3.56 (m, 2H); 4.08-4.16 (m, 4H); 4.68 (s, 3H); 4.73 (s, 3H); 7.14-7.22 (m, 2H); 7.43-7.52
(m, 2H); 9.46 (bs, 1H); 11.35 (s, III).
Intermediate 116: 4-[2-(4-Amino-2-oxopiperidin-l-vnethvl1-3-oxo-3,4-dihydro-2//-
1.4-benzoxa2Jne-6-carbonitrile
tert-Butyl {l-[2-(6-cyano-3-oxo-2,3-dihydro-4/f-l,4-benzoxazin-4-yl)ethyl]-2-
oxopiperidin-4-yl}carbamate (Intermediate 117, 225 mg, 0.54 mmol) was reacted as
described for Intermediate 106. The crude trifluoro acetate of the title compound was
obtained as a red oil, 232 mg (quantitative), and used without further purification for the next
step.
MS (ESI: 315 (MH4) for dyH^Ch
Intermediate 117: tert-Butvl ll-r2-(6-cvano-3-oxo-2,3-dihydro-47/-1.4-benzoxay:iri-
4-vl)ethyl]-2-oxopiperidin-4-vl)carbamate
ter/-Butyl {l-[2-(6-cyano-3-oxo-2,3-dihydro-4//-l,4-benzoxazin-4-yl)ethyl]piperidin-
4-yl}carbamate (Intermediate 59, 835 mg, 2.1 mmol) was reacted with sodium periodate (2.8
g, 13.1 mmol) and ruthenium (IV) oxide hydrate (30 mg, .21 mmol) as described for
Intermediate 115 for 16 hours, except, chloroform was used for aqueous workup. The
product was obtained as a colorless solid, 230 mg (27%),
MS (ESV 415 (MH+) forC2iH26N405
'H-NMR(DMSO-d/0 5: 1.36 (s, 9H); 1.42 -1.57 (m, 2H); 1.87 (d, 1H); 2.00 (dd, 1H);
2.32 (dd, 1H); 3.38 - 3.48 (m, 2H); 3.51 - 3.63 (m, 1H); 4.07 (t, 2H); 4.72 (s, 2H); 6.94 (d,
1H); 7.14 (d, 1H); 7.48 (dd, 1H); 7.84 (d, 1H).
Example 59
6-({4-[3-(7~Methoxy-2-oxo-2fir-3,l-benzoxazin-l(4/f)-y1)propyl]p»Perazin-lyl}
methyl)-2£r-pyrido[3,2-6][l,4]oxazin-3(4J?)-one
7-Methoxy-1 -(3-piperazin-1 -ylpropyl)-1,4-dib.ydro-2ff-3,1 -benzoxazin-2-one
trifluoroacetate (Intermediate 118, crude, 886 mg, 1.66 mmol) was converted to the free base
withT/.A'-diisopropylethylamine and reacted with 3-oxo-3,4-dihydro-2H-pyrido[3,2-
b][l,4]oxazine-6-carbaldehyde (WO 2004/058144) (220 mg, 1.23 mmol) and sodium
triacetoxy borohydride (521 mg, 2.46 mmol) as described for Example 55 to give the free
base of the product as a pink foam after chromatography on silica gel with dichloromethane/
methanol (93:7), 86 mg (21%).
MS (ESV. 468.19 (MH+) for C24H29N505
IHNMRfDMSO-d^o: 1.60-1.75 (m, 2H); 2.19 - 2.44 (m, 9H); 3.37-3.43 (m, 2H);
3.72 (s, 2H); 3.83-3.96 (m, 2H); 4.53 (s, 2H); 4.60 (s, 2H); 6.56 (d, 1H); 6.78 (d, 1H); 6.88 -
7.02 (m, 2H); 7.29 (d, 1H); 11.22 (s, 1H).
Intermediate 118: 6-Methoxv-4-f3-piperazin-l-ylpropyl)-2#-l .4-benzoxazin-3(4/jlone
tert-Eutyl {l-[2-(7-methoxy-2-oxoquinolin-l(2/f)-yl)propyl]piperidin-4-yl}carbamate
(Intermediate 119, 500 rag, 1.23 mmol) was reacted as described for Intermediate 106. The
crude trifluoro acetate of the title compound was obtained as a yellow oil, 866 mg
(quantitative), and used without further purification for the next step.
MS fESV 306 (MH+) for
Intermediate 119: fer/-Butyl4-[2-('6-methoxv-3-oxo-2.3-dihvdro-4//-1.4-benzoxaxiii-
4-vnpropvllDiperazine- 1 -carboxvlate
6-Methoxy-2//-l,4-benzOxazin-3(4//)-one (Intermediate 48, 440 mg, 2.5 mmol) was
deprotonated with sodium hydride (125 mg, 60% in oil, 3.2 mmol) and alkylated with tertbutyl
4-{3-[(methylsulfonyl)oxy]propyl}piperazine-l-carboxylate (Intermediate 120, 2.5
mmol) as described for Intermediate 2. Chromatography on silica gel with dichloromethane/
2-propanol (95:5) gave 1.25 g (quantitative) of the product as a yellow oil.
MS ffiSV 406 (MH4) for C2oH29N305
'H-NMRfCDClv) 5: 1.45 (s, 9H); 1.78 - 1.90 (m, 2H) 2.36 - 2.40 (m, 6H); 3.43 (m,
4H); 3.77 (s, 3H); 3.95 (t, 2H); 4.52 (s, 2H); 6.49 (dd, 1H); 6.67 (d, 1H); 6.89 (d, 1H).
Intermediate 120: tert-Butvl 4-l3-r(methvlsulfonyl')oxv1propvnpiperazine-lcarboxylate
tert-Butyl 4-(3-hydroxypropyl)piperazine-l-carboxylate (Intermediate 121, 2.38 g,
9.8 mmol) was reacted with methanesulfonyl chloride (0.91 mL, 1 1.7 mmol) in the presence
of triethylamine (1.9 mL, 13.7 mmol) as described for Intermediate 6. The crude product
was used without further purification for the next step.
IHNMRCCDCl-DS: 1.44(s,9H); 1. 94- 2.04 (m,2H); 2.43-2.51 (m,6H);3.01 (s,
3H); 3.50-3.40 (m, 4H); 4.28-4.33 (m, 2H).
Intermediate 121: tert-Butvl 4-(3-hvdroxvnropvl')piperazine-l -carboxvlate
A mixture of tert-bntyl piperazine-1-carboxylate (2.75 g, 14.8 mmol), l-bromo-3-
propanol (1,43 mL, 16.2 mmol) and potassium carbonate (2.25 mL, 27.5 mmol) in acetonitrile
(75 mL) was heated at 95°C for 4 hours. The solvent was removed under reduced pressure,
and the residue was taken up in dichloromethane (300 mL) and washed with water, brine,
dried over sodium sulfate and concentrated under reduced pressure. Chromatography on silica
gel with methanol in dichloromethane (0-10%) gave a tan solid 2.88 g (80% yield).
MS fESV 245 (MH*) for daEW^Os.
'H-NMR fCDClO 5: 1.44 (m, 9H); 1.70-1.82 (m, 2H); 2.40-2.53 (m, 2H); 2.62-2.65
(m, 2H); 3.43-3.50 (m, 4H); 2.77 (m, 2H); 3.73-3.82 (m, 2H).
Example 60
4-{3-[4-(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-yImethyl)piperazin-l-yl]propyl}-
6-methoxy-2/?-l,4-benzoxazin-3(4.H)-one
7-Methoxy-l-(3-piperazin-l-ylpropyl)-l,4-dihydro-2//-3,l-benzoxazin-2-one
trifluoroacetate (Intermediate 118, crude, 963 mg, 1.81 mmol) was converted to the free base
with A^JV-diisopropylethylamine and reacted with 2,3-dihydro[l,4]dioxino[2,3-e]pyridine-7-
carbaldehyde (WO 2004/058144) (203 mg, 123 mmol) and sodium triacetoxy borohydride
(240 mg, 1.10 mmol) as described for Example 55 to give the free base of the product as an
oil after chromatography on silica gel with dichloromethane/ methanol (93:7), 125 mg (22%).
MS (ES): 455.15 (MH4) for CwHsMOs
'HNMRfDMSO-De'l 8:1.67 (s, 2H); 2.26 - 2.41 (m, 8H); 3.41 (s, 2H); 3.72 (s, 3H);
3.88 (s, 2H); 4.29 (d, 4H); 4.52 (s, 2H); 6.56 (d, 1H); 6.78 (s, 1H); 6.83 - 6.99 (m, 3H); 7.99
(s, 1H).
Example 61
4-[2-({l-[(2£)-3-(2,5-Difluorophenyl)prop-2-en-l-yl]piperidin-4-yl}amino)ethyll-
6-methoxy-2Lff-l,4-benzoxazin-3(4fO-one
1 -[(2£)-3-(2,5-difluorophenyl)prop-2-en-1 -yl]piperidin-4-amine trifluoroacetate
(Intermediate 122,430 mg, 0.85 mmol) was converted to the free base with N,Ndiisopropylethylamine
and reacted with (6-methoxy-3-oxo-2,3-dihydro-4//-l,4-benzoxazin-4-
yl)acetaldehyde (Intermediate 125,197 mg, 0.90 mmol) and sodium triacetoxy borohydride
(132 mg, 2.10 mmol) as described for Example 55 and purified by Reverse Phase
Chromatography with 20 to 75% acetonitrile/ water containing 0.1% TFA to give the
trifluoroacetic acid salt of the product, 31 mg.
MS (ESV. 458.27 (MH*) for
lHNMRfDMSO-D6)8:1.85-1.72 (m, 1H); 2.30-2.21 (m, 1H); 3.24-2.8 (m, 2H);
4.05-3.72 (m, 5H); 4.13-4.40 (m, 2H); 4.60 (br s, 2H); 6.61-6.98 (m, 2H); 7.21-7.41 (m, 2H);
7.60 (brs, 1H); 9.04 (brs, 1H).
Intermediate 122: l-r(2£^-3-C2.5-Difluorophenynprop-2-en-l-vl1piperidin-4-amine
ter/-Butyl {l-[(2£)-3-(2,5-difluorophenyl)prop-2-en-l-yl]piperidin-4-yl}carbamate
(Intermediate 123, 299 mg, 0.85 mmol) was reacted as described for Intermediate 106. The
crude trifluoro acetate of the title compound was obtained as an oil, 430 mg (quantitative),
and used without further purification for the next step
MS (ESV 253 (MH+) for Ci4Hi8F2N2.
Intermediate 123: tert-Butvl (l-[(2g)-3-C2.5-difluorophenvnprop-2-en-lyl]
piperidin-4-yn carbamate
A mixture of ter/-butyl piperidin-4-ylcarbamate (248 mg, 1.2 mmol), potassium
carbonate (188 mg, 1.4 mmol) and 2-[(ljE)-3-chloroprop-l-en-l-yl]-l,4-difiuorobenzene
(Intermediate 124,257 mg, 1.4 mmol) in ethanol (7 mL) was heated to 80 °C for 18 hours.
The mixture was concentrated under reduced pressure, the residue taken up in
dichloromethane (20 mL) and water (20 mL), the aqueous phase was back extracted with
dichloromethane (2 x 2C mL) and the combined organic phases were dried over sodium
sulfate. Chromatography on silica gel with dichloromethane/methanol (95:5) gave 300 mg
(69%) of product as a brown foam.
MS (ES): 353 (MH4) for C^K^NaCb
'HNMRrCDClO 5 1.41 -1.53 (m, 11H); 1.96 (d, 2H); 2.07 - 2.21 (m, 2H); 2.92 (d,
2H); 3.18 (d, 2H); 3.48 (d, 1H); 4.45 (s, 1H); 6.27 - 6.39 (m, 1H); 6.63 (d, 1H); 6.85 - 7.01
(m, 2H); 7.12 (ddd, 1H); 7.24 - 7.28 (m, 1H).
Intermediate 124: 2-r(l£)-3-Chloroprop-l-en-l-vl]-1.4-difluorobenzene
A mixture of (2£>3-(2,5-difluorophenyl)prop-2-en-l-ol (Intermediate 70, 700 mg,
4.12 mmol), 1,4-dioxane (5 mL), and hydrochloric acid (12.1 M, 1 mL) was heated in the
microwave at 100 °C for 3 hours. It was concentrated to dryness under reduced pressure, the
residue taken up in ethyl acetate (10 mL), washed with water (1x10 mL), saturated sodium
bicarbonate solution, brine and dried over sodium sulfate. The solvent was removed under
reduced pressure to give 688 mg (89% yield) of product as a yellow oil.
'HNMRfCDClOS 4.24 (dd, 2H); 6.38 (dt, 1H); 6.75 (d, 1H); 6.88 - 7.04 (m, 2H);
7.13(ddd,lH).
Intermediate 125; C6-Methoxy-3-oxo-2.3-dihydro-4//:-1.4-ben20xazin-4-
vDacetaldehyde
To a solution of oxalyl chloride (0.26 mL, 3.0 mmol) in dichloromethane (10 mL) at -
70°C was added a solution of dimethyl sulfoxide (DMSO, 0.426 mL, 6.0 mmol) in
dichloromethane (10 mL), After thirty minutes a solution of 4-(2-hydroxyethyl)-6-methoxy-
2//-l,4-benzoxazin-3(4//)-one (Intermediate 126, 550 mg, 2.5 mmol) in dichloromethane
(3.5 mL) was added dropwise and it was stirred for 90 minutes. Triethyl amine (1.74 ml, 12.5
mmol) was added it was stirred at -70°C for another 45 minutes. The reaction was quenched
with water and warmed to 0°C. It was diluted with dichloromethane, the aqueous phase was
extracted with dichloromethane (3 x 25 mL) and the combined organic phases were washed
with IN HC1 (2 X 25 mL), water (25 mL), 1M sodium carbonate solution (2 X 25 mL), water,
brine, dried over magnesium sulfate and concentrated at reduced pressure. Chromatography
on silica gel with dichloromethane/ methanol (96:4) gave the product as a yellow oil, 292 mg
(53%).
MS (ES^: 221 (MH4) for CuHi2NO4
'H NMR CCDCM 5 3.71-3.78 (m, 3H); 4.63 (s, 2H); 4.69 (s, 2H); 6.22 (d, 1H); 6.53
(dd, 1H); 6.95 (d, 1H); 9.67 (s, 1H).
Intermediate 126: 4-(2-Hvdroxyethvn-6-methoxv-27/-l .4-benzoxazin-3(4//)-one
To a solution of 4-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-6-methoxy-2//-l,4-
benzoxazin-3(4//)-one (Intermediate 127,1.38 g, 4.1 mmol) in tetrahydrofuran (40 mL) was
added tetrabutyl ammonium fluoride (1M in tetrahydrofuran (THF), 4.1 mL, 4.1 mmol). The
reaction was stirred at room temperature for two hours. The solvent was removed under
reduced pressure and the residue was taken up in dichloromethane, washed with water and
dried over magnesium sulfate. Chromatography on silica gel using dichloromethane/
methanol (95:5) gave the title compound as a yellow oil (570 mg, 62%).
'HNMRCCDClrl 5 ppm: 3.77 (s, 3H); 3.92 (t, 2H); 4.08 (t, 2H); 4.55 (s, 2H); 6.52
(dd, 1H); 6.68 (d, 1H); 6.90 (d, 1H).
Intermediate 127: 4-(2-{ rterNButylfdimethvl)silvlloxv}ethvlV6-methoxv-2fl'-l .4-
benzoxazin-St^flVone
To a solution of 6-methoxy-2/y-l,4-benzoxazin-3(4//)-one (Intermediate 48) (800
mg, 4.5 mraol) in DMF (16 mL) was added sodium hydride (60% in mineral oil, 260 mg, 6.5
mmol). After 20 minutes, (2-bromoethoxy)(tert-butyl)dimethylsilane (1.4 mL, 6.5 mmol) was
added and it was heated to 70°C in the microwave for 40 minutes. The reaction mixture was
partitioned between water (100 mL) and ethyl acetate (100 mL). The aqueous phase was
extracted with ethyl acetate (4 x 50 mL). The combined organic phases were washed with
water (6 x 250 mL), dried over magnesium sulfate and concentrated at reduced pressure to
afford the product as a yellow oil which was used without further purification. (1.38 g, 91 %).
'HNMR(CDCM 6: -0.02 (s, 6H); 0.83 (s, 9H); 3.77 (s, 3H); 3.84 - 3.91 (m, 2H); 4.01
(t, 2H); 4.52 (s, 2H); 6.50 (dd, 1H); 6.82 (d, 1H); 6.87 (d, 1H).
Example 62
4-(3-{4-[(2JE)-3-(2,5-Difluorophenyl)prop-2-en-l-yl]piperazin-l-yl}propyl)-6-
methoxy-2£T-l,4-benzoxazin-3(4J?)-one
A solution of 6-methoxy-4-(3-piperazin-l-ylpropyl)-2//-l ,4-benzoxazin-3(4//)-one
trifluoroacetate (Intermediate 118, 985 mg, 1.52 mmol) in dry ethanol (10 mL) was
converted to the free base with N,N-diisopropylethylamine for 30 min and then was added 2-
[(lJ^-4-chloroprop-l-en-l-yl]-l,4-difluorobenzene (Intermediate 124, 315 mg, 1.67 mmol),
and potassium carbonate (230 mg, 1.67 mmol). The mixture was heated at 80°C for 18 hours,
cooled to room temperature and then concentrated to dryness under reduced pressure. The
residue was partitioned between water (50 mL) and dichloromethane (100 mL). The organic
phase was dried over sodium sulfate and concentrated under reduced pressure.
Chromatography on silica gel with dichloromethane/ methanol (95:5) gave the free base of the
title compound as a yellow foam. The free base was taken up in dichloromethane(14 mL),
followed by the addition of 2M HC1 in ether (0.41 mL). The precipitate was collected by
filtration and to give the bis hydrochloride salt of the product as a colorless solid, 171 mg
(79%).
MS (ESV 458.30 (MET*) for CasHjsF^Os
'HNMRfDMSO-Dei 8 1.90-2.04 (bs, 2H); 3.15-3.30 (m, 6H); 3.75 (s, 3H); 3.95 (m,
3H); 4.57 (s, 2H); 6.45-6.54 (m, 1H); 6.57-6.61 (m, 1H); 6.81 (d, 1H); 6.93 (d, J = 9Hz, 1H);
7.26-7.33 (m, 2H); 7.56 (m, 1H).
Example 63
6-K{l-[2-(6-Methoxy-2-oxo-l,7-naphthyridin-l(2fi)-yl)ethyl]piperidin-4-
yI}amino)methyl]-2fl-pyrido[3,2-A][l,4]oxazin-3(4fl)-one
A solution of l-[2-(4-aminopiperidin-l-yl)ethyl]-6-methoxy-l,7-naphthyridin-2(l/f)-
one (Intermediate 128, crude, 116 mg, 0.38 mmol) and 3-oxo-3,4-dihydro-2#-pyrido[3,2-
£][l,4]oxazine-6-carbaldehyde [WO2004/058144] (82 mg, 0.46 mmol) in
chloroform/methanol (6 mL, 10:1) was heated over 3 A molecular sieves at 70°C for 18 hours.
The reaction mixture was cooled to 0°C, and sodium triacetoxy borohydride (180 mg, 0.84
mmol) was added. The resulting reaction mixture was allowed to warm to room temperature
and stirred for 18 hours. The reaction was diluted with dichloromethane (50 raL) and water
(10 mL). The aqueous phase was separated and evaporated to give a solid. The solid was
suspended in methanol and filtered. The resultant solid was dissolved in dichloromethane :
methanol(l: 1) and treated with 2N HC1 in ether to obtain the dihydrochloride salt. The
colorless precipitate was collected by filtration and gave 28 mg (14%) of the bishydrochloride
salt of the product.
MSfESY1": 465 (MH)+ for CwIfegNeC^
'H NMR rDMSQ-Dg) 5 ppm: 2.04-2.19 (m, 2H); 2.19-2.31 (m, 1H); 2.32-2.45 (m,
3H); 3.05-3.21 (m, 4H) 3.69-3.84 (m, 2H); 3.89 (a, 3H); 4.05-4.20 (m, 2H); 4.62-4.75 (m,
4H); 6.83 (d, 1H); 7.20 (s, 1H); 7.30 (d, 1H); 7.42 (d, Hi); 7.92 (d, 1H); 8.78 (s, 1H); 9.94 (s,
lH);11.39(s,2H).
Intermediate 128: l-[2-f4-Aminopiperidin-l-yl)ethyl]-6-methoxy-1.7-naphthyridin-
2fLHVone
A solution of tert-butyl {l-[2-(6-chloro-2-oxo-l,7-naphthyridin-l(2#)-
yl)ethyl]piperidin-4-yl}carbamate (Intermediate 129, 335 mg, 0.83 mmol) was treated with a
solution of sodium methoxide in methanol (0.5 M, 4 mL). The reaction was sealed in a tube
and heated at 150°C for 4 hours using microwave irradiation. The reaction was diluted with
water and ethyl acetate. The layers were separated. The aqueous phase was washed with ethyl
acetate twice. The organic extracts were combined dried over magnesium sulfate and
evaporated at reduced pressure to give 116 mg (64%) of the crude product as a yellow oil.
MS fES^: 303 (MH^for
Intermediate 129: tert-Butvl n-[2-(7-methoxv-2-oxoquinolin-lf2fflvllethvnpiperidin-
4-yl} carbamate
6-Chloro-l,7-naphthyridin-2(l#)-one (J. Org. Chem. 1990, 55,4744-4750) (360 mg,
2.0 ramol) was deprotonated with sodium hydride (100 mg, 60% in oil, 2.4 mmol) and
alkylated with 2-{4-[(ter/-butoxycarbonyl)arnino]piperidin-l-yl}ethyl methanesulfonate
(Intermediate 6) 2.75 mmol) as described for Intermediate 2. Chromatography on silica gel
with methanol in dichloromethane (0-10%) gave 334 mg (20%) of the product as a colorless
solid.
MS (ES1: 407 (MH4) for C2oH27ClN403
'H-NMR rDMSO-dg> 8: 1.19-1.32 (m, 1H); 1.36 (s, 9H); 1.56-1.70 (m, 2H); 2.01 (s,
2H); 2.51-2.57 (m, 2H); 2.67-2.75 (m, 1H); 2.83-2.93 (m, 2H); 3.10-3.25 (m, 2H); 3.29-3.31
(m, 1H); 4.30-4.40 (m, 2H); 6.71-6.80 (m, 1H); 6.91 (d, 1H); 7.87 (s, 1H); 7.91 (d, HI); 8.74
(s, 1H).
Example 64
Methyl l-[(2£)-3-(2,5-difluorophenyl)prop-2-en-l-yl]-4-[3-(6-cyano-3-oxo-2,3-
dihydro-4/M,4-benzoxazin-4-yl)propyl]piperidine-3-carboxylate
A solution of methyl 4-[3-(6-cyano-3-oxo-2,3-dihydro-4H-l,4-benzoxazin-4-
yl)propyl]piperidine-3-carboxylate trifluoroacetate (Intermediate 130, crude, 171,0.48
mmol), (2£)-3-(2,5-difluorophenyl)acrylaldehyde [FR 2872164] (81 mg, 0.48 mmol), and
triethylamine (0.13 mL. 0.96 mmol) in chloroform/methanol (6 mL, 10:1) was heated over 3
A molecular sieves at 70°C for 3 hours. The reaction mixture was cooled to 0°C, and sodium
triacetoxy borohydride (200 mg, 0.94 mmol) was added. The resulting reaction mixture was
allowed to warm to room temperature and stir for 18 hours. The reaction was diluted with
ethyl acetate (25 mL) and water (10 mL). The aqueous phase was separated and washed twice
with ethyl acetate. The organic layers were combined, dried over magnesium sulfate and
evaporated at reduced pressure. Chromatography on silica gel with diethyl ether gave the title
compound as a off-white foam, (79 mg, 32%).
MSfES^) 510 (MH)+ for CHHfoFzNsO*
'H NMR fDMSO-d^ S 1.10-1.21 (m, 1H); 1.23-1.34 (m, 1H); 1.44-1.55 (m, 3H);
1.67-1.79 (m, 2H); 1.95-2.07 (m, 1H); 2.18-2.29 (m, 1H); 2.31-2.43 (m, 1H); 2.64-2.70 (m,
1H); 2.71-2.80 (m, 1H); 2.82-2.89 (m, 1H); 3.06-3.17 (m, 2H); 3.57 (d, 3H); 3.84-3.96 (m,
2H); 4 4.77 (s, 2H); 6.40-6.51 (m, 1H); 6.56-6.63 (m, 1H); 7.12 (ddd, 1H); 7.17 (d, 2H); 7.20-
7.28 (m, 1H); 7.47-7.56 (m, 2H); 7.72 (d, 1H).
Intermediate 130: Methvl 4-[3-f6-cyano-3-oxo-2.3-dihvdro-4//-1.4-benzoxazin-4-
vnpropyripiperidine-3-carboxylate
A solution of l-tert-bntyl 3-methyl 4-[3-(6-cyano-3-oxo-2,3-dihydro-4//-l,4-
benzoxazin-4-yl)propyl]piperidine-l,3-dicarboxylate (Intermediate 131,220 mg, 0.48 mmol)
was reacted as described for Intermediate 106. The crude trifluoro acetate of the title
compound was used without further purification for the next step (quantitative).
Intermediate 131; 1-tert-Butvl 3-methyl 4-[3-(6-cyano-3-oxo-2.3-dihydro-4//-1.4-
benzoxazin-4-vnpropvl1piperidine-1.3-dicarboxvlate
A solution of 3-oxo-3,4-dihydro-2//-l,4-benzoxazine-6-carbonitrile (Intermediate
60) (265 mg, 1.53 mmol) in dry ditnethylformamide (DMF) (5 mL) was treated at 0°C with
sodium hydride (105 mg, 60% in oil, 2.63 mmol) and then stirred for 30 minutes at room
temperature. A solution of \-tert-butyl 3-methyl 4-{3-
[(methylsulfonyl)oxy]propyl}piperidine-l,3-dicarboxylate in DMF (Intermediate 132, 0.31
mmol/ mL, 5 mL, 1.53 mmol) was then added and the resulting mixture was stirred at room
temperature for 96 hours. The reaction was diluted with ethyl acetate and water. The aqueous
layer was adjusted to pH3 with IN HC1. The layers were separated. The aqueous phase was
extracted once with ethyl acetate. The combined organic phases were washed four times with
water, dried over magnesium sulfate and evaporated at reduced pressure. Chromatography on
silica gel with (10 -35%) acetone in hexanes gave 445 mg (64 %) of the product as a white
semi-solid (as a mixture of diastereomers).
MS (ES\. 458 (MH4) for C24H3iN306
'HNMR rCPClO 5: 1.43 and 1.44 (two s, 9H); 1.47-1.9 (m, 7H); 2.56-2.83 (m, 2H);
2.94-3.2 (m, 1H); 3.65 and 3.70 (two s, 3H); 3.76-3.99 (m, 2H); 4.02-4.21 (m, 1H); 4.67 and
4.70 (two s, 2H); 7.04 (m, 1H); 7.11 and 7.18 (two brs, 1H); 7.30 (m, 1H).
Intermediate 132: l-ter/-Butvl3-methvl4-(3-[(methvlsulfonvnoxv1propyl)
piperidine-1.3-dicarboxvlate
A mixture of l-fc/-/-butyl 3-methyl 4-(3-hydroxypropyl)piperidine-l,3-dicarboxylate
(Intermediate 133, 460 mg, 1.53 mmol) in dry dichloromethane (5 mL) and triethyl aminc
(0.3 mL, 2.14 mmol) was treated at 0°C with a solution of methanesulfonyl chloride (0.14
mL, 1.83 mmol) in dichloromethane (5 mL). After 2 hours minutes the reaction was complete
by TLC (dichloromethane : methanol 10:1). The reaction was diluted with ethyl acetate and
water. The layers were separated. The organic layer was washed with 0.1N HC1, water,
saturated sodium bicarbonate, dried over magnesium sulfate. The solvent was removed under
reduced pressure and the crude preparation of the mesylate was used without delay for the
next step.
Intermediate 133: l-te;-/-Butyl 3-methvl 4-(r3-hydroxypropyl')piperidine-1.3-
dicarboxvlate
A solution of 1-tert-butyl 3-methyl 4-allylpiperidine-l,3-dicarboxylate
[W02002/072572] (715 mg, 2.53 mmol) in tetrahydrofuran (5 mL) at 0°C was treated with a
solution of 9-BBN in tetrahydrofuran (0.5M, 10.2 mL, 5.1 mmol). After one hour the reaction
mixture was allowed to warm to room temperature for 3 hours. The reaction mixture was
cooled to 0°C and treated with water (3 mL), NaOH (3N, 6 mL) and hydrogen peroxide (30%
solution, 6 mL). The reaction was allowed to warm to room temperature and stir for one hour.
The reaction was diluted with ethyl acetate and water. The layers were separated. The
aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried
over magnesium sulfate and concentrated at reduced. Chromatography on silica gel with
methanol in dichloromethane (0-10%) gave the product as a colorless oil as a mixture of
diastereomers (460 mg, 60%).
MS rest: 302(MH*) for Ci5H27NO5
'HNMRrCDClOS: 1.28-1.39 (m, 1H); 1.43 and 1.44 (two s, 9H); 1.46-1.54 (m, 211);
1.56-1.67 (m, 3H); 1.73-1.85 (m, 2H); 2.58-2.63 (m, 1H); 3.02-3.12 (m, 1H); 3.27 (dd, 1H);
3.60-3.64 (m, 2H); 3.65 and 3.69 (two s, 3H); 3.71-3.81 (m, 1H); 3.87-3.98 (m, 1H).
Example 65
4-[3-(6-Cyano-3-oxo-2,3-dihydro-4H-l,4-benzoxazin-4-yI)propyI]-l-[(2E)-3-(2,5-
difluorophenyl)prop-2-en-l-yl]piperidine-3-carboxylicacid
A solution of methyl l-[(2E)-3-(2,5-difluorophenyl)prop-2-en-l-yl]-4-[3-(6-cyano-3-
oxo-2,3-dihydro-4H-l,4-benzoxaztn-4-yl)propyl]piperidine-3-carboxylate (Example 64) (73
mg, 0.143 mmol) in methanol (12 mL) and water (5 mL) was treated with sodium hydroxide
solution (IN, 1 mL). After 64 hours, the pH was adjusted to 6 with IN HC1. The mixture was
extracted with ethyl acetate (3 x 30 mL). The combined organic extracts were dried over
magnesium sulfate and concentrated at reduced pressure. Chromatography on silica gel using
methanol in dichloromethane (0-10%) and trituration with diethyl ether gave the title
compound as a colorless solid, mixture of diastereomers, 10 mg (14%).
MS fES~): 496 (MH)+ for CwKfoFiNaC^
'HNMRCCDCMS: 1.40-1.45 (m, 1H); 1.47-1.52 (m, 1H); 1.60-1.65 (m, 1H); 1.65-
1.77 (m, 3H); 2.25-2.37 (m, 2H); 2.70-2.77 (m, 1H); 3.08-3.16 (m, 1H); 3.23-3.30 (m, 1H);
3.30-3.40 (m, 2H); 3.64-3.72 (m, 1H); 3.73-3.84 (m, 1H); 3.86- 3.95 (m, 1H); 3.95-4.07 (m,
1H); 4.60-4.71 (m, 3H); 6.21-6.31 (m, 1H); 6.67 (d, 1H); 6.87-6.95 (m, 1H); 6.96-7.01 (m,
1H); 7.01-7.07 (m, 1H); 7.09-7.15 (m, 1H); 7.28-7.31 (m, 1H).
Example 66
7-Fluoro-3-methyl-l-[2-(4-{[(3-oxo-3,4-dihydro-2jET-pyrido[3,2-fi][l,4]oxazin-6-
yl)methyl]amino}piperidin-l-yl)ethyl]quinazoIine-2,4(lJy,3/7)-dione
l-[2-(4-Aminopiperidin-l-yl)ethyl]-7-fluoro-3-methylquinazoline-2,4(l/:/,3J!:/)-dione
trifluoroacetate salt (Intermediate 134) (0.476 rnrnol, 380 mg crude) was converted to the
free base with ./V.N-diisopropylethylamine (0.5 mL, 3.0 mmol) and reacted with 3-oxo-3,4-
dihydro-2H-pyrido[3,2-b][l,4]oxazine-6-carbaldehyde (WO 2004/058144) (102 mg, 0.571
mmol) and sodium triacetoxy borohydride (222 mg, 1.05 mmol) as described for Example
55. The reaction was diluted with dichloromethane and water. The layers were separated. The
aqueous layer was extracted with dichloromethane twice. The combined organic layers were
dried over magnesium sulfate and evaporated at reduced pressure. Chromatography on silica
gel using methanol in dichloromethane (0-9%) with 1% concentrated ammonium hydroxide
(aqueous) gave the product as a waxy material. This material was taken up in
dichloromethane and washed well with water. The organic phase was dried over magnesium
sulfate and evaporated to obtain the title compound as a colorless solid (48 mg, 21%).
MSfES): 483 (MH)+ for Ci^vFNeC^
'HNMRfDMSQ-De) 8: 1.14-1.28 (m, 2H); 1.71-1.82 (m, 2H); 1.94-2.06 (m, 21-1);
2.33-2.44 (m, 2H); 2.83-2.92 (m, 2H); 3.26-3.30 (m, 3H); 3.65-3.72 (m, 211); 4.17 (t, 2H);
4.60 (s, 2H); 7.00 (d, 1H); 7.13 (td, 1H); 7.29 (d, 1H); 7.36 (dd, 1H); 8.09.(dd, 1H); 11.18 (s,
1H).
Intermediate 134: l-f2-f4-Aminopiperidm-l-vl)emvl1-7-fluoro-3-methylquinazoline-
2.4(m3/fl-dione
tert-Butyl {l-[2-(7-fluoro-3-methyl-2,4-dioxo-3,4-dihydroquinazolin-l(2//)-
yl)ethyl]piperidin-4-yl}carbamate (Intermediate 135) (200 mg, 0.476 mmol) was reacted as
described for Intermediate 106. The crude trifluoro acetate of the title compound was used
without further purification for the next step (quantitative).
MSfES): 321 (MH)+ for
Intermediate 135: tert-Butvl n-r2-C7-fluoro-3-methvI-2.4-dioxo-3.4-
dihvdroquinazolin- 1 ( 2/f)-vDethvnpiperidin-4-vll carbamate
7-Fluoro-3-methylquinazoline-2,4(l//,3//)-dione [Intermediate 136] (388 mg, 2.0
mmol) was deprotonated with sodium hydride (100 mg, 60% in oil, 2.4 mmol) and alkylated
with 2-{4-[(ter^butoxycarbonyl)amino]piperidin-l-yl}ethyl methanesulfonate (Intermediate
6) 2.75 mmol) as described for Intermediate 2. Chromatography on silica gel using ethyl
acetate in hexanes (10-30%) gave the title compound as a yellow oil (200 mg, 24%).
MS fESV 421 (MH)+ for C2iH29FN4O4
'H NMR rCDCM 8: 1.2-1.3 (m, 2H); 1.43 (s, 9H); 1.44-1.5 (m, 1H); 1.9- 2.0 (m, 2H);
2.15-2.35 (m, 2H); 2.65 (m, 2H); 2.85- 3.0 (m, 1H); 3.45 (s, 3H); 3.46- 3.52 (m, 1H); 4.15-
4.25 (m, 2H); 4.35- 4.5 (m, 1H); 6.8- 6.9 (m, 1H); 6.91-7.0 (m, 1H); 8.2-8.26 (m, 1H).
Intermediate 136: 7-Fluoro-3-methylquinazoline-2.4flH.3/f)-dione
A suspension of sodium hydride (60% in mineral oil, 368 mg, 9.2 mmol) in
dimethylformamide (12 mL) was cooled to 0°C and treated with 2-amino-4-fluoro-A'-
methylbenzamide [Intermediate 137] (0.67g, 4.0 mmol). Phenyl chloroformate (0.6 mL, 0.73
g, 4.7 mmol) was added over 40 minutes. After 1 hour a further portion of phenyl
chloroformate (0.6 mL, 0.73 g, 4.7 mmol) was added. The reaction was allowed to warm to
room temperature and stir for two hours. The reaction was slowly added to 200 mL of ice.
The solid was filtered, washed with methanol to obtain the product (395 mg, 51%).
MS (ES): 193 (M-H)' for C9H7FN202
'HNMRfDMSO-dd 8: 3.23 (s, 3H); 6.89 (dd, 1H); 7.04 (td, 1H); 7.98 (dd, 1H);
11.56(s,
Intermediate 137: 2-Ammo-4-fluoro-N-rnethvlbenzamide
A mixture of 2-amino 4-fluoro benzoic acid (2.5g, 16.13 mmol) and 1,3 dimethyl urea
(5.85 g, 66.5 mmol) was heated at 150°C for 24 hours. The reaction was diluted with water,
filtered and extracted twice with ethyl acetate. The organic extracts were dried over
magnesium sulfate and concentrated at reduced pressure. Chromatography on silica gel with
ethyl acetate in hexanes (0-50%) gave the title compound as a waxy solid (670 mg, 25%)
MSCESV: 169 (MH)* for C8H9FN20
*H NMR fDMSO-Dei 8:2.69 (d, 3H); 6.29 (td, 1H); 6.43 (dd, 1H); 6.74 (s, 2H); 7.49
(dd, 1H); 8.08-8.22 (m, 1H).
Example 67
7-ChIoro-l-(2-{4-[(2,3-dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]
piperidin-l-yl}ethyl)-l,8-naphthyridin-2(lH)-one
1 -[2-(4-Aminopiperidin-1 -yl)ethyl]-7-chloro-1,8-naphthyridin-2(l H)-one
trifluoroacetate (Intermediate 138, crude, 405 mg, 0.76 mmol), di-isopropyl ethylamine (
0.38 mL, 2.27 mmol), 2,3-dihydro[l,4]dioxino[2,3-c]pyridine-7-carbaldehyde [WO
2004/058144] (180 mg, 1.1 mmol) and sodium cyanoborohydride (100 mg, 1.56 mmol) were
reacted as described for Example 21. Chromatography on silica gel using methanol in
dichloromethane (0-20% with 1% aqueous ammonium hydroxide) followed by reverse phase
Chromatography with 20-75% acetonitrile/ water/10 mM NEUOAc Buffer) gave the title
compound (39 mg, 11%).
MS (ES): 456 (MH)+ for C23H26C1N503
'HNMRfCDCIO 5 1.32 -1.43 (m, 2H); 1.87 (d, 2H); 2.10 - 2.21 (m, 2H); 2.51 - 2.61
(m, 1H); 2.69 (t, 2H); 3.08 (d, 2H); 3.81 (s, 2H); 4.21 - 4.32 (m, 4H); 4.58 (t, 2H); 6.68 (d,
1H); 6.78 (s, 1H); 7.11 (d, 1H); 7.58 (d, 1H); 7.75 (d, 1H); 8.05 (s, 1H).
Intermediate 138; l-r2-(4-Aminopiperidin-l-yl)ethyl]-7-chloro-1.8-naphthyridin-
2flHVone
tert-Butyl {1 -[2-(7-chloro-2-oxo-l ,8-naphthyridin-1 (2H)-yl)ethyl]piperidin-4-
yl}carbamate (Intermediate 139, 308 mg, 0.76 mmol) was reacted as described for
Intermediate 106. The crude trifluoro acetate of the title compound was used without further
purification for the next step (quantitative).
Intermediate 139; tert-Butvl n-r2-f7-chlQro-2-oxo-1.8-naphthvridin-l('2H')-
vlkthyl]piperidin-4-yl} carbamate
A solution of 7-chloro-l,8-naphthyridin-2(lH)-one FJ. Ore. Chem. 1990, 55,4744-
4750] in dry DMF (20 mL) (540 mg, 3,0 ramol) at 0°C was treated with sodium hydride (144
mg, 60% in mineral oil, 3.6 mmol). The reaction mixture was allowed to warm to room
temperature and stirred for 1 hour. The reaction was cooled using an ice bath. A solution of 2-
{4-[(ter/-butoxycarbonyl)amino]piperidin-lyl} ethyl methanesulfonate in DMF (Intermediate
6), 0.33 mmol/ mL, 10 mL, 3.3 mmol) was then added over 1 hour. The reaction was allowed
to warm to room temperature and stirred overnight. The reaction mixture was diluted with
water and extracted with dichloromethane (3 x 50 mL). The combined organic layers were
washed with saturated sodium chloride solution (3x10 mL), dried over sodium sulfate and
evaporated. Chromatography on silica gel using methanol in dichloromethane (0-15%) gave
the title compound as a brown foam (711 mg, 58%).
MS (ESI: 407 (MH)+for CzoHbClN^
'HNMRCCDC10 5 1.42 (s, 11H); 1.84 - 1.99 (m, 2H); 2.12 - 2.22 (m, 1H); 2.22 -
2.37 (m, 2H); 2.66 - 2.80 (m, 2H); 3.03 - 3.19 (m, 1H); 3.39 - 3.55 (m, 1H); 4.34 - 4.48 (m,
1H); 4.62 (t, 2H); 6.72 (d, 1H); 7.15 (d, 1H); 7.61 (d, 1H); 7.78 (d, III).
Example 68
l-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmcthyl)amino]piperidin-lyl}
ethyI)-7-methoxy-l,8-naphthyridin-2(lII)-one
A solution of 7-chloro-l-(2-{4-[(2,3-dihydro[l,4]dioxino[2,3-c]pyridin-7-
ylmethyl)amino]piperidin-l-yl}ethyl)-l,8-naphthyridin-2(lH)-one (Example 67) (95 mg,
0.21 mmol) in methanol (5 mL) was treated with a solution of sodium methoxide (0.5 M, 1
mL, 0.5 mmol). The reaction mixture was sealed in a tube and heated at 150 C for 1 hour
using microwave irradiation. The reaction mixture was concentrated at reduced pressure,
partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl
acetate (3 x 10 mL) and chloroform/methanol (4:1) (3 x 15 mL). The combined organic
extracts were dried over sodium sulfate and concentrated at reduced pressure.
Chromatography on silica gel using methanol in dichloromethane (0-50%) gave the product
as a colorless solid (29 mg, 31%)
MS ffiSV 452 (MH)+
'HNMRfCDCM 8 1.39 -1.54 (m, 2H); 1.90 (d, 2H); 2.13 - 2.28 (m, 2H); 2.47 - 2.62
(m, 1H); 2.64 - 2.76 (m, 2H); 3.06 (d, 2H); 3.80 (s, 2H); 3.99 (s, 3H); 4.26 (dd, 4H); 4.55 -
4.68 (m, 2H); 6.55 (dd, 2H); 6.80 (s, 1H) 7.53 (d, 1H); 7.68 (d, 1H); 8.06 (s, 1H).
Example 69
!-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-cIpyridin-7-ylmethyl)amino]piperidin-lyl}
ethyl)-7-fluoroquinoxaIin-2(l/f)- A mixture of l-[2-(4-aminopiperidin-l-yl)ethyl]-7-fluoroquinoxalin-2(l//)-one
(Intermediate 140, 85 mg, 0.29 ramol), 2,3-dihydro[l,4]dioxino[2,3-c]pyridine-7-
carbaldehyde (WO 2004/058144) (49 mg, 0.29 mmol) and molecular sieves 3 A in dry
methanol/ chloroform (1:1,10 mL) was heated to 70 °C for 3 hours. The reaction was allowed
to cool to room temperature and sodium triacetoxy borohydride (190 mg, 0.88 mmol) was
added. After 30 minutes, the reaction was filtered through celite, the filtrate was concentrated
to dryness, taken up in 15% methanol/ chloroform, and washed with saturated sodium
bicarbonate solution. The aqueous phase was reextracted twice with 15%
methanol/chloroform. The combined organic phases were dried over magnesium sulfate,
filtered, and concentrated to dryness. Chromatography on silica gel with 5% methanol in
dichloromethane containing 0.25% ammonium hydroxide gave 70 mg (54%) of the title
compound as an off-white solid.
MS (ES): 440 (MH4) for CzsHjeFNsCb
'HNMR (DMSO-D6) 5 1.11 -1.24 (m, 2H); 1.73 (d, 2H); 2.00 (t, 2H); 2.18 (s, 1H);
2.25 - 2.38 (m, 1H); 2.51 - 2.56 (m, 2H); 2.87 (d, 2H); 3.64 (s, 2H); 4.24 - 4.35 (m, 6H); 6.92
(s, 1H); 7.24 (td, 1H); 7.52 (dd, 1H); 7.87 (dd, 1H); 7.99 (s, 1H); 8.18 (s, III).
Intermediate 140: l-[2-(4-Aminopiperidin-l-yl)ethyl]-7-fluoroquinoxalin-2d//)-one
A solution of tert-butyl {l-[2-(7-fluoro-2-oxoquinoxalin-l(2/:/)-yl)ethyl]piperidin-4-
yl}carbamate (Intermediate 141,240 mg, 0.62 mmol) in dichloromethane (20 mL) was
treated with trifluoroacetic acid (15 mL). After 45 minutes, the reaction was concentrated to
dryness, the residue taken up in methanol/ chloroform (15:85, 30 mL) and washed with
saturated sodium bicarbonate solution. The aqueous layer was re-extracted with methanol/
chloroform (15:85,3x30 mL. The combined organic phases were dried over magnesium
sulfate and concentrated to dryness to give 170 mg (quantitative) of the crude product as an
oil.
-J3T-/3/
MS (ES\. 291 (MH+) for Ci5H]9FN4O
Intermediate 141: tert-Eutvl {l-[2-(7-fluoro-2-oxoquinoxalin-lf2/f)-
vl)ethyl1piperidin-4-yU carbamate
and
Intermediate 142; tert-Butvl n-r2-C6-fluoro-2-oxoquinoxalin-l('2//)-
vDethy ripiperidin-4-vl} carbamate
A suspension of a 1:1 mixture of 7-fluoroquinoxalin-2(l#)-one (Intermediate 143)
and 6-fluoroquinoxalin-2(l//)-one (Intermediate 144) (1.5 g total, 9.1 mmol) was treated
with sodium hydride (60% in oil, 0.44 g, 11.0 mmol) at 0°C. The reaction was allowed to stir
at room temperature for 2 hours. The reaction mixture was cooled to 0 °C and 2-{4-[(tertbutoxycarbonyl)
amino]piperidin-l-yl} ethyl methanesulfonate (Intermediate 6,1.33
mmol/mL, 11.0 mmol), dissolved in dry DMF (5 mL) was added and it was stirred at room
temperature overnight. The reaction mixture was diluted with water and with diethyl ether (5x
50 mL). The combined organic phases were dried over sodium sulfate and concentrated to
dryness under reduced pressure. Chromatography with hexanes/ acetone (5:1 to 3:1). The
higher Rf material was isolated as a mixture of Intermediate 141 with an 0-alkylatcd isomcr,
which was rechromatographed on silica gel with hexanes/ ethyl acetate (1:3) to give pure
Intermediate 141 as a colorless solid, 0.24 g, 14%. Isolation of the lower Rf material from
the first column gave 0.38 g (21%) of pure Intermediate 142 as a colorless solid.
Intermediate 141:
MS (BS): 391 (MH") for C2oH27FN403
'HNMRfDMSO-De^ 8 1.25-1.38 (m, 11H); 1.56-1.68 (m, 2H); 2.01 (t, 2H); 2.50-
2.56 (m, 2H); 2.82-2.93 (m, 2H); 3.16 (s, 1H); 4.27 (t, 2H); 6.72 (d, 1H); 7.23 (t, 1H); 7.50 (d,
1H); 7.83-7.91 (m, 1H); 8.17 (s, 1H).
Intermediate 142:
MS (ES): 391 (MH4) for CaoI^FN^
^NMRfDMSO-De^ 5 1.24-1.38 (m, 11H); 1.65 (d, 2H); 2.03 (t, 2H); 2.51-2.58 (m,
2H); 2.88 (d, 2H); 3.11-3.26 (m, 1H); 4.31 (t, 2H); 6.75 (d, 1H); 7.57 (td, 1H); 7.63-7.71 (m,
2H); 8.29 (s, 1H).
Intermediate 143: 7-Fluoroauinoxalin-2d.ff)-one
and
Intermediate 144; 6-Fluoroqumoxalin-2(l/fl-one
A mixture of 4-fluorobenzene-l,2-diamine (5.0 g, 39.7 mmol) and ethyl oxoacetate
(50 wt % in toluene, 17 mL, 79.4 mmol) in ethanol (100 mL) was stirred for two hours at
room temperature. The precipitate was collected by filtration, washed with ethanol, and dried
under vacuum giving 4.5 g of a solid. !H NMR revealed a 1:1 mixture of Intermediates 143
and 144. This mixture was used for the next step,
MS (ES\. 165 (MH+) for C8H5FN20
Example 70
6-[({l-[2-(7-Fluoro-2-oxoquinoxalin-l(2//)-yl)ethynpiperidin-4-yl}amino)methyl]-
2#-pyrido[3,2-A|[l,4]oxazin-3(4//)-one
l-[2-(4-Aminopiperidm-l-yl)ethyl]-7-fluoroquinoxalin-2(l//)-°ne (Intermediate 140,
85 mg crude, 0.29 mmol), 3-oxo-3,4-dihydro-2#-pyrido[3,2-6][l,4]oxazine-6-carbaldehyde
(WO 2004/058144) (52 mg, 0.29 mmol) and sodium triacetoxy borohydride (190 mg, 0.88
mmol) were reacted as described according to Example 69 to give 90 mg (69%) of the free
base of the product.
MS (ESI: 453 (MH+) for C23H2jFN6O3
1HNMRroMSO-D6') 5 1.12-1.26 (m, 2H); 1.69-1.81 (m, 2H); 2.01 (t, 2H); 2.27-2.42
(m, 1H); 2.51-2.60 (m, 2H); 2.88 (d, 2H); 3.67 (s, 2H); 4.28 (t, 2H); 4.60 (s, 2H); 7.00 (d,
1H); 7.20-7.31 (m, 2H); 7.52 (dd, 1H); 7.88 (dd, 1H); 8.19 (s, 1H); 11.16 (s, 1H).
Example 71
l-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-lyl}
ethyl)-6-fluoroquinoxalin-2(LF7)-one
l-[2-(4-Aminopiperidin-l-yl)ethyl]-6-fluoroquinoxalin-2(l/:/)-one (Intermediate 145,
87 mg, 0.30 mmol), 2,3-dihydro[l,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO
2004/058144) (50 mg, 0.30 mmol), and sodium triacetoxy borohydride (200 mg, 0.90 mmol)
were reacted as described for Example 69 to give the free base of the title compound as an
oil. The free base was taken up in isopropanol (10 mL) and treated with 2.0M HC1 in ether (3
eq). Solvent was removed under reduced pressure. The resulting solid was triturated with
dichloromethane/hexanes (2mL/ lOmL). The precipitate was collected by filtration to give 45
mg (29%) of the bis-hydrochloride salt of the product.
MS (BSV 440 (MH+) for CzaJfefiFNsOs
1. 83-2.06 (m, 2H); 2.42 (d, 2H); 3.17 (t, 2H); 3.48-3.68 (m, 3H);
3.79-4.01 (m, 2H); 4.30-4.41 (m, 4H); 4.43-4.51 (m, 2H); 4.65-4.70 (m, 2H); T. 27-1 30 (m,
1H); 7.44-7.55 (m, 2H); 7.59 (dd, 1H); 8.20-8.25 (m, 2H).
Intermediate 145: l-r2-(4-Aminopiperidin-l -vnethyl1-6-fluoroquinoxalin-2n//)-orie
tert-Butyl { 1 -[2-(6-fluoro-2-oxoquinoxalin- 1 (2#)-yl)ethyl]piperidin-4-yl} carbamate
(Intermediate 142, 380 mg, 0.97 mmol) was reacted with trifluoroacetic acid in
dichloromethane as described for Intermediate 140 to give 260 mg (93%) of the crude
product as an oil.
MS fESV. 291 (MH+) for Ci5Hi9FN4O
Example 72
l-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-yImethyl)amino]piperidin-lyI}
ethyl)-7-methoxyquinoxalin-2(l//)-one
l-[2-(4-Aminopiperidin-l-yl)ethyl]-7-methoxyquinoxalin-2(l/f)-one (Intermediate
146, 60 mg crude, 0.20 mmol), 2,3-dihydro[l,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO
2004/058144) (33 mg, 0.20 mmol), and sodium triacetoxy borohydride (130 mg, 0.60 mmol)
were reacted as described for Example 69 to give the free base of the title compound as an
oil. The free base was taken up in isopropanol and treated with 4.0M HC1 in dioxane (3 eq).
Solvent was removed under reduced pressure to give 28 mg (27% yield) of the bishydrochloride
salt of the product.
MS (ESV 452 (MH+) for C24H29N504
1HNMRfD;0') 5 1.86-2.02 (m, 2H); 2.36-2.49 (m, 2H); 3.09-3.23 (m, 2H); 3.52 (t,
2H); 3.56-3.68 (m, 1H); 3.82-3.95 (m, 5H); 4.32-4.40 (m, 4H); 4.43-4.50 (m, 2H); 4.61 (t,
2H); 6.82 (d, 1H); 7.03 (dd, 1H); 7.29 (s, 1H); 7.71 (d, 1H); 7.97 (s, 1H); 8.22 (s, 1H).
Intermediate 146: 1 -[2-(4-Aminor>iperidin- 1 -vr)ethvl]-7-methoxvquinoxalin-2( I/Done
terf-Butyl { 1 -[2-(7-methoxy-2-oxoquinoxalin-l(2//)-yl)ethyl]piperidin-4-
yl}carbamate (Intermediate 147, 190 mg, 0.47 mmol) was reacted with trifluoroacetic acid in
dichloromethane as described for Intermediate 140 to give 110 mg of the crude product as an
oil.
MS (ES): 303 (MH+) for C^EfoN^
Intermediate 147: tert-Butvl n-[2-(7-methoxv-2-oxoquinoxalin-l(2#V
vl)ethyl]piperidin-4-yl} carbamate
7-methoxyquinoxalin-2(l/0-one (Intermediate 148,300 mg, 1.70 mmol) was
deprotonated with sodium hydride (100 mg, 60% in oil, 2.56 mmol) and alkylated with 2-{4-
[(tert-butoxycarbonyl)amino]piperidin-l-yl} ethyl methanesulfonate (Intermediate 6) (3.4
mmol) as described for Intermediate 2. Chromatography on silica gel with 25% acetone in
hexanes gave 200 mg (29%) of the product as a colorless solid.
MS (ES): 403 (MH+) for C21H3oN404
'HNMRCDMSO-D6U 1.26-1.40 (m, 11H); 1.57-1.72 (m, 2H); 1.97-2.11 (m, 2H);
2.51-2.61 (m, 2H); 2.85-2.98 (m, 2H); 3.19 (s, 1H); 3.92 (s, 3H); 4.32 (t, 2H); 6.76 (d, 1H);
6.95-7.04 (ra, 2H); 7.70-7.78 (m, 1H); 8.04 (s, 1H).
Intermediate 148: 7-Methoxyquinoxalin-2f Iffl-one
A suspension of 2-chloro-7-methoxyquinoxaline (Intermediate 149, 720 mg, 3.70
mmol) in 5M HC1 (25 mL) was heated to 110 °C for 1 hour. The reaction was cooled to room
temperature and let stand for 24 hours. The resulting precipitate was collected by filtration. A
second crop of material was collected after concentration the mother liquor. The two crops
were combined and crystallized from methanol to give 550 mg (85%) of the product as an oftwhite
solid.
MS (ES): 177 (MH+) for C9H8N2O2
'HNMR(DMSQ-D6) 5 3.83 (s, 3H); 6.76 (d, 1H); 6.91 (dd, 1H); 7.69 (d, III); 7.94 -
8.00 (m,lH); 12.32 (s, 1H).
Intermediate 149: 2-Chloro-7-methoxvquinoxaline
A solution of 4-methoxybenzene-l,2-diamine (16.8 g, 0.12 mmol) in ethanol (250 mL)
was treated with a solution of ethyl oxoacetate (50 wt % in toluene, 50 mL, 0.23 mmol)
dropwise with cooling in an ice bath. The reaction was allowed to warm to room temperature
and after 2 hours, a precipitate was collected by filtration giving 15 g of a brown solid as a 2:1
mixture of 6-methoxyquinoxalin-2(l/^)-one to 7-methoxyquinoxalin-2(l//)-onc. These
isomers were inseparable by TLC. The mixture was suspended in phosphorus oxychloride
(150 mL) and heated to reflux for 1 hour. The reaction was cooled to room temperature and
was quenched on ice. The pH of the mixture was adjusted to pH 8 with solid sodium
carbonate, it was extracted with ethyl acetate, washed with brine, dried over sodium sulfate,
filtered, and concentrated to dryness to give 10.4 g of a crude mixture of 2-chloro-6-
methoxyquinoxaline and the desired 2-chloro-7-methoxyquinoxaline. Chromatography on
silica gel with 5% ethyl acetate in hexanes afforded 0.77 g of the product as a colorless solid.
MS (ES): 195 (MH^ for C9H7C1N20
'HNMRfCDCM 5 3.96 (s, 3H); 7.29 (d, 1H); 7.41 (dd, 1H); 7.97 (d, 1H); 8.63 (s,
1H).
Example 73
6-[({l-[2^7-Methoxy-2-oxoquinoxalin-l(2.H)-yl)ethyl]piperidin-4-
yl}amino)methyl]-2#-pyrido[3,2-&][l,4]oxazin-3(4#)- l-[2-(4-Aminopiperidin-l-yl)ethyl]-7-methoxyquinoxalin-2(l//)-one (Intermediate
146, 60 mg crude, 0.20 mmol), 3-oxo-3,4-dihydro-2//-pyrido[3,2-6][l,4]oxazme-6-
carbaldehyde (WO 2004/058144) (36 mg, 0.20 mmol), and sodium triacetoxy borohydride
(130 mg, 0.60 mmol) were reacted as described according to Example 69 to give the free
base of the product, which was crystallized from dichloromethane/ethyl acetate to give 45 mg
(50%) as a colorless solid.
MS QBS): 465 (MH4) for C24H28N604
8 1.06-1.39 (m, 2H); 1.66-1.87 (m, 2H); 2.04 (t, 2H); 2.33-2.49
(m, 1H); 2.56 (t, 2H); 2.92 (d, 2H); 3.70 (s, 2H); 3.92 (s, 3H); 4.32 (t, 2H); 4.61 (s, 2H); 6.86 -
7.09 (m, 3H); 7.30 (d, 1H); 7.75 (d, 1H); 8.04 (s, 1H); 11.18 (s, 1H).
Example 74
6-[({l-[2-(7-Methoxy-2-oxoquinoxalin-l(2/?)-yI)ethyl]piperidin-4-
yl}amino)methyl]-2flr-pyrido[3,2-A][l,4]thiazin-3(4£0-one
l-[2-(4-Aminopiperidin-l-yl)ethyl]-7-methoxyquinoxalin-2(l/Z)-one (Intermediate
146, 250 mg crude, 0.83 mmol), 3-oxo-3,4-dihydro-2#-pyrido[3,2-Z>][l,4]thiazme-6-
carbaldehyde (WO 2004/058144) (160 mg, 0.83 mmol), and sodium triacetoxy borohydride
(530 mg, 2.50 mmol) were reacted as described according to Example 69. Chromatography
on silica gel with 10% methanol in dichloromethane containing 0.25% ammonium hydroxide
afforded the free base of the product. This was triturated with dichloromethane and the
precipitate was collected by filtration giving 230 mg (58%) of the title compound as a
colorless solid.
MS fBSV 481 (MH+) for C24H28N603S
'HNMRnDMSO-D6> 5 1.27 (s, 2H); 1.69 -1.90 (m, 2H); 2.04 (t, 2H); 2.39-2.48 (m,
1H); 2.56 (t, 2H); 2.93 (d, 2H); 3.53 (s, 2H); 3.75 (s, 2H); 3.92 (s, 3H); 4.33 (t, 2H); 6.91 -
7.05 (m, 2H); 7.10 (d, 1H); 7.67 - 7.83 (m, 2H); 8.04 (s, 1H); 10.88 (s, 1H).
Example 75
l-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-lyl}
ethyl)-6,7-difluoroquinoxaIin-2(l/7)-one
l-[2-(4-Aminopiperidin-l-yl)ethyl]-6,7-difluoroquinoxalm-2(l/i)-one (Intermediate
150,190 mg, 0.62 rnrnol), 2,3-dihydro[l,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO
2004/058144) (100 mg, 0.62 mmol), and sodium triacetoxy borohydride (390 mg, 1.90 mmol)
were reacted as described according to Example 69. Chromatography on silica gel with 10%
methanol in dichloromethane containing 0.25% ammonium hydroxide gave the free base of
the product as an oil. The free base was taken up in dichloromethane (2 mL) and diluted with
diethyl ether (10 mL). A solution of HC1 in diethyl ether (2M, 2.2 eq) was added. The
resulting precipitate was collected by filtration to give 180 mg (55%) of the bis-hydrochloride
salt of the product.
MS (ES): 458 (MH+) for CaH^NjOs
'HNMR(D7CD 5 1.82 - 2.06 (m, 2H); 2.40 (d, 2H); 3.16 (t, 2H); 3.48-3.68 (m, 311);
3.89 (d, 2H); 4.27-4.38 (m, 4H); 4.39-4.49 (m, 2H); 4.63 (t, 2H); 7.15-7.28 (m, 1H); 7.44-7.61
(m, 1H); 7.69-7.85 (m, 1H); 8.10-8.28 (m, 2H).
Intermediate 150: l-r2-f4-Aminopiperidin-l-vl')ethvl]-6.7-difluoroquinoxalin-2(l//)-
one
tert-Eutyl {1 -[2-(6,7-difluoro-2-oxoquinoxalin-1 (2#)-yl)ethyl]piperidin-4-
yl}carbamate (Intermediate 151, 500 mg, 1.23 mmol) was reacted with trifluoroacetic acid in
dichloromethane as described for Intermediate 140 to give 380 mg (quantitative) of the crude
product as an oil.
MS flBS): 309 (MH1) for
Intermediate 151: tert-ButvI (142-('6.7-difluoro-2-oxoquinoxalin-l(2.flV
ynetfayyipip6ridin-4-yUcarbamate
6,7-Difluoroquinoxalin-2(l//)-one (Intermediate 152, 1.0 g, 5.50 mmol) was
deprotonated with sodium hydride (60% in oil, 0.26 g, 6.60 mmol) and alkylated with 2-{4-
[(ter/-butoxycarbonyl)amino]piperidin-l-yl} ethyl methanesulfonate (Intermediate 6) (6.6
mmol) as described for Intermediate 2. Chromatography on silica gel with 5% toluene/ethyl
acetate gave 500 mg (23%) of the product as a colorless solid,
MS (ES): 409 (MH+) for €20^2^03
'HNMRfDMSQ-D6^ 5 1.10-1.45 (m, 11H); 1.54-1.75 (m, 2H); 1.90-2.13 (m, 2H);
2.52-2.59 (m, 2H); 2.86 (d, 2H); 3.16 (s, 1H); 4.28 (t, 2H); 6.75 (d, 1H); 7.81 (dd, 1H); 7.96
(dd, 1H); 8.25 (s, 1H).
Intermediate 152: 6.7-Difluoroquinoxalin-2(l/in-one
To a stirred solution of 4,5-difluorobenzene-l,2-diamine (4.7 g, 32.6 mmol) in ethanol
(75 mL) was added ethyl oxoacetate (50 wt % in toluene, 13,3 mL, 65.3 mmol). The reaction
was stirred at room temperature overnight. The resulting precipitate was collected by
filtration, washed with ethanol, and dried under reduced pressure to give 4.3 g (73%) of the
product as a colorless solid.
MS (ES): 183 (MH+) for CgH4F2N2O
*H NMR (DMSO-D6) 5 7.23 (dd, 1H); 7.93 (dd, 1H); 8.19 (s, 1H); 12.54 (s, 1H).
Example 76
6-[({l-[2-(6,7-Difluoro-2-oxoquinoxalin-l(2iO-yl)ethyl]piperidin-4-
yl}amino)methyl]-2#-pyrido[3,2-i][l,4]oxazin-3(4#)-one
1 -[2-(4-Aminopiperidin- 1 -yl)ethyl]-6 ,7-difluoroquinoxalin-2( 1 //)-one (Intermediate
150, 190 mg, 0.62 mmol), 3-oxo-3,4-dihydro-2//-pyrido[3,2-&][l,4]oxazine-6-carbaldehyde
(WO 2004/058144) (1 10 mg, 0.62 mmol), and sodium triacetoxy borohydride (390 mg, 1.90
mmol) were reacted as described according to Example 69 to give 180 mg (62%) of the free
base of the product as a colorless solid.
MS (ES): 471 (MH*) for CasKWy^Os
5 1.12-1.26 (m, 2H); 1.69-1.83 (m, 2H); 2.01 (t, 2H); 2.42 (s,
1H); 2.53 (t, 2H); 2.88 (d, 2H); 3.69 (s, 2H); 4.29 (t, 2H); 4.60 (s, 2H); 7.01 (d, 1H); 7.30 (d,
1H); 7.82 (dd, 1H); 7.97 (dd, 1H); 8.25 (s, 1H); 11.18 (s, 1H).
Example 77
l-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-clpyridin-7-ylmethyl)amino]piperidin-lyl}
ethyl)-7,8-difluoroquinoxalin-2(l//)-one
l-[2-(4-Aminopiperidin-l-yl)ethyl]-7,8-difluoroquraoxalin-2(l/f)-one (Intermediate
153,130 mg, 0.42 mmol), 2>3-dihydro[l,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO
2004/058144) (70 mg, 0.42 mmol), and sodium triacetoxy borohydride (270 mg, 1.30 mmol)
were reacted as described according to Example 71 to give 35 mg (16%) of the bishydrochloride
salt of the product as a colorless solid.
MS (ESV. 458 (MH+) for CzsHbFaNsOj
'HNMRfD2C» 5 1.89-2.02 (m, 2H); 2.43 (d, 2H); 3.18 (t, 2H); 3.52-3.64 (m, 3H);
3.88 (d, 2H); 4.29-4.34 (m, 4H); 4.38-4.43 (m, 2H); 4.71-4.77 (m, 2H); 7.17 (s, 1H); 7.27 -
7.38 (m, 1H); 7.62-7.69 (m, 1H); 8.15 (s, 2H).
Intermediate 153: l-r2-(4-Aminopiperidin-l-vl')ethvn-7.8-difluoroquinQxalin-2(l/Jr)-
pne
tert-Butyl {1 -[2-(7,8-difluoro-2-oxoquinoxalin-1 (2#)-yl)ethyl]piperidin-4-
yl}carbamate (Intermediate 154, 320 mg, 0.78 mmol) was reacted with trifluoroacetic acid in
dichloromethane as described for Intermediate 140 to give 240 mg (quantitative) of the crude
product as an oil.
MS (ESY. 309 (MH+) for CisHigF^O
Intermediate 154: tert-Butyl ll-r2-(7.8-difluoro-2-oxoquinoxalin-l(2/7V
ynethyl]piperidin-4-yl)carbamate
7,8-Difluoroquinoxalin-2(l.ff)-one (Intermediate 155 - a mixture of regioisomers
containing 30% 5,6-difluoroquinoxalin-2(l//)-one, 1.0 g, 5.50 mmol) was deprotonated with
sodium hydride (60% in oil, 0.26 g, 6.60 mmol) and alkylated with 2-{4-[(tertbutoxycarbonyl)
amino]piperidin-l-yl}ethyl methanesulfonate (Intermediate 6) (6.6 mmol)
as described for Intermediate 2. Chromatography on silica gel with 70-100% ethyl acetate in
hexanes gave 320 mg of the product as a colorless solid.
MS fES): 409 (MH+) for €20*^2^03
'HNMRfDMSO-Dei 5 1.30 (d, 2H); 1.37 (s, 911); 1.64 (d, 2H); 2.07 (t, 2H); 2.59 (t,
2H); 2.81 (d, 2H); 3.20 (s, 1H); 4.36 (t, 2H); 6.76 (d, 1H); 7.48 (td, 1H); 7.72 (ddd, 1H); 8.23
(s, 1H).
Intermediate 155: 7.8-Difluoroquinoxalin-2(l/f)-one
3,4-Difluorobenzene-l,2-diamine (4.6 g, 31.6 mmol) and ethyl oxoacetate (50 wt % in
toluene, 13.0 mL, 63.2 mmol) were reacted as described for Intermediate 152 to give 3.7 g of
product as an off white solid, mixture with 30% of the regioisomer 5,6-difiuoroquinoxalin-
2(l.H)-one. The mixture was carried on to the next step.
MS fES): 183 (MH*)
Example 78
6-[({l-[2-(7,8-Difluoro-2-oxoquinoxalin-l(2J2>yl)ethyl]piperidin-4-
yl}amino)methyl]-2/f-pyrido[3,2-A)[l,4]oxazin-3(4/T)-one
l-[2-(4-Aminopiperidin-l-yl)ethyl]-7,8-difluoroquinoxalin-2(l/f)-one (Intermediate
153, 130 mg, 0.42 mmol), 3-oxo-3,4-dmydro-2#-pyrido[3,2-Z>][l,4]oxazine-6-carbaldehyde
(WO 2004/058144) (70 mg, 0.42 mmol), and sodium triacetoxy borohydride (270 mg, ] .30
mmol) were reacted as described for Example 69 to give 82 mg (41%) of the free base of the
product.
MS CBS): 471 (MH4) for Caal^NeCb
lHNMRfDMSO-Dfl5 1.07-1.22 (m, 2H); 1.69 (d, 2H); 1.98 (t, 2H); 2.35 (s, IH);
2.52 (t, 2H); 2.76 (d, 2H); 3.63 (s, 2H); 4.30 (t, 2H); 4.54 (s, 2H); 6.95 (d, IH); 7.24 (d, IH);
7.35-7.47 (m, IH); 7.61-7.71 (m, IH); 8.17 (s, IH); 11.12 (s, IH).
Example 79
6-[({l-[2-(6,7-Dimethoxy-2-oxoquinoxalin-l(2fl)-yl)ethyl]piperidin-4-
yI}araino)methyl]-2#~pyrido[3,2-&][l,4]oxazin-3(4#)-one
1 -[2-(4-Aminopiperidin- 1 -yl)ethyl]-6,7-dimethoxyquinoxalin-2( l//)-one
(Intermediate 156, 75 mg, 0.23 mmol), 3-oxo-3,4-dihydro-2#-pyrido[3,2-6][l,4]oxazine-6-
carbaldehyde (WO 2004/058144) (40 mg, 0.23 mmol), and sodium triacetoxy borohydride
(150 mg, 0.69 mmol) were reacted as described according to Example 69 to give 78 mg
(68%) of the free base of the product as a colorless solid.
MS (ES): 495 (MH4) for C2sH3oN605
'HNMRfDMSO-D6^ 5 1.06-1.38 (m, 2H); 1.65-1.85 (m, 2H); 1.95-2.13 (m, 2H);
2.29-2.42 (m, IH); 2.51-2.64 (m, 2H); 2.92 (d, 2H); 3.67 (s, 2H); 3.85 (s, 3H); 3.88-4.04 (m,
3H); 4.24-4.45 (m, 2H); 4.52-4.66 (m, 2H); 6.94-7.09 (m, 2H); 7.21-7.37 (m, 2H); 7.98-8.11
(m, 1H);1 1.06 -11.23 (m, IH).
Intermediate 156: l-[2-(4-Aminopiperidin-l-yl)ethvl1-6j-dimethoxvquinoxalintert-
Butyl { I - [2-(6,7-dimethoxy-2-oxoquinoxalin- 1 (2#)-yl)ethyl]piperidin-4-
yljcarbamate (Intermediate 157, 100 mg, 0.23 mmol) was reacted with trifluoroacetic acid in
dichloromethane as described for Intermediate 140 to give 75 mg (quantitative) of the crude
product as an oil.
^: 333 (Mtf) for CnHaMOs
Intermediate 157: tert-Butvl (l-r2-f6.7-dimethoxv-2-oxoquinoxalin-l('2//)-
vl)ethvnpiperidin-4-vU carbamate
6,7-Dimethoxyquinoxalin-2(l/0-°ne (Intermediate 158, 540 mg, 2.60 mmol) was
deprotonated with sodium hydride (60% in oil, 2.90 mmol) and alkylated with 2-{4~[(tertbutoxycarbonyl)
arnino]piperidin-l-yl} ethyl methanesulfonate (Intermediate 6) (3.9 mmol)
as described for Intermediate 2. Chromatography on silica gel with 20-50% acetone in
hexanes gave 310 mg (28%) of the product as an off-white solid.
MS (ES^: 433 (MH1) for Cxfk^Os
'HNMRfDMSO-Dei 8 1.25-1.39 (m, 11H); 1.63 (d, 2H); 1.98 - 2.12 (m, 2H); 2.57 (t,
2H); 2.92 (d, 2H); 3.19 (s, 1H); 3.84 (s, 3H); 3.95 (s, 3H); 4.35 (t, 2H); 6.75 (d, 1H); 7.04 (s,
1H); 7.31 (s, 1H); 8.05 (s, 1H).
Intermediate 158: 6.7-Dimethoxyquinoxalin-2n/fl-one
A mixture of l,2-dimethoxy-4,5-dinitrobenzene (5.7 g, 25.0 mmol) in ethanol/ acetic
acid (140 mL, 1:1) was hydrogenated over palladium on carbon (10%, 1 g) at normal pressure
and room temperature for 3 hours, then filtered through a pad of celite. The filtrate containing
the crude diamine was treated with ethyl oxoacetate (50 wt % in toluene, 10 mL, 50 mmol)
and the reaction was stirred at room temperature overnight. The resulting precipitate was
collected by filtration. This material was suspended in a mixture of methanol/dichloromethane
and solvent was removed under reduced pressure to remove traces of acetic acid to give 2.0 g
(38%) of product as a solid.
MS (ESV. 207 (MH*) for CioHioN2O3
'HNMRfDMSO-D6) 5 3.81-3.83 (m, 3H); 3.83-3.85 (m, 3H); 6.78-6.81 (m, 1H);
7.25-7.27 (m, 1H); 7.97-8.01 (m, 1H); 12.26-12.34 (m, 1H).
Example 80
6-[({l-[2-(7-Methoxy-3-methyl-2-oxoquinoxaIin-l(2fl)-yl)ethyI]piperidin-4-
yl}amino)methyl]-2Jy-pyrido[3,2-*)[l,4]oxazin-3(4/0-one
l-[2-(4-Aminopiperidin-l-yl)ethyl]-7-methoxy-3-methylquinoxalin-2(l//)-°ne
(Intermediate 159, 75 mg, 0.24 mmol), 3-oxo-3,4-dihydro-2fl-pyrido[3,2-&][l,4]oxazine-6-
carbaldehyde (WO 2004/058144) (42 mg, 0.24 mmol), and sodium triacetoxy borohydride
(150 mg, 0.72 mmol) were reacted as described according to Example 69 to give 80 mg (73%
yield) of the free base of the product.
MS fESV 479 (MB1) for QwHjoNeC^
'HNMRrDMSO-D61 5 1.23 (q, 2H); 1.77 (d, 2H); 2.04 (t, 2H); 2.31 - 2.45 (m, 4H);
2.51 - 2.61 (m, 2H); 2.91 (d, 2H); 3.68 (s, 2H); 3.89 (s, 3H); 4.31 (t, 2H); 4.60 (s, 2H); 6.85-
7.10 (m, 3H); 7.29 (d, 1H); 7.59 - 7.73 (m, 1H); 11.17 (s, 1H).
Intermediate 159: l-r2-(4-Aminopiperidin-l-vl)ethvl1-7-methoxv-3-
methylquinoxalin-2(l//)-one
tert-Butyl {l-[2-(7-methoxy-3-methyl-2-oxoquinoxalin-l(2//)-yl)ethyl]piperidin-4-
yl}carbamate (Intermediate 160, 100 mg, 0.24 mmol) was reacted with trifluoroacetic acid in
dichloromethane as described for Intermediate 140 to give 75 mg (99% yield) of the crude
product as an oil.
MS (ES): 317 (MH+) for Ci7H24N402
Intermediate 160: tert-Butvl {l-r2-(7-methoxy-3-methvl-2-oxoquinoxalin-l(2J7)-
yl)ethyl]piperidin-4-yll carbamate
7-Methoxy-3-methylquinoxalin-2(l//)-one (Intermediate 161, 500 mg, 2.60 mmol)
was deprotonated with sodium hydride (60% in oil, 2.90 mmol) and alkylated with 2-{4-
[(/ert-butoxycarbonyl)amino]piperidin-l-yl}ethyl methanesulfonate (Intermediate 6) (3.9
mmol) as described for Intermediate 2. Chromatography on silica gel with 70% ethyl acetate
in hexanes, followed by a second chromatography on silica gel with 20% acetone in hexanes
gave 110 mg (10%) of the product as a colorless solid.
MS (ESY 417 (MH*) for CaEfezN^
'HNMRfDMSO-D6) 8 1.21-1.46 (m, 11H); 1.65 (d, 2H); 2.05 (t, 2H); 2.38 (s, 3H);
2.51-2.59 (m, 2H); 2.92 (d, 2H); 3.18 (s, 1H); 3.90 (s, 3H); 4.31 (t, 2H); 6.77 (d, 1H); 6.91-
7.00 (m, 2H); 7.58-7.73 (m, 1H).
Intermediate 161: 7-Methoxy-3-methvlauinoxalin-2n.fcn-one
A suspension of 3-chloro-6-methoxy-2-methylquinoxaline (Intermediate 162, 1.5 g,
7.21 mmol) in 5M HC1 (30 mL) was heated to 1 10 °C for 1 hour. The reaction mixture was
neutralized with saturated sodium carbonate solution, diluted with water and extracted with
ethyl acetate (3 times). The combined organic phases were dried over magnesium sulfate and
concentrated to a small volume under reduced pressure. The precipitate was collected by
filtration to give 1.0 g (71%) of product as an off-white solid.
MS (ES\. 191 (MH4) for CjoHidNjCfc
'HNMR(DMSO-D6) 8 2.34 (s, 3H); 3.80 (s, 3H); 6.73 (d, 1H); 6.83-6.89 (m, 1H);
7.59 (d,lH); 12.19 (s,lH).
Intermediate 162: 3-Chloro-6-methoxy-2-methvlquinoxaline
A suspension of 4-methoxybenzene-l,2-diamine (5.0 g, 36.2 mmol) in water (100 mL)
was heated under sonication for 5 minutes. 2-Oxopropanoic acid (2.5 mL, 36.2 mmol) was
added and it was stirred for 2 hours. The precipitate was collected by filtration and dried
under vacuum and heating, over phosphorus pentoxide, to give 3.0 g of a mixture of the
product together with 6-methoxy-3-methylquinoxalin-2(l.ff)-one. This mixture was suspended
in phosphorus oxychloride (30 mL) and heated to 1 15 °C for 30 min. The mixture was
quenched on ice and neutralized with solid sodium carbonate. The aqueous mixture was
extracted with ethyl acetate (4 times). The combined organic phases were dried over
magnesium sulfate, filtered, and concentrated to dryness under reduced pressure.
Chromatography on silica gel with 5% ethyl acetate in hexanes and isolation of the higher
migrating regioisomer gave 0.9 g of product as an off-white solid.
MS (BSV 209 (MH+) for Ci0H9ClN20
'HNMRfDMSO-Det 8 2.71 (s, 3H); 3.93 (s, 3H); 7.39 (d, 1H); 7.49 (dd, 1H); 7.95
Example 81
l.(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridm-7-ylmethyl)amino]piperidin-lyl}
ethyl)qumolin-2(lfl)-°ne
l-[2-(4-Aminopiperidin-l-yl)ethyl]quinolin-2(l#)-one (Intermediate 1.63, 170 mg
crude, 0.63 mmol), 2,3-dihydro[l,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO
2004/058144) (100 mg, 0.63 mmol), and sodium triacetoxy borohydride (400 mg, 1.90 mmol)
were reacted as described according to Example 69 to give the free base of the product as an
oil. The free base was taken up in dichloromethane (2 mL) and ethanol (8 mL) and treated
with a solution of 4M HCl/dioxane (2 eq). The resulting precipitate was collected by filtration
to give 188 mg (60%) of the bis-hydrochloride salt of the product as a colorless solid.
MS (ES\ 421 (MHT1) for QwHjMOs
6 1.86 - 2.06 (m, 2H); 2.36 - 2.54 (m, 2H); 3.06 - 3.27 (m, 2H); 3.46 -
3.70 (m, 3H); 3.89 (d, 2H); 4.29 - 4.42 (m, 4H); 4.42 - 4.53 (m, 2H); 4.65 - 4.70 (m, 2H);
6.66 (d, 1H); 7.29 (s, 1H); 7.34 (t, 1H); 7.47 (d, 1H); 7.59 - 7.78 (m, 2H); 7.95 (d, 1H); 8.22
(s, 1H).
Intermediate 163 : 1 -r2-(4-Aminopiperidin- 1 -yr)ethvl]quinolin-2( IfD-one
To a solution of tert-butyl {l-[2-(2-oxoquinolin-l(2#)-yl)ethyl]piperidin-4-
yl}carbamate (Intermediate 164, 220 mg, 0.59 mmol) in dioxanc (5 mL) was added a
solution of HC1 in dioxane (4M, 9 mL), followed by water (1 mL) and it was stirred at room
temperature over night. An addition 5 mL of HCl/dioxane was added to the reaction. After 1
hr, the reaction was concentrated to dryness. The crude product was partitioned between 10%
methanol/dichloromethane (50 mL) and 1M sodium hydroxide (50 mL). The aqueous phase
was back extracted with 10% methanol/dichloromethane (50 mL) and the combined organic
phases were washed with brine, dried over sodium sulfate and concentrated under reduced
pressure to give 170 mg (quantitative) of the crude product as an oil.
MS (ES\. 212 (MH+) for Ci6H2iN30
Intermediate 164: tert-Butvl n-r2-(2-oxoquinolin-l(2ffl-vl)ethvl1piperidin-4-
vDcarbamate
Quinolin-2(l/:/)-one (250 mg, 1.7 mmol) was deprotonated with sodium hydride (60%
in oil, 70 mg, 1.7 mmol) and alkylated with 2-{4-[(/er/-butoxycarbonyl)amino]piperidin-lyl}
ethyl methanesulfonate (Intermediate 6) (1.7 mmol) as described for Intermediate 141.
Chromatography on silica gel with 0-5% methanol in dichloromethane gave 220 mg (35%) of
product as a colorless solid.
MS (ESI: 372 (MH*) for C2,H29N3O3
Example 82
l-(2-{4-[(2,3-Daiydro[l,4]dioxinoI2,3-c]pyridin-7-ylmethyl)amino]piperidin-lyI}
ethyl)qiiinolin-4(lH)-one
l-[2-(4-Aminopiperidin-l-yl)ethyl]quinolin-4(l//)-one (Intermediate 165,180 mg
crude, 0.66 mmol), 2,3-dihydro[l,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO
2004/058144) (110 mg, 0.66 mmol), and sodium triacetoxy borohydride (420 mg, 2.0 mmol)
were reacted as described according to Example 81 to give the bis-hydrochloride salt of the
product 53 mg (16%) as a colorless solid.
MS fESV 421 (Mtf) for CwKMtyOa
'HNMR(D2C» 5 1.90-2.13 (m, 2H); 2.44 (d, 2H); 3.22 (t, 2H); 3.58-3.70 (m, 3H);
3.77 (d, 2H); 4.33-4.40 (m, 2H); 4.42 (s, 2H); 4.46 - 4.53 (m, 2H); 4.75-4.86 (m, 2H); 6.47 (d,
1H); 7.36 (s, 1H); 7.51 (t, 1H); 7.68 (d, 1H); 7.77-7.89 (m, 1H); 8.11-8.21 (m, 2H); 8.25 (s,
1H).
Intermediate 165: l-r2-(4-Aminopiperidin-l-yl')ethyl]quinolin-4(']//)-one
ter/-Butyl (l-[2-(4-oxoquinolin-l(4//)-yl)ethyl]piperidin-4-yl}carbamate
(Intermediate 166,480 mg crude, 1.29 mmol) was reacted with 4M HCl/dioxane in dioxane
as described for Intermediate 163 to give 180 mg (51%) of the crude product as an oil.
MS (ES^ 272 (MH4) for Ci6H2iN30
Intermediate 166: tert-Butvl (l-|'2-('4-oxoquinolin-l(4^D-vl')ethyl]piperidin-4-
vncarbamate
Quinolin-4(l//)-one (250 mg, 1.7 mmol) was deprotonated with sodium hydride (60%
in oil, 70 mg, 1.7 mmol) and alkylated with 2-{4-[(tert-butoxycarbonyl)amino]piperidin-] -
yl} ethyl methanesulfonate (Intermediate 6) (1.7 mmol) as described for Intermediate 141.
The precipitate formed in the reaction mixture was collected by filtration to give 480 mg (76
%) of product as a colorless solid.
MS (ESV. 372 (MH+) for
Example 83
Cis(±)6-[({l-[2-(5,7-difluoro-2-oxoquinoUn-l(2fl)-yOethyl]-3-methoxypiperidin-4-
yl} amino)methyl]-2//-pyrido [3,2-6] [1,4] oxazin-3(4J?)-one
Cis(±)l-[2-(4-amino-3-methoxypiperidin-l-yl)ethyl]-5,7-difluorocluinoIin-2(l//)-one
(Intermediate 167, 140 mg, 0.42 mmol), 3-oxo-3,4-dihydro-2/;/'-pyrido[3J2-i][l,4]oxazine-6-
carbaldehyde (WO 2004/058144) (75 mg, 0.42 mmol) and sodium triacetoxy borohydride
(250 mg, 1.20 mmol) were reacted as described according to Example 69. Chromatography
on silica gel with 5% methanol in dichloromethane containing 0.50% ammonium hydroxide
gave 120 mg (57%) of the free base of the product.
MS test: 500 (MH+) for CwIfcvFjNjOA
'HNMRfCDCl^ 5 1.66-1.87 (m, 2H); 2.22-2.44 (m, 2H); 2.55-2.83 (m, 3H); 2.93 (d,
1H); 3.14 (d, 1H); 3.34-3.45 (m, 3H); 3.47-3.56 (m, 1H); 3.80 - 3.86 (m, 2H); 4.25-4.49 (m,
2H); 4.63 (s, 2H); 6.65 (d, 1H); 6.67-6.77 (m, 1H); 6.99 (t, 2H); 7.21 (d, 1H); 7.88 (d, 1H).
Intermediate 167: Cisf±')l-r2-('4-amino-3-methoxvpiperidin-l-vl')ethvl1-5.7-
difluoroquinolin-2f l//Vone
Cis(±)l-{2-[4-(dibenzylamino)-3-methoxypiperidin-l-yl]ethyl}-5,7-difluoroquinolin-
2(l/i)-one (Intermediate 168, 240 mg, 0.46 mmol) was hydrogenated in methanol/
acetonitrile (10 mL, 9:1) over palladium hydroxide on carbon (20%, 120 mg) at room
temperature and normal pressure for 4 hours. The reaction mixture was filtered through celite
and the filtrate was concentrated to dryness under reduced pressure to give 140 mg (90%) of
crude product. This was used without further purification.
MS (ES): 338 (MH+) for
Intermediate 168: Cis(±M-(2-r4-rdibenzvlamino)-3-methoxvpiperidin-l-vHethvU-
5.7-difluoroquinolin-2nJ:f)-one
A solution of 5,7-difluoroquinolin-2(l#)-one (Intermediate 25, 300 mg, 1.70 mmol)
in dry DMF (10 mL) was treated with sodium hydride (60% in oil, 80 mg, 2.00 mmol) with
cooling in an ice bath. The reaction was stirred at room temperature for 90 min. The reaction
was again cooled in an ice bath and treated with a solution of cis(±)2-[4-(dibenzylamino)-3-
methoxypiperidin-l-yl]ethyl methanesulfonate in dry DMF (10 mL) (Intermediate 169, 1.2
eq, 2.00 mmol). The reaction was stirred at room temperature overnight. It was quenched with
a small amount of water and concentrated to dryness. Residual DMF was removed by coIk*
evaporating with toluene and the residue was partitioned between ethyl acetate (50 mL) and
water (20 mL). The biphasic mixture was filtered, the phases separated and the aqueous phase
was back extracted two times with ethyl acetate (2x 50 mL). The combined organic phases
were dried over magnesium sulfate, filtered, and concentrated to dryness. Chromatography on
silica gel with a gradient of 10-20% acetone in hexanes gave 240 mg (27%) of product as a
colorless solid.
MS (ESV 518 (MH4) for CaiH^NsOa
'HNMRfDMSO-Det 8 1.49-1.60 (m, 1H); 1.70-1.84 (m, 1H); 1.92-2.06 (m, 2H);
2.37-2.47 (m, 2H); 2.99-3.12 (m, 1H); 3.16-3.22 (m, 1H); 3.25 (s, 3H); 3.30-3.40 (m, 1H);
3.56 (s, 1H); 3.59-3.86 (m, 4H); 4.28 (t, 2H); 6.62 (d, 1H); 7.15-7.24 (m, 3H); 7.24-7.41 (m,
9H);7.96(d,lH).
Intermediate 169: Cis^2-r4-fdibenzvlammoV3-methoxvDroeridiri- 1-vllethvl
methanesulfonate
Cis(±)2-[4-(dibenzylamino)-3-methoxypiperidni-l-yl]ethanol (Intermediate 170, 740
mg, 2.1 mmol) was reacted with methanesulfonyl chloride (0.20 mL, 2.5 mmol) in the
presence of triethylamine (0.41 mL, 2.9 mmol) as described for Intermediate 6. The crude
product was presumed to be unstable and was used without further purification directly for the
next step.
Intermediate 170: Cis(±^2-r4-fdibenzvlaminoV3-memoxvpiperidin-l-vllethanol
A mixture of cis(±)^V-diben2yl-3-methoxypiperidin-4-amine (1.7 g, 5.5 mmol) (WO
2005/068461), bromoethanol (0.5 mL, 7.1 mmol), and//^/-diisopropylethylamine (1.4 mL,
8.3 mmol) were reacted as described for Intermediate 37, but heating for one hour at 70°C.
Chromatography on silica gel with 5% methanol in dichloromethane containing 0.25%
ammonium hydroxide gave 1.3 g (68%) of product as a colorless solid.
MS fESV 355 (NOT1) for CaHsoNjOz
>HNMRfDMSO-D6>> 8 1.44 -1.58 (m, 1H); 1.64 (d, 1H); 1.79 - 2.08 (m, 2H); 2.32 (t,
2H); 2.36 - 2.45 (m, 1H); 2.88 (d, 1H); 3.13 (d, 1H); 3.30 (s, 3H); 3.40 - 3.49 (m, 2H); 3.56 (s,
1H); 3.59 - 3.87 (m, 4H); 4.34 (s, 1H); 7.11 - 7.24 (m, 2H); 7.24 - 7.40 (m, 8H)
Example 84
7-Fluoro-2-oxo-l-[2-(4-{[(3-oxo-3,4-dihydro-2^-pyrido[3,2-6][l,4]oxazin-6-
yl)raethylJamino}piperidin-l-yl)ethyl]-l,2-dihydroquinoline-5-carbonitrile
and
Example 85
5-Fluoro-2-oxo-l-[2-(4-{[(3-oxo-3,4-dihydro-2^-pyrido[3,2-/;][l,4]oxazin-6-
yl)tnethyl]amino}piperidin-l-yl)ethyl]-l,2-dihydroquinolinc-7-carbonitrile
A mixture of the regioisomers l-[2-(4-aminopipcridin-l-yl)ethyl]-7-fluoro-2-oxo-l,2-
dihydroquinoline-5-carbonitrile (major isomer) and l-[2-(4-aminopiperidin-l-yl)ethyl]-5-
fluoro-2-oxo-l,2-dihydroquinoline-7-carbonitrile (minor isomer) (Intermediates 171 and
172,120 mg, 0.38 mmol), 3-oxo-3,4-dihydro-2#-pyrido[3,2-6][l,4]oxazine-6-carbaldehyde
(WO 2004/058144) (68 mg, 0.38 mmol) and sodium triacetoxy borohydride (230 mg, 1.1
mmol) were reacted as described according to Example 69. Chromatography on silica gel
with 10% methanol in dichloromethane containing 0.5% ammonium hydroxide followed by
reverse phase HPLC on a 50x250 mm ODS AQ column eluting with an isocratic gradient of
15% acetonitrile in water containing 0.1% TFA to give the bis TFA salts of Example 84 (68
mg) and Example 85 (21 mg), both as colorless solids.
Example 84:
MS CBS): 477 (MH*) for Cas^sFNeOa
'H NMR (DMSO-D6) 8 1.09 - 1.27 (m, 2H); 1.67 - 1.83 (m, 2H); 2.00 (t, 2H); 2.31 -
2.44 (m, IH); 2.51 - 2.55 (m, 2H); 2.87 (d, 2H); 3.67 (s, 2H); 4.33 (t, 2H); 4.53 - 4.64 (m,
2H); 6.81 (d, IH); 7.00 (d, IH); 7.28 (d, IH); 7.78 - 7.92 (m, 211); 7.98 (d, III); 11.16 (s, IH).
Example 85:
MS CES): 477 (MH*) for CijHjsFNeOs
'HNMRfDMSO-De) 8 1.12 - 1.30 (m, 2H); 1.69 - 1.83 (m, 2H); 1.95 - 2.10 (m, 2H);
2.33 - 2.46 (m, IH); 2.51 - 2.57 (m, 2H); 2.89 (d, 2H); 3.68 (s, 2H); 4.31 - 4.43 (m, 2H); 4,57
- 4.64 (m, 2H); 6.84 (d, IH); 7.01 (d, III); 7.29 (d, IH); 7.70 (d, IH); 7.99 (s, 111); 8.06 (d,
1.17(s, IH).
Intermediate 171: 1 -r2-(4-Aminopiperidin-1 -vr)ethvn-7-fluoro-2-oxo-1,2-
dihvdroquinoline-5-carbonitrile (major isomer)
and
Intermediate 172: l-[2-f4-Aminopiperidin-l-vnethyl]-5-fluoro-2-oxo-1.2-
dihvdroquinoline-7-carbonitriIe
A mixture of tert-butyl {l-[2-(5-cyano-7-fluoro-2-oxoquinolin-l(2#)-
yl)ethyl]piperidin-4-yl}carbaraate and tert-butyl {l-[2-(7-cyano-5-fluoro-2-oxoquinolinl(
2#)-yl)ethyl]piperidin-4-yl} carbamate (Intermediates 173 and 174, 170 mg, 0.41 mmol)
was reacted with trifluoroacetic acid in dichloromethane as described for Intermediate 140 to
give 120 mg (92% yield) of the mixture of regioisomers as an oil. This mixture was carried on
without further purification to the next step.
MS (ES): 315 (MH+) for Ci7Hi9FN40
Intermediate 173: tert-Butvl ll-r2-(5-cvano-7-fluoro-2-oxoquinolin-l(2fflvl)
ethyl]piperidin-4-yl} carbamate
and
Intermediate 174: tert-Butyl (l-r2-(7-cyano-5-fluoro-2-oxoquinolip-l('2/-/)-
vl)ethyl]piperidin-4-vncarbamate
A mixture of tert-butyl {l-[2-(5-bromo-7-fluoro-2-oxoquinolin-l(2//)-
yl)ethyl]piperidin-4-yl}carbamate and tert-buty\ {l-[2-(7-bromo-5-fluoro-2-oxoquinolinl(
2/i)-yi)ethyl]piperidin-4-yl}carbamate (Intermediates 175 and 176, 460 mg, 0.98 mmol)
was reacted with potassium cyanide (96 mg, 1.5 mmol), tributyl tin chloride (14 uL/mL in
heptane, 0.90 jiL, 0.003 mmol), 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene
(XANTPHOS) (3.0 mg, 0.005 mmol) and tris(dibenzylideneacetone)dipalladium (0) (5.0 mg,
0.005 mmol) as described for Intermediate 15. Chromatography on silica gel with acetone/
hexanes (1:4) gave 170 mg of the mixture of regioisomers. This mixture was carried on
directly to the next step.
MS CBS): 415 (MH+) for
Intermediate 175: tert-Butvl n-[2-C5-bromo-7-fluoro-2-oxoquinplin-l(2/f)-
yl)ethyl]piperidin-4-yl)carbamate
and
Intermediate 176: tert-Butvl IH2-f7-bromo-5-fluoro-2-oxoquinolin-l(2f/);
yl)ethyl1piperidin-4-vl)carbamate
A mixture of 5-bromo-7-fluoroquinolin-2(l.f/)-one and 7-bromo-5-fluoroquinolin-
2(l//)-one (Intermediate 177 and 178, 3.0 g, 9.4 mmol) was reacted with sodium hydride
(60% in oil, 0.20 g, 5.0 mmol) and 2-{4-[(/erC-butoxycarbonyl)amino]piperidin-l-yl}ethyl
methanesulfonate (Intermediate 6, 9.4 mmol) as described for Intermediate 141.
Chromatography on silica gel with a gradient of 50-75% ethyl acetate in hexanes gave 0.63 g
(33%) of the regioisomeric product mixture, which was carried on without further purification
to the next step.
MS (ES\. 468, 470 (MET) for
Intermediate 177: 5-Bromo-7-fluoroquinolin-2(l/f)-one
and
Intermediate 178: 7-Bromo-5-fluoroquinolin-2(l//)-one
The compounds were prepared from (2£)-AL(3-bromo-5-fluorophenyl)-3-
phenylacrylamide (Intermediate 179, 3.0 g, 9.4 mmol) and aluminium trichloride (6.2 g, 46.9
mmol) as described for Intermediate 17, but the reaction mixture was heated to 90 °C for 30
min, to give 1.5 g of 3:1 mixture of 5-Bromo-7-fluoroquinolin-2(l//)-onc and 7-bromo-5-
fluoroquinolin-2(l/:/)-one. This mixture was carried on to the next step without further
purification.
MS (RS): 242, 244 (MH1) for C9H5BrFNO
Intermediate 179: (2£r)-JV-(3-Bromo-5-fluorophenyn-3-phenvlacrvlamide
The compound was prepared from 3-bromo-5-fluoroaniline (Intermediate 180, 5.3 g,
27.9 mmol) and cinnamoylchloride (5.6 g, 33.5 mmol) in the presence of 2,6-lutidine (5.0 mL,
41 .9 mmol) as described for Intermediate 18 to give the product as a colorless solid, 7.6 g
(85% yield).
MS (BS): 320, 322 (MH+) for CuHnBrFNO
'HNMRfDMSO-Pe) 56.77 (d, 1H); 7.18 - 7.30 (m, Hi); 7.40 - 7.52 (m, 3H); 7.55 -
7.70 (m, 4H); 7.75 (s, 1H); 10.56 (s, 1H).
Intermediate 180: 3-Bromo-S-fluoroaniline
To a solution of Af-(3-bromo-5-fluorophenyl)acetamide (Intermediate 181, 8.7 g, 37.4
mmol) in ethanol (30 mL) was added concentrated hydrochloric acid (80 mL). The reaction
was heated to 100 °C for 1 hr. It was cooled to room temperature and neutralized with 5N
sodium hydroxide. The crude product was extracted with ethyl acetate (2x 100 mL), the
combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and
concentrated to dryness. Chromatography on silica gel with a gradient of 5-10% ethyl acetate
in hexanes gave 5.3 g (75%) of the product as a yellow oil.
MS (ESI: 190, 192 (MH+) for C6H5BrFN
'H NMR (DMSO-D615 5.46 - 6.00 (m, 2H); 6.24 - 6.37 (m, 1H); 6.44 - 6.53 (m, III);
6.54 - 6.61 (m, 1H).
Intermediate 181: Af-C3-Bromo-5-fluoroprienyl)acetarnidc
A mixture of acetamide (2.8 g, 47.2 mmol), palladium acetate (0.50 g, 0.80 mmol),
XANTPHOS (0.68 g, 1.2 mmol) and cesium carbonate (18 g, 55.2 mmol) was degassed and
purged with nitrogen twice. Dry dioxane (50 mL) was added followed by l,3-dibromo-5-
fluorobenzene (10 g, 39.4 mmol). The reaction was heated to 105 °C overnight and then
allowed to cool to room temperature. Dichloromethane was added and the mixture was stirred
vigorously for 1 hr. The mixture was filtered. The filtrate was concentrated to dryness.
Chromatography on silica gel with 25% ethyl acetate in hexanes gave 4.0 g (44%) of the
product as a colorless solid.
MS (ESV. 232, 234 (Mil1') for C8H7BrFNO
1HNMR(T)MSO-D6) 8 2.01 - 2.13 (m, 311); 7.13 - 7.24 (m, 111); 7.42 - 7.54 (m, I I I ) ;
7.57 - 7.67 (m, 1H); 10.22 - 10.35 (m, 1H).
Example 86
7-Fluoro-l-[2-(4-{[(2-oxo-l,2-dihydroquinolin-3-yI)methyI]amino}piperidin-lyl)
ethyl] quinoxalin-2(l//)-one
A mixture of l-[2-(4-aminopiperidin-l-yl)ethyl]-7-fluoroqinnoxalin-2(ljy)-onc
(Intermediate 140, 130 mg, 0.448 mmol), 2-oxo-l,2-dihydroquinolinc-3-carbaldehyde (65
mg, 0.448 mmol) and 3A molecular sieves (100 mg) in methanol (6.0mL) was heated at
reflux for 2.5 hours under nitrogen atmosphere. It was cooled to 0°C and sodium triacctoxy
borohydride (189.5 mg, 0.996 mmol) was added and the mixture was allowed to warm to
room temperature and stirred overnight. The mixture was filtered and purified through silica
gel plug (eluting with 15% methanol in methylene chloride) to give title compound (71 mg).
MS fES); 448.52 (MH*) for C25H26FN5O2
'HNMRrDMSO-D6) 5 1.13 -1.32 (m, 2H); 1.79 (d, 2H); 2.02 (t, 2H); 2.35 - 2.45 (m,
IH); 2.52 - 2.59 (m, 2H); 2.90 (d, 2H); 3.61 (s, 2H); 4.27 (t, 2H); 7.15 (t, IH); 7.24 - 7.33 (m,
2H); 7.43 (t, IH); 7.51 (d, IH); 7.63 (d, IH); 7.79 - 7.92 (m, 2H); 8.17 (s, IH).
Examples 87-96
The following compounds were synthesized following the procedure described for
Example 86, except the compounds were purified by reverse phase HPLC with methanol/
water, containing 0.1% TFA to give the TFA salts of the final products.
Ex
87
88
Compound
l-[2-(4-{[(2,2-Dimethyl-
3,4-dihydro-2#-
chromen-6-yl)methyl]
amino}piperidin-lyl)
ethyl]-5,7-difluoro
quinolin-2(l//)-one
l-[2-(4-{[(l,3-Dimethyl-
2-oxo-2,3 -dihydro- 1 Hbenzimidazol-
5-yl)
methyl]amino}piperidinl-
yl)ethyl]-5,7-
difluoroquinolin-2(l H)-
one
'H NMR (DMSO-D6) 8 ppm
1. 27 (s,6H); 1.64-1. 89 (m,4H);
2.21 - 2.39 (m, 2H); 2.73 (t, 2H);
2.95 - 3.18 (m, 2H); 3.80 (s, 2H);
4.08 (s, 2H); 4.53 (s, 211); 6.67 (d,
IH); 6.76 (d,lH); 7.19 (d, IH);
7.24 (s, IH); 7.31 (t, IH); 7.43 (d,
IH); 8.03 (d, IH); 9.02 (s, 2H);
9.75 (s, IH)
1. 80 (s,2H); 2.34 (s,2H); 3.01 -
3.18 (m,2H); 3.45 (s, 6H); 3.80
(s, 2H); 4.24 (s, 2H); 4.53 (s, 2H);
6.67 (d, 1 H); 7.22 (s,2H); 7.25-
7.36 (m, 2H); 7.43 (d, IH); 8.03
(d, lH);9.18(s, 2H)
ES
482
(MH)+
482
(MII)+
Aldehyde
2,2-dimethyl
chromane-6-
carbaldehyde
1,3-dirnethyl-
2-oxo-2,3-
dihydro-lf/-
benzirnidazolc;
-5-
carbaldchydc
Ex
89
90
91
92
Compound
5,7-Difluoro-l-(2~{4-
[(5,6,7,8-tetrahydronaphthalen-
2-ylmethyl)
amino]piperidin- 1 -yl}
ethyl)quinolin-2( 1 H)-onc
5,7-Difluoro-l-[2-(4-
{[(6-fluoro-4//-l,3-
benzodioxin-8-yl)methyl]
amino} piperidin- 1 -yl)
ethyl]quinolin-2(l//)-one
5,7-Difluoro-l-(2-{4-
[(l/Wndol-6-yImethyl)
amino]piperidin- 1 -
yl} ethyl)quinolin-2( 1 H)-
one
l-(2-{4-[(2,3-Dihydro-
17/-inden-5-ylmethyl)
amino]piperidin-l -
yl}etb.yl)-5,7-
difluoroquinolin-2( 1 //)-
one
'H NMR (DMSO-D6) 5 ppm
1. 72 (s,4H); 1.77-1. 92 (m, 2H);
2.32 (s, 2H); 2.71 (s, 4H); 3.09 (s,
2H); 3.58 (s, 2H); 3.79 (s, 2H);
4.12 (s, 2H); 4.54 (s, 2H); 6.66 (d,
lH);7.07-7.14(ra, IH); 7.20 (s,
2H); 7.30 (t, IH); 7.43 (d, IH);
8.02 (d, IH); 9.23 (s, 2H)
1.84 (d, 2H); 2.33 (s, 2H); 3.09 (s,
2H); 3.29 - 3.44 (m, 2H); 3.80 (s,
2H);4.16(s,2H);4.54(s, 2H);
4.91 (s, 2H); 5.32 (s, 2H); 6.66 (d,
IH); 7.01- 7.14 (m, 1H);7.19-
7.34 (m,2H); 7.43 (d,lH); 8.01
(d, IH); 9.35 (s, 2H)
1.85 (d, 2H); 2.35 (s, 2H); 3.09 (s,
2H);3.31 (s, 2H); 3.80 (s, 2H);
4.30 (s, 2H); 4.54 (s, 2H); 6.45 (s,
HI); 6.66 (d, III); 7.13 (d, IH);
7.29 (t, IH); 7.42 (s, 2H); 7.50 -
7.68 (m,2H); 8.0 1 (d, IH); 9.22
(s,2H); 11.39(s, III)
1.73 - 1.89 (m, 2H); 1.94-2.09
(m, 211); 2.22 - 2.41 (m, 2H); 2.86
(t, 4H); 3.28 (s,2H); 3.43 -3.54
(m, 2H); 3.78 (s, 211); 4.16 (s,
2H); 4.53 (s, 2H); 6.67 (d, IH);
7.20-7.31(111, 311); 7.37 (s, Hi);
7.42 (d, IH); 8.02 (d, IH); 9.15 (s,
2H)
ES
452
(MH)+
474
(MH)+
437
(MH)+
438
(Mil)'
Aldehyde
5,6,7,8-
tetrahydronaphthalene-
2-
carbaldehydc
6-fluoro-4//-
1,3-
benzoclioxine-
8-
carbaldehyde
l//-indolc-6-
carbaldehydc
iI
indane-5-
carbaldehyde
4 $-3
Ex
93
94
95
96
Compound
5,7-Difluoro-l-[2-(4-
{[(1-methyl- 1/7-1,2,3-
benzotriazol-5-yl)methyl]
amino} piped din- 1-
yl)ethyl]quinolin-2(l//)-
one
5,7-Difluoro-l-(2-{4-
[(ljy-indol-5-ylmethyl)
amino]piperidin-lyl}
ethyl)quinolin-2(l//)-
one
5,7-Difluoro-l-[2-(4-
{ [(4-methyl-3 ,4-dihydro-
2H-1 ,4-benzoxazin-7-yl)
methyl]amino} piperidinl-
yl)ethyl]quinolin-
2(l//)-one
l-(2-{4-[(2,l,3-
Benzoxadiazol-5-
ylraethyl)amino]
piperidin- 1 -yl} ethy l)-7-
fluoroquinoxalin-2 ( 1 II)-
one
1H NMR (DMSO-D6) 8 ppm
1. 72-1. 95 (m,2H); 2.35 (s,2H);
2.99- 3.18 (m, 211); 3.31 (s, 2H);
3.79 (s, 2H); 4.32 (s, 3H); 4.41 (s,
2H); 4.54 (s, 2H); 6.66 (d, IH);
7.29 (t, IH); 7.42 (d, IH); 7.69 (d,
IH); 7.94 (d,!H); 8.02 (d, IH);
8.23 (s, IH); 9.43 (s, 2H)
1.80(s,2H);2.36(s,2H);3.11 (s,
2H); 3.40 (s, 2H); 3.80 (s, 2H);
4.26 (s, 2H); 4.52 (s, 2H); 6.47 (s,
IH); 6.67 (d, IH); 7.21 (d, IH);
7.3 l(t,!H); 7.37- 7.52 (m,3H);
7.70 (s, IH); 8.03 (d, IH); 9.04 (s,
IH NMR (DMSO-D6) 8 ppm 1 .73
(s, 2H); 2.30 (s, 211); 2.83 (s, 3H);
2.97-3.15(m,2H);3.24(s,2H);
3.30 - 3.38 (m, 2H); 3.79 (s, 2H);
4.03 (s, 2H); 4.22 (s, 2H); 4.53 (s,
2H); 6.63 - 6.75 (m, 211); 6.85 (s,
IH); 6.90 (d, IH); 7.31 (t, IH);
7.43 (d, IH); 8.04 (d, IH); 8.90 (s,
IH)
1.13-1.29(m,2H); 1.78(d,2H);
1. 95 - 2.07 (m,2H); 2.3 1-2.43
(m, IH); 2.51- 2.58 (m,2H); 2.89
(d, 2H); 3.82 (s, 2H); 4.27 (t; 2H);
7.23 (td, 1 H); 7.5 1 (dd, IH); 7.58
(d, IH); 7.80 - 7.89 (m, 2H); 7.96
(d, 1H);8.18(S,1H)
ES
453
(MH)+
437
(MH)+
469
(MH)H
423
(MH)+
Aldehyde
1 -methyl- IH-
1,2,3-
benzotriazolc-
5-
carbaldehyde
l/f-indole-5-
carbaldehyde
4-methy 1-3,4-
dihydro-2//-
1,4-
ben/oxazine-
7-
carbaldehydc
2,1,3-
bcnzoxadiaxol
e-5-
carbaldehydc
Example 97
1 ,4-bcnzodioxine-6-sulfonamide
To a solution of l-[2-(4-aminopiperidin-l-yl)ethyl]-7-fluoroquinoxalin-2(I//)-one
(Intermediate 140, 130 mg, 0.448 ramol) in rnethylene chloride (10 mL) was added
diisopropylethylamine (0.156 mL, 0.996 ramol) and 2,3-dihydro-l,4-benzodioxine-6-sulfonyl
chloride (1 16 mg, 0.493 mmol) and the reaction was stirred for 2.5 hours at room temperature.
It was washed with saturated sodium bicarbonate solution and brine, dried over sodium
sulfate, and concentrated. The residue was dissolved in HC1 in dioxane (4M, 8.0 mL),
concentrated, suspended in ethyl acetate and filtered to give the HC1 salt of title compound
(15.9 rag).
MS (ESV 489 (MH+) for QaHfoF^OsS
'H NMR (DMSO-D61 8 1.62 - 1.83 (m, 3H); 2.92 - 3.11 (m, 211); 3.16 - 3.28 (m, 3H);
3.41 - 3.50 (m, 3H); 3.59 (d, 2H); 4.47 - 4.59 (m, 2H); 7.05 (d, 1H); 7.23 - 7.34 (m, 2H); 7.78
(dd, 1H); 7.83 - 7.96 (m, 2H); 8.15 - 8.23 (m, 1H); 10.61 (s, 1H).
Example 98
A'-{l-[2-(7-FIuoro-2-oxoquinoxaIin-l(2//)-y))ethyl]pipcridin-4-yl}-3-oxo-3,4-
dihydro-2//-l,4-ben/oxazinc-6~sulfonamide
l-[2-(4-Aminopiperidin-l-yl)ethyl]-7-fluoroquinoxalin-2(l//)-onc (Intermediate 140,
130 mg, 0.448 mmol) was reacted as described for Example 97 with 3-oxo-3,4-dihydro-2/fl,
4-benzoxazine-6-sulfonyl chloride (122 mg, 0.493 mmol) to give the HC1 salt of title
compound (89 mg).
MS fESV 502 (Mil") for C23H24FN505S
'H NMR (DMSO-D6) 8 1.55 - 1.93 (m, 3I-T); 2.94 - 3.09 (m, 2H); 3.17 - 3.30 (m, 211);
3.50 (d, 1H); 3.61 (d, 2H); 4.53 (d, 211); 4.69 (s, 2H); 7.12 (d, Hi); 7.28 (t, 1H); 7.32 - 7.42
(m, 2H); 7.73 (d, 1H); 7.83 - 7.95 (m, 1H); 8.02 (d, 1H); 8.20 (s, 1H); 10.14 (s, III); 1 1.04 (s,
1H).
Example 99
5-FIuoro-A'-{l-[2-(7-fluoro-2-oxoquinoxaIin-l(2J:0-yl)ethyI]pipcridin-4-yl}-l//-
indoIe-2-carboxamide
A mixture of l-[2-(4-aminopiperidin-l-yl)ethyl]-7-fluoroquinoxalin-2(l//)-one
(Intermediate 140, 130 mg, 0.448 mmol), 5-fluoro-l//-indole-2-carboxylic acid (96.3 mg,
0.538 mmol), AK3-Dimethylaminopropyl)-7V'-ethylcarbodiimide (EDC)(124mg, 0.645 mmol)
and 1-Hydroxybenzotriazole hydrate (HOBT) (87mg, 0.645 mmol) in dichloromethane/ DMF
(4:1, 10 mL) was stirred for 2.5 hours at room temperature. The solvent was removed under
reduced pressure and the residue was suspended in methanol, stirred for 45 minutes and then
filtered to give title compound (161 mg).
MS (ES): 452 (MH+) for €24*^2^02
'HNMR fDMSO-Dei 5 1. 78 - 2.15 (m, 4H); 3.10 - 3.29 (m, 2H); 3.57 (s, 1H); 3.75
(d, 2H); 4.07 (s, 1H); 4.61 (s, 2H); 6.95 - 7.10 (m, 1H); 7.19 (s, 1H); 7.23 - 7.34 (m, 1H); 7.39
(d, 2H); 7.75 - 7.88 (m, 1H); 7.88-7.98 (m, 1H); 8.23 (s, 1H); 8.67 (d, 1H); 10.44 (s, 111);
11.74(8, 1H).
Example 100
4-ylnicotinamide
l-[2-(4-Aminopiperidin-l-yl)ethyl]-5,7-difluoroquino]in-2(lf/)-one (Intermediate 23,
100 mg, 0.326 mmol) was reacted as described for Example 99 with 6-morpholin-4-
ylnicotinic acid (81mg, 0.391mmol), EDC (94 mg, 0.489 mmol) and IIOBT (66 mg, 0.489
mmol) to give title compound (43.6 mg).
MS (ESV 498 (MH*) for QasHWFiiNsOa
6 1.81 - 2.12 (m, 5H); 3.09 - 3.24 (m, 2H); 3.46 - 3.60 (in, 4H);
3.62 - 3.78 (m, 6H); 3.97 - 4.18 (m, 1H); 4.63 (s, 2H); 6.67 (d, 1H); 6.85 (d, 1H); 7.30 (t, 1H);
7.74 (d, 1H); 7.93 - 8.07 (m, 2H); 8.37 (d, 1H); 8.63 (s, 1H); 10.66 (s, 1H).
Example 101
A^-{l-[2-(5,7-Difluoro-2-oxoquinolin-l(2//)-yl)ethyl]piperidin-4-yl}-2,3-dihydro-
1 ,4-benzodioxine-2-carhoxamide
l-[2-(4-Aminopiperidin-l-yl)ethyl]-5,7-difluoroquinolui-2(l//)-one (Intermediate 23,
100 mg, 0.326 mmol) was reacted as described for Example 99 with 2,3-dihydro-l,4-
benzodioxine-2-carboxylic acid (71 mg, 0.391 mmol), EDC (94 mg, 0.489 mmol) and HOBT
(66 mg, 0.489 mmol) to give title compound (73.9 mg).
MS (ES^: 470 (MH+) for CzsHzsFaNsCU
1HNMR(T)MSO-D6>) 8 1.71 - 2.05 (m, 4H); 3.06 - 3.21 (m, 2H); 3.22 - 3.29 (m, 2H);
3.67 (s, 1H); 3.80 - 4.03 (m, 1H); 4.17 (dd, 1H); 4.31 - 4.45 (m, 1H); 4.51 - 4.67 (m, 211);
4.70 - 4.79 (m, 1H); 6.58 - 6.73 (m, 1H); 6.85 (d, 2H); 6.92 - 7.02 (m, 1H); 7.30 (t, 1H); 7.65
(d, 1H); 8.03 (d, 1H); 8.41 (d, 1H); 10.19 (s, 1H).
Example 102
Ar-{l-[2-(5,7-Difluoro-2-oxoquinolin-l(2JH)-yl)ethyl]piperidin-4-yI}-l-methyI-1//-
l,2,3-benzotriazole-5-carboxamide
l-[2-(4-Aminopiperidin-l-yl)ethyl]-5,7-difluoroqumolin-2(l//)-one (Intermediate 23,
100 mg, 0.326 mmol) was reacted as described for Example 99 with 1-methyl-l//-l,2,3-
benzotriazole-5-carboxylic acid (70 mg, 0.391mmol), EDC (94 mg, 0.489 mmol) and HOBT
(66 mg, 0.489 mol) to give title compound (67.6 mg).
MS QBS): 467 (MH+) for CaiEWWiCfe
'HNMR(DMSO-D6^ 5 1.86 - 2.03 (m, 2H); 2.07 (s, 2H); 3.12 - 3.25 (m, 2H); 3.42 -
3.61 (m, 1H); 3.73 (d, 2H); 4.09 (s, 1H); 4.33 (s, 3H); 4.64 (t, 2H); 6.68 (d, 1H); 7.30 (t, 1H);
7.73 (d, 1H); 7.92 (d, 1H); 8.05 (t, 2H); 8.61 (s, 1H); 8.76 (d, 1H); 10.60 (s, III).
Example 103
jV-{l-[2-(5,7-Difluoro-2-oxoquinolin-I(2//)-yI)cthyI]piperidin-4-yI}-3-(2-inethyll,
3-thiazol-4-yl)benzamide
l-[2-(4-Aminopiperidin-l-yl)ethyl]-5,7-difluoroquinolin-2(l//)-one (Intermediate 23,
100 mg, 0.326 mmol) was reacted as described for Example 99 with 3-(2-methyl-l,3-thiazol-
4-yl)benzoic acid (86 mg, 0.391 mmol), EDC (94 mg, 0.489 mmol) and HOBT (66 mg, 0.489
mmol). Solvent removed and the obtained solids were stirred in HCl/dioxane (8.0 mL, 4M)
and then filtered to give the HC1 salt of title compound (39 mg).
MS (ES): 509 (MH+) for C27H26F2N4O2S
'HNMRfDMSQ-De) 6 1.91 - 2.17 (m, 4H); 2.73 (s, 3H); 3.10 - 3.39 (m, 3H); 3.50 (s,
1H); 3.71 (d, 2H); 4.64 (s, 2H); 6.68 (d, 1H); 7.30 (t, III); 7.51 (t, 1H); 7.72 - 7.89 (m, 2H);
7.98 - 8.13 (m, 3H); 8.42 (s, 1H); 8.73 (d, 1H); 10.85 (s, 1H).
Example 104
^-{l-[2-(5,7-Difluoro-2-oxoquinoIin-l(2/7)-yl)ethyl]pipcridin-4-y]}-4-(5-methyll,
2,4-oxadiazol-3-yI)benzamide
1 -[2-(4-Aminopiperidin- 1 -yl)ethyl]-5,7-difluoroquinolin-2( l//)-one (Intermediate 23 ,
100 mg, 0.326 ramol) was reacted as described for Example 99 with 4-(5-methyl- 1,2,4-
oxadiazol-3-yl)benzoic acid (80 mg, 0.391 mmol), EDC (94 mg, 0.489 mmol) and HOBT (66
mg, 0.489 mmol). Solvent removed and the obtained solids were suspended in ethyl acetate
and then filtered to give title compound (71,9 mg).
MS CBS): 494 (MH*) for CaOfc^NsOa
5 1.77 - 1.97 (m, 2H); 1.98 - 2.15 (m, 2H); 2.68 (s, 3H); 3.10 -
3.27 (m, 2H); 3.75 (d, 2I-I); 4.05 (s, 1H); 4.60 (t, 2H); 6.69 (d, 1H); 7.32 (t, 1H); 7.46 - 7.68
(m, 1H); 7.96 - 8.15 (m, 5H); 8.72 (d, 1H); 9.86 (s, 1H).
Example 105
3-Oxo-4-[2-((2JR,51S)-5-{[(3-oxo-3,4-dihydro-2flr-pyrido[3,2-6][l,4]oxazin-6-
yl)methyl]amino}piperidin-2-yl)ethyl]-3,4-dihydro-21T-l,4-benzoxa/ine-6-carbonitrilc
To a solution of fer/-butyl (2^,5iS)-2-[2-(6-cyano-3-oxo-2,3-dihydro-4#-l,4-
benzoxazin-4-yl)ethyl] -5 - { [(3 -oxo-3 ,4-dihydro-2W-pyrido[3 ,2-b] [ 1 ,4] ox azin-6-
yl)methyl]amino}piperidine-l-carboxylate (Intermediate 182, 0.138 g) in dioxane (2 mL)
was added 4M HCl/dioxane (1 mL). After 1 hour at room temperature, the reaction was
concentrated and evaporated twice from methanol. The solid was suspended in methanol and
filtered to yield 73 mg of the name compound as a bis HC1 salt.
MS (BSI) 463 (MTI+) for Ca^eNeC^
1.58 - 1.63 (m, 1H); 1.65 - 1.74 (m, HI); 1.75 - 1.86 (m, 1H);
1.92 - 2.03 (m, 1H); 2.13 - 2.23 (m, 1H); 2.29-2.38 (m, 1H); 3.02 - 3.14 (m, 1H); 3.14 - 3.24
(m, 3H); 3.59 - 3.70 (m, 1H); 3.70 - 3.78 (m, 1H); 4.01 - 4.13 (m, 211); 4.1 8 - 4.28 (m, 211);
4.70 (s, 2H); 4.82 (s, 2H); 7.19 (d, 1H); 7.26 (d, 1H); 7.46 (d, 1H); 7.54 (dd, 1H); 7.77 (d,
1H); 9.51 (s, 1H); 9.70 (s, 1H); 9.82 (s, 1H); 11.36 (s, 1H).
Intermediate 182: tert-Butvl C2/;.5^-2-[2-C6-cvano-3-oxo-2.3-dihvdro-4//-1.4-
benzoxazin-4-vl')ethyn-5-ir('3-oxo-3.4-dibvdro-2//-pvrido[3.2-6][1.4]oxazin-6-
vl)methyl]amino)piperidine-l-carboxylate
A mixture of tert-butyl (2^,55)-5-amino-2-[2-(6-cyano-3-oxo-2)3-dihydro-4/f-l,4-
benzoxazin-4-yl)ethyl]piperidine-l-carboxylate (Intermediate 183, 0.14 g), 3-oxo-3,4-
dihydro-2#-pyrido[3,2-Z>][l,4]oxazine-6-carbaldehyde (WO 2004/058144) (75 mg) and 3 A
molecular sieves powder (70 mg) in methanol (8 mL) was heated at 80 °C for 1 hour. The
solution was cooled to 0°C and NaCNBHa (33 mg) was added. After stirring at room
temperature overnight, the reaction was filtered and concentrated. The residue was purified
chromatography on silica gel with a gradient of 0-5% methanol in methylene chloride to give
0.14 g.
MS fESD 563 (MH+) for CwH^NsC^
'HNMRf CDC1Q8 1.37 -1.43 (m. 1H): 1.44-1.51 (s, 9H);1.70- 1.81 (m,2H);2.11
(m, 1H); 2.89 - 3.00 (m, 1H); 3.01 - 3.12 (m, 1H); 3.94 - 4.05 (m, 1H); 4.20 - 4.32 (m, 1H);
4.33 - 4.44 (m, 1H); 4.64 (s, 2H); 4.67 (s, 2H); 6.99 (d, 1H); 7.04 (d, 1H); 7.17 - 7.24 (m, 211);
7.32 (dd, 1H).
Intermediate 183: /erf-Butyl (2&5SV5-ammo-2-[2-(6-cyano-3-oxo-23-dihydro-4/'-/'-
1,4-benzoxazin-4-yl)ethynpiperidine-1 -carboxylate
tert-Butyl(2/?,55)-5-azido-2-[2-(6-cyano-3-oxo-2,3-dihydro-4//-l,4-hen7.oxazin-4-
yl)ethyl]piperidine-l-carboxylate (Intermediate 184, 0.31 g) was hydrogenated in methano]
(10 mL) over 10% Pd/C (90 mg) at normal pressure and room temperature overnight. The
reaction was degassed, filtered and purified by chromatography on silica gel with a gradient
of 0-10% methanol in methylene chloride to give 0.29 g.
MS (ESI) 401 (Mil*) for CjiIfcgN^
Intermediate 184: tert-Butvl f2&5SV5-azido-2-f2-f6-cvano-3-oxo-2.3-dihydro-4#-
1.4-benzoxazin-4-yl)ethyl]piperidine-1 -carboxylate
To a solution of ter/-butyl (2#,57?)-2-[2-(6-cyano-3-oxo-2,3-dihydro-4//-l,4-
benzoxazin-4-yl)ethyl]-5-hydroxypiperidine-l-carboxylate (Intermediate 185, crude, 0.8 g)
in THF (20 mL) were successively added triphenylphosphine (1.30 g),
diisopropylazodicarboxylate (1 mL) and diphenyl phosphoryl azide (0.90 g). After 4 hours,
the reaction was diluted with ethyl acetate, washed with saturated solution of sodium
hydrogen carbonate (NaHCOs) and brine, dried over sodium sulfate and concentrated.
Chromatography on silica gel with a gradient of 0-5% methanol in methylene chloride gave
0.31 g of product.
MS (ESTi 427 (MH4) for
Intermediate 185: fert-Butyl (2^5#)-2-[2-(6-cvano-3-oxo-2.3-dihvdro-4#-1.4-
benzoxazin-4-ynethyl1-5-hvdroxvpiperidine- 1 -carboxylate
To a solution of tert-butyl (2^,5/?)-5-{[/er?-butyl(dimethyl)silyl]oxy}-2-[2-(6-cyano-
3-oxo-2,3-dihydro-4//-l,4-benzoxazin-4-yl)ethyl]piperidine-l-carboxylate (Intermediate
186, 1.01 g) in THF (10 mL) was added tetrabutylammonium fluoride (TBAF) (4 mL). After
5 hours, the reaction was diluted with ethyl acetate, washed with NaHCOa and brine, dried
over sodium sulfate and concentrated. The crude reaction mixture was used without further
purification in the next step.
MS (ESP 402 (MH+) for C2iH27N3O5
Intermediate 186: tert-Butyl (2&5^)-5-{[te;^butyl(;dimethvlXsilyl]oxY}-2-f2-(6-
cyano-3-oxo-2.3-dihydro-4//- 1 .4-benzoxazin-4-ynethyl]piperidine- 1 -carboxylate
To a solution of tert-butyl (2/?,5^)-5-{[/er/-butyl(dimethyl)silyl]oxy}-2-(2-
hydroxyethyl)piperidine-l -carboxylate (Intermediate 187, 1.27 g) in methylene chloride (15
mL) at 0 °C were added diisopropylethylamine (1.2 mL) and methanesulfonyl chloride (0.50
mL). At the same time in a separate flask, to a solution of3-oxo-3,4-dihydro-2/7-l ,4-
benzoxazine-6-carbonitrile (Intermediate 60) (0.66 g) in DMF (8 mL) at 0 °C was added
60% suspension in oil of NaH (0.25 g). After 30 minutes, the mesylate solution was diluted
with methylene chloride, washed with NaHCOa and brine, dried over sodium sulfate and
concentrated. This residue was dissolved in DMF (5 mL) and added to the sodium salt of
Intermediate 60. The reaction was stirred over the weekend, diluted with ethyl acetate,
washed with NaHCCb and brine, dried over sodium sulfate and concentrated to give the
product.
MS (ESP 516 (MH1) for
Intermediate 187: /ert-Butvl (2/;.5^V5-(rfer/-butvl(dimethvl)silvl]oxyl-2-(2-
hydroxvethyDpiperidine- 1 -carboxylate
To a solution of tert-bnlyl (lR,5^)-5-{[ier/-butyl(dimethyl)silyl]oxy}-2-
vinylpiperidine-1 -carboxylate (Intermediate 188, 1.39 g) in THF (20 mL) at 0 °C was added
9-BBN (0.5 M, 15 mL). After 45 minutes, the reaction was diluted with water (3 mL), 3 N
NaOH (12 mL) and 30% H^Oa (12 mL). After 15 minutes, the reaction was allowed to warm
to room temperature. After 30 minutes, the reaction was diluted with ethyl acetate, washed
with 1 N HC1, NaHCOa and brine, dried (NazSO,)), filtered and concentrated.
Chromatography on silica gel with a gradient of 0-5% methanol in methylene chloride gave
1. 27 g of product.
MS fESn 360 (MH4) for
Intermediate 188: ferf-Butyl(2J?.5/?)-S-{[ vinvlpiperidine- 1 -carboxylate
To a suspension of /.inc dust (12.2 g) in THF (200 mL) and diiodomethane (5 mL) at 0
°C was added trimethyl aluminium (2M in hexanes, 6 mL). After the addition the reaction was
carefully warmed to room temperature (exothermic reaction!). The reaction was then cooled
with an ice bath and a solution of tert-buiyl (2/Z,5/Z)-5-{[/er/-butyl(dimethyl)silyl]oxy}-2-
formylpiperidine-1 -carboxylate (Intermediate 189, 6.84 g) in THF (40 mL) was added. After
6 hours it was warmed to room temperature, the reaction was diluted with ethyl acetate and
slowly quenched with a saturated aqueous solution of NaHCOs. The organic phase was
collected and washed with NaHCOs and brine, dried (NajSO^, filtered and concentrated.
Chromatography on silica gel with a gradient of 0-100% methylene chloride in hexanes gave
3.96 g of product.
MS (ESP 341 (MH+) for QgHssNOaSi
'HNMRfCDCIO 5 0.06 (s, 6H); 0.87 (s, 911); 1.42 - 1.44 (m, 1H); 1.44 (s, 9H); 1 .63 -
1.81 (m, 2H); 2.44 - 2.73 (m, 1H); 3.43 - 3.63 (m, 1H); 3.77 - 4.16 (m, 1H); 4.50 - 4.92 (m,
1H); 4.97 - 5.13 (m, III); 5.13 - 5.26 (m, 1H); 5.58 - 5.84 (m, 1H).
Intermediate 189: ter/-Butyl f2/?.SJ?)-S-{[ter/-butylfdimethvl)silyl]oxy}-2-
formylpiperidine- 1 -carboxylate
To a solution of oxalyl chloride (2.4 mL) in methylene chloride (75 mL) at -78 °C
was slowly added dimethylsulfoxide (3 mL) in methylene chloride (25 mL). After 10 minutes,
a solution of tert-butyl (2/?,5-R)-5-{[tert-butyl(dimethyl)silyl]oxy}-2-
(hydroxymethyl)piperidine-l-carboxylate (Intermediate 190, 7.60 g) in methylene chloride
(40 mL) was slowly added. After 30 minutes at -78 °C, diisopropylethylamine (10 mL) was
added and the reaction warmed to room temperature. The reaction was diluted with ethyl
acetate, washed with 0.5 M HC1, NaHCOa and brine solutions, dried QS^SCU), filtered and
concentrated. Chromatography on silica gel with a gradient of 0-30% ethyl acetate in hexanes
gave 6.84 g of product.
MS (ESP 344 (MH+) for
Intermediate 190: /er/-ButyU2J?.5^)-5-([/erf-butvlfdimethyl)silvl1oxvl-2-
( hydroxymethvDpiperidine- 1 -carboxvlate
To a solution of 1-re/Y-butyl 2-ethyl (2R,5R)-5-{[tertbutyl(
dimethyl)silyl]oxy}piperidine-l,2-dicarboxylate (Intermediate 191, 9.99 g) in THF
(100 mL) was added lithium aluminium hydride (1M in THF, 30 mL). After 2 hours, the
reaction was quenched with ethyl acetate, washed with 1 N HC1, NaHCC-3 and brine solutions,
dried (NaaSC^), filtered and concentrated yielding 7.9 g of product.
MS (ESP 346 (MH4) for Ci7H3sNO4Si
Intermediate 191: 1-tert-Butvl 2-ethvl (2R.5K\-5-Utertbutyl(
dimethvl)silvl]oxylpiperidine-1.2-dicarboxylate
To a solution of l-/ert-butyl 2-ethyl (2fl)-5-oxopiperidine-l ,2-dicarboxylate (8.8 g)
(Bioorganic & Medicinal Chemistry Letters (2002), 12(1 0), 1387-1390) in mcthanol (200
mL) at 0 °C was added sodium borohydride (1.80 g). After 2 hours, the reaction was
concentrated to dryness. The residue was dissolved in ethyl acetate and washed with 1 N HC1,
NaHCOa and brine solutions, dried (Na2SO4), filtered and concentrated. The crude alcohol
was dissolved in DMF (200 mL) and tread with imidazole (7.5 g) and t-BDMSCl (1 1.5 g).
After stirring overnight at room temperature, the reaction was diluted with ethyl acetate and
washed with 1 N HC1, NaHCOs and brine solutions, dried (Na2SO4), filtered and
concentrated. Chromatography on silica gel with a gradient of 0-25% ethyl acetate in hexanes
gave 9.99 g of product.
MS (ESP 388 (MH*) for Ci^NOsSi
IHNMRfCDCIO 8 (rotamers) 0.06 (m, 6H); 0.86 & 0.87 (s, 9H); 1 .22 - 1 .30 (rn, 3H);
1.42 & 1.46 (s, 9H); 1.61 - 1.73 (m, 1H); 1.77 - 1.91 (m, 1H); 2.18 - 2.31 (m, 1H); 2.58 &
2,69 (dd, 1H); 3.42 - 3.62 (m, 1H); 3.97 & 4.13 (dd, 1H); 4.14 - 4.25 (m, 2H); 4.60 & 4.81 (d,
1H).
Example 106
yl)methyl]amino}piperidin-2-yl)ethyl]-3,4-dihydro-2//-l,4-benzoxazine-6-carbonitriIc
The title compound was prepared following the procedure described for Example 105,
except, starting from l-tert-butyl 2-methyl (25)-5-oxopiperidine-l,2-dicarboxylate
(Bioorganic & Medicinal Chemistry Letters (2002), 12(10), 1387-1390).
MS (BSD 463 (MH4) for C24H26N6O4
'H NMR (DMSO-D61 S 1.58 - 1.63 (m, 1H); 1.65 - 1.74 (m, 1H); 1.75 - 1.86 (m, 1H);
1.92 - 2.03 (m, 1H); 2.13 - 2.23 (m, 1H); 2.29 - 2.38 (m, 1H); 3.02 - 3.14 (m, 1H); 3.14 - 3.24
(m, 3H); 3.59 - 3.70 (m, 1H); 3.70 - 3.78 (m, 1H); 4.01 - 4.13 (m, 2H); 4.18 - 4.28 (m, 2H);
4.70 (s, 2H); 4.82 (s, 2H); 7.19 (d, 1H); 7.26 (d, III); 7.46 (d, 1H); 7.54 (dd, 1H); 7.77 (d,
III); 9.51 (s, 1H); 9.70 (s, 1H); 9.82 (s, 1H); 1 1.36 (s, III).
Example 107
6-[({l-[2-(5,7-Difluoro-2-oxoquinoxalin-l(2//)-yl)ethyl]pipcridin-4-
yl}amino)methyl]-2//-pyrldo[3,2-A][l,4Joxa/in-3(4//)-onc
To a solution of l-[2-(4-minopiperidin-l-yl)ethyl]-5,7-diiluoroqumoxalin-2(l//)-one
(Intermediate 192, 0.158 g) in methanol (10 mL) were added 3 A molecular sieve power
(0.15 g) and 3-oxo-3,4-dihydro-2#-pyrido[3,2-&][l,4]oxazine-6-carbaldchyde (WO
2004/058144) (92 mg). After 2 hours at reflux, the reaction was cooled to 0°C and
NaBH(OAc)3 (0.19 g) was added. The reaction was allowed to warm to room temperature and
was stirred overnight. It was diluted with ethyl acetate, filtered, washed with saturated
solutions of NaaCOa and brine, dried over sodium sulfate and concentrated. Chromatography
on silica gel with 0-20% methanol in dichloromethane. Fractions containing product were
collected, concentrated, dissolved in a minimum of CPIzCk, precipitated with diethyl ether,
and filtered to yield 104 mg of product.
MS (ESI) 471 (MH*) for Czal^NfA
'H NMR (CDCM 6 1.15 - 1.35 (m, 2H); 1.73 - 1.88 (m, 2H); 1.93 - 2.09 (m, 2H); 2.51
- 2.58 (m, 2H); 2.83 - 2.95 (m, 2H); 3.16 (d, 1H); 3.71 - 3.84 (m, 1H); 4.21 - 4.34 (m, 2H);
4.61 (s, 2H); 7.02 (d, 1H); 7.26 - 7.48 (m, 1H); 8.19 (s, IE),
Intermediate 192: l-f2-('4-Aminopiperidin-l-vl')ethvl]-5.7-difluoroquinoxalin-2(l^none
To a solution of tert-butyl {l-[2-(5,7-difluoro-2-oxoquinoxalin-l(2/i)-
yl)ethyl]piperidin-4-yl}carbamate (Intermediate 193, 0.21 g) in dioxane (3 mL) and water (1
mL) was added 4 M HCl in dioxane (1 mL). After 30 minutes, additional 4 M HCl/dioxane (3
mL) was added. After 1 hour, the reaction was diluted with chloroform and poured into a
saturated solution of Na2CC>3. The organic solution was collected, dried (Na2S04), filtered and
concentrated yielding 0.158 g of crude titled compound,
MS ("BSD 309 (MH4) for Ci5Hi8F2N40
Intermediates 193: tert-Butyl (l-[2-f5,7-difluoro-2-gxoquinoxalin-l(2//)-
vl)ethyl]piperidin-4-yUcarbamate
and
Intermediate 194: tert-Butyl n-[2-(6,8-difluoro-2-oxoquinoxalin-U2/JV
vnethyl]piperidin-4-yl}carbamate
A mixture of 5,7-difluoroquinoxalin-2(l//)-one and 6,8-difluoroquinoxalin-2(l//)-one
(Intermediate 195) (1.05 g, 5.77 mmol) was deprotonated with sodium hydride (0.31 g, 60%
in oil, 7.75 mmol) and alkylated with 2-{4-f(?er/'-butoxycarbonyl)amino]piperidin-l-yl} ethyl
methanesulfonate (Intermediate 6) (5.8 mmol) as described for Intermediate 2. The residue
obtained after aqueous workup was titurated in diethyl ether and filtered yielding 0.73 g of
/e/V-butyl {1 -[2-(5,7-difluoro-2-oxoquinoxalin-1 (2#)-yl)ethyl]piperidin-4-yl}carbamate
(Intermediate 193). The filtrate was concentrated and the residue was purified by
chromatography on silica gel with 0-20% acetone in dichloromethanc to yield 111 mg of tertbutyl
{1 -[2-(6,8-difluoro-2-oxoquinoxalin-1 (2#)-yl)ethyl]piperidin-4-yl}carbamate
(Intermediate 194).
Intermediate 193:
MS (BSD 409 (Mir) for CrolfeeFMOs
'HNMRfCDCIO 5 1.33 -1.42 (m, 2H); 1.44 (s, 9H); 1.89 -1.97 (m, 2H); 2.24 (td,
2H); 2.65 (t, 2H); 2.84 - 2.89 (m, 2H); 3.41 - 3.52 (m, III); 4.27 (t, 2H); 4.41 (s, Hi); 6.87 (td,
1H); 6.93 (dt, 1H); 8.23 (s, 1H).
Intermediate 194:
MS (ESI) 409 (MH4)
'HNMRfCDCM 8 1.31 -1.42 (m, 211); 1.44 (s, 9H); 1.86 -1.96 (m, 2H); 2.23 (td,
2H); 2.67 (t, 2H); 2.84 - 2.91 (m, 2H); 3.39 - 3.51 (m, 1H); 4.34 - 4.45 (m, 1H); 4.46 - 4.53
(m, 2H); 7.13 (ddd, 1H); 7.36 - 7.44 (m, 1H); 8.30 (s, 1H).
Intermediate 195; 5.7-Difluoroquinoxalin-2(l#Vone and 6.8-difluoroquinoxaliii-
To a solution of l,2-diamino-3,5-difluorobenzene (5.11 g) in methanol (100 mL) was
added ethylglyoxalate (16 mL). After 6 hours at room temperature, the precipitate was
collected by filtration and washed with methanol yielding 2.1 g products, 1:1 mixture of 5,7-
difluoroquinoxalin-2(l//)-oneand6,8-difluoroquinoxalin-2(l/f)-one.
MS (ESP 182 (MH+) for C8H4F2N2O
Example 108
6-[({l-I2-(6,8-Difluoro-2-oxoquinoxalin-l(2//)-yl)ethyl]piperidin-4-
yl}amino)methyl]-2flr-pyrido[3,2-6] [1,4] oxazin-3(4/J)-one
l-[2-(4-Aminopiperidin-l-yl)ethyl]-6,8-difluoroquinoxalin-2(l//)-one (Intermediate
196, 52 mg) was reacted with 3-oxo-3,4-dihydro-2//-pyrido[3,2-k][l,4]oxazine-6-
carbaldehyde (WO 2004/058144) and sodium acetoxyborohydride as described for Example
107 yielding 29 mg of the title compound.
MS (ESP 471 (MH+) for C23H24F2N6O3
'HNMR(DMSQ-D6) 8 1.16 -1.28 (m, 2H); 1.71 - 1.82 (m, 2H); 2.04 (t, 2H); 2.35 -
2.47 (m, 2H); 2.54 - 2.61 (m, 2H); 2.81 - 2.90 (m, 2H); 3.70 (s, 2H); 4.32 - 4.42 (m, 211); 4.61
(s, 2H); 7.02 (d, 1H); 7.30 (d, 1H); 7.61 (d, III); 7.72 (ddd, 1H); 8.33 (s, III); 11.17 (s, III).
Intermediate 196: 1 -[2-(4-Aminopiperidin-1 -yl)e1hyl1-6.8-difluoroquinoxajfa-20ff)-.
one
ter/-Butyl {1 -[2-(6,8-difluoro-2-oxoquinoxalin-l (2//)-yl)ethyljpiperidin-4-
yljcarbamate
(Intermediate 194) was deprotected with HC1 in dioxane as described for
Intermediate 192.
MS (ESP 309 (MH+) for CUH18F2N4O
Example 109
2-Oxo-l-[2-(4-{[(3-oxo-3,4-dihydro-2flr-pyrido[3,2-6][l,4]oxa/in-6-
yl)methyl]amino}piperidin-l-yl)ethyl]-l,2-dihydroquinoxaline-6-carbonitriIc
1 -[2-(4-Aminopiperidin~1 -yl)etliyl]-2-oxo-1,2-dihydroquinoxaline-6-carbcmitrile
(Intermediate 197,0.125 g) was reacted with 3-oxo-3,4-dihydro-2#-pyrido[3,2-
6][l,4]oxazine-6-carbaldehyde (WO 2004/058144) (0.17 g) and NaBH(OAc)3 (0.27 g) as
described for Example 107. The residue was purified by reverse phase HPLC with
acetonitrile in water containing 0.1% TFA. Fractions containing product were concentrated to
remove acetonitrile, neutralized with NaaCOj solid, extracted with ethyl acetate, dried
(NajSO^, filtered and concentrated. The residue was suspended in diethyl ether and filtered to
yield 127 mg of a colorless solid.
MS fESD 460 (MH+) for C24H25N703
'HNMRfDMSO-.D6) 5 1.14 - 1.25 (m, 2H); 1.70 - 1.80 (m, 211); 1.96 - 2.07 (m, 2H);
2.33 - 2.43 (m, IH); 2.51 - 2.57 (m, 2H); 2.87 (d, 2H); 3.67 (s, 2H); 4.33 (t, 2H); 4.61 (s, 2H);
7.01 (d, IH); 7.30 (d, III); 7.79 (d, IH); 8.05 (dd, IH); 8.36 (d, 211); 11.16 (s, III).
Intermediate 197: l-[2-(4-Aminopiperidin-l-yl)ethyn-2-oxQ-1,2-djhydroquinoxaline-
6-carbonitrile
To a solution of /e;-/-butyl {l-[2-(6-cyano-2-oxoquinoxalin-l(27/)-yl)ethyl]pipcridin-
4-yl}carbamate (Intermediate 198, 0.38 g) in methylene chloride (4 mL) was added at 0°C
TFA (2 mL). After 1 hour, the reaction was diluted with chloroform, washed with saturated
solution of NajCOs, dried (Na2SO4), filtered and concentrated yielding 0.25 g of crude
product.
MS (ESI) 298 (MH+) for C,6Hi9N50
Intermediate 198: tert-Butyl {1 -[2-(6-cvano-2-oxoquinoxalin-1 (211)-
ynethyIjpiperidin-4-yl} carbamate
and
Intermediate 199: te/-/-Butyl {l-r2-(7-cyano-2-oxoquinoxalin-V(2fflyl)
ethyl]piperidin-4-yl) carbamate
A mixture of 2-oxo-l,2-dihydroquinoxaline-6-carbonitrile and 3-oxo-3,4-
dihydroquinoxaline-6-carbonitrile (Intermediate 200, 0.83 g, 4.8 mmol) was deprotonatcd
with sodium hydride (0.30 g, 60% in oil) and alkylated with 2-{4-[(tertbutoxycarbonyl)
amino]piperidin-l-yl}ethyl methanesulfonate (Intermediate 6) (4.8 inmol)
as described for Intermediate 2. Chromatography on silica gel with 0-25% acetone in
dichloromethane gave 38 mg of tert-butyl {l-[2-(7-cyano-2-oxoquinoxalin-l(2//)-
yl)ethyl]piperidin-4-yl}carbamate (Intermediate 199) and 0.39 g of te/7-butyl {l-[2-(6-
cyano-2-oxoquinoxalin-l(2//)-yl)ethyl]piperidin-4-yl}carbarnate (Intermediate 198).
MS (ESP 398 (MH+) for C2iH27N5O3
Intermediate 198:
'HNMR(CDCIV) 8 1.31 -1.41 (m, 2H); 1.44 (s, 9H); 1.88 - 1.98 (m, 2H); 2.19 - 2.29
(m, 2H); 2.67 (t, 2H); 2.83 - 2.93 (m, 2H); 3.41 - 3.52 (m, 1H); 4.35 (t, 2H); 4.43 (m, HI);
7.48 (d, 1H); 7.80 (dd, 1H); 8.20 (d, 1H); 8.35 (s, III).
Intermediate 199:
'HNMRfCDC1061.32 - 1.42 (m, 2H); 1.44 (s, 9H); 1.89 - 1.97 (m, 2H); 2.19 - 2.30
(m, 2H); 2.68 (t, 2H); 2.83 - 2.93 (m, 2H); 3.42 - 3.53 (m, 1H); 4.33 (t, 211); 4.42 (s, 1H); 7.59
(dd, 1H); 7.79 (s, 1H); 7.97 (d, 1H); 8.37 (s, 1H).
Intermediate 200: 2-Oxo-1.2-dihvdroquinoxalinc-6-carbonitrile and 3-oxo-3.4-
dihvdroquinoxaline- 6-carbonitrile
To a solution of 3,4-diaminobenzonitrile (0.99 g) in methanol (20 mL) was added
ethylglyoxalate (3.5 mL). After stirring overnight at room temperature, the precipitate was
collected and washed with methanol. The filtrate was concentrated to give a second crop of
product yielding 0.83 g from both batches, 1:1 mixture of 2-oxo-l,2-dihydroquinoxaline~6-
carbonitrile and 3-oxo-3,4-dihydroquinoxaline-6-carbonitrile as a brown solid.
MS (ESP 172 (MH1) for C9H5N30
Example 110
3-Oxo-4-[2-(4-{[(3-oxo-3,4-dihydro-2#-pyrido[3,2-6][l,4]oxazin-6-
yl)methyl]amino}piperidin-l-yl)ethyl]-3,4-dihydroquinoxaline-6-carbonitrilc
1 -[2-(4-Aminopiperidin-l -yl)ethyl]-2-oxo-1,2-dihydroquinoxaline-7-carbonitrile
(Intermediate 201, O.llg) was reacted with 3-oxo-3,4-dihydro-2/:/-pyrido[3,2-
6][l,4]oxazine-6-carbaldehyde (WO 2004/058144) and sodium acetoxyborohydride as
described for Example 107 yielding 17 mg of a colorless solid.
MS (ESP 460 (MH+) for
1HNMR(DMSQ-D6U 1.22 -1.33 (m, 2H); 1.80 -1.91 (m, 2H); 1.98 - 2.08 (m, 2H);
2.55 - 2.67 (m, 3H); 2.90 - 3.01 (m, 2H); 3.79 - 3.90 (m, 1H); 4.35 (t, 2H); 4.64 (s, 2H); 7.05
(d, 1H); 7.34 (d, 1H); 7.79 (d, 1H); 7.99 (d, 1H); 8.21 (s, 1H); 8.38 (s, 1H); 11.23 (s, 1H).
Intermediate 201; 1 -f 2-(4-Aminopiperidin-1 -yl)ethyl]-2-oxo-1.2-dihvdroquinoxaline-
7-carbonitrile
tert-Butyl {1 -[2-(7-cyano-2-oxoquinoxalin-1 (2//)-yl)ethyl]piperidin-4-yl} carbamate
(Intermediate 199) was deprotected with TFA as described for Intermediate 197 to
give the crude free base of the product.
MS fESI) 298 (MH4) for Ci6Hi9N5O
Example 111
6-[({l-[2-(6-Methoxy-3-oxopyrido[2,3-A]pyrazin-4(3//)-yI)ethyl]piperidin-4-
yl}amino)methyl]-2#-pyrido[3,2-A][l,4]oxazin-3(4#)-one
4-[2-(4-Aminopiperidin-l-y])ethyl]-6-methoxypyrido[2,3-6]pyrazin-3(4//)-onc
(Intermediate 202, 0.125 g) was reacted with 3-oxo-3,4-dihydro-2//-pyrido[3,2-
6][l,4]oxazine-6-carbaldehyde (WO 2004/058144) (50 rag) and sodium acetoxyborohydridc
(110 mg) as described for Example 107. Chromatography on silica gel with 0-20% methanol
in dichloromethane and trituration of the product from ether gave 37.6 mg of the title
compound as acetic acid salt.
MS (ESP 466 (MH+) for CalfotyC^
'H NMR (DMSQ-D6) 8 1.18 (q, 2H); 1.74 (d, 2H); 2.03 (t, 2H); 2.32 - 2.41 (m, HI);
2.61 (t, 2H); 2.90 (d, 2H); 3.66 (s, 2H); 3.98 (s, 3H); 4.41 (t, 2H); 4.59 (s, 2H); 6.83 (d, 1H);
6.99 (d, 1H); 7.27 (d, 1H); 8.10 (s, 1H); 8.12 (d, 1H); 11.15 (s, 1H).
Intermediate 202; 4-[2-(4-Aminopiperidin-1 -yl)ethyl]-6-mcthpxypyrido[2,3-
fcjpyrazin-S^ffi-one
/e/-/-Butyl {l-[2-(6-methoxy-3-oxopyrido[2,3-A]pyrazm-4(3//)-yl)ethyl]piperidin-4-
yl}carbamate (Intermediate 203,0.213 g) was deprotected with TFA as described for
Intermediate 197 to give the crude free base of the product, 0.15 g.
MS (ESP 304 (MET*) for Ci5H2iN502
Intermediate 203: te^-ButvHl-['2-(6-methoxv-3-oxopyridof2J-A1pyrazin-4(3//)_-
vl)ethyI]piperidin-4-yl)carbamate
6-Methoxypyrido[2,3-6]pyrazin-3(4H)-one (Intermediate 204, 0.085 g, 0.48 mmol)
was deprotonated with sodium hydride (0.030 g, 60% in oil, 0.7.5 mmol) and alkylatcd with
2-{4-[(ter/-butoxycarbonyl)amino]piperidin-l-yl}ethyl methanesulfonate (Intermediate 6)
(1.05 mmol) as described for Intermediate 2, Chromatography on silica gel with 0-25%
acetone in dichloromethane gave 0.13 g of the title compound.
MSfESD 404 (MH+) for C2oH29N504
*H NMR fCDCM 5 1.31 -1.40 (m, 2H); 1.40 -1.46 (m, 9H); 1.87-1.95 (m, 2H); 2.15
- 2.27 (m, 2H); 2.69 - 2.75 (m, 2H); 2.93 - 3.02 (m, 2H); 3.40 - 3.51 (m, 1H); 4.02 (s, 3H);
4.35 - 4.46 (m, 1H); 4.51 - 4.60 (m, 2H); 6.73 (d, 1H); 8.02 (d, 1H); 8.15 (s, 1H).
Intermediate 204: 6-Methoxvpvridor2.3-/;]pyra7in-3(4//)-one
To a solution of 3,4-diamino-6-methoxypyridine (1.11 g) in mcthanol (20 mL) was
added ethylglyoxalate (3.5 mL). After stirring overnight at room temperature, it was filtered
and washed with methanol (the precipitate contained the undesired regioisomer, 6-
methoxypyrido[2,3-Z>]pyrazin-2(l//)-one). The filtrate was concentrated and suspended in
diethyl ether to give 0.18 g product.
MS (BSD 178 (MH4) for C8H7N302
'HNMR(DMSO-D6) 8 6.77 (d, 1H); 8.01 (s, 1H); 8.07 (d, III); 12.83 (s, 1H).
Example 112
4-(2-{4-[(2,3-DihydroIl,41dioxino[2,3-c]pyridin-7-ylmethyl)amino]pipcridin-lyl}
ethyl)-6-methoxypyrido[2,3-6]pyrarin-3(4/3>one
4-[2-(4-Aminopiperidin-l-yl)ethyl]-6-methoxypyrido[2,3-i]pyrazin-3(4/;/)-one
(Intermediate 202, 75 mg) was reacted with 2,3-dihydro[l,4]dioxino[2,3-c]pyridine-7-
carbaldehyde (WO 2004/058144) (48 mg) and sodium acetoxyborohydride (0.11) as
described for Example 107. Chromatography on silica gel with 0-2% methanol in
dichloromethane to give 72 mg of the product.
MS (BSD 453 (MH1) for C^H^NeC^
'HNMRfDMSQ-D6) 8 1.18 (q, 2H); 1.74 (d, 2H); 2.02 (t, 2H); 2.30 - 2.40 (m, 1H);
2.60 (t, 2H); 2.89 (d, 2H); 3.65 (s, 2H); 3.98 (s, 3H); 4.26 (dd, 2H); 4.29 - 4.34 (m, 2H); 4.40
(t, 2H); 6.83 (d, 1H); 6.92 (s, 1H); 7.98 (s, 1H); 8.10 (s, 1H); 8.12 (d, 1H).
Example 113
6-[({l-[2-(6-ChIoro-l-oxido-3-oxo-l,2,4-benzotriazin-4(3/0-yl)ethyl]piperidin-4-
yI}amino)methyl]-2/y-pyrido[3,2-£][l,4]oxazin-3(4i9)-one
4-[2-(4-Aminopiperidin-l-yl)ethyl]-6-chloro-l,2,4-benzotriazin-3(4//)-one 1-oxide
(Intermediate 205, 0.517 g) was reacted with 3-oxo-3,4-dihydro-2H-pyrido[3,2-
6][l,4]oxazine-6-carbaldehyde (WO 2004/058144) (117 mg) and sodium acetoxyborohydride
(340 mg) as described for Example 107. Chromatography on silica gel with 0-20% methanol
in dichloromethane gave 60 mg of the title compound as acetic acid salt.
MS (ESP 486 (MH1) for CjoBtwClNvCU
'H NMR (DMSO-Dei 8 1.13 -1.24 (m, 2H); 1.69 -1.79 (m, 2H); 2.02 (t, 2H); 2.31 -
2.42 (m, 1H); 2.57 (t, 211); 2.88 (d, 2H); 3.27 - 3.39 (m, 2H); 3.67 (s, 2H); 4.26 (t, 2H); 4.60
(s, 2H); 7.00 (d, 1H); 7.28 (d, 1H); 7.43 (dd, 1H); 7.91 (d, 1H); 8.20 (d, 1H); 11.15 (s, 1H).
Intermediate 205: 4-r2-(4-Aminopiperidm-l-vl)ethvn-6-chloro-l,2.4-benzotriazin-
3(4/f)-one 1-oxide
tert-Butyl {1 -[2-(6-chloro-1 -oxido-3-oxo-1,2,4-benzotriazin-4(3fl>yl)cthyl]pipcridin-
4-yl}carbamate (Intermediate 206,0.65 g) was deprotected with TFA as described for
Intermediate 197 to give the crude free base of the product, 0.517 g.
MS (ESI) 324 (MH+) for Ci4Hi8ClN502
Intermediate 206: terf-Bytyl (l-r2-(6-chlQro-l-oxido-3-oxo-1.2.4-benzotriazin-
4(3//)-yl)ethyl]piperidin-4-yUcarbamate
6-Chloro-l,2,4-benzotriazm-3(4//)-one 1-oxide (FR 2621583, 1.50 g) was
deprotonated with sodium hydride (0.42 g, 60% in oil) and alkylated with 2- {4-[(tertbutoxycarbonyl)
amino]piperidin-l-yl}ethyl methanesulfonate (Intermediate 6) (1
equivalent) as described for Intermediate 2. The residue obtained after aqueous work up was
suspended in diethyl ether and filtered to yield 1.30 g of product,
MS (ESP 424 (Mil1) for Ci9H26ClNs04
'HNMR(CDCIV) 6 1.30 - 1.41 (m, 2H); 1.44 (s, 9H); 1.88 - 1.96 (m, 211); 2.21 - 2.30
(m, 2H); 2.74 (t, 2H); 2.83 - 2.92 (m, 2H); 3.41 - 3.52 (m, 1H); 4.27 (t, 211); 4.34 - 4.45 (m,
1H); 7.30 (dd, 1H); 7.53 (d, 1H); 8.27 (d, 1H).
Example 114
6-Chloro-4-(2-{4-[(2,3-dihydro[l,4]dioxino[2,3-c]pyridin-7-
ylmethyl)amino]piperidin-l-yI}ethyl)-l,2,4-benzotriazin-3(4/0-onel-oxide
4-[2-(4-Aminopiperidm-l-yl)ethyl]-6-chloro-l,2,4-benzotriazin-3(4#)-one 1-oxide
(Intermediate 205, (0.25 g) was reacted with 2,3-dmydro[l,4]dioxino[2,3-c]pyridine-7-
carbaldehyde (WO 2004/058144) (0.14 g) and sodium acetoxyborohydride (0.34 g) as
described for Example 107. Chromatography on silica gel with 0-20% methanol in
dichloromethane gave 60 mg of the title compound as acetic acid salt (0.37 g).
MS (ESP 473 (MH4) for CzjIfcClNfiC^
IH NMR rPMSO-Pe^ 6 1.14 -1.25 (m, 2H); 1.68 - 1.78 (m, 2H); 2.02 (t, 2H); 2.31 -
2.42 (m, IH); 2.57 (t, 2H); 2.88 (d, 2H); 3.67 (s, 2H); 4.22 - 4.30 (m, 4H); 4.33 (dd, 2H); 6.93
(s, IH); 7.44 (dd, IH); 7.91 (d, IH); 8.00 (s, IH); 8.21 (d, IH).
Example 115
6-[({l-[2-(6-Chloro-3-oxo-l,2,4-ben/otriazin-4(3«)-yl)ethyl]piperidin-4-
yl}amino)methyl]-2//-pyrido[3,2-A][l,4]oxazin-3(4/J)-one
4-[2-(4-Aminopiperidin-l-yl)ethyl]-6-chloro-l,2,4-benzotriazin-3(4//)-one
(Intermediate 207, 67 mg) was reacted with 3-oxo-3,4-dihydro-2//-pyrido[3,2-
6][l,4]oxazine-6-carbaldehyde (WO 2004/058144) (360 mg) and sodium acetoxyborohydridc
(76 mg) as described for Example 107. Chromatography on silica gel with 0-20% methanol
in dichloromethane and trituration from ether gave 33 mg of the title compound.
MS (ESP 470 (MHH) for C22H24C1N703
'HNMRfPMSQ-P61 5 1.30 -1.42 (m, 2H); 1.88 -1.97 (m, 2H); 1.98 - 2.08 (m, 211);
2.58 - 2.67 (m, 2H); 2.90 - 3.02 (m, 2H); 3.28 - 3.34 (m, 2H); 3.95 - 4.07 (m, 2H); 4.26 (t,
2H); 4.66 (s, 2H); 7.08 (d, IH); 7.39 (d, IH); 7.56 (dd, IH); 7.87 (d, IH); 8.43 (d, IH); 11.27
(s, IH).
Intermediate 207: 4-[2-C4-Aminopiperidin-l-yl)ethyl1-6-chloro-l1214-benxotriazin-
3(4//)-one
tert-Butyl {l-[2-(6-chloro-3-oxo-l,2,4-benzotriazin-4(3//)-yl)ethyl]piperidin-4-
yl}carbamate (Intermediate 208, 74 mg) was deprotected with TFA as described for
Intermediate 197 to give the crude free base of the product, 67 mg.
MS (ESP 307 (MH") for Ci4Hi8ClN50
Intermediate 208; tert-Butvl I l-[2-(6-chloro-3-oxo-1.2,4-benzotriazin-4r3#)-
vnethyl]piperidin-4-yl} carbamate
To a solution of /ert-butyl {l-[2-(6-chloro-l-oxido-3-oxo-l,2,4-benzotriazin-4(3//)-
yl)ethyl]piperidin-4-yl} carbamate (Intermediate 206) (0.43 g) in acetic acid (8 inL) arid
water (2 mL) was added zinc dust (0.50 g). After 30 minutes, the solution was filtered and the
filtrate concentrated. The residue was then treated with potassium ferricyanide (1.0 g) in water
(20mL). After 2 hours, the reaction was diluted with ethyl acetate. The aqueous layer was
collected, the pH adjusted with solid Na2CC>3 and extracted with ethyl acetate. The combined
organic washes were dried (NajSO^, filtered and concentrated. The residue was purified by
chiomatography on silica gel with 0-25% acetone in dichloromethane to yield 66 mg of the
product.
MS (ESP 407 (MH+) for dsH^ClNsOs
'H NMR (CDCK) 8 1.32 -1.40 (m, 2H); 1.44 (s, 9H); 1.91 (d, 2H); 2.20 - 2.30 (m,
2H); 2.75 (t, 2H); 2.87 (d, 2H); 3.40 - 3.52 (m, 1H); 4.24 (t, 2H); 4.40 (s, 1H); 7.42 (dd, III);
7.46 (s,!H); 8.38 (d,!H).
Example 116
4-(2-{(21S',57Z)-S-|(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-
ylmethyl)amino]piperidin-2-yl}ethyl)-3-oxo-3,4-dihydro-2//-l,4-benzoxazine-6-
carbonitrile
The product was obtained following the procedure described for Example 105,
except, the enantiomer of Intermediate 183, tert-butyl (25,5/?)-5-amino-2-[2-(6-cyano-3-
oxo-2,3-dihydro-4//-l,4-benzoxazin-4-yl)ethyl]piperidine-l-carboxylate (prepared by the
exact route as Intermediate 183, but starting from l-?ert-butyl 2-ethyl (2S,5S)-5-{[tertbutyl(
dimethyl)silyl]oxy}piperidine-l,2-dicarboxylate, the enantiomer of Intermediate 191)
was reacted with 2,3-dihydro[l,4]dioxino[2,3-c]pyridine-7-carbaldehyde to yield the named
compound.
MS (ESP 449 (MH*) for Ca^NsC^
'H NMR (DMSO-D61 5 ppm 1.42-1.81 (m, 3H); 1.85 - 2.03 (m, Hi); 2.16 (d, 1 H);
2.28 (d, 1H); 2.98 - 3.11 (m, 1H); 3.38 - 3.58 (m, 111); 3.68 (d, 211); 4.28 (s, 2H); 4.38 (dd,
4H); 4.80 (s, 2H); 7.18 (d, 1H); 7.31 (s, 1H); 7.52 (d, 1H); 7.75 (s, III); 8.26 (a, 111); 9.46 -
9.79 (m, 2H); 9.98 (s, 1H).
-^^
Example 117
6-[(1-[2-(7-Bromo-l-oxo-2,3-dihydro-lH-pyrido[2,3-b][1,4]oxazin-lyl)
ethyl]piperidin-4-yl}amino)methyl]-2/f-pyrido[3,2-b][l,4]oxazin-3(4H)-one
l-[2-(4-Aminopiperidin-l-yl)ethyl]-7-bromo-lH'-pyrido[2,3-b)][l,4]oxazin-2(3//)-one
(Intermediate 209) (2.0 mmol), (3-oxo-3,4-dihydro-2H-pyrido[3,2-b][l,4]oxazine-6-
carbaldehyde (WO 2004/058144) (356 mg, 2.0 mmol) and sodium cyanoborohydride (496
ing, 4 equiv) were reacted as described under Example 21 to give the product as an off-white
solid 420mg( 41% yield),
MS (ESP); 517. 52 (MH4) for C22H25BrN604
1'H-NMR(DMSO-d6) δ 1.13 (t, 2H); 1.34 (q, 5H); 1.85 (d, 2H); 1.98 (t, 211); 2.45 (m,
2H); 2.71 (m, 1H); 2.91 (d, 2H); 3.00 (m, 2H); 3.89 (m, 2H); 3.99 (m, 211); 4.63 (s, 2H); 4.85
(s, 2H); 7.05 (d, 1H); 7.35 (d, 1H); 7.94 (dd, 1H); 11.25 (bs, 1H).
Intermediate 209 : l-r2-(4-Aminopiperidin-l-vl)ethvl1-7-bromo-l //-pyrido[2.3-
6in .41oxazin-2f 3#)-onc
ter/-Butyl {l-[2-(7-bromo-2-oxo-2,3-dihydro-l//-pyrido[2,3-6][l,4]oxazin-lyl)
ethyl]piperidin-4-yl}carbamate (Intermediate 210) (0.85 g) was reacted as described for
Intermediate 14. The crude trifluoro acetate of the title compound was used without further
purification for the next step (quantitative yield).
MS (ESP'): 3557 357 (MH*) for Ci4Hi9BrN402
Intermediate 210:tert-Butyl {l-r2-(7-bromo-2-oxo-2,3-dihydro- t//-pyrido[2,3-
b] [ 1,4]oxazin-1 -vnethyl]piperidin-4-yl} carbamate
6-Bromo-2H-pyrido[3)2-6][l,4]oxazin-3(4/f)-one (Intermediate 21.1) (460 mg, 2.0
mmol) was deprotonated with sodium hydride and alkylated with 2-{4-[(tertbutoxycarbonyl)
amino]piperidin-l-yl}ethylmethanesulfonate (Intermediate 6) (2.1 mmol)
as described for Intermediate 2. Chromatography on silica gel with methanol/
dichloromethane gave the product as an oil (0.85 g, 93% yield).
MS (ESP): 455, 457 (MH4) for Ci9H27BrN404
Intermediate 211: 7-Bromo-l//-pyrido[2.3-^][l,41oxazin-2r3/jr)-one
Ethyl [(5-bromo-3-nitropyridin-2-yl)oxy]acetate (intermediate 212) (4.3g, 14.1
mmol) was dissolved in anhydrous THF (10 mL) and concentrated HC1 (10 mL) was added at
**?&
0 ° C. Tin chloride (5.0 g, 26.4 mmol) was added in small portions. The reaction was stirred
for 1 hr and heated at 65 °C overnight. The reaction mixture was concentrated under reduced
pressure, extracted with chloroform, dried over magnesium sulfate and concentrated.
Chromatography on silica gel with methanol/ chloroform gave the product as a light pink
solid (1.2 g, 37% yield).
MS (ESP): 229/231(MH+) for C7H5BrN2O2
1H-NMR (DMSO-d6) δ: 4.80 (s, 2H); 7.32 (s, 1H); 7.87 (s, 1H); 10.94 (bs, III).
Intermediate 212: Ethyl [(5-bromo-3-nitropyridin-2-yl)oxt]acetate
A mixture of 5-bromo-2-chloropyridin-3-ol (4.73 g, 19.9 mmol) and ethyl glycolate
(2.9 g, 27. 8mrnol) in anhydrous dioxane (20 rnL) was treated with sodium hydride (1.12 g,
60% in mineral oil, 28 mmol) in portions (exothermic reaction!). The reaction was then
quenched with water and extracted with chloroform and dried over magnesium sulfate.
Chromatography on silica gel with ethyl acetate/ hexanes gave the product as a light yellow
solid (4.8 g, 79% yield).
MS (ESP): 305, 307(Mtf) for C9H9BrN2O5
1H-NMR (PMSO-d6) δ ppm: l.l7 (t, 3H); 4.12 (q, 2H); 5.10 (s, 211); 8.64 (s, 1H);
8.76 (s, 1H).
Example 118
2-Oxo-l-[2-(4-{f(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][l,4]oxazin-6-
yl)methyl]amino}piperidin-l-yI)ethyl]-2,3-dihydro-lH-pyrido|2,3-i][l,4)oxazinc-7-
carbonitrile
and
Example 119
2-Oxo-l-[2-(4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][l,4]oxazin-6-
yl)methyl]amino}piperidin-l-yl)ethyl]-2,3-dihydro-lH-pyrido[2,3-b]ll,4]oxazine-7-
carboxamide
A mixture of 6-[({l-[2-(7-bromo-2-oxo-2,3-dihydro-l//-pyrido[2,3-&][ 1,4]oxazin-1 -
yl)ethyI]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-i][l,4]oxaxin-3(4H-oac (Example
117) (110 mg, 0.21 mmol), zinc cyanide (80 mg, 0.683mmol) and
tetrakis(triphenylphosphinc) palladium(O) (25 mg, 0.0215mmol) in anhydrous DMF (2.5 mL)
over molecular sieves 3A was vortexed and then heated in the microwave at 200 °C for one
hour. Reverse phase chromatography and generation of the free base as described for
Example 21 gave 20 mg (20%) of Example 118 and 20 mg (20%) of Example 119, both as
off-white solids,
Example 118
MS (ESP):. 464(MII+) for C23H25N704
1H-NMR(DMSO-d6) δ: 1.74 (m, 2H); 2.18 (m, 2H); 3.02 (m, 2H); 3.80 (m, 2H); 3.90
(m, 2H); 4.23 (m, 4H); 4.70 (s, 2H); 5.01 (s, 2H); 7.11 (d, 1H); 7.44 (d, 1H); 8.08 (s, 1H);
8.40 (s, 1H); 9.28 (s, 1H); 9.75 (bs, 1H); 11.35 (bs, 1H).
Example 119:
MS (ESP): 482(MH+) for C23H27N7O5
1H-NMR (DMSO-d6) δ 1.74 (m, 2H); 2.36 (m, 2H); 3.10 (m, 2H); 3.80 (m, 2H); 4.23
(m, 2H); 4.32 (m, 4H); 4.56 (s, 2H); 4.70 (s, 2H); 4.94 (s, 4H); 7.11 (d, 1H); 7.44 (d, 1H);
7.62 (s, 1H); 7.91 (s, 1H); 8.08 (s, 1H); 8.38 (s, III); 9.30 (bs, 2H); 9.60 (bs, 1H); 11.35 (bs,
1H).
Example 120
l-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-2-
methylpiperidin-l-yl}ethyl)-5,7-difluoroquinolin-2(lH)-one
A solution of l-[2-(4-amino-2-methylpiperidin-l-yl)emyl]-5,7-difluoroquinolin-
2(lH)-one (Intermediate 213, crude, 220 mg, 0.69 mmol) and 2,3-dihydro[l,4]dioxino[2,3-
c]pyridine-7-carbaldehyde (WO 2004/058144) (114 mg, 0.69 mmol) in dry
dichloroethane/methanol (4 mL, 4:1) was heated over 3 A molecular sieves at 80 °C for 3
hours. The reaction mixture was cooled to 0°C, and sodium triacetoxy borohydride (299 mg,
1.38 mmol) was added. The resulting reaction mixture was stirred at room temperature for 16
hours and then was filtered through a 0.45 urn membrane and concentrated to dryness under
reduced pressure. The residue was taken up in dichloromethane (20 mL) and saturated
aqueous sodium hydrogen carbonate solution (5 mL). The pH of the aqueous phase was
adjusted to pH~10 with 1M aqueous sodium hydroxide solution. The aqueous phase was back
extracted twice with dichloromethane (4x 20 mL) and the combined organic phases were
dried over sodium sulfate and concentrated under reduced pressure. Chromatography on silica
gel with dichloromethane/methanol (17:3) gave 195 mg (69%) of the title compound as a
white foam.
MS (ESP): 471.22 (MH+) for C25H28F2 N403
1H NMR (300 MHz. DMSO-d^ 8: 0.82-0.91 (m,4H); 1.16-1.26 (m, HI); 1.74-1.90
(m, 2H); 2.16-2.25 (m, 2H); 2.34 -2.42 (m, 2H); 2.85-2.95 (m, 1H); 3.08 (d, 1H, J = 11.5 Hz);
3.76 (s, 2H); 4.27-4.34 (m, 6H); 6.63 (d, 1H, J= 9.8 Hz); 6.96 (s, 1H); 7.18-7.32 (m, 2H);
7.94 (d, 1H, J = 9.8 Hz); 8.03 (s, 1H),
The intermediates for Example 120 were prepared as follows:
Intermediate 213: l-[2-(4-Amino-2-methvlpiperidin-l-vl')ethvl]-5.7-difluoroquinolin-
2d/fl-one
A solution of l-{2~[4-(dibenzylamino)-2-methylpiperidin-l-yl]ethyl}-5,7-
difiuoroquinolin-2(l//)-one (Intermediate 214 358 mg, 0,71 mmol) in methanol (6 mL) was
treated with palladium hydroxide on carbon (100 mg). The reaction was stirred at room
temperature under hydrogen gas for 18 hours, filtered through celite, rinsed with methanol
(100 mL), and concentrated under reduced pressure to afford 225 mg (96%) of a yellow oil.
MS (ESP): (MH+) for C17H21F2N3O.
1H-NMR(DMSO-d6) δ: 0.74-0.87 (m, 4H); 1.04-1.17 (dq, III, J= 12.1, 11.9, 3.7 H/.);
1.54-1.67 (m, 2H); 2.16-2.26 (m, 2H); 2.30-2.39 (m, 1H); 2.84-2.95 (m, HI); 3.02-3.08 (ra,
1H); 4.26 (t, 2H, J Hz).
Intermediate 214; 1- {2-[4-(Dibenzylamino)-2-methylpipcndin- l-yllethyll -5.7-
difluoroqumolin-2( H)-one
A solution of 5,7-difluoroquinolin-2(1H)-one (40 mg, 1.9 mmol) in dry
dimethylformamide (DMF) (5 mL) was treated at 0 °C with a cooling bath under stirring with
sodium hydride (80 mg, 60% in oil, 2.0 mmol). The cooling bath was removed and the
mixture was stirred for 30 minutes at room temperature. A solution of 2-[4-(benzylamino)-2-
methylpiperidin-1-yl]ethyl methanesulfonate in DMF (Intermediate 215, 0.58 mmol/ mL, 3.5
mL, -2,03 mmol) was then added and the resulting mixture was stirred over night at room
temperature. The DMF was removed under reduced pressure, and the residue was taken up in
ethyl acetate (100 mL) and saturated aqueous sodium hydrogencarbonate solution (30 mL).
The aqueous phase was back extracted once with ethyl acetate (50 mL). The combined
organic phases were dried over sodium sulfate and concentrated under reduced pressure.
Chromatography on silica gel with hexanes/acetone (2:1) gave 365 mg (39% yield) of the
product as a yellow solid.
)^
?&9*\'T
MS (ESP): 502 (MH+) for C3,H33F2N30
1H-NMR (DMSO-d6) δ: 0.89 (d, 3H, J = 5.5 Hz); 1.10-1.23 (m, 1H); 1.46-1.54 (m,
1H); 1.70 (t, 2H, J - 14.3 Hz); 2.10-2.16 (m, 2H); 2.35-2.44 (m, 211); 2.82-2.89 (m, 1H); 3.12
(d, 1H, J « 10.4 Hz); 3.54 (s, 4H); 4.21-4.26 (m, 2H); 6.61 (d, 1H, 9.8 Hz); 7.16-7.34 (m,
12H); 7.95 (d, 1H).
Intermediate 215: 2-[4-(Dibenzvlamino)-2-metbylpiperidin-l -yl]ethyl
methanesulfpnate
A mixture 2-[4-(dibenzylainino)-2-methylpiperidin-l-yl]ethanol (Intermediate 216,
660 mg, 1,9 mmol) in dry dichloromethane (6 mL) and triethyl amine (0.375 mL, 2.7 mmol)
was treated at 0°C with rnethanesulfonyl chloride (0.175 mL, 8.4 mmol). After 45 minutes the
reaction was complete by TLC (chloroform/methanol 6:1, rf 0.54). Potassium phosphate
buffer (pH 7, 1M, 25 mL) was added, dichloromethane was removed under reduced pressure
and it was extracted with ice cold ethyl acetate (2 x 100 mL) and dried over sodium sulfate.
The solvent was removed under reduced pressure and the crude preparation of the mesylate
was used without delay for the next step.
MS (ESP): 417.18 (MH+) for C23H32N2O3S.
Intermediate 216; 2-F4-(Dibenzvlamino)2-methylpiperidin-1 -yllethanol
To a solution of N,N-dibenzyl-2-methyIpiperidin-4-amine (Intermediate 217, 880 mg,
3.0 mmol) in acetonitrile (6 mL) was added triethylamine (0.85 ml, 6.0 mmol) and 2-
bromoethanol (0.32 mL, 4.5 mmol). The reaction is stirred at 70°C at 300 watts in the
microwave for 20 minutes. Acetonitrile was removed under reduced pressure, the residue was
taken up in dichloromethane (100 mL) and saturated aqueous sodium hydrogen carbonate
solution (30 mL) and the aqueous phase was back extracted three times with dichloromethane
(3x 70 mL). The combined organic phases were dried over sodium sulfate and concentrated to
dryness under reduced pressure. Chromatography of the residue on silica gel with
dichloromethane/methanol (10:1) gave 660 mg (65% yield) of the product as an orange solid.
MS (ESP): 339.22 (MH4) for C22H3oN2O.
1H-NMR(DMSO-d6)δ: 1.01 (d, 3H, J=5.8 Hx), 1.22-1.34 (m, 1H); 1.48-1.56 (m,
1H); 1.69 (d, 2H, J- 11.1 Hz); 1.95-2.11 (m, 2H); 2.14-2.30 (m,. 1H); 2.38-2.43 (m, 1H); 2.64-
2.80 (m, 1H); 2.84-3.00 (m, 1H); 3.37-3.41 (m, 1H); 3.55 (s, 4H); 4.24-4.35 (m, 1H); 7.15-
7.22 (m, 2H); 7.24-7.34 (m, 8H).
Intermediate 217: N.N-Dibenzvl-2-methvlpiperidin-4-amine
A mixture of ethyl 4-(dibenzylamino)-2-methylpiperidine-l-carboxylate
(Intermediate 218,1.28 g, 3.78 mmol) in dry isopropyl alcohol (30 mL) was added
potassium hydroxide (0.65 mL, 8.4 mmol). The reaction was stirred at 105 °C for 6 hours. 2-
Propanol was removed under reduced pressure, the residue was taken up in dichloromethane
(100 mL), filtered through a 0.5 μm membrane, and concentrated under reduced pressure.
Chromatography of the residue on silica gel with dichloromethane/methanol/ammonium
hydroxide (85:15:0.1) gave 882 mg (79% yield) of the product as a red oil.
MS (ESP): 295.18 (MH+) for C2oH26N2.
1H-NMR(DMSO-d6) δ: 0.98 (d, 3H, J= 5.8 Hz); 1.07-1.14 (m, 1H); 1.37 (dq, 1H, J
=12.0,4.2 Hz); 1.68 (t, 2H, J= 13 Hz); 2.26-2.36 (m, 2H); 2.40-2.46 (m, 1H); 2.91-2.97 (m,
1H); 3.56 (s, 4H); 7.16-7.20 (m, 2H); 7.25-7.34 (m, 8H).
Intermediate 218: Ethvl 4-rdibenzvlamino')-2-methvlpiperidine-1 -carboxvlate
A mixture of ethyl 4-(benzylamino)-2-methylpiperidine-l-carboxylate (Intermediate
219,1.57 g, 5.7 mmol), cesium carbonate (3.72 g, 11.4 mmol) and benzyl bromide (1.36 mL,
11.4 mmol) in dry DMF (20 mL) was heated at 80°C for 16 hours. The DMF was removed
under reduced pressure, the residue was taken up in ethyl acetate (150 mL) arid water (75 mL)
and the aqueous phase was back extracted once with ethyl acetate (3x150 mL). The combined
organic phases were washed with brine (100 mL) and were dried over sodium sulfate.
Chromatography on silica gel with hexanes/ethyl acetate (3:2) gave 1.43 g (68% yield) of the
product as a yellow oil.
MS (ESP): 367 (MH+) for C23H30N2O2.
1H-NMR (DMSO-d6) δ: 1.07-1.16 (m, 6H); 1.47-1.61 (m, 2H); 1.72-1.93 (m, 2H);
2.56-2.70 (m, 1H); 3.11-3.19 (m, 1H); 3.48-3.63 (m, 6H); 3.89-4.00 (m, 2H); 7.17-7.21 (m,
2H); 7.29-7.38 (m, 8H).
Intermediate 219: Ethyl 4-(benzvlamino)-2-methylpiperidine-l-carboxvlate
A solution of ethyl 2-methyl-4-oxopiperidine-l-carboxylate (2.20 grams, 11.9 mmol)
and benzyl benzylamine in dichloroethane/methanol (4:1, 50 mL) was heated over 3 A
molecular sieves at 90°C for 16 hours. The reaction mixture was cooled to 0°C, and sodium
triacetoxy borohydride (5.03 g, 23.8 mmol) was added. The resulting reaction mixture was
stirred at room temperature for 30 minutes and then was filtered through a 0.45 urn membrane
-JtfTand
concentrated to dryness under reduced pressure. The residue was taken up in aqueous IN
HC1 solution and washed with ether (2 x 50 mL). The pH of the aqueous phase was adjusted
to apH of approximately 7 with 1M aqueous sodium bicarbonate solution. The aqueous phase
was back extracted twice with ether (4x 50 mL) and the combined organic phases were dried
over sodium sulfate and concentrated under reduced pressure. Chromatography on silica gel
with dichloromethane/methanol (94:6) gave 1.57 g (47% yield) of a yellow oil.
MS (ESP): 277 (MH+) for C16H24N2O2
1'H-NMR (DMSO-d£) δ: US (t, 3H, J = 7.1 Hz); 1.30 (d, 3H, J = 6.8 Hz); 1.52-1.59
(m, 3H); 1.61-1.71 (m, 1H); 2.80-2.82 (m, 1H); 3.22-3.27 (m, 1H); 3.57-3.73 (m, 3H); 3.95-
4.06 (m, 3H); 7.18-7.34 (m, 5H).
Example 121
l-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-lyl}
ethyl)-2-oxo-l,2-dihydroquinoline-7-carbonitrile
A mixture of 7-chloro-l-(2-{4-[(2,3-dihydro[l,4]dioxino[2,3-c]pyridin-7-
ylmethyl)amhio]piperidin-l-yl}ethyl)quinolin-2(lH)-one (2.11 g, crude, ~3.47 mmol) and
zinc cyanide (244 mg, 2.1 mmol) in dry DMF (8 mL) was degassed and flushed with nitrogen
three times. Zinc (174 mg, 0.059 mmol, 51.6 mM solution in heptane) was added, followed by
4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (63 mg, 0.11 mmol) and
tris(dibenzylideneacetone)dipalladium (0) (100 mg, 0.11 mmol) and it was degassed and
flushed with nitrogen like above. The mixture was stirred for 30 minutes at room temperature
and then degassed and flushed with nitrogen again. It was heated at 120°C for 3 hours. The
solvent was removed under reduced pressure and the residue taken up in chloroform/isopropyl
alcohol (3:1,50 mL) and filtered through celite and concentrated under reduced pressure.
Chromatography by reverse phase (Column: Atlantis Hilic; Gradient: 90% ACE/0.1% TFA;
5% Water/0.1% TFA; and 5% IsopropanoVO.1% TFA; Flow Rate: 1 mL/min.) afforded 418
mg (20%) of a brown oil as a TFA salt.
MS fESPV 447.14 (MH+) for C24H26N603
1H NMR (300 MHz. DMSO-d6) δ:1.75-1.87 (m, 2H); 2.29-2.38 (d, 2H, .7=12.6 Hz);
3.00-3.20 (m, 2H); 3.37-3.49 (m, 2H); 3.90 (d, 2H, .7=12.6 Hz); 4.24 (br s, 2H); 4.35 (d, 2H, J
= 4.6 Hz); 4.39 (d, 2H, J = 4.6 Hz); 4.62-4.72 (m, 2H); 6.95 (d, 1H, 1 = 9.6); 7.12 (s, 1H);
8.02 (d, 1H, J = 7.7 Hz); 8.11 (d, 1H, J = 9.6 Hz); 8.21 (s, 1H); 8.47 (d, 1H, J = 7.7); 9.18-
9.45 (m, 2H).
Example 122
Cis±l-[(2E)-3-(2,5-difluorophenyl)prop-2-en-l-yl}-4-[3-(6-methoxy-3-oxo-2,3-
dihydro-4;H-l,4-benzoxazin-4-yl)propyl]piperiduie-3-carboxylic acid
A solution of methyl Cis(±)-l-[(2£)-3-(2,5-difluorophenyl)prop-2-en-l-yl]-4-[3-(6-
methoxy-3-oxo-2,3-dihydro-4H-l,4-benzoxazin-4-yl)propyl]piperidine-3-carboxylate
(Example 123) (105 mg, 0.204 mraol) in methanol (1 mL) was treated with a solution of
sodium hydroxide (IN, 1 mL) the reaction was warmed to 30 °C for 18 hours. The
temperature was increased to 60 °C for 6 hours. The solvents were evaporated, the reaction
was diluted with ethyl acetate and water. The pH was adjusted to 7 with IN HC1. The layers
were separated. The aqueous phase was extracted with ethyl acetate (2 X 20mL). The organic
layers were combined dried over magnesium sulfate and concentrated at reduced pressure.
The residue was taken up and dichloromethane and precipitated with ether in a dry
ice/acetone bam. The solvent was decanted. The solid was dried under high vacuum to obtain
21 mg (20%) of an off-white solid.
MS(ESP'): 501 (MH+) for C27H3oF2N205
1H-NMR (400 MHZ.DMSO-d6) δ114 -1.26 (m, IH) 1.41 -1.53 (m, 1H) 1.57 -1.68
(m, 2H) 1.74 - 1.84 (m, III) 1.98 - 2.10 (m, IH) 2.89 - 2.97 (m, IH) 2.98 - 3.04 (m, IH) 3.04 -
3.12 (m, IH) 3.12 - 3.20 (m, IH) 3.22 - 3.34 (m, IH) 3.34 - 3.45 (m, 2H) 3.71 (s, 3H) 3.81 -
3.86 (m, IH) 3.88 - 3.96 (m, 3H) 4.46 (s, 2H) 6.47 - 6.58 (m, 2H) 6.63 (s, IH) 6.85 (d, 2H)
7.06 - 7.18 (m, 2H) 7.39 - 7.48 (m, IH) 8.11 (s, IH)
Example 123
Methyl cis(±)l-[(2E)-3-(2,5-difluorophenyl)prop-2-en-l-yll-4-[3-(6-methoxy-3-
oxo-2,3-dihydro-4H-l,4-benzoxazin-4-yl)propyl]piperidine-3-carboxyIatc
A solution of methyl 4-[3-(6-methoxy-3-oxo-2,3-dihydro-4//-l,4-benzoxazin-4-
yl)propyl]piperidine-3-carboxylate (Intermediate 220) (150 mg, 0.414 mmol) in ethanol (2
mL) was treated with K2CO3 (63 mg, 0.455 mmol) followed by a solution of 2-[(lE)-3-
chloroprop-l-en-l-yl]-l,4-difluorobenzene (Intermediate 124) (86 mg, 0.455 mmol) in
ethanol (1 mL). The reaction was warmed to 40°C for 18 hours. The reaction was partitioned
between ethyl acetate and water. The aqueous layer was extracted with dichloromethane (2 X
20 mL). The organic extracts were combined, dried over MgSO4 and concentrated at reduced
pressure to obtain a yellow oil. Chromatography on silica gel eluting with (0-2.5%) methanol
in dichloromethane gave the title compound as a yellow oil (120 mg, 56 %).
MS(ESP):515 (MH4) for C28H32F2N205 (
1H-NMR (400 Mz. DMSQ-d6 δ 1.19 -1.30 (m, 2H) 1.39 -1.49 (m, 2H) 1.49 -1.61
(m, 2H) 1.66 - 1.78 (m, 2H) 2.16 - 2.28 (m, 1H) 2.36 (s, 1H) 2.64 - 2.75 (m, 1H) 3.03 - 3.15
(m, 2H) 3.54 (s, 3H) 3.73 (s, 3H) 3.81 - 3.92 (m, 2H) 4.52 (s, 2H) 6.39 - 6.51 (m, 1H) 6.56
(dd, 7=8.6,2 Hz, 2H) 6.71 (d, ,7=2 Hz, 1H) 6.92 (d, 7=8.6 Hz, 1H) 7.07 - 7.18 (m, 1H) 7.18 -
7.30 (m, 1H) 7.46 - 7.57 (m, 1H).
The intermediates for Example 2 were prepared as follows:
Intermediate 220; Methyl 4-[3-(6-methoxv-3-oxo-2.3-dihvdro-4H-1.4-benzoxazin-4-
yl)propvl1piperidme-3-carboxvlate
To an ice-cooled solution of 6-methoxy-2H-l,4-benzoxazin-3(4H)-one (Intermediate
48) (407 mg, 2.29 mmol) in DMF was added sodium hydride (110 mg, 2.75 mmol). After
stirring for 2 hours a solution of l-tert-butyl 3-methyl 4-{3-
[(methylsulfonyl)oxy]propyl}piperidine-l,3-dicarboxylate (868 mg, ~2.29 mmol)
(Intermediate 132) hi DMF (5 mL) was added. The reaction was allowed to stir at room
temperature for five days. The reaction was diluted with ethyl acetate and water. The pH was
adjusted to approximately 3 with IN HC1. The layers were separated. The aqueous layer was
extracted with ethyl acetate (3 X 30 mL). The combined organic layers were washed with
water (4X 50 mL), dried over magnesium sulfate and concentrated at reduced pressure to
obtain a semi-solid. Chromatography on silica gel eluting with (0-2.5 %) methanol in
dichloromethane gave the product as a mixture of diastereomers. Reverse phase separation
using a 50-60 % gradient of acetonitrile in water with 0.1% trifluoroacetic acid gave the cis
diastereomer as the faster eluting peak. Upon evaporation of the organic components and
extraction of the aqueous with 20% methanol in dichloromethane 150 mg of the cis
diastereomer was obtained.
1HNMR(CDCl3): δ1.19 -1.30 (m, 1H); 1.32 -1.40 (m, 2H); 1.64 -1.75 (m, 2H);
1.77 -1.89 (m, 2H); 1.94 - 2.04 (m, 1H); 2.93 - 3.01 (m, 1H); 3.06 - 3.11 (m, 1H); 3.13 - 3.20
(m, 1H); 3.47 - 3.53 (m, 1H); 3.54 - 3.60 (m, 1H); 3.74 (s, 3H); 3.79 (s, 3H); 3.82 - 3.90 (m,
1H); 3.90 - 4.00 (m, 1H); 4.49 - 4.57 (m, 2H); 6.49 - 6.56 (m, 2H); 6.89 - 6.97 (m, 1H).
The trans compound was obtained as a mixture of amine and Boc protected material
(138 mg) through neutralization of the aqueous layer with sodium bicarbonate before
extraction with 20% methanol in dichloromethane. The mixture was dissolved in ethanol (3
mL) and heated in the microwave at 150°C for four hours.
MS(ESP): 363 (MH+) for C19H26N2O5
Example 124
l-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-lyI}
ethyl)-7-methoxy-3,4-dihydroquinoxalin-2(lH)-one
To a solution of l-(2-{4-[(2,3-dihydro[l,4]dioxino[2,3-c]pyridin-7-
ylmethyl)amino]piperidin-l-yl}ethyl)-7-methoxyquinoxalin-2(lH)-one (Example 72, 0.125
g) in ethanol (4 mL) was added sodium borohydride (40 mg). After 3 hour at room
temperature, additional sodium borohydride (47 mg) was added. After 30 minutes the reaction
was quenched with acetone and concentrated. Chromatography on silica gel with a gradient of
dichloromethane to 20% methanol in dichloromethane gave 108 mg of the product as a
colorless solid.
MS (ESI) 454 (MH4) for C24H31N504
1HNMR (DMSO-D6) δppm): 1.36 (m, 2H); 1.78 - 1.88 (m, 2H); 1.98 (t, 2H); 2.41 (t,
2H); 2.52 - 2.60 (m, 1H); 2.89 (d, 2H); 3.63 (d, 2H); 3.67 (s, 3H); 3.77 - 3.87 (m, 211); 3.88 -
3.95 (m, 2H); 4.25 - 4.30 (m, 2H); 4.31 - 4.36 (m, 2H); 5.65 (s, 1H); 6.46 (dd, 1H); 6.62 (d,
1H); 6.66 (d, 1H); 6.95 - 7.01 (m, 1H); 8.05 (s, 1H).
Example 125
5,7-Difluoro-l-[2-(4-{[(l-oxo-l,3-dihydro-2-benzofuran-5-yl)methyl]amino}
piperidin-l-yl)ethyl]quinolin-2(lH)-one
The compound was prepared following the procedure described for Examples 87-96.
MS (ES). 454 (MH+) for C25H25N3O3
1HNMR (DMSO-D6) δ(ppm): 1.83 (s, 2H); 2.32 (s, 2H); 3.07 (s, 1H); 3.31 (s, 2H);
3.45 (s, 2H); 3.80 (s, 2H); 4.39 (s, 2H); 4.53 (s, 2H); 5.45 (s, 2H); 6.66 (d, 1H); 7.29 (t, 1H);
7.42 (d, 1H); 7.73 (d, 1H); 7.80 (s, 1H; 7.94 (d, 1H); 8.01 (d, 1H); 9.49 (s, 1H).
Example 126
6-[({l-[2-(7-Methoxy-2-oxoquinoxalin-l(2H)-yl)propyl]piperidin-4-
yl}amino)methyl]-2H-pyrido[3,2-b][l,4]oxazin-3(4H)-one
l-[2-(4-ammopiperidin-l-yl)-l-methylethyl]-7-methoxyquinoxalin-2(l/0-°ne
(Intermediate 221) (160 mg crude, 0.51 mmol), 3-oxo-3,4-dihydro-2H-pyrido[3,2-
6][l,4]oxazine-6-carbaldehyde (WO 2004/058144) (91 mg, 0.51 mmol), and sodium
triacetoxy borohydride (320 mg, 1.5 mmol) were reacted as described according to Example
69. Chromatography on silica gel eluting with 5% methanol/dichloromethane containing
0.25% ammonium hydroxide gave 105 mg (63%) of the title compound as an off-white solid.
MS (ESP): 479 (MH4) for C25H30N6O4
1HNMR (DMSO-D6) δ(ppm): 0.96 (d, 3H); 0.99 - 1.14 (m, 2H); 1.71 (t, 2H); 1.95 (s,
1H); 2.10 (t, 1H); 2.22 - 2.41 (m, 2H); 2.89 - 3.01 (m, 1H); 3.03 - 3.14 (m, 1H); 3.64 (s, 2H);
3.90 (s, 3H); 4.11 (q, 1H); 4.27 - 4.40 (m, 1H); 4.55 - 4.66 (m, 2H); 6.93 - 7.04 (m, 3H); 7.23
- 7.33 (m, 1H); 7.69 - 7.80 (m, 1H); 8.04 (s, 1H); 11.16 (s, 1H).
Intermediate 221; l-[2-(4-Aminopiperidin4-vl)-l-methvlethvl]-7-
metfapxyquinoxarm-2( lH)-one
A solution of tert-butyl {l-[2-(7-methoxy-2-oxoquinoxalin-l(2/f)-yl)propyl]piperidin-
4-yl}carbamate (Intermediate 222,200 mg, 0.48 mmol) in dichloromethane (30 mL) was
treated with trifluoroacetic acid (3 mL). After 2 hours, the reaction was concentrated to
dryness, The residue was partitioned between 15% methanol/chloroform. The aqueous phase
was re-extracted 3x with 15% methanol/chloroform. The combined organic phases were dried
over magnesium sulfate, filtered, and concentrated to dryness giving 160 mg (100%) of the
crude product as an oil.
MS (ESP):. 317 (MH+) for C17H24N4O2
Intermediate 222; tert-Butvl {1-[2-(7-methoxy-2-oxoquinoxalin-l(2H)-
vl)propyl]piperidin-4-yl} carbamate
A solution of 7-methoxyquinoxalin-2(lH)-one (Intermediate 148, 590 mg, 3.35
mmol) in dry DMF (10 mL) was cooled in an ice bath under nitrogen and treated with sodium
hydride (60%, 160 mg, 4.02 mmol). The reaction was stirred at room temperature for ~90
minutes. The reaction was again cooled in an ice bath and treated with a solution of 2-{4-
[(tert-butoxycarbonyl)amino]piperidin-l-yl}-l-methylethyl methanesulfonate in dry DMF
(Intermediate 223, ~0.43 mmol/ml, 4.3 mmol). The reaction was stirred at room temperature
overnight. The reaction mixture was concentrated to dryness. Residual DMF was coevaporated
Ix with toluene. The resulting residue was partitioned between ethyl acetate and
water. The aqueous phase was re-extracted 3x with ethyl acetate. The organic phases were
combined, dried over magnesium sulfate, filtered, and concentrated to dryness.
Chromatography on silica gel with 25% acetone/hexanes gave 410 mg (29%) of product
which contained ~10% starting material (7-methoxyquinoxalin-2(1H)~one). This material was
used directly in the next step.
MS (ESP): 417 (MH+) for C22H32N404
1HNMR (DMSO-D6) δ (ppm): 0.96 (d, 3H); 1.10 -1.26 (m, 2H); 1.31 -1.42 (m, 9H);
1.53 - 1.72 (m, 2H); 2.14 (t, 1H); 2.37 (t, 1H); 2.94 (d, 1H); 3.04 - 3.15 (m, 2H); 3.87 - 3.96
(m, 3H); 4.06 - 4.20 (m, 2H); 4.32 (dd, 1H); 6.71 (d, 1H); 6.95 - 7.05 (m, 2H); 7.71 - 7.78 (m,
1H); 8.04 (s, 1H).
Intermediate 223; 2- (4-[(tert-Butoxvcarbonyl)amino]piperidin-1 -yl) -1 -methvlethyl
methanesulfonate
tert-Butyl [l-(2-hydroxypropyl)piperidin-4-yl]carbamate (Intermediate 224,1.1 g,
4.3 mmol), triethylamine (0.90 mL, 6.5 mmol) and methanesulfonyl chloride (0.37 mL, 4.7
mmol). Were reacted as described for Intermediate 6. The crude mesylate was directly used
for the next step.
Intermediate 224; tert-Butvl ri-f2-hydroxypropvr)piperidin-4-vncarbamate
tert-Butyl piperidin-4-ylcarbamate (2.0 g, 10.0 mmol), l-bromopropan-2-ol (2.8 g,
20.0 mmol, commercial product which also contained 30% of the regioisomer 2-
bromopropan-1-ol), triethylamine (4.2 mL, 30.0 mmol), and acetonitrile (15 mL) were
combined in a microwave vial and heated to 70 °C for 4 hours. The reaction mixture was
concentrated to dryness. The crude product was partitioned between ethyl acetate/water. The
aqueous phase was re-extracted 2x with ethyl acetate. The combined organic phases were
dried over magnesium sulfate, filtered, and concentrated to dryness. The product was purified
by flash chromatography on silica gel eluting with a gradient of 20-30% methanol in
dichloromethane to give 1.7 g of the desired product as an oil.
1HNMR (DMSO-D6) δppm 1.01 (d, 3H); 1.26 -1.48 (m, 11H); 1.64 (d, 2H); 1.85 -
2.04 (m, 2H); 2.03 - 2.27 (m, 2H); 2.78 (d, 2H); 3.09 - 3.29 (m, 1H); 3.62 - 3.81 (m, 1H); 4.23
(d, 1H); 6.75 (d, 1H).
Example 127
S,7-Dlfluoro-l-(2-{4-[(5,6,7,8-tetrahydro-l,8-naphthyridin-2-
ylmethyl)amino]piperidin-l-yl}ethyl)quinolin-2(1H)-one
l-[2-(4-Aminopiperidin-l-yl)ethyl]-5J7-difluoroquinolin-2(lH)-one (Intermediate
23) (126 mg, 0.410 mmol), 5,6,7,8-tetrahydro-l,8-naphthyridine-2-carbaldehyde
(JOG 2004, 69,1959-1966) (66 mg, 0.410 mmol) and sodium triacetoxy borohydride (52 mg,
0.82 mmol) were reacted as described for Example 6, to give 84.82 mg of the mono acetate
salt of the product as a pale yellow foam.
MS (ES): 454.54 (MH4) forC25H29F2N50
1HNMR (DMSO-D6) δ (ppm): 1.12 -1.27 (m, 2H); 1.67 -1.79 (m, 4H); 2.01 (t, 2H);
2.29 - 2.42 (m, 1H); 2.60 (t, 2H); 2.88 (d, 2H); 3.22 (t, 2H); 3.51 (s, 2H); 4.29 (t, 2H); 6.28 (s,
1H); 6.40 (d, 1H); 6.61 (d, 1H); 7.05 (d, 1H); 7.16 - 7.26 (m, 1H); 7.31 (d, 1H); 7.96 (d, 1H).
All cited publications, patents, and patent documents are incorporated by reference
herein, as though individually incorporated by reference. The invention has been described
with reference to various specific and preferred embodiments and techniques. However, it
should be understood that many variations and modifications may be made while remaining
within the spirit and scope of the invention.

CLAIMS
What is claimed is:
1. A compound of formula I:
(Formula Removed)
or a pharmaceutically acceptable salt thereof, or N-oxides thereof, wherein: L is a group of formula L1-L15:
(Formula Removed)
wherein indicates the point of attachment;
Z3, Z6, and Z7 are C or N provided that when Z3, Z6, or Z7 is N, then R2a, R2C, or R2d are absent; and
R2a, R2b, R2c, R2d, R2e, and R2f, are each independently H, halo, cyano, carboxy, nitro, carbamoyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkyl, hydroxy,
halo(C1-C6)alkyl, halo(C1-C6)alkoxy, (C1-C6)alkoxy, NHCO-(C1-C6)alkyl, SO2(C1-C6)alkyl) S02NH(C1-C6)alkyl, or S02N((C1-C6)alkyl)2;
R2g, Rag1, and Rag" are each independently H, (C1-C6)alkyl, or halo(C1-C6)alkyl;
U1 is CRaRb — CRcRd or CRaRb— CRcRd— CReRf, wherein Ra, Rb, Rc, Rd, Re, and Rf are each independently hydrogen or (C1-C6)alkyl;
M is a group of formula M1-M5:
(Formula Removed)
wherein R2 is H or carboxy, and wherein indicate points of attachment; Ry and Ry1 are each independently H, halo, hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy, CO2R", wherein R" is H, (C1-C6)alkyl, or halo(C1-C6)alkyl, or Ry and Ry' together with the carbon to which they are attached form C=0; or Ry and Ry' together form a bridge; X and Y are each independently CH2, 0, or NR'; " " is a bond or is absent; n is 1, or 2, or 3; when M is a group of formula Ml or M4, U2 is NR1— W, wherein W is CH2, CO, SO2,
(Formula Removed)

^ , CH2CH2, CH2CH=CH, or CH2OC, wherein each hydrogen may be optionally
replaced by halo or (C1-C6)alkyl;
when M is a group of formula M2, M3, or M5, U2 is W wherein W is as defined herein above;
R1 at each occurrence is independently H, (C1-C6)alkyl, -CO-(C1-C6)alkyl, -(C1-C6)alkylcarboxy, -C02(C1-C6)alkyl, -CO-NH(C1-C6)alkyl, -CO-N(C1-C6)alkyl)2, or SO2(C1-C6)alkyl, any of which may be optionally substituted on carbon with halo, hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy, SO2(C1-C6)alkyl,NH2,NII(C1-C6)alkyl, or N((C1-C6)alkyl)2;

when W is CH2, CO or S02, R is aryl, heteroaryl, heterocyclyl or ortho-fused bicyclic
(Formula Removed)
heteroaryl, or when W is CH2CH2, CH2CH=CH, or CH2C=C, R is aryl, heteroaryl, heteroaryloxy, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylamino; wherein any R may be optionally substituted on carbon; and wherein any ring nitrogen in R may be optionally substituted by (C1-C6)alkyl; and
any of L, U1, M, U2, or R may be optionally substituted on carbon by one, two or three substituents selected from halo, nitro, cyano, hydroxy, oxo, trifluoromethoxy, trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulphamoyl, methyl, ethyl, ethenyl, ethynyl, methoxy, ethoxy, methoxycarbonyl, ethoxycarbonyl, heteroaryl, heterocyclyl, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, or acetylamino; with the proviso that when L is a group of formula L8 or L15, W is not CO.
2. A compound or a pharmaceutically acceptable salt thereof, according to claim 1, wherein
L is:

(Formula Removed)
, wherein indicates the point of
attachment;
Z is CH or N when " ---- " is a bond, or Z is 0 or NH when "---- "is absent; and R2a, R2b R2c, and R2d are each independently H, halo, cyano, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkyl, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, (C1-C6)alkoxy, NHCO-(C1-C6)alkyl, SO2(C1-C6)alkyl, SO2NH(C1-C6)alkyl, orso2N((C1-C6)alkyl)2.
3. A compound or a pharmaceutically acceptable salt thereof, according to either claim 1
or 2, wherein
(Formula Removed)
L is .wherein" "indicates the point of attachment; and
ZisCHorNwhen" is a bond, or, when " ' is absent, Z is 0 or NH.
4. A compound or a pharmaceutically acceptable salt thereof, according to any one of
claims 1-3, wherein U1—M— U2 is:
(Formula Removed)
wherein " '""* " uidicates the point of attachment;
Ry is H, F, hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy, or carboxy; and
R1 is H, (C1-C6)alkyl, -(C1-C6)alkylcarboxy, -CO-(C1-C6)alkyl, -C02(C1-C6)alkyl,
-CO-NH(C1-C6)alkyl, -CO-N((C1-C6)alkyl)2, or SO2(C1-C6)alkyl.
5. A compound or a pharmaceutically acceptable salt thereof, according to any one of
claims 1-4, wherein Ry is H, hydroxy, fluoro, or methoxy.
6. A compound or a pharmaceutically acceptable salt thereof, according to any one of
claims 1-5, wherein R is
2,1,3-benzothiadiazol-5-yl; 3-oxo-3,4-dihydro-2H-1,4-benzothiazin-6-yl; 2,3-dihydro-benzo[l,4]dioxin-6-yl;

1,2,3-benzothiadiazol-5-yl;
3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl;
7-fluoro-3-oxo-3,4-dihydro-2tf-l,4-benzoxazin-6-yl;
2-oxo-2,3-dihydro-lH-pyrido[2,3-b][l,4]thiazin-7-yl;
2,3-dihydro-[l,4]dioxino[2,3-c]pyridin-7-yl;
3-oxo-3,4-dihydro-2H-pyrido[3,2-b] [ 1,4]oxazin-6-yl;
[l,2,3]thiadiazolo[5,4-b]pyridin-6-yl;
3-oxo-3,4-dihydro-2H-pyrido[3,2-b][l,4]thiazin-6-yl;
7-chloro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][l,4]thiazin-6-yl;
7-fluoro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][l,4]thiazin-6-yl;
2-thienylthio; or
2,5-difluorophenyl.
7. A compound or a pharmaceutically acceptable salt thereof, according to any one of
(Formula Removed)
claims 1-6, wherein R is , wherein
indicates the point of attachment.
8. A compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1-3 which is a compound of formula II:
(Formula Removed)
R2a, R2b, R2C, and R2d are each independently H, fluoro, chloro, cyano, (C1-C6)alkyl, halo(C1-C6)alkyl, halo(C1-C66)alkoxy, (C1-C6)alkoxy;
Z is CH orN when " " is a bond, or Z is O or NH when " — " is absent;
M is a group of formula M1a or M2-M5:

(Formula Removed)
in the trans configuration relative to "*";
Ry and Ry1 are each independently H, hydroxy, fluoro, chloro, methoxy, carboxy, CO2(C1-C6)alkyl, or (C1-C6)alkyl, or together with tlie carbon to which they are attached form C=0; or Ry and Ry' together form a bridge;
X is CH2, NH, N(C1-C6)aIkyl, N[CO-(C1-C6)alkyl], N[SO2(C1-C6)alkyl] or O;
Y is CH2, NH, N(C1-C6)alkyl, N[CO-(C1-C6)alkyl], N[SO2(C1-C6)alkyl] or O;
when M is a group of formula Mia or M4, U2 is NR'-W, wherein R' is IT, (C1-C6)alkyl, -(C1-C6)alkylcarboxy, -CO-(C,-C6)alkyl, -CO2(C,-C6)alkyl, -CO-NH(C1-C6)alkyl, -CO-N((C1-C6)alkyl)2, any of which may be optionally substituted on carbon with halo, hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy, S02(C1-C6)alkyl, NII2, NH(C1-C6)alkyl, or N((C1-C6)alkyl)2; and W is CH2, CO, SO2, CII2CH2, CH2CH=CH, or CII2C=C, wherein each hydrogen may he optionally replaced by halo or (C1-C6)alkyl;
when M is a group of formula M2, M3, or M5, U2 is W wherein W is as defined herein above; and
when W is CH2) CO or S02, R is aryl, hetcroaryl, heterocyclyl or ortho-fused bicyclic heteroaryl, or when W is CH2CH2, CH2CH-CH, or CH2CsC, R is aryl, hcteroaryl, heteroaryl(C1-C6)alkyloxy, heteroaryl(C1-C6)alkylthio, heteroaryl(C1-C6)alkylsulfinyI, heteroaryl(C1-C6)alkylsulfonyl, heteroaryl(C1-C6)alkylamino; wherein any R may be optionally substituted on carbon; and wherein any ring nitrogen in R may be optionally substituted by (C1-C6)alkyl.

9, A compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1-3 or 5-7 which is a compound of formula III:
(Formula Removed)
wherein
R2a, R2b, R2c, and R2d are each independently H, fluoro, chloro, cyano, (C1-C6)alkyl. halo(C1-C6)alkyl, halo(C1-C6)alkoxy, (C1-C6)alkoxy;
Z is CH or N when " is a bond, or, when is absent, Z is 0 or NH;
Y1 is N or CRj, wherein R2 is H, hydroxy, or carboxy;
U2 is NR'-W, wherein W is CH2, CO, SO2, CH2CH2, CH2CH=CH, or CH2CsC, wherein each hydrogen may be optionally replaced by halo or (C1-C6)alkyl; and
(Formula Removed)
R is , wherein" indicates
the point of attachment.
10. A compound, or a phannaceutically acceptable salt thereof, according to any one of claims 1-7 which is a compound of formula IV:

(Formula Removed)

wherein
R2a, R2b, R2c, and R2d are each independently H, fluoro, chloro, cyano, nitro, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkyl, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, (C1-C6)alkoxy,NHCO-(C1-C6)alkyl> S02(C1-C6)alkyl, S02NH(C1-C6)alkyl, or S02N((C1-C6)alkyl)2;
Z is CH or N when " "" " is a bond, or, when " "-- "is absent, Z is 0 or NH;
R'isHor(C1-C6)alkyl;
W is CO, SO2, or CH2, wherein each hydrogen may be optionally replaced by halo or (C1-C6)alkyl; and
(Formula Removed)
R is , wherein indicates
the point of attachment.
11, A compound according to any one of claims 1-7 or 9, or a pharmaceutically acceptable salt thereof, which is a compound of formula V:
(Formula Removed)
wherein
R2a, R2b, R2C, and R2d are each independently H, fluoro, chloro, cyano, nitro, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkyl, halo(C1-C6)allcyl, halo(C1-C6)alkoxy, (C1-C6)alkoxy, NHCO-(Ci-C6)alkyl, S02(C1-C6)alkyl, S02NH(C1-C6)alkyl, or S02N((C1-C6)alkyl)2;
Z is CH or N when " " is a bond, or, when " "is absent, Z is O or NH; and
(Formula Removed)

12. A compound, or a pharmaceutically acceptable salt thereof, which is
l-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-l-yl}ethyl)-7-methoxyquinolin-2(lH)-one;
l-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)ainino]piperidin-l-yl}ethyl)-7-methoxyquinolin-4(lH)-one;
Methyl l-(2-{4-[(2,3-dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1 -yl} ethyl)-6-methoxy- lH-indole-2-carboxylate;
6-[({ 1 -[2-(7-Methoxy-2-oxoquinolin-1 (2H)-yl)ethyl]piperidin-4-yl} amino)methyl]-2H-pyrido[3,2-b] [ 1,4]oxazin-3 (4H)-one;
1 -(2- {4-[(2,3-Dihydro[ 1,4]dioxino[2,3-c]pyridin-7-ylmethyl)arnmo]piperidin-1 -yl} ethyl)-2-oxo-1,2-dihydroquinoline-7-carbonitrile;
2-Oxo-1 -[2-(4- {[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b] [ 1,4]oxazin-6-yl)methyl]amino} piperidin-1 -yl)ethyl]-1,2-dihydroquinoline-7-carbonitrile;
6-[({l-[2-(7?8-Difluoro-2-oxoquinolin-l(2H)-yl)ethyl]piperidin-4-yl}amino)methyl]-2#-pyrido[3,2-b][l,4]oxazin-3(4H)-one;
6-[({l-[2-(5,7-Difluoro-2-oxoquinolin-l(2H)-yl)ethyl]piperidin-4-yl}amino)methylj-2//-pyrido[3,2-6][l,4]oxazin-3(4H)-one;
6-[({l-[2-(7-Fluoro-2-oxoquinolin-l(2H)-yl)ethyl]piperidin-4-yl}amino)methyl]-2//-pyrido[3,2-b] [1,4]oxazin-3(4H)-one;
l-(2-{4-[(2)3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-l-yl}ethyl)-7-fluoroquinolin-2(l,H)-one;
6-[( {1 -[2-(7-Methoxy-2-oxo-3,4-dihydroquinolin-1 (2H)-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][l,4]oxazin-3(4H)-one;
(3S,4R)-l-[2-(5>7-Difluoro-2-oxoquinolin-l(2H-yl)ethyl]-4-[(2,3-dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidine-3-carboxylic acid;
(3S,4R)- l-[2-(5,7-Difluoro-2-oxoquinolin-1 (2H)-yl)ethyl]-4- {[(2E)-3-(2,5-difluorophenyl)prop-2-en-1 -yl]amino}piperidine-3-carboxylic acid;
Methyl (3S',4R)-l-[2-(5,7-difluoro-2-oxoquuiolin-l(2H)-yl)ethyl]-4-[(2,3-dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidine-3-carboxylate;
Methyl (3S,4R)-l -[2-(5,7-difluoro-2-oxoquinolin-l(2H-yl)ethyl]-4- {[(2E)-3-(2,5-difluorophenyl)prop-2-en-1 -yl]amino}piperidine-3-carboxylate;
(3R)4R)-l-[2-(5,7-Difluoro-2-oxoquinolin-l(2H)-yl)ethyl]-4-[(2,3-dihydro[l,4]dioxino[2,3-6']pyridin-7-ylmethyl)amino]pipcridinc-3-carboxylic acid;

(3R,4R)-l-[2-(5,7-Difluoro-2-oxoquinolin-l(2H)-yl)ethyl]-4-{[(2E)-3-(2,5-difluorophenyl)prop-2-en-l-yl]amino}piperidine-3-carboxylic acid;
Methyl (3R,4R)-l-[2-(5,7-difluoro-2-oxoquinolin-l(2H)-yl)ethyl]-4-[(2,3-dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidine-3-carboxylate;
Methyl (3S,4R)-l-[2-(5,7-difluoro-2-oxoquinolin-l(2H)-yl)ethyl]-4-{[(2E)-3-(2,5-difluorophenyl)prop-2-en-l-yl]amino}piperidine-3-carboxylate;
Cis(±)6-[({l-[2-(5,7-Difluoro-2-oxoquinolin-l(2H)-yl)ethyl]-3-hydroxypiperidin-4-yl}amino)methyl]-2H-pyrido[3,2-6][l,4]oxazin-3(4H)-one;
4-(2-{4-[(2)3-Dihydro[l,4]dioxino[213-c]pyridin-7-ylmethyl)amino]pipendin-l-yl}ethyl)-6-methoxy-2H-l,4-benzoxazin-3(4H)-one;
6-[({l-[2-(6-Methoxy-3-oxo-2,3-dihydi-o-4H-l,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2b][l,4]oxazin-3(4H)-one;
6-[({l-[2-(6-Methoxy-3-oxo-2,3-dihydro-4H-l,4-benzothia7.in-4-yl)ethyl]piperidin-4-yl}araino)methyl]-2H-pyrido[3,2-b][l,4]oxazin-3(4H)-one;
4-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylraethyl)amino]piperidin-l-yl}ethyl)-6-methoxy-2H-1,4-benzothiazin-3(4H)-one;
6-[({l-[2-(6-Fluoro-3-oxo-2,3-dihydro-4H-l,4-benzoxazin-4-yl)cthyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][l,4]oxazin-3(4H)-one;
4-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-l-yl} cthyl)-6-fluoro-2H-1,4-benzoxazin-3 (4H)-onc;
6-[({l-[2-(6-Chloro-3-oxo-2,3-dihydro-4H-l,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][l,4]oxazin-3(4H)-one;
6-[({l-[2-(6-Methoxy-3-oxo-2,3-dihydro-4H-l,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-Z)][lJ4]thiazin-3(4H)-one;
3-Oxo-4-[2-(4-{[(3-oxo-3,4-dihydro-2H-pyrido[3)2-b][l,4]oxazin-6-yl)methyl]amino}piperidin-l-yl)ethyl]-3,4-dihydro-2H-l,4-benzoxazinc-6-carbonitrile;
6-{[(l-{2-[3-Oxo-6-(trifluoromethoxy)-2,3-dihydro-4H-ls4-benzoxazin-4-yl]ethyl}piperidin-4-yl)aTnino]methyl}-2H-pyrido[3,2-b)][l,4]oxazin-3(4H)-one;
6-[({l-[2-(6-Fluoro-3-oxo-2,3-dihydro-4H'-l,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}amino)methyl]-2H'-pyrido[3,2-Z)][l)4]thiazin-3(4H)-one;
4-(2-{4-[(2,3-Dihydro[l,4]dioxino[2(3-c]pyridin-7-ylmethyl)amirio]piperidin-l-yl}ethyl)-3-oxo-3,4-dihydro-2H-l,4-benzoxazine-6-carbonitrile;

6-[({l-[2-(6-Bromo-3-oxo-2,3-dihydro-4H-l)4-benzoxazin-4-yl)ethyl]piperidin-4-yl} amino)methyl]-2H-pyrido[3,2-b] [ 1,4]oxazin-3(4H)-one;
6-[( {1 -[2-(6-Hydroxy-3 -oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidin-4-yl} amino)methyl]-2//-pyrido[3,2-b] [ 1,4]oxazin-3(4H)-one;
4-{2-[4-({[2-(2,5-Difluorophenyl)cyclopropyl]methyl}amino)piperidin-l-yl]ethyl}-3-oxo-3,4-dihydro-2/f-l,4-benzoxazine-6-carbonitrile;
6-[({l-[2-(6,8-Difluoro-3-oxo-2,3-dihydro-4H-l,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}amino)metb.yl]-2Hr-pyrido[3,2-6][l,4]oxazin-3(4H)-one;
4-[2-(4-{[(2E)-3-(2,5-Difluorophenyl)prop-2-en-l-yl]amino}piperidin-l-yl)ethyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile;
6-[(trans-4-[2-(6-Methoxy-3-oxo-2,3-dihydro-4H-l,4-benzoxazin-4-yl)ethyl]cyclohexyl} amino)methyl]-2H-pyrido[3,2-b] [ 1,4]oxazin-3(4H)-one;
3-Oxo-4-[2-(tran.s-4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][l,4]oxazin-6-yl)raethyl]amino}cyclohexyl)ethyl]-3,4-dihydro-2H-l)4-benzoxazine-6-carbonitrile;
6-Bromo-4-[2-(4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][l,4]oxazin-6-yl)methyl]amino}piperidin-1 -yl)ethyl]-2tf-pyrido[3,2-b] [ 1,4]oxazin-3(4H)-one;
6-[({l-[2-(6-Nitro-3-oxo-2,3-dihydro-4//-l)4-benzoxazin-4-yl)ethyl]piperidin-4-yl} amino)methyl]-2H-pyrido [3,2-b] [ 1,4] oxazin-3 (4H)-one;
3-Oxo-4-[2-(4-{t(3-oxo-3,4-dihydro-2H'-pyrido[3,2-b][l,4]oxazin-6-yl)methyl] amino} piperid in-1 -yl)ethyl]-3,4-dihydro-2//-pyrido [3,2-b] [ 1,4]oxazine- 6-carbonitrile;
3-Oxo-4-[2-(4-{[(3-oxo-3,4-dihydro-2Hr-pyrido[3)2-b][l,4]oxazin-6-yl)methyl]amino}piperidin-l-yl)ethyl]-3,4-dihydro-2H-pyrido[3,2-i][l,4]oxazinc-6-carboxamide;
Methyl 3-oxo-4-[2-(4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-i][l,4]oxaxin-6-yl)methyl]amino}piperidin-l-yl)ethyl]-3,4-dihydro-2H-l,4-benzoxazine-6-carboxylate;
6-[({l-[2-(6-AcetyI-3-oxo-2,3-dihydro-4H-l,4-bcnzoxazin-4-yl)ethyl]piperidin-4-yl} amino)methyl]-2H-pyrido[3,2-b] [ 1,4]oxazin-3 (4H)-one;
6-Acetyl-4-(2-{4-[(2,3-dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1 -yl} ethyl)-2H-1,4-benzoxazin-3 (4H)-one;
4-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]pipcridin-l-yl} ethyl)-6-methyl-2H-1,4-bcnzoxazin-3(4H)-one;

3-Oxo-4-[2-(6-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-A][l,4]oxazin-6-yl)methyl]amino}-3-azabicyclo[3.1.0]hex-3-yl)ethyl]-3,4-dihydro-2//-l,4-benzoxazine-6-carbonitrile;
4-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-l-yl} etiayl)-2H-1,4-benzoxazin-3(4H)-one;
6-{[(l-{2-[6-(l-Hydroxyethyl)-3-oxo-2,3-dihydro-4H-l,4-benzoxazin-4-yl]ethyl}piperidin-4-yl)amino]methyl}-2H-pyrido[3,2-b][l,4]oxazin-3(4H)-one;
Ethyl N- {1 -[2-(6-cyano-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidiri-4-yl} -N-[(2E)-3 -(2,5-difluorophenyl)prop-2-en-1 -yl]glycinate;
6-{[(l-{2-[6-(Methylsulfonyl)-3-oxo-2,3-dihydro-4H-l,4-benzoxazin-4-yl]ethyl}piperidin-4-yl)amino]methyl}-2H-pyrido[3,2-b][l,4]oxazin-3(4H)-one;
6-{[(l-{2-[6-(Ethylsulfonyl)-3-oxo-2,3-dihydro-4H-l,4-bcnzoxazin-4-yl]ethyl}piperidin-4-yl)amino]methyl}-2H-pyrido[3,2-b][l,4]oxazm-3(4H)-one;
6-[( {1 -[2-(7-Methoxy-2-oxo-2H-3,1 -benzoxazin-1 (4H)-yl)ethyl]piperidin-4-yl} amino)methyl]-2H-pyrido[3,2-b)][l ,4]oxazin-3(4H)-one;
7-Methoxy-3-methyl-l-[2-(4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][l,4]oxazin-6-yl)methyl]amino}piperidin-l-yl)ethyl]quinazoline-2,4(lH,3H-dione;
4-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-2-oxopiperidin-l--yl} ethyl)-6-methoxy-2H-1,4-benzoxazin-3(4H)-one;
6-[({ 1 -[2-(6-Methoxy-3-oxo-2,3-dihydro-4H-l ,4-benzoxazin-4-yl)ethyl]-2-oxopiperidin-4-yl}amino)methyl]-2Hr-pyrido[3,2-H][l)4]oxazin-3(4H)-oue;
3-Oxo-4-[2-(2-oxo-4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][l,4]oxazin-6-yl)methyl]amino}piperidin-1 -yl)ethyl]-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile;
6-( {4-[3-(7-Methoxy-2-oxo-2H~3,1 -benzoxazin-1 (4H)-yl)propyl]piperazin-1 -yl}methyl)-2H-pyrido[3,2-b][l,4]oxazin-3(4H)-one;
4-{3-[4-(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)piperazin-l-yl]propyl}-6-methoxy-2H-1,4-benzoxazin-3 (4H)-one;
4-[2-({l-[(2E)-3-(2,5-Difluorophenyl)prop-2-en-l-yl]piperidin-4-yl}amino)ethyl]-6-methoxy-2H-l,4-benzoxazin-3(4H|)-one;
4-(3-{4-[(2E)-3-(2,5-Difluorophenyl)prop-2-en-l-yl]piperazin-l-yl}propyl)-6-raethoxy-2H-1,4-benzoxazin-3(4H)-one;
6-[({l-[2-(6-Mcthoxy-2-oxo-l,7-naphthyridin-l(2H)-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][l,4]oxazin-3(4H)-one;

Methyl l-[(2E)-3-(2,5-difluorophenyl)prop-2-en-l-yl]-4-[3-(6-cyano-3-oxo-2,3-dihydro-4/f-l,4-benzoxazin-4-yl)propyl]piperidine-3-carboxylate;
4-[3-(6-Cyano-3-oxo-2,3-dihydro-4H-l34-benzoxazin-4-yl)propyl]-l-[(2E)-3-(2,5-difluorophenyl)prop-2-en-l -yl]piperidine-3-carboxylic acid;
7-Fluoro-3-methyl-l-[2-(4-{[(3-oxo-3,4-dihydro-2H-pyridof3)2-b][l,4]oxazin-6-yl)methyl]amino}piperidin-l-yl)ethyl]quinazoline-2,4(lH,3H)-dione;
7-Chloro-1-(2-{4-[(2,3-dibydro[l ,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-l-yl}ethyl)-l,8-naphthyridin-2(lH)-one;
l-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-l-yl} ethyl)-7-methoxy-1,8-naphthyridin-2( 1 H)-one;
l-(2-{4-[(2,3-Dihydro[l,4]dioxmo[2,3-c]pyridin-7-ylmethyl)araino]piperidin-l-yl}ethyl)-7-fluoroquinoxalin-2(lH)-one;
6-[({l-[2-(7-Fluoro-2-oxoquinoxalin-l(2H)-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-6][l,4]oxazin-3(4H)-one;
1 -(2- {4-[(2,3-Dihydro[ 1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1 -
yl}ethyl)-6-fluoroquinoxalin-2(lH)-one;
l-(2-{4-[(2>3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-l-yl}ethyl)-7-methoxyquinoxalin-2(lH)-one;
6-[({l-[2-(7-Methoxy-2-oxoquinoxaIin-l(2H)-yl)ethyl]piperidin-4-yl}amino)methyl|-2H-pyrido[3,2-b][l,4]oxazin-3(4H)-one;
6-[( {1 -[2-(7-Methoxy-2-oxoquinoxalin-1 (2H)-y l)ethyl]piperidin-4-yI} amino)methj'l j-2H-pyrido[3,2-6][l,4]thiazin-3(4H)-one;
l-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmeth}'l)amino]piperidin-l-y 1} ethyl)-6,7-difluoroquinoxalin-2( lH)-one;
6-[({l-[2-(6,7-Difluoro-2-oxoquinoxalin-l(2H)-yOetM]piperid'n-4-yl}amino)methyl]-2H-pyrido[3,2-b][l,4]oxazin-3(4H)-one;
l-(2-{4-[(213-Dihydro[l)4]dioxino[2,3-c]pyridin-7-ylmcthyl)amino]piperidin-l-yl}ethyI)-7,8-difluoroquinoxalin-2(lH)-one;
6-[({l-[2-(7J8-Difluoro-2-oxoquinoxalin-l(2H)-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][l,4]oxazin-3(4H)-one;
6-[({l-[2-(6J7-Dimethoxy-2-oxoquinoxalin-l(2H)-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,-2b][ 1,4]oxazin-3(4H)-one;

6-[({l-[2-(7-Methoxy-3-methyl-2-oxoquinoxalin-l(2H)-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][l,4]oxazin-3(H)-one;
l-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]pipcridin-l-
yl} ethyl)quinolin-2(1H)-°neJ
l-(2-{4-[(2,3-Dihydrofl,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-l-yl} ethyl)quinolin-4( 1 H) -one;
Cis(±)6-[({l-[2-(5,7-difluoro-2-oxoquinolin-l(2H)-yI)ethyl]-3-methoxypiperidin-4-yl}amino)methyl]-2H-pyrido[3)2-6][l,4]oxazin-3(4H)-oric;
7-Fluoro-2-oxo-l-[2-(4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-6][l>4]oxazin-6-yl)methyl]amino}piperidin-l-yl)ethyl]-l,2-dihydroquinoline-5-carbonitrile;
5-Fluoro-2-oxo-l-[2-(4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][l,4]oxazin-6-yl)methyl]amino}piperidin-l-yl)ethyl]-l,2-dihydroquinoline-7-carbonitrile;
7-Fluoro-l-[2-(4-{[(2-oxo-l,2-dihydroquinolin-3-yl)methyl]amino}piperidin-l-yl)ethyl]quinoxalin-2( 1H)-one;
1 -[2-(4-{[(2,2-Dimethyl-3,4-dihydro-2H-chromen-6-yl)methyl]amino}piperidin- 1 -yl)ethyl]-5,7-difluoroquinolin-2(lH)-one;
l-[2-(4-{[(l,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)methyl]amino}pipcridin-l-yl)ethyl]-57-difluoroquinolin-2(lH)-one;
5,7-Difluoro-l -(2- {4-[(5,6)7,8-tetrahydronaphthal6n-2-ylraethyl)amino]pipcridin- 1 -yl}ethyl)quinolin-2(l//)-one;
5,7-Difluoro-l -[2-(4-{[(6-fluoro-4H:-l,3-benzodioxin-8-yl)methyl]amino}piperidin-l-
yl)ethyl]quinolin-2(lH)-°ne;
5,7-Difluoro- 1 -(2- {4-[ClH"-indol-6-ylraethyl)atnino]piperidin-l-yl} ethyl)quinolin-
2(lH)-one;
l-(2-{4-[(2,3-Dihydro-1H-inden-5-ylmethyl)amino]piperidin-l-yl}ethyl)-5,7-difluoroquinolin-2(lH)-one;
5,7-Difluoro-l-[2-(4-{[(l-methyl-lH-l,2,3-benzotriazol-5-yl)methyl]amino}pipt;ridin-1 -yl)ethyl]quinolin-2( lH)-one;
5,7-Difluoro-1-(2-{4-[( lH-indol-5-ylmethyl)amino]piperidin-1-yl} ethyl)quinolin-
2(lfl)-one;
5,7-Difluoro-l-[2-(4-{[(4-methyl-3,4-dihydro-2H-l,4-ben/oxazin-7-yl)methyl]amino}piperidin-l-yl)cthyl]quinolin-2(lH)-one;

1 -(2- {4-[(2,1,3-Benzoxadiazol-5-ylmethyl)aminojpiperidin-1 -yl} ethyl)-7-fluoroquinoxalin-2(lH)-one;
N- {l-[2-(7-Fluoro-2-oxoquinoxalin-l (2H)-yl)ethyl]piperidin-4-yl} -2,3-dihydro-1,4-benzodioxine-6-sulfonamide;
N- {1 -[2-(7-Fluoro-2-oxoquinoxalin-1 (2H)-yl)ethyl]piperidin-4-yl} -3-oxo-3,4-dihydro-2H-l,4-benzoxazine-6-sulfonamide;
5-Fluoro-N- {1 -[2-(7-fluoro-2-oxoquinoxalin-1 (2H)-yl)ethyl]piperidin-4-yl} - IH-indole-2-carboxamide;
N-{l-[2-(5,7-Difluoro-2-oxoquinolin-l(2H)-yl)ethyl]piperidin-4-yl}-6-inorpholin-4-yhiicotinamide;
N- {1 -[2-(5,7-Difluoro-2-oxoquinolin-l (2H)-yl)ethyl]piperidin-4-yl} -2,3-dihydro-1,4-benzodioxine-2-carboxamide;
N- {1 -[2-(5,7-Difluoro-2-oxoquinolin-1 (2H)-yl)ethyl]piperidin-4-yl) -1 -methyl-1H-l,2,3-benzotriazole-5-carboxamide;
N-{l-[2-(5,7-Difluoro-2-oxoquinolm-l(2H)-yl)ethyl]piperidm-4-yl}-3-(2-methyl-l,3-thiazol-4-yl)benzamide;
N- {1 -[2-(5,7-Difluoro-2-oxoquino lin-1 (2H)-y l)ethyl]piperidin-4-yl} -4-(5-mcthyl-1,2,4-oxadiazol-3-yl)benzamide;
3-Oxo-4-[2-((2R;5S)-5-{[(3-oxo-3)4-dihydro-2H-pyrido[3,2-][l>4]oxazin-6-yl)methyl]amino}piperidin-2-yl)ethyl]-3,4-dihydro-2H-l,4-benzoxazine-6-carbonitrile;
3.0xo-4-[2-((2S,5R)-5-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-6][l,4]oxazin-6-yl)methyl]amino}piperidin-2-yl)ethyl]-3,4-dihydro-2H-l,4-benzoxazine-6-carbonitrile;
6-[( {1-[2-(5,7-Difluoro-2-oxoquinoxalin-1 (2H)-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-6][l,4]oxazin-3(4H)-one;
6-[({l-[2-(6,8-Difluoro-2-oxoquinoxalin-l(2H)-yl)ethyl]piperidin-4-yl} amino)methyl]-2//-pyrido[3,2-6] [ 1,4]oxazin-3 (4H)-one;
2-Oxo-l-[2-(4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-6][l,4]oxazin-6-yl)methyl]amino}piperidin-l-yl)ethyl]-l,2-dihydroquinoxaline-6-carbonitrile;
3-Oxo-4-[2-(4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-6][l,4]oxazin-6-yl)methyl]amino}piperidin-l-yl)ethyl]-3,4-dihydroquinoxaline-6-carbonitrile;
6-[({l-[2-(6-Methoxy-3-oxopyrido[2,3-b]]pyrazin-4(3H)-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3J2-b][l,4]oxazin-3(4H)-one;

4-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-l-yl}ethyl)-6-methoxypyrido[2,3-6]pyrazin-3(4H)-one;
6-t({l-[2-(6-Chloro-l-oxido-3-oxo-l,2,4-benzotriazin-4(3H)-yl)etliyl]piperidin-4-yl} amino)methyl]-2H-pyrido[3,2-b] [1,4]oxazin-3(4H)-one;
6-Chloro-4-(2-{4-[(2,3-diihydro[l,4]dioxmo[2)3-c]pyridin-7-ylmethyl)amino]piperidin-1 -yl} ethyl)-1,2,4-benzotriazin-3 (4H)-one 1 -oxide;
6-[({l-[2-(6-Chloro-3-oxo-l,2,4-benzotriazin-4(3H-yl)ethyl]piperidin-4-yl} amino)methyl]-2H-pyrido[3,2-b][ 1,4]oxazin-3(4H)-one;
4-(2-{(2S)5R)-5-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-2-yl}ethyl)-3-oxo-3,4-dihydro-2H-l,4-benzoxazine-6-carbonitrile;
6-[({l-[2-(7-Bromo-2-oxo-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-l-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-6][l,4]oxazin-3(4H)-one;
2-Oxo-l-[2-(4-{[(3-oxo-3,4-dihydro-2H-pyrido[3)2-i][l,4]oxazin-6-yl)methyl]amino}piperidin-l-yl)ethyl]-2,3-dihydro-lH-pyrido[2,3-6][l,4]oxazine-7-carbonitrile;
2-Oxo-1 -[2-(4- {[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b] [ 1,4]oxazin-6-yl)methyl]amino}piperidin-l-yl)ethyl]-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazine-7-carboxamide;
l-(2-{4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-2-methylpiperidin-l-yl}ethyl)-5,7-difluoroquinolin-2(lH)-one;
1 -(2- {4-[(2,3-Dihydro[l ,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1 -yl}ethyl)-2-oxo-l,2-dihydroquinoline-7-carbonitrile;
Cis±4(l-[(2H)-3-(2,5-difluorophenyl)prop-2-en-l-yl]-4-[3-(6-methoxy-3-oxo-2,3-dihydro-4/f-l,4-benzoxazin-4-yl)propyl]piperidine-3-carboxylicacid;
Methyl (Cis±4)-l-[(2H)-3-(2,5-difluofophenyl)prop-2-en-l-yl]-4-[3-(6-methoxy-3-oxo-2,3-dihydro-4H-l,4-benzoxazin-4-yl)propyl]piperidine-3-carboxylate;
Cis±l-(2-{4-[(2,3-dihydro[l,4]dioxino[2,3-c]pyridm-7-ylmethyl)amino]-3-hydroxypiperidin-1 -yl} ethyl)-2-oxo-1,2-dihydroquinoline-7-carbonitrile;
Cis±l-[2-(3-hydroxy-4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][l,4]oxazin-6-yl)methyl]amino}piperidin-l-yl)ethyl]-2-oxo-l,2-dihydroquinoline-7-carbonitrile;
5,7-Difluoro-1 -(2- {4-[(5,6,7,8-tetrahydro-1,8-naphthyridin-2-ylmethyl)amino]piperidin-1 -yl} ethyl)quinolin-2(lH)-one;

Cis±l-(2-{4-[(2,3-dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3-methoxypiperidin-1 -yl} ethyl)-2-oxo-1,2-dihydroquinoline-7-carbonitrile;
Cisil-[(2-[3-methoxy-4-{[(3--oxo-3,4-dihydro-2H-pyridotS^-Altl.^oxazin-e-yl)methyl]amino}piperidin-1 -yl)ethyl]-2-oxo-l ,2-dihydroquinoline-7-carbonitrile;
Cis±l-(2-{4-[(2,3-dihydro[l,4]dioxmo[2,3-c]pyridin-7-ylmethyl)amino]-3-fluoropiperidin-l-yl}ethyl)-2-oxo-l,2-dihydroquinoline-7-carbonitrile;
Cis±l-[2-(3fluoro-4-{[(3-oxo-3,4-dihydro-2H'-pyrido[3,2-A][l,4]oxazin-6-yl)methyl]amino}piperidin-l-yl)ethyl]-2-oxo-l,2-dihydroquinoline-7-carbonitrile;
Cis±l-(2-{4-[(2,3-dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3-hydroxypiperidin-l-yl}ethyl)-7-fluoroquinoxalin-2(lH)-one;
Cis±6-[({l-[2-(7-fluoro-2-oxoquinoxalin-l(2H)-yl)ethyl]-3-hydroxypiperidin-4-yl}amino)methyl]-2flr-pyrido[3,2-6][l,4]oxazin-3(4fl)-one;
Cis±l -(2- {4-[(2,3 -dihydro[l ,4]dioxino[2,3-c]pyridin-7-ylmethyl)araino]-3-methoxypiperidin-1 -yl} ethyl)-7-fluoroquinoxalin-2(lH)-one;
Cis±6-[({l-[2-(7-fluoro-2-oxoquinoxalin-l(2H)-yl)ethyl]-3-methoxypiperidin-4-yl} amino)methyl]-2H-pyrido[3,2-b] [ 1,4]oxazin-3 (4H)-one;
Cis±l-(2-{4-[(2,3-dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3-fluoropiperidin-l-yl}ethyl)-7-fluoroquinoxalin-2(lH)-one;
Cis±6-[({l-[2-(7-fluoro-2-oxoquinoxalin-l(2H)-yl)ethyl]-3-fluoropiperidin-4-yl}amino)methyl]-2Hr-pyrido[3,2-6][l,4]oxazin-3(4H-one;
Cis± l-(2- {4-[(2,3-dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3-hydroxypiperidin-1 -yl} ethyl)-7-methoxyquinoxalin-2(lH)-one;
Cis±6-[({l-[2-(7-methoxy-2-oxoquinoxalin-l(2H)-yl)ethyl]-3-hydroxypiperidin-4-yl}amino)methyl]-2H-pyrido[3,2-6][l,4]oxazin-3(4H)-one;
Cis±l -(2- (4-[(2,3-dihydro[l ,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3-metboxypiperidin-l-yl}ethyl)-7-methoxyquinoxalin-2(lH)-one;
Cis±6-[({l-[2-(7-methoxy-2-oxoquinoxalin-l(2H)-yl)ethyl]-3-methoxypiperidin-4-yl}amino)methyl]-2H-pyrido[3,2-6][l,4]oxazin-3(4H)-one;
Cis±l-(2-{4-[(2,3-dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3-fluoropiperidin-1 -yl} ethyl)-7-methoxyquinoxalin-2( 1 H)-one;
Cis±6-[({l-[2-(7-methoxy-2-oxoquinoxalin-l(2H)-yl)ethyl]-3-fluoropiperidin-4-yl}amino)methyl]-2//-pyridot3,2-b][l,4]oxazin-3(4H)-one;

Cis±4-[2-(3-hydroxy-4-{[(3-oxo-3,4-dihydro-2/ir-pyrido[3)2-b][l,4]oxazin-6-yl)methyl]amino}piperidin-l-yl)ethyl]-3-oxo-3,4-dihydro-2H-l,4-benzoxazine-6-carbonitrile;
Cis±4-[2-(3-methoxy-4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-fe][l,4]oxazin-6-yl)methyl]amino}piperidin-l-yl)ethyl]-3-oxo-3,4-dihydro-2H'-l,4-benzoxazine-6-carbonitrile;
Cis±4-[2-(3-fluoro-4-{[(3-oxo-3,4-dihydro-2H-pyrido[3)2-6][l,4]oxazin-6-yl)methyl]amino}piperidin-l-yl)ethyl]-3-oxo-3,4-dihydro-2H-l,4-benzoxazine-6-carbonitrile;
1 -(2- {4-[(2,3-Dihydro[l ,4]dioxino[2,3-c]pyridin-7-ylmetliyl)amino]piperidin-1 -yl} ethyl)-7-methoxy-3,4-dihydroquinoxalin-2( lH)-one;
5,7-Difluoro-l -[2-(4- {[(1 -oxo-1,3-dihydro-2-benzofuran-5-yl)methyl]amino}piperidin-l-yl)ethyl]quinolin-2(lH)-one;
6-[({l-[2-(7-Methoxy-2-oxoquinoxalin-l(2^0-yl)propyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-6][l,4]oxazin-3(4H)-°ne; or
5,7-Difluoro-l-(2-{4-[(5,6,718-tetrahydro-l,8-naphthyridin-2-ylmethyl)amino]piperidin-1 -yl} ethyl)quinolin-2(lH)-one.
13. A pharmaceutical composition comprising a compound according to any one of claims
1-12, or a pharmaceutically acceptable salt thereof, admixed with a pharmaceutically
acceptable adjuvant, carrier, or excipient.
14. A method of treating a bacterial infection comprising administering a therapeutically
effective amount of a compound, or a pharmaceutically acceptable salt thereof, according to
any one of claims 1-12 to a mammal in need thereof.
15. A method of treating a bacterial infection in a warm-blooded animal, such as a human
being, in need of such treatment, which comprises administering to said animal an effective
amount of a compound, or a pharmaceutically acceptable salt thereof, according to any one of
claims 1-12 or a pharmaceutically-acceptable salt thereof.
16. A method for inhibiting bacterial DNA gyrase in a warm-blooded animal, such as a
human being, in need of such treatment which comprises administering to said animal an
effective amount of a compound, or a pharmaceutically acceptable salt thereof, according to
any one of claims 1-12 or a pharmaceutically acceptable salt.

17. A compound, ot a pharmaceutically acceptable salt thereof, according to any one of
claims 1-12 or a pharmaceutically acceptable salt thereof for use as a medicament.
18. The use of a compound, or a pharmaceutically acceptable salt thereof, according to
any one of claims 1-12 or a pharmaceutically acceptable salt thereof in the manufacture of a
medicament for use in the production of an anti-bacterial effect in a warm-blooded animal
such as a human being.
19. The use of a compound, or a pharmaceutically acceptable salt thereof, according to
any one of claims 1-12 or a pharmaceutically acceptable salt thereof in the manufacture of a
medicament for use in the treatment of a bacterial infection hi a warm-blooded animal such as
a human being.
20. A process for making a compound, or a pharmaceutically acceptable salt thereof,
according to any one of claims 1-12, comprising one of the following:
(a) N-alkylation of L with X-U1M, wherein X is a leaving group in the presence of a base to form LU1M, wherein U1 is CH2CH2, followed by attachment of U2 and R via functional group manipulation, alkylation, or reductive amination;
(Formula Removed)
(b) N-alkylation of L with HO-U1M, under Mitsunobu conditions to form LU1M,
followed by attachment of U2and R via functional group manipulation, alkylation, or reductive amination;
(Formula Removed)
(c) N-alkylation of L with bromo- or chloroacetic acid or a derivative thereof to form
(Formula Removed)

followed by

(Formula Removed)

activation of the acid moiety in
ii) amide coupling to form LU1M, wherein U1 is CH2CO,
iii) attachment of U2 and R via functional group manipulation, alkylation, or
reductive animation; and iv) optional reduction of the carbonyl moiety in Ui to form a compound wherein
(Formula Removed)
(d) N-alkylation of L with X-(CH2)nCH=CH2 wherein X is a leaving group and n is 1 or 2 to form L-(CH2)nCH=CH2, followed by: i) oxidative cleavage using an oxidant such as ozone or sodium periodate (with
reductive workup) to form L-(CH2)nCH2OH;
ii) conversion of the alcohol moiety in L-(CH2)nCH2OH to a leaving group; iii) reaction of L--(CH2)nCH2-Y with M, in the presence of a base to form LUjM;
and iv) attachment of U2 and R via functional group manipulation, alkylation, or
reductive amination;
(Formula Removed)
X,Y = leaving group n= 1 or 2
(e) N-alkylation of L with X-(CH2)nCH=CH2 wherein X is a leaving group and n is 1 or 2 to form L-(CH2)nCH=CH2, followed by: i) hydroboration followed by an oxidative workup to form to form L-
(Formula Removed)
ii) conversion of the alcohol moiety in L-CH2CH2OH to a leaving group; iii) reaction of L-CH2CH2-"LG" with M, hi the presence of a base to form LUiM; and
iv) followed by attachment of U2 and R via functional group manipulation, alkylation, or reductive animation; or
(Formula Removed)
X,Y = leaving group n- 1 or 2
(0 Oxidation of the alcohol intermediate in d) and e) supra to the aldehyde
(Formula Removed)
.followed by
i) reductive animation with MU2; to form LUiMU2, wherein Ul is CH2CH2; ii) reductive animation with R.
(Formula Removed)
21. A compound of formula (I) and/or a pharmaceutical composition and/or a method of treating and/or the use of a compound and/or a process substantially as herein described with reference to the given examples.

Documents:

9254-delnp-2007-abstract.pdf

9254-delnp-2007-Claims-(27-05-2014).pdf

9254-DELNP-2007-Claims.pdf

9254-delnp-2007-Correspondence Others-(14-03-2014).pdf

9254-delnp-2007-Correspondence Others-(15-04-2014).pdf

9254-delnp-2007-Correspondence Others-(18-02-2014).pdf

9254-delnp-2007-Correspondence Others-(27-05-2014).pdf

9254-DELNP-2007-Correspondence-Others-(22-05-2009).pdf

9254-delnp-2007-correspondence-others.pdf

9254-delnp-2007-description (complete).pdf

9254-delnp-2007-form-1.pdf

9254-DELNP-2007-Form-18-(22-05-2009).pdf

9254-delnp-2007-form-2.pdf

9254-delnp-2007-Form-3-(14-03-2014).pdf

9254-delnp-2007-Form-3-(18-02-2014).pdf

9254-delnp-2007-form-3.pdf

9254-delnp-2007-form-5.pdf

9254-delnp-2007-pct-210.pdf

9254-delnp-2007-pct-304.pdf

Petitions under Rule 137.pdf

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Patent Number

263869

Indian Patent Application Number

9254/DELNP/2007

PG Journal Number

48/2014

Publication Date

28-Nov-2014

Grant Date

25-Nov-2014

Date of Filing

30-Nov-2007

Name of Patentee

ASTRAZENECA AB

Applicant Address

SE-151 85 SODERTALJE, SWEDEN.

Inventors:

#	Inventor's Name	Inventor's Address
1	GENG, BOLIN	ASTRAZENECA R&D BOSTON, 35 GATEHOUSE DRIVE, WALTHAM, MASSACHUSETTS 02451, U.S.A.
2	BREAULT, GLORIA	ASTRAZENECA R&D BOSTON, 35 GATEHOUSE DRIVE, WALTHAM, MASSACHUSETTS 02451, U.S.A.
3	EYERMANN, CHARLES, JOSEPH	ASTRAZENECA R&D BOSTON, 35 GATEHOUSE DRIVE, WALTHAM, MASSACHUSETTS 02451, USA
4	MORNINGSTAR, MARSHALL	ASTRAZENECA R&D BOSTON, 35 GATEHOUSE DRIVE, WALTHAM, MASSACHUSETTS 02451, USA
5	RECK, FOLKERT	ASTRAZENECA R&D BOSTON, 35 GATEHOUSE DRIVE, WALTHAM, MASSACHUSETTS 02451, USA

PCT International Classification Number

C07D 401/06

PCT International Application Number

PCT/GB2006/002207

PCT International Filing date

2006-06-16

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	60/691,340	2005-06-16	U.S.A.