Indian Patents
Title of Invention

"A PIPERIDINE HYDROXYL-ALKYL AMIDE COMPOUND"
Abstract The invention provides compounds of formula (DChemical formula should be inserted here. Please see paper copyjwherein: X is CH2, O, S(O)2 or NR10; Y is a bond, CH2, MR35 CH2NH, CH2NHC(O), CH(OH) CH(NHCOR33), CH(NHSO2R34) CH2O or CH2S Z isC(O), or when Y is a bond Z can also be S(O)2; Rl is optionally substituted aryloptionally substituted heterocyclyl or G4-6 cycloalkyl fused to a benzene ring; and R2 R3 R4 R5, R6, R7 and Rs, R9, R10, R32, R33, Rand R35 are as defined herein;are modulators of chemokine (especially CCR3) activity (for use in, for example,treating asthma). The invention also provides a process for making 4-(3,4-dichlorophenoxy)piperidine, which is useful as an intermediate for making certain compounds of the invention.
Full Text CHEMICAL COMPOUNDS
The present invention concerns piperidine derivatives having pharmaceutical activity, to processes for preparing such derivatives, to pharmaceutical compositions comprising such derivatives and to the use of such derivatives as active therapeutic agents, The invention also provides a process for making 4-(3,4-dichlorophenoxy)piperidine, which is useful as an intermediate for making certain compounds of the invention.
Phannaceutically active piperidine derivatives are disclosed in WO 01/62728, WO 01/62729 and WO 01/62757.
Chemokines are chemotactic cytokines that are released by a wide variety of cells to attract macrophages, T cells, eosinophils, basopbils and neutrophils to sites of inflammation and also play a role in the maturation of cells of the immune system. Chemokines play an important role in immune and inflammatory responses in various diseases and disorders, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. These small secreted molecules are a growing superfamily of 8-14 kDa proteins characterised by a conserved four cysteine motif. The chemokine superfamily can be divided into two main groups exhibiting characteristic structural motifs, the Cys-X-Cys (C-X-C, or a) and Cys-Cys (C-C, or P) families. These are distinguished on the basis of a single amirio acid insertion between the NH-proximal pair of cysteine residues and sequence similarity.
The C-X-C chemoldnes include several potent chemoattractants and activators of aeutrophils such as interleukin-8 (IL-8) and neutrophil-activating peptide 2 (NAP-2).
The C-C chemoldnes include potent chemoattractants of monocytes and lymphocytes, but not neutrophils, such as human monocyte chemotactic proteins 1-3 (MCP-1, MCP-2 and MCP-3), RANTES (Regulated on Activation, Normal T Expressed and Secreted), eotaxins and the macrophage inflammatory proteins la and ip (Mff-la andMIP-lp).
Studies have demonstrated that the actions of the chemoldnes are mediated by subfamilies of G protein-coupled receptors, among which are the receptors designated CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CXCR1, CXCR2, CXCR3 and CXCR4. These receptors represent good targets for drug development since agents which modulate these, receptors would be useful in the treatment of disorders and diseases such as those mentioned above.

Histamine is a basic amine, 2-(4-iiru\iazolyl)-emylamine, and is formed from histidine by histidine decarboxylase. It is found in most tissues of the body, but is present in high concentrations in the lung, skin and in the gastrointestinal tract. At the cellular level inflammatory cells such as mast cells and basophils store large amounts of histamine. It is recognised that the degranulation of mast cells and basophils and the subsequent release of histamine is a fundamental mechanism responsible for the clinical manifestation of an allergic process. Histamine produces its actions by an effect on specific histamine G-protein coupled receptors, which are of three main types, HI, H2 and H3. Histamine HI antagonists comprise the largest class of medications used in the treatment of patients with allergic disorders, especially rhinitis and urticaria. Antagonists of HI are useful in controlling the allergic response by for example blocking the action of histamine on post-capillary venule smooth muscle, resulting in decreased vascular permeability, exudation and oedema. The antagonists also produce blockade of the actions of histamine on the HI receptors on c-type nociceptive nerve fibres, resulting in decreased itching and sneezing.
Viral infections are known to cause lung inflammation. It has been shown experimentally that the common cold increases mucosal output of eotaxin in the airways. Instillation of eotaxin into the nose can mimic some of the signs and symptoms of a common cold. (See, Greiff L et al Allergy (1999) 54(11) 1204-8 [Experimental common cold increase mucosal output of eotaxin in atopic individuals] and Kawaguchi M et al Int. Arch. Allergy Immunol (2000) 122 SI 44 [Expression of eotaxin by normal airway epithelial cells after virus A infection].)
The present invention provides a compound of formula (I):

erein:
XisCH2,0,S(O)2orNR10;
Y is a bond, CH2, NR35, CH2NH, CH2NHC(0), CH(OH), CH(NHC(O)R33),
CH(NHS(0)2R34), CH20 or CH2S;
Z is C(O), or when Y is a bond Z can also be S(0)2;
R1 is optionally substituted aryl, optionally substituted heterocyclyl or €4.5 cycloalkyl
fused to a benzene ring; ._.
R4 is hydrogen, Ci-6 alkyl (optionally substituted by C3.6 cycloalkyl) or C3.6 cycloalkyl;

R2, R3, R5, R6, R7 and R8 are, independently, hydrogen, d-g alkyl or C3.6 cycloalkyl; m and n are, independently, 0 or 1;
R9 is optionally substituted aryl or optionally substituted heterocyclyl; R10, R32 and R35 are, independently, hydrogen, C\.6 alkyl or C3.6 cycloalkyl; R33 and R34 are Cw alkyl or C3-6 cycloalkyl;
wherein the foregoing aryl and heterocyclyl moieties are, where possible, optionally substituted by: halogen, cyano, nitro, hydroxy, oxo, S(O)kR12, OC(O)NR13R14, NR!5R16, NRI7C(0)R18, NR19C(O)NR20R21, S(O)2NR22R23, NR24S(O)2R25, C(0)NR26R27, C(O)R2SJ CO2R29, NR30CO2R3J, C,_6 alkyl (itself optionally mono-substituted by NHC(O)phenyl), Ci-6 haloalkyl, CM alkoxy(C]^)alkyl, Ci_6 alkoxy, CM haloalkoxy, CM alkoxy(Ci_ e)alkoxy, CM alkylthio, C2-6 alkenyl, C2.6 alkynyl, C3.io cycloalkyl, methylenedioxy, difluoromethylenedioxy, phenyl, phenyl(Ci^)alkyl, phenoxys phenylthio, phenyl(Cj. R13, R14, R15, R16, R17, R18, R19, R20, R2:, R22, R23, R24, R26, R27, R29 and R30 are, independently, hydrogen, Q-e alkyl (optionally substituted by halogen, hydroxy or C3.jo cycloalkyl), CH2(C2.6 alkenyl), C3.6 cycloalkyl, phenyl (itself optionally substituted by halogen, hydroxy, nitro, NH2, NH(CM alkyl), NH(CM alkyl)2, S(0)2(CM alkyl), S(0)2NH2, S(0)2NH(CM alkyl), S(O)2N(CM alkyl)2, cyano, CM alkyl, CM alkoxy, C(0)NH2, C(0)NH(CM alkyl), C(0)N(CM alkyl)2, C02H, C02(CM alkyl), NHC(O)(CM alkyl), NHS(O)2(CM alkyl), C(0)(C!-4 alkyl), CF3 or OCF3) or heterocyclyl (itself optionally substituted by halogen, hydroxy, nitro, NH2, NH(Ci-4 alkyl), N(Ci-4 alkyl)2, S(O)2(CM alkyl), S(O)2NH2, S(O)2NH(CM alkyl), S(O)2N(CM alkyl)2, cyano, CM alkyl, CM alkoxy, C(O)NH2, C(O)NH(CM alkyl), C(O)N(CM alkyl)2, CO2H, CO2(CM alkyl), NHC(0)(CM alkyl), NHS(0)2(CM alkyl), C(0)(CM alkyl), CF3 or OCF3); alternatively NR13R14, NR15R16, NR20R21, NR^R23, NR26R27, may, independently, form a 4-7 membered heterocyclic ring selected from the group: azetidine (itself optionally .

suDstituted by Jiydroxy or CM alkyl), pyrrolidine, piperidine, azepine, 1,4-morphoIine or 1,4-piperazine, the latter optionally substituted by CM alkyl on the distal nitrogen; R1 , R25, R28 andR31 are, independently, C\.6 alkyl (optionally substituted by halogen, hydroxy or C3-io cycloalkyl), CH2(C2^ alkenyl), phenyl (itself optionally substituted by halogen, hydroxy, nitro, NH2, NH(CM alkyl), N(CM alkyl)2 (and these alkyl groups may join to form a ring as described for R13 and R14 above), S(0)2(Ci-4 alkyl), S(0)2NH2} S(0)2NH(Ci.4 alkyl), S(O)2N(CM alkyl)2 (and these alkyl groups may join to form a ring as described for R13 and R14 above), cyano, CM alkyl, CM alkoxy, C(O)NH2, C(0)NH(CM alkyl), C(0)N(Ci-4 alkyl)2 (and these alkyl groups may join to form a ring as described for R13 and R14 above), C02H, CO2(CM alkyl), NHC(O)(CM alkyl), NHS(0)2(CM alkyl), C(O)(Ci-4 alkyl), CF3 or OCF3) or heterocyclyl (itself optionally substituted by halogen, hydroxy, nitro, NH2, NH(CM alkyl), N(€M alkyl)2 (and these alkyl groups may join to form a ring as described for R13 and R14 above), S(O)2(CM alkyl), S(O)2NH2, S(O)2NH(Ci-4 alkyl), S(O)2N(C]_4 alkyl)2 (and these alkyl groups may join to form a ring as described for R13 and R14 above), cyano, CM alkyl, CM alkoxy, C(0)NH2, C(O)NH(CM alkyl), C(O)N(CM alkyl)2 (and these alkyl groups may join to form a ring as described for R13 and R14 above), CO2H, CO2(CM alkyl), NHC(O)(CM alkyl), NHS(O)2(CM alkyl), C(O)(CM alkyl), CF3 or OCF3);
provided that when X is CH2 and m and n are both 0 then Y is not NR3^; or an N-oxide thereof; or a pharmaceutically acceptable salt, solvate or solvate of a salt thereof.
Certain compounds of the present invention can exist in different isomeric forms (such as enantiomers, diastereomers, geometric isomers or tautomers). The present invention covers all such isomers and mixtures thereof in all proportions.
Suitable salts include acid addition salts such as a hydrochloride, dihydrochloride, hydrobromide, phosphate, sulfate, acetate, diacetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulfonate or j>toluenesulfonate.
The compounds of the invention may exist as solvates (such as hydrates) and the present invention covers all such solvates.
Halogen includes fluorine, chlorine, bromine and iodine. Alkyl groups and moieties are straight or branched chain and are, for example, methyl, ethyl, n-propyl, iso-propyl or tert-butyl. Alkyl groups preferably comprise 1-6 carbon atoms.

Alkenyl is, for example, vinyl or allyl. Alkenyl groups preferably comprise 2-6 carbon atoms.
Alkynyl is, for example, propargyl. Alkynyl groups preferably comprise 2-6 carbon atoms.
Cycloalkyl is monocyclic and is, for example, cyclopropyl, cyclopentyl or cyclohexyl. Cycloalkyl groups preferably comprise 3-6 carbon atoms.
Cycloalkyl fused to a benzene ring is, for example, bicyclo[4.2.0]octa-l,3,5-trienyl. Aryl is preferably phenyl or naphthyl.
Heterocyclyl is an aromatic or non-aromatic 5 or 6 membered ring, optionally fused to one or more other rings, comprising at least one heteroatom selected from the group comprising nitrogen, oxygen and sulfur; or an N-oxide thereof, or an S-oxide or S-dioxide thereof. Heterocyclyl is, for example, furyl, thienyl (also known as thiophenyl), pyrrolyl, 2,5-dihydropyrrolyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, piperidinyl, morpholinyl, pyridinyl, 1,6-dihydropyridinyl (for example in a 6-oxo-l,6-dihydropyridinyl moiety), pyrimidinyl, indolyl, 2,3-dihydroindolyl, benzo[b]fUryl (also known as benzfuryl), benz[b]thienyl (also known as benzthienyl or benzthiophenyl), 2,3-dihydrobenz[b]thienyl (for example in a l,l-dioxo-2,3-dihydrobenz[b]thienyl moiety), indazolyl, benzimidazolyl, benztriazolyl, benzoxazolyl, benzthiazolyl, 1,2-dihydrobenzthiazolyl (for example in a 1H-benztbiazol-2-one-yl moiety), 2,3-dmydrobenzthiazolyl (for example in a 2,3-dihydrobenzthiazol-2-one-yl moiety), 1,2,3-benzothiadiazolyl, an imidazopyridinyl (such as imidazo[l,2-a]pyridinyl), thieno[3,2-b]pyridin-6-yl, 1,2,3-benzoxadiazolyl (also known as benzo[l,2,3]thiadiazolyl), 2,1,3-benzothiadiazolyl, benzofurazan (also known as 2,1,3-benzoxadiazolyl), quinoxalinyl, 3,4-dihydro-lH-2,l-benzothiazinyl (for example in a 2-dioxo-3,4-dihydro-lH-2,l-benzothiazinyl moiety), a pyrazolopyridine (for example 1H-pyrazolo[3,4-b]pyridinyl), a purine, 3,7-dihydro-purinyl (for example in a 3,7-dihydro-purin-2,6-dione-8-yl moiety), quinolinyl, isoquinolinyl, 1,2-dihydroisoquinolinyl (for example in a 2H-isoquinolin-l-one-yl (alternatively called 1-oxo-1,2-dihydroisoquinolinyl or 1,2-dihydroisoquinolinyl-l-one) moiety), a naphthyridinyl (for example [l,6]naphthyridinyl or [l,8]naphthyridinyl)3 l,4-dihydro[l,8]naphthyridinyl (for example in a lH-[l,8]naphthyridin-4-one-yl moiety), or a benzothiazinyl, 4H-benzo[l,4]thiazinyl (for example in a 4H-benzo[l,4]thiazin-3-one-yl moiety); or an N-oxide thereof (such as a pvridine N-oxide), or an S-oxide or S-dipxide thereof. 1,2-Dihydropyridinyl (an alternative numbering for a 1,6-dihydropyridinyl) can also be present in a 2-oxo-l,2-

dihydropyridinyl moiety; and 2,3-dihydro-lH-indazolyl can also be present in a 3-oxo-2,: dihydro-lH-indazolyl moiety.
Heterocyclyl also includes cinnolinyl, phthalazinyl, 3,4-dihydrophthalazinyl (for example in a 4-oxo-3,4-dihydroplithalaziayl moiety), benzoxazinyl, 2,3-dihydro-4H-l,4-benzoxazinyl (for example in a 3-oxo-2,3-diliydro-4H-l,4-benzoxazinyl moiety), 3,4-dmydro-2H-l54-benzoxazinyl (for example in a 3-oxo-3,4-dihydro-2H-l,4-benzoxazmyl moiety), isoindolyl, l)3-diliydro-2H-isoindolyl (for example in a l,3-dioxo-l,3-dihydro-2H-isoindolyl moiety), pyrazolotriazinyl (for example pyrazolo[5,l-c][l,2,4]triazinyl), pyrazinyl, pyridazinyl, 9H-purinyl, pyrazolopyrimidinyl (for example pyrazolo[l,5-a]pyrimidinyl), imidazobenzothiazolyl (for example imidazo[2,l-b][l,3]ben2othiazolyl), 1,2,5-oxadiazolyl, imidazopyrimidinyl (for example imidazo[l,2-a]pyrimidinyl), quinolinyl, 1,2-dihydroquinolinyl (for example in a 2-oxo-l,2-dihydroquinolinyl moiety) or 2,1,3-benzoxadiazolyl (for example as a 1-oxide); or it may additionally be anN-oxide thereof, or an S-oxide or S-rdioxide thereof. Further examples of heterocyclyl are 1,3-benzothiazole, 2,3-dihydro-l,3-benzothiazole (for example in a 2-oxo-2,3-dihydro-l,3-benzothiazole moiety), 4,5,6,7-tetrahydroindazole, 2,3-dihydro-lH-benzimidazole (for example in a 2-oxo-2,3-dihydro-lH-benzimidazole moiety) and 1,4-dihydroquinoline (for example in a 4-oxo-l,4-dihydroquinolin.e moiety).
An N-oxide of a compound of formula (I) or (la) is, for example, a 1-oxy-piperidinyl compound.
Heteroaryl is an aromatic heterocyclyl. Thus it is, for example furyl, thienyl, pyrrolyl, tbiazolyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, pyridinyl, pyrimidinyl, indolyl, benzo[b]furyl, benz[b]thienyl, indazolyl, benzimidazolyl, benztriazolyl, benzoxazolyl, benzthiazolyl, 1,2,3-benzothiadiazolyl, an imidazopyridinyl, thieno[3,2-b]pyridin-6-yl 1,2,3-benzoxadiazolyl, 2,l,3-benzothiadiazolyl,benzofurazan, quinoxalinyl a pyrazolopyridine, a purine, quinolinyl, isoquinolinyl, a naphthyridinyl, a benzothiazinyl, sinnolinyl, phthalazinyl, benzoxazinyl, isoindolyl, pyrazolotriazinyl pyrazinyl, pyridazinyj pyrazolopyrimidinyl, imidazobenzothiazolyl, imidazopyrimidinyl quinoUnyl or 2,1,3-benzoxadiazolyl; or an N-oxide thereof (such as a pyridine N-oxide), or an S-oxide or S-dioxide thereof.
Haloalkyl is an alkyl group carrying one or more (such as 1 to 6) halogen atoms and is, for example, CF3. Alkoxyalkyl is, for example, CH3OCH2, CH3CH2OCH2 or CH3CH20(CH2)2. Haloalkyloxy is an alkoxy group carrying one or more (such as 1 to 6)

halogen atoms and is, for example, OCF3. Alkoxyalkoxy is, for example, CH3OCH2O, CH3CH2OCH2O or CH3CH20(CH2.)20. Phenylalkyl is, for example, benzyl, phenyleth-1-yl or phenyleth-2-yl. Phenylalkoxy is, for example benzyloxy. Heteroarylalkyl is, for example, pyridinyhnethyl or pyrimidinybnemyL Heteroaryloxy is, for example, pyridinyloxy or pyrimidinyloxy. Heteroarylalkoxy is, for example, pyridinyknethoxy or pyrimidinyknethoxy.
In one aspect the present invention provides a compound of formula (I) wherein: X is CH2, 0, S(O)2 or MR10; Y is a bond, CH2, NR35, CH2NH, CH2NHC(O), CH(OH), CH(NHC(O)R33), CH(NHS(0)2R34), CH2O or CH2S; Z is C(O), or when Y is a bond Z ca also be S(0)2; R1 is optionally substituted aryl, optionally substituted heterocyclyl or C^ cycloalkyl fused to a benzene ring; R4 is hydrogen, Ci-6 alkyl (optionally substituted by C-. 6 cycloalkyl) or C3^ cycloalkyl; R2, R3, R5, R6, R7 and R8 are, independently, hydrogen, C 6 alkyl or C3_6 cycloalkyl; m and n are, independently, 0 or 1; R9 is optionally substituted aryl or optionally substituted heterocyclyl; R10, R32, R33 and R35 are, independently, hydrogen or Cj.6 alkyl; R34 is Ci-e alkyl; wherein the foregoing aryl and heterocyclyl moieties are, where possible, optionally substituted by: halogen, cyano, nitro, hydroxy, oxo, S(O)kR12, OC(0)NR13R14, NR15R16, NR17C(O)R18, NR19C(0)NR20R21, S(O)2NR22R2: NR24S(O)2R25, C(O)NR26R27, C(O)R28, CO2R29, NR30CO2R31, d.6 alkyl, Cw haloalkyl, Ct-6 alkoxy(Ci-6)alkyl, C\.6 alkoxy, C\.6 haloalkoxy, C].6 alkoxy(Ci.6)alkoxy, Cw alkylthic C2.6 alkenyl, C2.6 alkynyl, C3.io cycloalkyl, memylenedioxy, difluoromethylenedioxy, phenyl, phenyl(d-4)alkyl, phenoxy, phenylthio, phenyl(CM)alkoxy, heteroaryl, heteroaryl(CM)alkyl, heteroaryloxy or heteroaryl(Ci-4)alkoxy; wherein .any .of the immediately foregoing phenyl and heteroaryl moieties are optionally substituted with halogen, hydroxy, nitro, S(O),{Ci-4 alkyl), S(O)2NH2, cyano, CM alkyl, CM alkoxy, C(O)NH2, C(O)NH(CM alkyl), CO2H, CO2(CM alkyl), NHC(O)(CM alkyl), NHS(O)2(Ci-
alkyl), C(O)(CM alkyl), CF3 or OCF3; k and r are, independently, 0, 1 or 2; R13, R14,R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, K26, R27, R29, R30, and R31 are, independently, hydrogen, Ci-6 alkyl (optionally substituted by halogen, hydroxy or C3.io cycloalkyl), CH2(C2.
hydroxy, nitro, NH2, NH(CM alkyl), N(CM alkyl)2, S(O)2(CM alkyl), S(O)2NH2, S(0)2NH(CM alkyl), S(0)2N(CM alkyl)2, cyano, CM alkyl, CM alkoxy, C(O)NH2, C(0)NE(CM alkyl), C(O)N(CM alkyl)2, C02H, CO2(Ci^ alkyl), KHC(O)(CM alkyl), NHS(0)2(CM alkyl), C(O)(CM alkyl), CF3 or OCF3); alternatively NR13R14, NR15R16, NR20R21, NR^R23, NR26R27, may, independently, form a 4-7 membered heterocyclic ring, azetidine, pyrrolidine, piperidine, azepine, 1,4-morphoUne or 1,4-piperazine, the latter optionally substituted by CM alkyl on the distal nitrogen; R12, R25 and R28 are, independently, C^ alkyl (optionally substituted by halogen, hydroxy or C3.30 cycloalkyl), CH2(C2_6 alkenyl), phenyl (itself optionally substituted by halogen, hydroxy, nitro, NH2, NH(CM alkyl), N(CM alkyl)2 (and these alkyl groups may join to form a ring as described for R13 and R14 above), S(O)2(CM alkyl), S(O)2NH2, S(O)2NH(CM alkyl), S(O)2N(CM alkyl)2 (and these alkyl groups may join to form a ring as described for R13 and R14 above), cyano, CM alkyl, CM alkoxy, C(O)NH2, C(O)NH(CM alkyl), C(O)N(CM alkyl)2 (and these alkyl groups may join to form a ring as described for R13 and R14 above), CO2H, C02(CM alkyl), NHC(0)(CM alkyl), NHS(O)2(CM alkyl), C(0)(CM alkyl), CF3 or OCF3) or heterocyclyl (itself optionally substituted by halogen, hydroxy, nitro, NH2, NH(CM alkyl), N(CM alkyl)2 (and these alkyl groups may join to form a ring as described for R13 andR14 above), S(0)2(CM alkyl), S(O)2NH2, S(0)2NH(CM alkyl), S(O)2N(CM alkyl)2 (and these alkyl groups may join to form a ring as described for R13 and R14 above), cyano, CM alkyl, CM alkoxy, C(O)NH2, C(O)NH(CM alkyl), C(O)N(CM alkyl)2 (and these alkyl groups may join to form a ring as described for R13 and R14 above), CO2H, COZ(CM alkyl), NHC(0)(C,-4 alkyl), NHS(O)2(CM alkyl), C(O)(CM alkyl), CF3 or OCF3); provided that when X is CH2 and m and n are both 0 then Y is not NR35; or an N-oxide thereof; or a pharmaceutically acceptable salt, solvate or solvate of a salt thereof.
hi another aspect the present invention provides a compound of formula (la):
R^ ^ N—CR2R3 (CH2)rn-
R4 O
OH
• CR5R6 (CR7Ra)n—N—n—R9
H II
(la)
wherein: X is CH2, O, S(O)2 or NR10; R1 is optionally substituted aryl or optionally substituted heterocyclyl; R4 is hydrogen, Q.6 alkyl (optionally substituted by C3_e cycloalkyl) or C3.6 cycloalkyl; R2, R3, R5, R6, R7 and R8 are, independently, hydrogen, Q-6 alkyl or C3-e cycloalkyl; m and n are, independently, 0 or 1; R9 is optionally substituted

aryl or optionally substituted heterocyclyl; R10 is hydrogen or d-6 alkyl; wherein the foregoing aryl and heterocyclyl moieties are, where possible, optionally substituted by: halogen, cyano, nitro, hydroxy, oxo, S(O)kR12, OC(O)NR13R14, NR15R16, NRJ7C(O)R18, NR19C(0)NR20R21, S(0)2NR22R23, NR^CThR25, C(0)NR26R27, C(0)R28, C02R29, NR30C02R31, d-6 alkyl Q.6 haloalkyl, d-6 alkoxy(d-6)alkyl, d-6 alkoxy, d.6 haloalkoxy, d-6 alkoxy(d-6)alkoxy, d-s alkylthio, C2.6 alkenyl, C2.6 alkynyl, C3.i0 cycloalkyl, methylenedioxy, difluoromethylenedioxy, phenyl, phenyl(d-4)alkyl, phenoxy, phenylthio, phenyl(CM)alkoxy, heteroaryl, heteroaryl(d-4)alkyl, heteroaryloxy or heteroaxyl(d-4)alkoxy; wherein any of the immediately foregoing phenyl and heteroaryl moieties are optionally substituted with halogen, hydroxy, nitro, S(O)r(d-4 alkyl), S(0)2NH2) cyano, CM alkyl, CM alkoxy, C(O)NH2, C(0)NH(d^ alkyl), CO2H, CO2(CM alkyl), NHC(0)(d-4 alkyl), NHS(0)2(d.4 alkyl), C(O)(CM alkyl), CF3 or OCF3; k andr are, independently, 0, 1 or 2; R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R26, R27, R29, R30, and R3J are, independently, hydrogen, d_6 alkyl (optionally substituted by halogen, hydroxy or C3.io cycloalkyl), CH2(C2^ alkenyl), phenyl (itself optionally substituted by halogen, hydroxy, nitro, NH2, NH(d^ alkyl), NH(d-4 alkyl)2, S(O)2(d-4 alkyl), S(O)2NH2, cyano, CM alkyl, CM alkoxy, C(O)NH2, C(O)NH(d^ alkyl), CO2H, CO2(d-4 alkyl), NHC(O)(CM alkyl), NHS(0)2(d-4 alkyl), C(O)(CM alkyl), CF3 or OCF3) or heterocyclyl (itself optionally substituted by halogen, hydroxy, nitro, NH2, NH(d-4 alkyl), N(d-4 alkyl)2, S(O)2(CM alkyl), S(O)2NH2, S(O)2NH(CM alkyl), S(O)2N(d-4 alkyl)2, cyano, CM alkyl, CM alkoxy, C(0)NH2j C(O)NH(CM alkyl), C(O)N(d-4 alkyl)2, C02H, CO2(d-4 alkyl), NHC(0)(CM alkyl), NHS(O)2(d-4 alkyl), C(O)(d-4 alkyl), CF3 or OCF3); alternatively NR13R14, NR15R16, NR20R21, NR^R23, NR26R27, may, independently, form a 4-7 membered heterocyclic ring, azetidine, pyrrolidine, piperiduie, azepine, 1,4-morpholine or 1,4-piperazine, the latter optionally substituted by d-4 alkyl on the distal nitrogen; R12, R2S and R28 are, independently, d_6 alkyl (optionally substituted by halogen, hydroxy or C3.i0 cycloalkyl), CH2(C2.6 alkenyl), phenyl (itself optionally substituted by halogen, hydroxy, nitro, NH2, NH(CM alkyl), N(CM alkyl)2 (and these alkyl groups may join to form a ring as described for R13 and R14 above), S(O)2(CM alkyl), S(O)2NH2, S(0)2NH(CM alkyl), S(0)2N(Ci4 alkyl)2 (and these alkyl groups may join to form a ring as described for R13 and R14 above), cyano, d-4 alkyl, d-4 alkoxy, C(O)NH2, C(0)NH(d-4 alkyl), C(0)N(d-4 alkyl)2 (and these alkyl groups may join to form a ring as described for R13 and R14 above), CO2H, C02(CM alkyl), NHC(0)(d-4 alkyl), NHS(O)2(CM alkyl), .

C(0)(C]-4 alkyl), CF3 or OCF3) or heterocyclyl (itself optionally substituted by halogen, hydroxy, nitro, NH2) NH(CM alkyl), N(CM alkyl)2 (and these alkyl groups may join to form a ring as described for R13 and R14 above), S(0)2(CM alkyl), S(O)2NH2, S(O)2NH(Ci 4 alkyl), S(O)2N(CM alkyl)2 (and these alkyl groups may join to form a ring as described for R13 and R14 above), cyano, CM alkyl, CM alkoxy, C(0)NH2, C(O)NH(CM alkyl), C(0)N(CM alkyl)2 (and these alkyl groups may join to form a ring as described for R13 anc R14 above), CO2H, C02(CM alkyl), NHC(0)(Cj-4 alkyl), NHS(0)2(CM alkyl), C(0)(CM alkyl), CFs or OCFs); or an N-oxide thereof; or a phannaceutically acceptable salt, solvate or solvate of a salt thereof.
In a further aspect the present invention provides a compound of formula (I) wherein: X is O; Y is a bond, CH2, NR35, CH2NH, CH(OH), CH(NHC(0)R33), CH(NHS(O)2R34) or CH2O; Z is C(O), or when Y is a bond Z can also be S(O)2; R1 is optionally substituted phenyl; R4 is hydrogen or C].6 alkyl; R2, R3, R5, R6, R7 and R8 are, when present, all hydrogen; m and n are, independently, 0 or 1; R9 is optionally substituted aryl or optionally substituted heterocyclyl; R32 and R35 are, independently, hydrogen or C\* alkyl; R33 and R34 are d-6 alkyl; wherein the foregoing phenyl, aryl and heterocyclyl moieties are, where possible, optionally substituted by: halogen, cyano, hydroxy, oxo, S(O)2R12, NR15R16, NR17C(O)R18, S(O)2NR22R23, NR^SfO)^25, C(O)NR26R27, CO2R29, Ci.6 alkyl (itself optionally mono-substituted by NHC(O)phenyl), CF3, OCF3, phenyl or heteroaryl; wherein any of the immediately foregoing phenyl and heteroaryl moieties are optionally substituted with halogen, CM alkyl, €1.4 alkoxy or CF3; R15, R16, R17, R18, R22, R23, R24, R26, R27 and R29 are, independently, hydrogen, C w alkyl (optionally substituted by hydroxy) or C3.e cycloalkyl; alternatively NR22R23 may form an azetidine ring (itself optionally substituted by hydroxy or CM alkyl); R12 and R25 are, independently, C\^ alkyl or phenyl; or a phannaceutically acceptable salt thereof.
hi a still further aspect R1 is phenyl optionally substituted (for example with one, two or three of) by halogen (especially fluoro or chloro), cyano, CM alkyl (especially methyl), CM alkoxy (especially methoxy), S(O)2(CM alkyl), S(O)2NH2, S(O)2NH(CW alkyl), S(0)2NH(C3-6 cycloalkyl), C(0)2(CM alkyl), C(O)NH(CM alkyl) or C(O)NH2.
hi another aspect R1 is phenyl optionally substituted (for example with one, two or three of) by halogen (especially fluoro or chloro), cyano, CM alkyl (especially methyl) or CM alkoxy (especially methoxy). In a further aspect R1 is phenyl substituted by one, two
i .«• •*•
or three of: fluoro, chloro, methyl or cyano. hi another aspect R1 is phenyl substituted by

one, two or three of: fluoro, cnloro or methyl. Thus, R1 is, for example, 2-methyl-4-cnlorophenyl, 3-methyl-2,4-dichlorophe:nyl, 3,4-difluorophenyl, 3-fluoro-4-chlorophenyl or 4-chlorophenyl. In a still further aspect R1 is 3,4-dichlorophenyl. In another aspect X is 0. In yet another aspect Y is a bond.
In another aspect Z is C(O).
In a further aspect m is 0.
In a still further aspect n is 0.
In another aspect m and n are both 0.
In another aspect R4 is hydrogen or Ci-6 alkyl (such as methyl). In yet another aspect R4 is hydrogen.
In yet another aspect R2, R3, R5, R6, R7 and R8 are all hydrogen; and in a further aspect n is 0, and R2, R3, R5 and R6 are all hydrogen.
In a further aspect R2, R3, R4, R5, R6, R7 and R8 are, when present, all hydrogen.
In a still further aspect R9 is mono- or di- substituted phenyl, unsubstituted heterocyclyl or mono- or di- substituted heterocyclyl, the substituents being chosen from those described above.
In another aspect R9 is optionally substituted heterocyclyl wherein the heterocyclyl group is: thienyl, pyrrolyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, 1,2,5-oxadiazolyl, pyridinyl, 1,6-dihydropyridinyl (for example in a 6-oxo-l,6-dihydropyridinyl or a 2-oxo-l,2-dihydropyridinyl moiety), pyrimidinyl, indolyl, indazolyl, 2,3-dihydro-lHT indazolyl (for example in a 3-oxo-2J3-dihydro-lH-indazolyl moiety), an imidazopyridinyl (such as iimdazo[l,2-a]pyridinyl), 2,1,3-benzotm'adiazolyl, quinoxalinyl, quinolinyl, 1,2-dihydroquinolinyl (for example in a 2-oxo-l,2-dihydroquinolinyl moiety), 1,4-dmydroquinoline (for example in a 4-oxo-l,4-dmydroquinoline moiety), isoquinolinyl, 1,2-dihydroisoquinolinyl (for example in a 2H-isoquinolin-l-one-yl (alternatively called 1-oxo-l,2-dihydroisoquinoLinyl or 1,2-dihydroisoquinolinyl-l-one) moiety), cinnolinyl, 3,4-dihydrophthalazinyl (for example in a 4-oxo-3,4-dihydrophthalazrnyl moiety), 2,3-dihydro-4H-l,4-benzoxazinyl (for example in a 3-oxo-2,3-dihydro-4H-l,4-benzoxazinyl moiety), 3,4-dihydro-2H-l,4-benzoxazinyl (for example in a 3-oxo-3,4-dihydro-2H-l,4-benzoxazinyl moiety), l,3-dihydro-2H-isoindolyl (for example in a l,3-dioxo-l,3-dihydro-2H-isoindolyl moiety), pyrazolotriazinyl (for example pyrazolo[5,l-c][l,2,4]triazinyl), pyrazolopyrimidinyl (for example pyrazolo[l,5-a]pyrimidinyl), imidazobenzothiazolyl (for

example Mdazo[2,l-bj[l,3]benzothiazolyl), inu'dazopyiimidinyl (for example imida2o[l,2-a]pyrimidinyl), or 2,1,3-benzoxadiazolyl (for example as a 1-oxide), 1,3-benzothiazole, 2,3-dmydro-l,3-benzothiazole (for example in a 2-oxo-2,3-dihydro-l,3-benzothiazole moiety), 4,5,6,7-tetrahydroindazole or 2,3-dihydro-lH-benzimidazole (for example in a 2-oxo-2,3-dihydro-lH-benzimidazole moiety).
In yet another aspect the aryl (such as phenyl) or heterocyclyl group R9 is unsubstituted or substituted by one or more of: oxo (where possible), halogen, CM alkyl, CF3, CM alkoxy, S(O)2(CM alkyl), S(O)2NH2, S(O)2NH(C,^ alkyl), S(O)2N(CM alkyl)2 or OCF3.
In a further aspect when R9 is heterocyclyl it is an optionally substituted thienyl, quinolinyl, 1,2-dihydroquinolinyl, 1,3-benzthiazolyl, 2,3-dihydro-l,3-benzothiazolyl, imidazo[l,2-a]pyridinyl, isoquinolinyl or 1,2-dihydroisoquinoh'nyl; or a 1,2-dihydropyridone, a 1,6-dihydropyridone, a pyrazolyl, apyrrolyl or an indolyl.
In yet another aspect R9 is phenyl or heterocyclyl (as defined anywhere above), either of which is optionally substituted by: halo, hydroxy, nitro, cyano, oxo, amino, CM alkyl (itself optionally substituted by S(O)2(Ci-4 alkyl) or S(O)2phenyl), CM alkoxy, S(O)kR12 {wherein k is 0, 1 or 2 (preferably 2); and R12 is CM alkyl, CM hydroxyalkyl, C3. 7 cycloalkyl(CM alkyl) (such as cyclopropylmethyl) or phenyl}, C(O)NH2, NHS(O)2(CM alkyl), S(0)2NH2, S(O)2NH(CM alkyl) or S(0)2N(CM alkyi)2 (and these alkyl groups may join to form a ring as described for R13 and R14 above). In another aspect R32 is hydrogen.
In a further aspect R13, R14,R15, R16, R17, R18, R19, R20, R2], R22, R23, R24,R26, R27, R29, R30, and R33 are, independently, hydrogen, Q-e alkyl (optionally substituted by halogen, hydroxy or C3.io cycloalkyl), CH2(C2_6 alkenyl), phenyl (itself optionally substituted by halogen or CM alkyl) or heterocyclyl (itself optionally substituted by halogen or CM alkyl); and R12, R25 and R28 are, independently, Ci-6 alkyl (optionally substituted by halogen, hydroxy or C3.i0 cycloalkyl), CH2(C2-e alkenyl), phenyl (itself optionally substituted by halogen or CM alkyl) or heterocyclyl (itself optionally substituted by halogen or CM alkyl).
In a still further aspect RI33 R14, R15, R16, RI75 R18, R19, R20, R21, R22, R23, R24,R26, R27, R29 and R30 are, independently, hydrogen, d.6 alkyl (optionally substituted by halogen, hydroxy or C3.j0 cycloalkyl), CH2(C2-6 alkenyl), phenyl (itself optionally substituted by halogen or CM alkyl) or heterocyclyl (itself optionally substituted by

halogen or CM alkyl); and R12, R25, R28 and R31 are, independently, C\* alkyl (optionaUy substituted by halogen, hydroxy or C3.10 cycloalkyl), CH2(C2-6 alkenyl), phenyl (itself optionally substituted by halogen or CM alkyl) or heterocyclyl (itself optionally substituted by halogen or CM alkyl).
In yet another aspect R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R26, R27, R29 and R30 are, independently, hydrogen or CM alkyl; and R12, R25, R28 and R31 are, independently, Ci.6 alkyl (optionally substituted by hydroxy)or phenyl. In a further aspect R10 is hydrogen.
In another aspect R35 is hydrogen or Ci.6 alkyl (such as methyl); (for example R35 is hydrogen).
In yet another aspect R33 is C^ alkyl (such as methyl). In a further aspect R34 is Q.6 alkyl (such as methyl).
In a still further aspect the present invention provides a compound of formula (I) or (la) wherein: R1 is phenyl optionally substituted by 2 halogens (such as chlorine); X is O; m is 0; n is 0 or 1; R2, R3, R4, R5, R6, R7 and R8 are all hydrogen; and R9 is phenyl, thienyl, quinolinyl, 1,3-benzthiazolyl, 2,3-dihydro-l,3-benzothiazolyl, imidazo[l,2-a]pyridinyl or 1,2-dihydroisoquinolinyl optionally substituted by S(O)2(CM alkyl) (for example S(O)2CH3), halogen (for example chlorine or fluorine), NH2, CM alkoxy (such as OCBb), cyano or, where possible, oxo.
In another aspect the present invention provides a compound of formula (I) or (la) wherein: R1 is phenyl optionally substituted by 1 or 2 halogens (such as chlorine), or by 1 or 2 halogens (such as chlorine) and a CM alkyl (such as methyl); X is O; m is 0; n is 0 or 1; R2, R3, R4, R5 and R6, and, when present, R7 and R8 are all hydrogen; and R9 is phenyl, thienyl, quinolinyl, 1,3-benzthiazolyI, 253-dihydro-l,3-benzothiazolyl, imidazo[l,2-ajpyridinyl, 1,2-dihydroisoqumolinyl, 1,2-dihydropyridinyl, 1,6-dihydropyridinyl or pyrazolyl, all optionally substituted by S(O)2(Ci-4 alkyl) (for example S(O)2CHs), S(O)2NH2j S(0)2NH(CM alkyl), S(0)2N(CM alkyl)2 (and the two alkyl groups may join together to form an azetidine ring), halogen (for example chlorine or fluorine), NEb, CM alkyl (such as CH3), CM alkoxy (such as OCH3), CF3, cyano or, where possible, oxo.
In a further aspect the present invention provides a compound of formula (I) or (la) wherein: R1 is phenyl optionally substituted by 1 or 2 halogens (such as chlorine), and optionally substituted by 0 or 1 C\.6 alkyl (such as methyl); X is O; m is 0; n is 0 or 1; R2, R3, R4, R5 and R6, and, when present, R7 and R8 are all hydrogen; and R9 is phenyl, thieny]

quinolinyl, 1,3-benzthiazolyl, 2,3-dihydro-l,3-benzothiazolyl, imidazo[l,2-a]pyridinyl, 1,2-dmydroisoquinolinyl, 1,2-dihydropyridinyl, 1,6-dihydropyridinyl, pyrazolyl, pyrrolyl or indolyl, all of which are optionally substituted by S(O)2(CM alkyl) (for example S(0)2CH3), S(0)2NH2j S(0)2NH(CM alkyl), S(O)2N(CM alkyl)2, halogen (for example chlorine or fluorine), NH2, CM alkoxy (such as OCH3), CM alkyl (such as methyl), CF3, OCF3, cyano or, where possible, oxo.
hi a still further aspect the present invention provides a compound of formula (I) or (la) wherein: R1 is phenyl optionally substituted by 1 or 2 halogens (such as chlorine), and optionally substituted by 0 or 1 Ci_6 alkyl (such as methyl); X is 0; m is 0; n is 0 or 1; R2, R3, R4, R5, R6, R7 and R8 are all hydrogen; and R9 is phenyl, thienyl, quinolinyl, 1,3-benzthiazolyl, 2,3-dihydro-l,3-benzothiazolyl, imidazo[l,2-a]pyridinyl or 1,2-dihydroisoquinolinyl, all of which are optionally substituted by S(O)2(Ci-4 alkyl) (for example S(O)2CH3), halogen (for example chlorine or fluorine), NH2, CM alkoxy (such as OCH3), CM alkyl (such as methyl), CF3, OCF3, cyano or, where possible, oxo.
In another aspect the present invention provides a compound of formula (I) or (la) wherein R9 is isoquinolinyl, l-oxo-l,2-dihydroisoquinolinyl, quinolinyl, 2-oxo-1,2-dihydroquinolinyl, 2-oxo-1,2-dihydropyridinyl, 6-oxo-l,6-dihydropyridinyl orpyrazolyl; each optionally substituted by halogen (such as fluorine), CM alkyl (such as methyl or ethyl), CF3, CM alkoxy (such as methoxy), S(O)2(CM alkyl) (for example S(O)2CH3), S(O)2NH2, S(0)2NH(CM alkyl), S(O)2N(CM alkyl)2 or OCF3.
hi a further aspect the present invention provides a compound of formula (I) or (la wherein R9 is isoquinolinyl, l-oxo-l,2-dihydroisoquinolmyl, quinolinyl or 2-oxo-1,2-dihydroquinohnyl; each optionally substituted by halogen (such as fluorine), CM alkyl (such as methyl or ethyl), CF3, CM alkoxy (such as methoxy), S(0)2(CM alkyl) (for example S(O)2CH3) or OCF3.
In a still further aspect R9 is l-oxo-l,2-dihydroisoquinolinyl optionally substituted by halogen (such as fluorine), CM alkyl (such as methyl or ethyl), CF3, CM alkoxy (such as methoxy), S(0)2(CM alkyl) (for example S(0)2CH3) or OCF3. Alternatively, R9 is 2-oxo-l,2-dihydroquinolinyl optionally substituted by halogen (such as fluorine), Ci-4 alkyl (such as methyl or ethyl), CF3, CM alkoxy (such as methoxy), S(O)2(CM alkyl) (for example S(O)2CH3) or OCF3.
In another aspect R9 is an oxo-substituted dihydropyridinyl (such as 6-oxo-l,6-dihydropyridin-3-yl, 2-oxo-l,2-dihydropyridin-5-yl or 2-oxo-l,2-dihydropyridin-4-yl), an

oxo-substituteddihydroisoquinolinyl (such as l-oxo-l,2-dmydroisoquinolin-4-yl), an oxo-substituted dihydrophthalazinyl (such as 4-oxo-3,4- dihydrophthalazin-1-yl), pyrazinyl (such as pyrazin-4-yl), pyrrolyl (such as pyrrol-3-yl) or indolyl (such as indol-3-yl), each of which is not further substituted or substituted by: halogen (such as chloro or fluoro), alkyl (such as methyl), CF3 or C3.5 cycloalkyl (such as cyclopropyl).
hi a further aspect R9 is an oxo-substituted dihydropyridinyl (such as 6-oxo-l,6-dihydropyridin-3-yl, 2-oxo-l,2-dihydropyridin-5-yl or 2-oxo-l,2-dihydropyridin-4-yl), an oxo-substituted dihydroisoquinohnyl (such as l-oxo-l,2-dihydroisoquinoHnyl-4-yl) or pyrazinyl (such as pyrazin-4-yl), each of which is not further substituted or substituted by: halogen (such as chloro or fluoro), CM alkyl (such as methyl) or CFs. An example of a compound of formula (I) or (la) is:
N- {(lR)-3-[4-(3,4-diclilorophenoxy)piperidin-1 -yl]-2-hydroxypropyl} -2-
(methylsulfonyl)benzamide;
7V-{(2J?)-3-[4-(354-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-4-
(methylsulfonyl)b enzamide;
2-chloro-N- {(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl} -4-
(methylsulfonyl)benzamide;
4-aniino-A^{(2^)-3-[4-(3J4-dicUorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-3-
methoxybenzamide;
JV-{(2/?)-3-[4-(3,4-dichlorophenoxy)piperidui-l-yl]-2-hydroxypropyl}-3-(methylsulfonyl)benzamide; Ar-{(ZR)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-5-
(methylsulfonyl)thiophene-2-carboxamide; A^-{(2J?)-3-[4-(354-dicUorophenoxy)piperidin-l-yl]-2-hydroxypropyl}quinohne-6-
carboxamide; JV-{(2/?)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-2-oxo-2,3-dihydro-
l,3-benzothiazole-6-carboxamide acetate salt; JV-{(2jf?)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-6-
fluoroimidazo[ 1,2-a]pyridine-2-carboxamide;
N-{ (2R)-3 - [4-(3 54-dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl} -1 -oxo-1,2-
dihydroisoquinoline-4-carboxamide;
A/'-{(2^)-3-[4-(3,4-dicmorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-l,3-benzothiazole-
6-carboxamide;

3-cyano-A^-{(2^)-3-[4-(3,4-dichIoroph.enoxy)piperidin-l-yl]-2-liydroxypropyl}ben2ainide,-
jV-{4-[4-(3,4-diclilorophenoxy)piperidin-l-yl]-3-liydroxybutyl}-2-
(methylsulfonyl)benzamide;
//-{4-[4-(3,4-dicWorophenoxy)piperidin-l-yl]-3-hydroxybutyl}-2-oxo-2,3-dihydro-l,3-benzotbiazole-6-carboxainide;
4-amino-M-{4-[4-(3,4-dic]ilorophenoxy)piperidin-l-yl]-3-hydroxybutyl}-3-
methoxybenzamide;
//-{4-[4-(3,4-dichlorophenoxy)piperidi3i-l-yl]-2-]iydroxybutyl}-2-
(methylsulfonyl)benzamide;
N- {(2R)-3 -[4-(2,4-dichloro-3 -methylphenoxy)piperidin-1 -yl] -2-hydroxypropyl} -2-
(raethylsulfonyl)benzamide;
N- {(2R)-3 -[4-(2,4-dichloro-3 -methylphenoxy)piperidin-1 -yl]-2-hydroxypropyl} -1 -oxo-
1,2-dihydroisoquinoline-4-carboxamide;
N- {(25)-3-[4-(3,4-dichloroplienoxy)piperidin-l -yl]-2-hydroxypropyl}-2-
(methylsulfonyl)benzamide;
N- {(2J?)-3-[4-(3 ?4-dicMorophenoxy)piperidin-1 -yl]-2-hydroxypropyl} -3-
[(methylamino)sulfonyl]benzamide;
3,5-bis(acetylamino)-JV'-{(2^)-3-[4-(334-dichlorophenoxy)piperidin-l-yl3-2-
hydroxypropyl}benzamide;
3-(Acetylamino)-jV'-{(2JR)-3-[4-(3,4-dichloroplienoxy)piperidin-l-yl]-2-
hydroxypropyl} benzamide;
A^{(2y?)-3-[4-(3,4-dicMorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-lJ^pyrazole-4-
carboxamide; 2-(Acetylarnino)-5-bromo-JV-{(2/2)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-
hydroxypropyl} benzamide; JV-{(2/2)-3-[4-(3,4-Diclilorophenoxy)piperidin-l-yl]-2-liydroxypropyl}-2-oxo-l,2-
dihydropyridine-3-carboxamide; A^-{(2/?)-3-[4-(3,4-Dichloropherioxy)piperidin-l-yl]-2-liydroxypropyl}-l-oxo-l,2-
dihydroisoquinoline-5-carboxamide; ^-{(2^)-3-[4-(3J4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}quinoline-4-
carboxamide; //-{(lS)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hvdroxvDroDvl)-lJSr-iridole-4-
carboxamide;

2-(Acetylamino)-7V"-{(2J2)-3-[4-(3,4-dicMoropIienoxy)piperidin-l-yl]-2-hydroxypropyl}benzamide;
2-(Acetylamino)-5-cUoro-^-{(2^)-3-[4- 2-(Acetylamino)-4-cMoro-J\T-{(lR)-3-[4-(334-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl} benzamide;
5-ChIoro-//-{(2J?)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-liydroxypropyl}-2-
[(methylsulphonyl)aminojbenzainide;
4-Chloro-//-{(2/?)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-2-
[(methylsulphonyl)amino]benzamide;
2-Amino-4-chloro-A'-{ (2^)-3-[4-(3,4-dicblorophenoxy)piperidin-1 -yl]-2-
hydroxypropyl}benzamide;
5-CUoro-7V-{(2^)-3-[4-(3,4-dicMorophenoxy)piperidiii-l-yl]-6-oxo-lJ6-dihydropyridine-
3-carboxamide;
2-(Aminosulphonyl)-4-chloro-^- {(2^?)-3 -[4-(3,4-dichlorophenoxy)piperidin-1 -yl]-2-
hydroxypropyl}benzamide;
N-{ (2/?)-3-[4-(3,4-dichlorophenoxy)pipeiidia-1 -yl]-2-hydroxypropyl}-7//'-indazole-3-
carboxamide;
l-^rt-Butyl-JV-{(2^)-3-[4-(3,4-dichloroplienoxy)pipeiidin-l-yl]-2-hydroxypropyl}-3-
methyl-y/f-pyrazole-S-carboxamide;
Ar-{(2^)-3-[4-(3,4-DicMorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-4,5J6,7-tetrahydro-
2/J-indazole-3-carboxamide:; ^-{(2/?)-3-[4-(3,4-DicWorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-3-(trifluoromethyr
2//-pyrazole-4-carboxamide;
JV-{(2/?)-3-[4-(354-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-2- . methylimidazo [ 1,2-a]pyridine-3-carboxaniide; N-{ (lft)-3-[4-(3,4-Dichlorophenoxy)piperidin-l -yl]-2-hydroxypropyl}-4-(^-pyrazol-3-
yl)benzamide; ^-{(2J?)-3-[4 carboxamide; Ar-{(2JR)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-2-
hydroxyquinoline-4-carboxamide;

Ar-{3-[4-(3,4-dichlorophenoxy)piperidiii-l-yl]-2-hydroxypropyl}-2-oxo-253-dihydro-lif-benzimidazole-1 -carboxamide;
A^{(lR)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-4-oxo-334-dihydrophthalazine-1 -carboxamide;
AT-{(2J?)-3-[4-(3,4-Diclilorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-l^-indole-3-carboxamide;
J¥-{(lR)-3-[4-(4-Chlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-2-
(methylsulfonyl)benzamide;
N-{ (2J?)-3-[4-(4-CMorophenoxy)piperidin-1 -yl]-2-hydroxypropyl} -1 -oxo-1,2-
dihydroisoquinoline-4-carboxamide;
jV-{(2/?)-3-[4-(4-Chloro-3-fluorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-l-oxo-l,2-
dihydroisoquinoline-4-carboxamide;
7V-{(2JR)-3-[4-(3)4-Difluoroplienoxy)piperidin-1 -yl]-2-hydroxypropyl} -1 -oxo-1,2-
dihydroisoquinoline-4-carboxamide;
N- {(25)-3-[4-(3,4-Dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl} -//-methyl-1 -oxo-
1,2-dihydroisoqurnoline-4-carboxamide;
JV-{(2iS)-3-[4-(3,4-DicWorophenoxy)pipe:ridin-l-yl]-2-hydroxypropyl}-JV-methyl-l^'-
indazole-3 -carboxamide;
JV-{(26)-3-[4-(334-DicWorophenoxy)piperidm-l-yl]-2-hydroxypropyl}-JV'-methyI-4-oxc
3,4-dihydrophthalazine-l -carboxamide;
Benzoicacid, 3-[[2-[[(2R)-3-[4-(354-dicMorophenoxy)-l-piperidinyl]-2-
hydroxypropyl]amino]-2-oxoethyl]atnino]-, methyl ester ;
Propanamide,.A'"-[2-[[2-[[(2JR)-3-[4-(3,4-dLchlorophenoxy)-l-piperidinyl]-2-
hydroxypropyl]amino]-2-oxoethyl]amino]phenyl]-;
Propanamide,JV-[2-[[2-[[(ZR)-3-[4-(3,4-dichlorophenoxy)-l-piperidmyl]-2-
hydroxypropyl]amino]-2-oxoethyl]amino]phenyl]-;
(2S)-N-{ (2R)-3>-[4-(3,4-Dichlorophenoxy)piperidm-1 -yl]-2-hydroxypropyl}-2-hyroxy-2
phenylethanamide;
2-[2-({(2^)-3-[4-(3,4-DicMorophenoxy)piperidin-l-yl]-2-hydroxypropyl}amino)-2-
oxoethoxyjbenzamide;
^-{(lff)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-2-(3-oxo-2)3
dihydro-^^/-l,4-benzoxazin-4-yl]acetamide;

N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-liydroxypropyl}-2-methoxybenzamide;
N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-2-(methylamino)benzamide;
N-{(2R)-3-[4-(3,4-dicMorophenoxy)piperidin-l-yl]-2-hydroxypropyl}nicotinarnide;
N-{(2R)-3-[4-(3,4-dicMorophenoxy)piperidin-l-yl]-2-hydroxypropyl}isonicotiiiamide;
N-{(2R)-3-[4-(3)4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-3-
(dimethylamino)benzamide;
N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-2-(l,3-dioxo-l,3-
dihydro-2H-isoindol-2-yl)acetamide;
N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-6-
hydroxynicotinamide;
N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-2-(lH-indol-3-
yl)acetamide;
N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}bicyclo[4.2.0]oc
1,3,5-triene-7-carboxamide;
N-{(2R)-3-[4-(3,4-dichlorophenoxy)pipeiidin-l-yI]-2-hydroxypropyl}-457-
dimethylpyrazolotSjl-cJtl^^jtriazine-S-carboxamide;
N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}pyrazine-2-
carboxamide; N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-9H-purine-6-
carboxamide; N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}quinoline-6-
carboxamide;
N-{(2R)-3-[4-(3J4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-2,7-
dimethylpyrazolo[l,5-a]pyrimidine-6-carboxarnide;
N- {(2R)-3-[4-(3,4-dichlorophenoxy)piperi.din-1 -yl]-2-hydroxypropyl} -2-(pyrimidin-2-
ylthio)acetamide; N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-liydroxypropyl}-5-fluoro-lH-indole-
2-carboxamide; N-{(2R)-3-[4-(354-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyI}-l33-benzothia2ole-
6-carboxamide;

N-{(2R)-3-[4-(3,4-dicMoroplienoxy)piperidin-l-yl]-2-hydroxypropyl}-5-phenyl-lJ3-oxazole-4-carboxamide;
N- {(2R)-3-[4-(3,4-dichloroplienoxy)piperidin-1 -yl]-2-hydroxypropyl} -6-hydroxypyridin 2-carboxamide;
N- {(2R)-3-[4-(3,4-cttcMorophenoxy)piperidin-1 -yl]-2-hydroxypropyl} -3-oxo-3,4-dihydro
2H-1,4-benzoxazine-7-carboxamide;
N- {(2R)-3-[4-(3,4-dichloroplienoxy)piperidin-1 -yl]-2-hydroxypropyl} -3-hydroxypyridine
2-carboxamide;
N- {(2R)-3-[4-(3,4-dichlorophenoxy)piperidm-1 -yl]-2-hydroxypropyl} - IH-benzimidazole
5-carboxamide;
N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-lH-indole-5-
carboxamide;
N- {(2R)-3-[4-(3,4-dichloroph.enoxy)piperidin-1 -yl]-2-hydroxypropyl} -1 -methyl-1H-
indole-2-carboxamide;
N- {(2R)-3-[4-(3,4-dicWorophenoxy)piperidin-1 -yl]-2-hydroxypropyl} -1 H-imidazole-4-
carboxamide;
N- {(2R)-3-[4-(3,4-dichloroplienoxy)piperidin-1 -yl]-2-hydroxypropyl} - lH-indole-6-
carboxamide;
N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-l-metliyl-lH-
indole- 3 -carboxamide;
N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-lH-indole-7-
carboxamide;
N- {(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl} -3-
[(methylamino)sulfonyl]benzamide;
N- {(2R)-3 -[4-(3,4-dichlorophenoxy)piperidin-1 -yl]-2-hy.droxypropyl} -3,4-
bis(methylsulfonyl)benzamide;
N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-liydroxypropyl}-2-pyridin-3-
ylacetamide; N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-5-liydroxy-lH-
indole-2-carboxamide; N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-lJ5-dimethyl-lH-
pyrazole-3 -carboxamide;

N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-liydroxypropyl}-5-(methylsulfonyl)-
lH-indole-2-carboxamide;
N- {(2R)-3-[4-(334-dichlorophenoxy)piperidin- l-yl]-2-hydroxypropyl} quinoxaline-6-
carboxamide;
N-{(2R)-3-[4-(3,4-dicMorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-lJ8-naphthyridine-2-carboxamide;
N-{(2R)-3-[4-(3,4-dcWorophenoxy)piperidin-l-yl]-2-hydroxypropyl}imidazo[2,l-
b][ 1,3]benzothiazole-2-carboxamide;
N- {(2R)-3 -[4-(3,4-dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl} -2,6-
dimethylimidazo[ 1,2-a]pyridine-3-carboxainide;
N- { (2R)-3 -[4-(3,4-dichlorophenoxy)piperidin-1 -yl] -2-hydroxypropyl} -3 -oxo-2,3 -dihydro-
lH-indazole-4-carboxamide;
N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyI}-3-hydroxy-lH-
indazole-6-carboxamide;
N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-3-(trifluoromethyl)-
1 H-pyrazole-4-carboxamide;
2-( I H-benzimidazol-1 -yl)-N- {(2R)-3-[4-(3,4-dichloroplienoxy)piperidiii-1 -yl]-2- '
hydroxypropyl} acetamide;
N- {(2R)-3-[4-(3,4-dicMorophenoxy)piperidin-1 -yI]-2-hydrbxypropyl} -1 -ethyl-3-methyl-
1 H-pyrazole-5-carboxamide;
N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-b.ydroxypropyl}-5-methyl-lH-
pyrazole-3 -carboxamide;
N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-4-methyl-l,2,5-
oxadiazole-3-carboxamide;
6-chloro-N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-
hydroxypropyl }imidazo [ 1 )2-a]pyridine-2-carboxamide;
N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperi.din-l-yl]-2-hydroxypropyl}-2-
methylimidazo[l,2-a]pyridine-3-carboxamide;
N-{(2R)-3-[4-(3,4-dicMorophenoxy)piperidin-l-yl]-2-hydroxypropyl}imidazo[l,2-
a]pyrimidine-2-carboxamide;
N- {(2R)-3 -[4-(3,4-dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl} -2-f(4-
methylpyrimidin-2-yl)tbio]acetamide;

N-{(2R)-3-[4-(3,4-dichloroplienoxy)pipericiin-l-yl]-2-hydroxypropyl}-4-hydroxyquinoline-2-carboxamide;
N-{(2R)-3-[4-(3,4-dicMorophenoxy)piperidin-l-yl]-2-hydroxypropyl}quinoline-8-carboxamide;
N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-5-
methylimidazo[l,2-a]pyridine-2-carboxainide;
N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}imidazo[l,2-
a]pyridine-2-carboxamide;
N- {(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl) -1,6-naphthyridii
2-carboxamide;
N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-2,l33-
benzoxadiazole-5-carboxamide 1-oxide;
N-{ (2J?)-3-[4-(3,4-Dicblorophenoxy)piperidin-1 -yl]-2-hydroxypropyl}-6-oxo-1,6-
dihydropyridine-3-carboxamide;
4-Chloro-7V-{(2^)-3-[4-(3,4-dicMorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-lJ7-
pyTazole-3-carboxamide;
A/-{(2/?)-3-[4-(3,4-DichIorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-5-phenyl-l,3-
oxazole-4-carboxamide;
N- {(2K)-3-[4-(3 )4-Dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl} -r3,5-dimethyl- IH
pyrazole-4-carboxamide;
(2^)-2-(Acetylamino)-A^-{(2JR)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-
hydroxypropyl} -2-phenylethanamide;
JA/"-{(2J?)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-2-(2-
hydroxyphenyl)acetamide;
(2jR)-^-{(2^)-3-[4-(3,4-DichloropIienoxy)pipeiidin-l-yl]-2-hydroxypropyl}-2-
[(methylsulfonyl)amino]-2-pb.enylethanamide;
(21S)-2-(Acetylamino)-7V"-{(2/?)-3-[4-(354-dichlorophenoxy)piperidin-l-yl]-2-
hydroxypropyl} -2-phenylethanamide; (2iS)-^-{(2^)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-2-
[(methylsulfonyl)amino]-2-phenylethanamide; l-{(R)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-3-o-tolyl-urea;
1 - {(R>3- [4-(3,4-Dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl} -3-p-tolyl-urea;

N- {(2S>3 -[4-(3,4-Dichlorophenoxy)piperidin-1 -yl] -2-hydroxy-2-methylpropyl} -1 -oxo-1,2-dihydroiso.quinolJiie-4-carboxamide;
Ar-{(21S)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxy-2-methylpropyl}-2-oxo-l,2-dihydroquinoline-4-carboxamide;
yV-{(21S)-3-[4-(3,4-DicMorophenoxy)pipe5ridin-l-yl]-2-hydroxy-2-methylpropyl}-4-oxo-
3,4-dihydrophthalazine-l -carboxamide;
(2,S)-^V"-{(2^-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxy-2-methylpropyl}-2-
hydroxy-2-phenethanamide;
N- {(2K)-3 -[4-(4-Chloro-2-methylphenoxy)piperidin-1 -yl] -2-hydroxypropyl} -1 -oxo-1,2-
dihydroisoquinoline-4-carboxamide;
JV-((2^)-3-{4-[2-(Aminocarbonyl)-3,4-dichlorophenoxy]piperidin-l-yl}-2-hydroxypropyl)-
1 -oxo-1,2-dihydroisoquinoline-4-carboxamide;
3-Cyano-//-{(26)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-
hydroxypropyl} benzenesulfonamide;
5-[({(2iS)-3-[4-(3,4-DicMorophenoxy)piperidin-l-yl]-2-hydroxypropyl}amino)-sulfonyl]-
2-methoxybenzamide;
N- {(25)-3-[4-(3,4-Dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl}-1 -oxo-1,2-
dihydroisoquinoline-4-sulfonamide acetate salt;
JV-{(2^)-3-[4-(3,4-Dichloropb.enoxy)piperidin-l-yl]-2-hydroxypropyl}-:2,4-
difluorobenzenesulfonamide;
N- {(2S)-3-[4-(3 54-dichlorophenoxy)piperidin-1 -yl]-2-
hydroxypropyljmethanesulfonamide;
N-{(2S)-3-[4-(3J4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}benzenesidfonaniide;
N-{(2S)-3-[4-(3,4-dichJorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-l-
phenylmethanesulfonamide;
N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-4-
methoxybenzenesulfonamide;
N-({5-[({(2S)-3-[4-(3,4-dichloroplienoxy)piperidin-l-yl]-2-
hydroxypropyl}amiiio)sulfonyl]-2-tbienyl}met±iyl)beiizaniide;
4-cyano-N-{(2S)-3-[4-(334-dichlorophenoxy)piperidin-l-yl]-2-
hydroxypropyl}benzenesulfonamide;
N-{5-[({(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-
hydroxypropyl}amino)sulfonyl]-4-methyl-l,3-thiazol-2-yl}acetamide;

N- {(2S)-3 -[4-(3,4-dichlorophenoxy)piperidin-l -yl]-2-hydroxypropyl}thiophene-2-
sulfonamide;
4-[({ (2S)-3-[4-(3,4-dichlorophenoxy)piperidin-l -yl]-2-
hydroxypropyl) amino)sulfonyl]benzoic acid;
N-{(2S)-3-[4-(334-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-2,5-
dimethoxybenzenesulfonamide;
N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-4-
(phenylsulfonyl)thiophene-2-sulfonamide;
N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-5-(l33-oxazol-5-
yl)thiophene-2-sulfonamide;
Nf-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-5-[l-methyl-5-
[trifluoromethyl)-lH-pyrazol-3-yl]thiophene-2-sulfonamide;
^- {(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl} -5-pyridin-2-
^lthiophene-2-sulfonamide;
J-chloro-N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-l,3-
limethyl- lH-pyrazole~4-sulfonamide;
sf-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-3,5-dimethylisoxazole-4-sulfonamide;
N-{(2S)-3-[4-(3}4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-2,lJ3-benzothiadiazole-4-sulfonamide;
N- {(2S)-3 -[4-(3,4-dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl} -1 -methyl-1H-imidazole-4-sulfonamide;
N-{(2S)-3-[4-(334-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-2,l,3-benzoxadiazole-4-sulfonamide; N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-5-isoxazol-3-
ylthiophene-2-sulfonamide;
methyl 3-[({(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-
hydroxypropyl} amino)sulfonyl]thiophene-2-carboxylate;
2,6-dichloro-N-{(2S)-3-[4-(3)4-dichlorophenoxy)piperidni-l-yl]-2-
'f
hydroxypropyl Jbenzenesulfonamide; N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-3-
methylbenzenesulfonamide;

3-cMoro-N-{(2S)-3-[4-(3,4-diciilorophenoxy)piperidiii-l-yl]-2-hydroxypropyljbenzenesulfonamide;
N-{(2S)-3-[4-(3,4-dichloroplienoxy)piperidin-l-yl]-2-hydroxypropyl}propane-2-sulfonamide;
N-{(2S)-3-[4-(3,4-dicMorophenoxy)piperidin-l-yl]-2-hydroxypropyl}propane-l-
sulfonamide;
N- {(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl}-5-methyl-1 -phenyl-
1 H-pyrazoIe-4-sulfonamide;
3-chloro-N-{(2S)-3-[4-(334-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-2-
methylbenzenesulfonamide;
methyl 5-[({(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1 -yl]-2-
hydroxypropyl}amino)sulfonyl]-2-methyl-3-fiiroate;
methyl 5-[({(2S)-3-[4-(334-dichlorophenoxy)piperidin-l-yl]-2-
hydroxypropyl} amino)sulfonyl] -1 -meth)d-1 H-pyrrole-2-carboxylate;
N-{(2S)-3-[4-(3s4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-3,4-
dimethoxybenzenesulfonamide;
5-chloro-N-{(2S)-3-[4-(3,4-dichloroplienoxy)piperidin-l-yl3-2-hydroxypropyl}thiophene
2-sulfonamide;
N- {(2S)-3 -[4-(3,4-dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl} T6-moipholin-4-
ylpyridine-3-sulfonamide;
N-{2-chloro-4-[({(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-
hydroxypropyl} amino)sulfonyl]phenyl} acetamide;
N- {(2S)-3 -[4-(3,4-dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl} -2,3-
dihydroxyquinoxaline-6-sulfonamide;
N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-2,4-
dimethoxybenzenesulfonamide; 5-[({(2S)-3-[4-(3)4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}amino)sulfonyl]-2-
methoxybenzamide;
N-{(2S)-3-[4-(3J4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-2-methylbenzenesulfonamide; N-{(2S)-3-[4-(354-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-2,4-dimethyl-l,3-
thiazole-5-sulfonamide;

N- {(2 S)-3 -[4-(3,4-dichlorophenoxy)piperidin-1 -ylj-2-hydroxypropyl} -2-
hydroxyquinoxaline-6-sulfonamide;
N-{(2S)-3-[4-(3J4-dichloropiienoxy)piperidin-l-yl]-2-liydroxypropyl}-4-inethyl-3,4-
dihydro-2H-l,44>enzoxazine-7-sulfonamide;
N-{(2S)-3-[4-(3,4-dicMorophenoxy)piperidin-l-yl]-2-hydroxypropyl}pyridine-3-
sulfonamide;
4-cyano-N- {(2S)-3 -[4-(3,4-dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl }biphenyl-2-
sulfonamide;
N- {(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl} -1,2-dimethyl-1H-
imidazole-4-sulfonamide;
4-acetyl-N- {(2 S)-3 -[4-(3,4-dichlorophenoxy)piperidin-1 -yl]-2-
hydroxypropyl} beiizenesulfonamide;
N-{(2S)-3-[4-(3,4-dichloiophenoxy)piperidin-l-yl]-2-liydroxypropyl}-4-
(methylsulfonyl)benzenesulfonamide;
2-chloro-4-cyano-N- {(2S)-3-[4-(3,4-dichlorophenoxy)-piperidin-1 -yl] -2-
hydroxypropyl}benzenesulfonamide;
N-{(2S)-3-[4-(3)4-dicMorophenoxy)piperidin-l-yl]-2-hydrox>^ropyl}-l,3,5-trimetb.yl-lH-
pyrazole-4-sulfonamide; ^-[(2JR)-3-[4-(3,4-Dichlorophenoxy)-l-piperidinyl]-2-hydroxypropyl]-'l,4-diliydro-4-oxo-
3-quinolinecarboxamide;
N- {(26)-3-[4-(4-Chloro-2-methylphenoxy)piperidin-1 -yl]-2-hydroxypropyl} -1 -oxo-1,2-
dihydroisoquinoline-4-carboxainide acetate;
Ar-{(21S)-3-{4-(3)4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-l-oxo-l,2-
dihydroisoquinoline-4-carboxamide;
JV-{(21S)-3-{4-(3!4-Dichlorophenoxy)piperidin-l-yl]-2-liydroxypropyl}-l-oxo-l32-
dihydroisoquinoIine-4-carboxamide;
A'-{(2^)-3-[4-(3)4-Dichlorophenoxy)piperidiii-l-yl]-2-liydroxypropyl}-7-
[(methylamino)sulfonyl]-1 -oxo-1,2-diliydroisoquinoline-4-carboxamide;
A^-{(2^)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-liydroxypropyl}-7-{[(2-
hydroxyeliiy^ammojsulfonylj-l-oxo-l^-dihydioisoquinoline^-carboxainide acetate salt;
7-[(Cyclopropylamino)sulfonyl]-]V-{(2/?)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-
hydroxypropyl} -1 -oxo-1,2-dihydroisoquinoline-4-carboxarnide;

7-(Azetidin-l-ylsulfonyl)-Ar-{(2J!)-3-[4-(3,4-dichlorophenoxy)piperidiii-l-yl]-2-
hydroxypropyl}-1-oxo-l,2-dihydroisoquinoline-4-carboxamide acetate salt;
7-( Aminosulfonyl)-^- {(2£>3-[4-(3,4-dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl} -
1 -oxo-1 ,2-dihydroisoquinoline-4-carboxainide;
N- {(Zff)-3-[4-(3,4-Dichlorophenoxy)piperidin-1 -yl] -2-hydroxypropyl} -7-
[(dimethylamino)sidfonylj-1 -oxo-1,2-ditLydroisoquinoline-4-carboxamide;
-/V-{(lR)-3-[4-(3,4-Dichloroplienoxy)piperidin-l-yl]-2-hydroxypropyl}-7-[(3-hydroxy-3-
methylazetidin-1 -yl)sulfonyl]-1 -oxo-1,2-diliydroisoquinoline-4-carboxainide acetate;
//-[(2J?)-3-(4-{3,4-Dichloro-2-[(cyclopropylamino)carbonyl]phenoxy}piperidiQ-l-yl)-2-
hydroxypropyl]-l-oxo-l,2-dihydroisoquinoline-4-carboxamide acetate salt;
N- {(2J?)-3-[4-(3 -Chloro-4-cyanopb.enoxy)piperidin-1 -yl]-2-hydroxypropyl} -1 -oxo-1,2-
dihydroisoquinoline-4-carboxamide;
A^-((2R)-2-Hydroxy-3 - {4-[4-(methylsulfonyl)phenoxy]piperidin-1 -yl}propyl)-1 -oxo-1,2-
dihydroisoquinoline-4-carboxamide;
N-{ (2J?)-3-[4-(4-Cyanophenoxy)piperidin-l -yl]-2-hydroxypropyl}-l -oxo-1,2-
dihydroisoquinoline-4-carboxamide;
N-((2R)-3 -{4-[2-(Aminocarbonyl)-4-chlorophenoxy]pipeiidin-1 -yl} -2-hydroxypropyl)-1 -
oxo-l,2-dihydroisoquinolme-4-carboxamide;
//-[(2J2)-3-(4-{4-CMoro-2-[(methylaniino)carbonyl]phenoxy}piperidin-l-yl)-2-
hydroxypropyl]-1 -oxo-1,2-diliydroisoquinoline-4-carboxaraide;
Methyl 5-chloro-2-{[1 -((lR)-2-hydroxy-3-{ [(1 -oxo-1,2-dihydroisoqiunolin-4-
yl)carbonyl]amino}propyl)piperidin-4-yl]oxy}benzoate acetate salt;
A^-((2^)-3-{4-[2-(Aminosulfonyl)-3,4-dicMorophenoxy]piperidin-l-yl}-2-hydroxypropyl)-
l-oxo-l,2-dihydroisoquinoline-4-carboxamide trifluoroacetate salt;
N-[(2R)-3-(4- {3,4-DichIoro-2-[(methylamino)sulfonyl]phenoxy }piperidin-1 -yl)-2-
hydroxypropyl]-! -oxo-1,2-dihydroisoquinoline-4-carboxamide acetate salt;
A^[(2^)-3-(4-{3,4-Dichloro-2-[(cyclopropylamino)sulfonyl]phenoxy}piperidin-l-yl)-2-
hydroxypropyl]-l-oxo-l,2-dihydroisoquinoline-4-carboxainide acetate salt; N- {(2R)-3 -[4-(3-Chloro- 4-cyanophenoxy)piperidin-1 -yl]-2-hydroxypropyl} -7-(methylsulfonyl)-1 -oxo-1,2-dihydroisoquinoline-4-carboxamide; ^-{(2^)-3-{4-(4-Chloro-2-methylphenoxy)piperidin-l-yl]-2-hydroxy-2-methylpropyl}-6-
(methyIsulphonyl)-ljy-indole-3-carboxamide;

^v-{(^>3-{4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-6-(methyisulphonyl)-l#-indole-3-carboxamide;
A^{(2JJ)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-7-jauoro-l-oxo-l32-dihydroisoquinoline-4-carboxamide;
]V-{(2J?)-3-[4-(4-Cliloro-2-me&ylphenoxy)piperidin-l-yl]-2-hydroxypropyl}-7-flTioro-l-oxo-1,2-dihydroisoquinoline-4-carboxamide;
7V-{(2J2)-3-[4-(4-CMoro-2-methylplienoxy)piperidin-l-yl]-2-hydroxypropyl}-6-(methylsulfonyl)-1 -oxo-1,2-dihydroisoquinoline-4-carboxamide; 2\T-{(2/?)-3-[4-(2,4-Diciiloro-3-methylphenoxy)piperidin-l-yl]-2-hydroxypropyl}-6-(methylsulfonyl)-1 -oxo-1,2-dihydroisoquinoline-4-carboxamide; J?V-{(2JX)-3-[4-(3>4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-7-(methylsulfonylj-l-oxo-l^-dihydroisoqiiinolkLe^-carboxainide acetate salt; A/-{(2J?)-3-[4-(3J4-DicWorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-7-(methyIsulfonyl)-l-oxo-l,2-dihydroisoquinoline-4-carboxamide acetate salt;
¥-{(2/?)-3-[4-(2)4-Dichloro-3-methylphenoxy)piperidin-l-yl]-2-liydroxypropyl}-7-'methylsulfonyl)-!-oxo-1,2-dihydroisoquinoline-4-carboxamide acetate salt; V- {(2fl)-3 -[4-(3 54-Dichloroptienoxy)piperidin-1 -yl]-2-hydroxypropyl} -6-(methylsulfonyl)-. -oxo-1,2-dihydroisoquinoline-4-carboxamide; ^-{(2/2)-3-[4-(3,4-DicWorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-6-fluoro-l-oxo-l,2-
dihydroisoquinoline-4-carboxamide;
JV-{(2J?)-3-[4-(4-Chloro-2-methylphenoxy)piperidin-l-yl]-2-liydroxypropyl}-6-fluoro-l-
oxo-1,2-dihydroisoquinoline-4-carboxamide;
N-((2K)-3- {4- [3,4-DicbJoro-2-(methylsulfonyl)phenoxy]piperidin-1 -yl} -2-hydroxypropyl)-
l-oxo-l^-dihydroisoquinoline^-carboxamide acetate salt;
]V-{(ZR)-3-[4-(3,4-Dichloropheiioxy)piperidm-l-yl]-2-hydroxypropyl}-6-oxo-4-
(trifluoromethyl)-l,6-dihydropyridine-3-caiboxamide acetate salt;
JV-{(2/?)-3-[4-(4-Chloro-2-inetliylphenoxy)piperidin-l-yl]-2-liydroxypropyl}-6-oxo-4-
(trifluoromethyl)-l,6-diliydropyridine-3-carboxainide acetate salt; A7-{(2^)-3-[4-(2,4-Dicliloro-3-methylplienoxy)piperidin-l-yl]-2-hydroxypropyl}-6-oxo-4-
(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide; ]V-{(2^)-3-[4-(3,4-dicMorophenoxy)piperidiii-l-yl]-2-hydroxypropyl}-2-(2-oxoqiiinoxalin-
l(19)-yl)acetamide;

Ar-{(2J2)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-3-oxo-3)4-
dihydroquinoxahne-1 (2f/)-carboxamide;
Ar-{(2^)-3-[4-(4-Chloro-2-methylphenoxy)piperidin-l-yl]-2-hydroxypropyl}-3-
(trifluoromethyl)-l#-pyrazole-4-carboxamide;
A'-{(2JR)-3-[4-(2,4-dichloro-3-methylphenoxy)piperidin-l-yl]-2-hydroxypropyl}-3-
(trifluoromethyl)-l#-pyrazole-4-carboxamide;
7V-{(2^)-3-{4-(3,4-Dichlorophenoxy)piperidin-l-yl}-2-hydroxypropyl}-l-oxo-l,2-
dihydro-2-methylisoquinoHne-4-carboxamide;
A^-{(2J2)-3-{4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-2-oxo-l32-dihydro-
1 -methylquinoUne-4-carboxamide;
N- {(ZR)-3-[4-(3,4-dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl} -8-fluoro-1 -oxo-1,2-
dihydroisoquinoline-4-carboxamide; or, .
A^-{(2R)-3-[4-(4-chloro-2-methylphenoxy)piperidin-l-yl]-2-hydroxypropyl}-8-fluoro-l-
oxo-1,2-dihydroisoquinoline-4-carboxamide.
A compound of formula (I) or (la) can be prepared by reacting a compound of formula (II):
OH
H
j—CR2R3 (CH2)
CR5R6 - (CR7R8)n-N (II)
m
R32

wherein X, R1, R2, R3, R4, R5, R6, R7, R8, R32, m and n are as defined above, with:
(i) when Y is a bond, CH2, NR35, CH2NH, CH2NHC(O), CH(OH), CH(NHCOR33), CH(NHS02R34), CH20 or CH2S, Z is C(0), R35 is not hydrogen and, R33 and R34 are as defined above, a compound of formula (Ilia):
L1—CO—Y R9 (Ilia)
wherein R9 is as defined above and L1 is a. leaving group (for example a hydroxyl or chloride leaving group) in the presence of a base (for example diwopropylelthylamine), optionally in the presence of a coupling agent (for example bromo-tris-pyrrolidinophosphonium hexafluorophosphate, PyBrOP or O-(7-azabenzotriazol-l-yl)-NjNjN'jN'-tetramethyluronium hexafluorophosphate); and,
(ii) when Y is NH and Z is C(0), a compound of formula (fflb):
Q N—R (1Mb)
wherein R9 is as defined above.

(iii) when Y is a bond and Z is S(O)2, a compound of formula (fflc): l_1 - S(0)2 - R9 (Hie)
wherein R9 is as defined above and L1 is a leaving group (for example a hydroxyl or chloride leaving group) in the presence of a base (for example pyridine).
A compound of formula (II) can be prepared as described in WO 00/58305 or WO 0 1/77 1 0 1 , or by reacting a compound of formula (IV):

(IV)
K
wherein X and R1 are as defined above, with:
(i) when m and n are 0, R2, R3, R5 and R6 are hydrogen, and R4 and R32 are as defined for formula (I), a compound of formula (V):

L2 CR2R3—f-CR5R6 (V)
hi which L2 is a leaving group (for example chloro or nosyloxy{3-NO2-CfiH4-S(0)20-}) followed by reaction with ammonia, an amine R32-NH2 or with sodium azide and subsequent reduction with, for example, triphenylphosphine;
(ii) when m and n are 0, R2 and R3 are hydrogen and R4, R5, R6 and R32 are as defined for formula (I), with a compound of formula (VI):
0
R2R3C—A CR5R6 NP1P2 (VI)
R4
hi which P1 and P2 are, alone or together, suitable protective groups (for example together they form phthalamide), or either P1 or P2 is R32, followed by deprotection using, for example when P1 and P2 form phtalamide, hydrazine;
(iii) when m is 0, n is 1, R2 and R3 are hydrogen and R4, R5, R6, R7, R8 and R32 are as defined for formula (T), with a compound of formula (VH):


CR5R6—CR7R8 NP1P2 (VII)


in which P1 and P2 are, alone or together, suitable protective groups (for example together they form phthalamide), or either P1 or P2 is R32, followed by deprotection using, for example when P1 and P2 form phtalamide, hydrazine;
(iv) when m and n are 1, R2 and R3 are hydrogen and R4, R5, R6, R7, Rs and R32 are as defined for formula (I), with a compound of formula (VIE):
OH

9 7 "?
L R RC C-
H,

R4

CR5R6 CR7R8 NP1P2 (VIII)

in which L2 is as defined for formula (V) and P1 and P2 are, alone or together, suitable protective groups (for example together they form phthalamide), or either P1 or P2 is R32, followed by deprotection using, for example when P1 and P2 form phthalamide, hydrazine;
91 *\ />
(v) when m is 1 and n is 0, R and R are hydrogen, R and R are, independently, hydrogen, Ci_6 alkyl or C3..6 cycloalkyl, and R4 and R32 are as defined for formula (I), with a compound of formula (IX):
OH

I

2

H2

R4

-CR5R6 NP1P (IX)

in which L2 is as defined for formula (V) and P1 and P2 are, alone or together, suitable
1 7 *5?
protective groups (for example together they form phthalamide), or either P or P is R , followed by deprotection using, for example when P1 and P2 form phthalamide, hydrazine;
(vi) when m is 1 and n is 0, R2, R3, R5 and R6 are hydrogen and R4 and R32 are as defined for formula (I), with a compound of formula (X):
O
L2 R2R3C—C /-CR5R6 (X)
R4
in which L2 is a leaving group (for example bromine) followed by reaction with ammonia, an amine R32-NH2 or with sodium azide and subsequent reduction with, for example, triphenylphosphine;
(vii) when m is 1 and n is 0, R2, R3, R5 and R6 are, independently, hydrogen, Cj.6 alkyl or C3.6 cycloalkyl, and R1, R4 and R32 are as defined for formula (I), with a compound of formula (XI):

u
--I CR5R6—NP1P2 (XI)
H
>2
in which P and P are, alone or together, suitable protective groups (for example together they form phthalamide), or either P1 or P2 is R32, followed by hydride reduction (for example with sodium borohydride), or by adding an appropriate organometallic species (for example R4MgX, where X is a halide); or,
. (viii) when m is 1 and n is 1 , R2, R3, R5 R6, R7 and R8 are, independently, hydrogen, C\^ alkyl or C3^ cycloalkyl, and R1, R4 and R32 are as defined for formula (I), with a compound of formula (XII):
O
H
in which P1 and P2 are, alone or together, suitable protective groups (for example together they form phthalamide), or either P1 or P2 is R32, followed by hydride reduction (for example with sodium borohydride), or by adding an appropriate organometallic species (for example R4MgW, where W is a halide).
When m is 0 and n is 0, R2, R3, R5 and R6 are, independently, hydrogen, Ci^ alkyl or €3.6 cycloalkyl, compounds or formula (II) can be prepared by reacting a compound of formula (XIII):


CR2R3— -L3 (XIII)
wherein X and R1 are as defined for formula (I), and L3 is hydrogen or a leaving group (for example ethoxy, N,0-dimethylhydroxylamine), with a, compound of formula (XIV):
M - CR5R— CO - L4 (XIV)
in which M represents a metal (for example Li or Na) and L4 is an amino group (for example ammonium) followed by rearrangement (for example with phenyliodonium diacetate, Tetrahedron Letters, 2001, 42, 1449.) and appropriate reduction (for example with sodium borohydride), or an appropriate organometalic addition (for example R MgW, where W is a halide') .
When m is 0, n is 1 and R2, R3, R5, R6, R7 and R8 are, independently, hydrogen, C,.fi alkyl or C3.6 cycloalkyl, compounds of formula (II) can be prepared by reacting a compound of formula (XX) :
wherein X, R1 and R4 are as described in formula (I) above and Z is an aldehyde protective
group (for example cyanohydrin or dithiane), with a compound of formula (XXI):
CR5R6=CR7R8 C(O) L5 (XXI)
in which R5, R6, R7 and R8 are as described above, and L5 is an alkoxy or amino group (for example ethoxy or ammonium) in presence of a base (for example LDA or /z-buryUthium), followed by hydrolytic removal of the group L5, rearrangement (for example with phenyliodoniuni diacetate) and appropriate reduction (for example with sodium borohydride), or an appropriate organometalic addition (for example R4MgW, where W is a halide).
A compound of formula (V) can be prepared by reacting a compound of formula (XXII):
H

with a peracid (for example /neta-chloroperbenzoic acid) or using Sharpless asymmetric epoxidation conditions (J. Am. Chem. Soc. 1980,102, 5974-5976), followed by activation of the alcohol as a leaving group (for example as nosyloxy). A compound of formula (VI) can be prepared:
(a) when both R5 and R6 are hydrogen, by reacting a compound of formula
(XXIII):
R2R3C 1 CR5R6 OH (XXIII)
R4
with a peracid (for example wzeta-chloroperbenzoic acid) or using Sharpless asymmetric epoxidation conditions, followed, for example, by a Mitsunobu reaction using phthalimide, l,Hazodicarbonyl)dipiperidine and tributylphosphine (Tetrahedron Lett. 1993, 34,1639).
(b) when R5 and R6 are, independently, hydrogen, Ci_6 alkyl or C3-6 cycloalkyl,
by reacting a compound of formula (XXIV):

o
R4 U CR5R6—NP1P2 (XXIV)
in which P and P2 are, alone or together, suitable protective groups (for example together they form phthalamide), or either P1 or P2 is R32, with a sulphur ylide (for example trmernylsulfomurnmethylide, J. Am. Chem. Soc. 1965, 87,1353-1364); or a phosphonium ylide (for example tiphenylphosphoniummethyh'de); followed by epoxidation of the resulting alkene using a peracid (for example meta-chloroperbenzoic acid).
A compound of formula (VII) can be prepared by reacting a compound of formula (XXV):
O
R4 U CR5R6-—CR7R8—NP1P2 (XXV)
in which P1 and P2 are, alone or together, suitable protective groups (for example together they form phthalamide), or either P1 or P2 is R32, with a sulfur ylide (for example trimethylsulfoniummethylide), or a phosphonium ylide (for example tiphenylphosphoniummethylide) followed by epoxidation of the resulting alkene using a peracid (for example /weto-chloroperbenzoic acid).
A compound of formula (VIII) can be prepared by reacting a compound of formula (XXV) with the anion of ethyl acetate (which can be prepared by the action of lithium diisopropylamide on ethyl acetate) followed by reduction of the resulting ester, or with, for example, vinyl magnesium Grignard and subsequent hydroboration (for example cathechol borane)/oxidation (for example hydrogen peroxide) of the alkene.
A compound of formula (DC) can be prepared from a compound of formula (XXIV) in a similar way as for compound (VIII).
A compound of formula (X) can be prepared by reacting a compound of formula (XXVI):
HO—R2R3C C pCR5R6 (XXVI)
"2 R4
with a peracid (for example wete-chloroperbenzoic acid), followed by selective activation of the primary alcohol as a leaving group (for example nosyloxy).
Further, compounds of formula (I) and (la) can be prepared by or by routine adaptation of: the routes described above, methods described in the art, or the Examples

recited below. The intermediates identified above are commercially available or can be prepared by using or adapting methods described in the art.
hi a further aspect of the invention there is provided a process for preparing 4-(3,4-dichlorophenoxy)piperidine comprising the steps of:
a. reacting 4-hydroxypiperidine with a suitable base in a suitable solvent at room
temperature; and,
b. heating the mixture so produced together with l,2-dichloro-4-fluorobenzene at a
temperature in the range 50-90°C, or at reflux of the solvent used.
hi a further aspect the present invention provides a process for preparing 4-(3,4-dichlorophenoxy)piperidine comprising reacting 4-hydroxypiperidine with a suitable base {such as an alkali metal (preferably sodium or potassium) CMO alkoxide [such as a QUO tertiary alkoxide (for example a 04.5 tertiary alkoxide)], for example potassium teri-butoxide or potassium 3,7-dimethyl-3-octanoxide} hi a suitable solvent {such as: an ether [for example tetrahydrofuran or methyl tert-butyl ester], an aromatic solvent [such as toluene] or a mixture of these solvents} at room temperature (10-30°C); heating the mixture so produced together with l,2-dichloro-4-fluorobenzene at a temperature in the range 50-90°C, or at reflux of the solvent used.
hi a still further aspect the present invention provides a process for preparing 4-(3,4-dichlorophenoxy)piperidine comprising reacting 4-hydroxypiperidine with a suitable base {such as an alkali metal (preferably sodium or potassium) CMO alkoxide (such as a C4.)o tertiary alkoxide), for example a Cj_6 alkoxide (such as a C^ tertiary alkoxide), for example potassium tert-butoxide} in a suitable solvent {such as: an ether [for example tetrahydrofuran or methyl tert-butyl ester], an aromatic solvent [such as toluene] or a mixture of these solvents} at room temperature (10-30°C)5 and heating the mixture so produced to a temperature in the range 50-90°C, or at reflux of the solvent used, and adding l,2-dichloro-4-fluorobenzene.
Examples of tertiary alkoxides are potassium tert-butoxide and potassium 3,7-dimethyl-3-octanoxide.
hi another aspect the present invention provides processes for the preparation of compounds of formula (I) and (la).
The intermediates of formula (VT), (VH) and (VHI) defined herein are novel and these intermediates, and processes for their preparation, are provided as further features of the invention.

The compounds of the invention have activity as Pharmaceuticals, in particular as modulators of chemokine receptor (especially CCR3) activity, and may be used in the treatment of autoimmune, inflammatory,, proliferative or hyperproliferative diseases, or unmunologically-mediated diseases (including rejection of transplanted organs or tissues and Acquired Immunodeficiency Syndrome (AIDS)). In one aspect examples of these conditions are:
(1) (the respiratory tract) obstructive diseases of airways including: chronic obstructive pulmonary disease (COPD) (such as irreversible COPD); asthma {such as bronchial, allergic, intrinsic, extrinsic or dust asthma, particularly chronic or inveterate asthma (for example late asthma or airways hyper-responsiveness)}; bronchitis {such as eosinophilic bronchitis}; acute, allergic, atrophic rhinitis or chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca or rhinitis medicamentosa; membranous rhinitis including croupous, fibrinous or pseudomenibranous rhinitis or scrofoulous rhinitis; seasonal rhinitis including rhinitis nervosa (hay fever) or vasomotor rhinitis; sarcoidosis; farmer's lung and related diseases; nasal polyposis; fibroid lung, idiopathic interstitial pneumonia, antitussive activity, treatment of chronic cough associated with inflammatory conditions of the airways or iatrogenic induced cough;
(2) (bone and joints) arthrides including rheumatic, infectious, autoimmune, seronegative
spondyloarthropathies (such as ankylosing spondylitis, psoriatic arthritis or Reiter's
disease), Beliefs disease, Sjogren's syndrome or systemic sclerosis;
(3) (skin and eyes) psoriasis, atopic dermatitis, contact dermatitis or other eczmatous
dermitides, seborrhoetic dermatitis, Lichen planus, Phemphigus, bullous Phemphigus,
Epidermolysis bullosa, urticaria, angiodermas, vasculitides erythemas, cutaneous
eosinophilias, uveitis, Alopecia areata or vernal conjunctivitis;
(4) (gastrointestinal tract) Coeliac disease, proctitis, eosinophilic gastro-enteritis,
mastocytosis, Crohn's disease, ulcerative colitis, irritable bowel disease or food-
related allergies which have effects remote from the gut (for example migraine,
rhinitis or eczema);
(5) (Allograft rejection) acute and chronic following, for example, transplantation of
kidney, heart, liver, lung, bone marrow, skin or cornea; or chronic graft versus host
disease; and/or

(6) (other tissues or diseases) Alzheimer's disease, multiple sclerosis, atherosclerosis, Acquired Immunodeficiency Syndrome (AIDS), Lupus disorders (such as lupus erythematosus or systemic lupus), erythematosus, Hashimoto's thyroiditis, myasthenia gravis, type I diabetes, nephrotic syndrome, eosinophilia fascitis, hyper IgE syndrome, leprosy (such as lepromatous leprosy), Peridontal disease, Sezary syndrome, idiopathic thrombocytopenia pupura or disorders of the menstrual cycle.
The compounds of the invention are also HI antagonists and may be used in the treatment of allergic disorders.
The compounds of the invention may also be used to control a sign and/or symptom of what is commonly referred to as a cold (for example a sign and/or symptom of a common cold or influenza or other associated respiratory virus infection).
According to a further feature of the invention there is provided a compound of formula (I) or (la), or a pharmaceutically acceptable salt thereof or a solvate thereof, for use in a method of treatment of a warm blooded animal (such as man) by therapy (including prophylaxis).
According to a further feature of the present invention there is provided a method for modulating chemokine receptor activity (especially CCR3 receptor activity), or antagonising HI, 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 formula (I) or (la), or a pharmaceutically acceptable salt thereof or a solvate thereof.
The invention also provides a compound of the formula (I) or (la), or a pharmaceutically acceptable salt thereof or a solvate thereof, for use as a medicament.
In another aspect the invention provides the use of a compound of formula (I) or (la), or a pharmaceutically acceptable salt thereof or a solvate thereof, in the manufacture of a medicament for use in therapy (for example modulating chemokine receptor activity (especially CCR3 receptor activity), or antagonising HI, in a warm blooded animal, such as man).
The invention further provides the use of a compound of formula (I) or (la), or a pharmaceutically acceptable salt thereof, hi the manufacture of a medicament for use in the treatment of:
(1) (the respiratory tract) obstructive diseases of airways including: chronic obstructive pulmonary disease (COPD) (such as irreversible COPD); asthma {such as bronchial, allergic, intrinsic, extrinsic or dust asthma, particularly chronic or inveterate asthma

(for example late asthma or airways hyper-responsiveness)}; bronchitis (such as eosinophilic bronchitis}; acute, allergic, atrophic rhinitis or chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca or rhinitis medicamentosa; membranous rhinitis including croupous, fibrinous or pseudomembranous rhinitis or scrofoulous rhinitis; seasonal rhinitis including rhinitis nervosa (hay fever) or vasomotor rhinitis; sarcoidosis; farmer's lung and related diseases; nasal polyposis; fibroid lung, idiopathic interstitial pneumonia, antitussive activity, treatment of chronic cough associated with inflammatory conditions of the airways or iatrogenic induced cough;
(2) (bone and joints) arthrides including rheumatic, infectious, autoimmune, seronegative
spondyloarthropathies (such as ankylosing spondylitis, psoriatic arthritis or Reiter's
disease), Behcet's disease, Sjogren's syndrome or systemic sclerosis;
(3) (skin and eyes) psoriasis, atopic dermatitis, contact dermatitis or other eczmatous
dermitides, seborrhoetic dermatitis, Lichen planus, Phemphigus, bullous Phemphigus,
Epidermolysis bullosa, urticaria, angiodermas, vasculitides erythemas, cutaneous
eosinophilias, uveitis, Alopecia areata or vernal conjunctivitis;
(4) (gastrointestinal tract) Coeliac disease, proctitis, eosinophilic gastro-enteritis,
mastocytosis, Crohn's disease, ulcerative colitis, irritable bowel disease or food-
related allergies which have effects remote from the gut (for example migraine,
rhinitis or eczema);
(5) (Allograft rejection) acute and chronic following, for example, transplantation of
kidney, heart, liver, lung, bone marrow, skin or cornea; or chronic graft versus host
disease; and/or
(6) (other tissues or diseases) Alzheimer's disease, multiple sclerosis, atherosclerosis,
Acquired Immunodeficiency Syndrome (AIDS), Lupus disorders (such as lupus
erythematosus or systemic lupus), erythematosus, Hashimoto's thyroiditis, myasthenia
gravis, type I diabetes, nephrotic syndrome, eosinophilia fascitis, hyper IgE syndrome,
leprosy (such as lepromatous leprosy), Peridontal disease, sezary syndrome, idiopathic
thrombocytopenia pupura or disorders of the menstrual cycle;
in a warm blooded animal, such as man.
In a further aspect a compound of formula (I) or (la), or a pharmaceutically acceptable salt thereof, is useful in the treatment of asthma {such as bronchial, allergic, intrinsic, extrinsic or dust asthma, particularly chronic or inveterate asthma (for example

late asthma or airways hyper-responsiveness)}; or rhinitis {including acute, allergic, atrophic or chronic rhinitis, such as rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca or rhinitis medicamentosa; membranous rhinitis including croupous, fibrinous or pseudomembranous rhinitis or scrofoulous rhinitis; seasonal rhinitis including rhinitis nervosa (hay fever) or vasomotor rhinitis}.
hi a still further aspect a compound of formula (I) or (la), or a pharmaceutically acceptable salt thereof, is useful in the treatment of asthma.
The present invention also provides the use of a compound of formula (I) or (la), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of asthma or rhinitis.
The present invention further provides a method of treating a chemokine mediated disease state (especially a CCR3 mediated disease state, especially asthma) in a warm blooded animal, such as man, which comprises administering to a mammal in need of such treatment an effective amount of a compound of formula (I) or (la), or a pharmaceutically acceptable salt thereof or solvate thereof.
In order to use a compound of the invention, or a pharmaceutically acceptable salt thereof or solvate thereof, for the therapeutic treatment of a warm blooded animal, such as man, in particular modulating chemokine receptor (for example CCR3 receptor) activity or antagonising HI, said ingredient is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
Therefore in another aspect the present invention provides a pharmaceutical composition which comprises a compound of the formula (I) or (la), or a pharmaceutically acceptable salt thereof or a solvate thereof (active ingredient), and a pharmaceutically acceptable adjuvant, diluent or carrier, hi a further aspect the present invention provides a process for the preparation of said composition which comprises mixing active ingredient with a pharmaceutically acceptable adjuvant, diluent or carrier. Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99 %w (per cent by weight), more preferably from 0.05 to 80 %w, still more preferably from 0.10 to 70 %w, and even more preferably from 0.10 to 50 %w, of active ingredient, all percentages by weight being based on total composition.
The pharmaceutical compositions of this invention may be administered in standard manner for the disease condition that it is desired to treat, for example by topical (such as to the lung and/or airways or to the skin), oral, rectal or parenteral administration. For

these purposes the compounds of this invention may be formulated by means known in the art into the form of, for example, aerosols, dry powder formulations, tablets, capsules, syrups, powders, granules, aqueous or oily solutions or suspensions, (lipid) emulsions, dispersible powders, suppositories, ointments, creams, drops and sterile injectable aqueous or oily solutions or suspensions.
A suitable pharmaceutical composition of this invention is one suitable for oral administration in unit dosage form, for example a tablet or capsule which contains between 0.1 mg and Ig of active ingredient.
In another aspect a pharmaceutical composition of the invention is one suitable for intravenous, subcutaneous or intramuscular injection.
Each patient may receive, for example, an intravenous, subcutaneous or intramuscular dose of O.Olmgkg'1 to lOOmgkg"1 of the compound, preferably in the range of O.lmgkg'1 to 20mgkg"J 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 will receive a daily oral dose which is approximately equivalent to the daily parenteral dose, the composition being administered 1 to 4 times per day.
The invention will now be illustrated by the following non-limiting Examples hi which, unless stated otherwise:
(i) when given, *H NMR data is quoted and is hi the form of delta values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, determined at 300MHz or 400MHz using perdeuterio DMSO-D6 (CD3SOCD3), methanol-D4 (CD3OD) or CDC13 as the solvent unless otherwise stated; (ii) mass spectra (MS) were run with an electron energy of 70 electron volts in the chemical ionisation (CI) mode using a direct exposure probe; where indicated ionisation was effected by electron impact (El) or last atom bombardment (FAB) or electrospray (ESI); where values for m/z are given, generally only ions which indicate the parent mass are reported, and unless otherwise stated the mass ion quoted is the positive mass ion -
(iii) the title and sub-title compounds of the examples and methods were named using the ACD/hidex name program version 4.55 from Advanced Chemistry Development, Inc; (iv) unless stated otherwise, reverse phase HPLC was conducted using a Symmetry,

NovaPak or Xterra reverse phase silica column; and (v) the following abbreviations are used:



(Table Remove)
Preparation 1
)-1 -Amino-3-[4-(3)4-dichlorophenoxy)piperidin-1 -yl]propan-2-ol Step 1: 2-{(21S)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-l//-isoindole-1,3 (2//)-dione
(Figure Remove)


1996, 7, 1641, 5g) in a mixture of 50 ml of ethanol and 15 ml of DMF was treated with 4-(3,4-dichlorophenoxy)-piperidine (6g). The mixture was stirred overnight at room temperature. The solution was concentrated under vacuum and the residue was azeotroped twice with toluene. The crude material was purified by chromatography (ethyl acetate) to give the subtitle compound as a yellow oil.
MS (APCI) 449/451 (M+H)+
]H NMR 5 (CDC13) 7.92-7.81(2H, m), 7.77-7.70 (2H, m), 7.30 (1H, d), 6.98 (1H, t), 6.74 (1H, dt), 4.34-4.20 (1H, m), 4.09-3.97 (1H, m), 3.83 (1H, dd), 3.73 (1H, dd)5 2.93-2.79 (1H, m), 2.73-2.60 (1H, m), 2.59-2.37 (3H, m), 2.31 (1H, t), 2.02-1.86 (2H, m), 1.86-1.67(2H,m).
Step 2: (2K)-1 -amino-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]propan-2-ol
I
(S)-2-[3-[4-(3,4-Dichlorophenoxy)-l-piperidinyl]-2-hydroxypropyl]-l^"-isoindole-l,3(2F)-dione (4g) in ethanol (100ml) was treated with 20 ml of hydrazine monohydrate and the resulting mixture was refluxed for 3h. The reaction was cooled and filtered. The
filtrate was evaporated and the product was chromatographed (ethyl acetate) to give the title compound as a yellow oil which solidified on standing (2.5g).
MS (APCI) 319/321 (M+H)+
JHNMR 6 (CDC13) 7.31 (1H, d), 7.00 (1H, d), 6.75 (1H, dd), 4.00 (1H, app. sept), 3.74-3.62 (1H, m), 2.94-2.84 (1H, m), 2.82 (1H, d), 2.72-2.61 (1H, m), 2.65 (1H, d); 2.60-2.49 (1H, m), 2.46-2.21(3H, m), 2.06-1.91 (2H, m), 1.90-1.72 (2H, m).
Preparation 2
4-Amino-l -[4-(3,4-dichlorophenoxy)piperidin-1 -yl]butan-2-ol Step 1: 2-{4-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-3-hydroxybutyl}-lJy-isoindole-l,3(2#)-dione
(Figure Remove)
A mixture of 4-(3,4-dichlorophenoxy)piperidine (WO 0058305, WO 0177101) (4.40g) and 2-(2-oxiran-2-yiethyl)-l/f-isoindole-l,3(2fl)-dione (J. Med. Chem. 1979, 22(6), 631-9. 5.00g) in ethanol (50 ml) was stirred at 60°C for 12k The mixture was cooled down and left overnight. The formed crystals were collected by filtration, washed with cold ethanol and dried under vacuum to afford the sub-title compound as a white solid (3-Og).
MS (APCI) 463/465 (M+H)*
!H NMR 6 (DMSO) 7.90-7.80 (4H, m), 7.49 (1H, d), 7.25 (1H, d), 6.97 (1H, dd), 4.53-4.33 (2H, m), 3.80-3.69 (1H, m), 3.69-3.58 (2H, m), 2.77-2.60 (2H, m), 2.38-2.17 (4H, m), 1.94-1.84 (2H, m), 1.85-1.75 (1H, m), 1.65-1.50 (3H, m).
Step 2: 4-amino-l-[4-(3,4-dichlorophenoxy)piperidin-l-yl]butan-2-ol
CIYY°vr/xl OH aA^ \^N^A~^NH2
A solution of mixture of 2-{4-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-3-hydroxybutyl}-l#-isoindole-l,3(2.ff)-dione (3.00g) in a mixture of ethanol (75 ml) and 35% aqueous hydrazine (15 ml) was heated at reflux 4k The mixture was cooled down and the solvents removed under vacuum. The residue was triturated with warm
dichloromethane. The white solid was removed by filtration and the filtrate dried over sodium sulfate. The mixture was filtered and the solvent was evaporated to afford the title compound as a yellow oil (2.10g) which was used without further purification in the next step.
MS (APCI) 333/335 (M+H)+
'H NMR 5 (CDC13) 7.29 (1H, d), 6.96 (1H, d), 6.76 (1H, dd), 4.40-4.25 (1H, m), 3.95-3.85 (1H, m), 3.20-3.00 (2H, m), 2.96-2.79 (1H, m), 2.78-2.63 (1H, m), 2.60-2.45 (1H, m), 2.41-2.23 (3H, m), 2.10-1.88 (2H, m), 1.88-1.70 (3H, m), 1.70-1.58 (1H, m).
Preparations
1 -Arnino-4-[4-(3,4-dichlorophenoxy)piperidin-l -yl]butan-2-o Step 1 : 4-(3 ,4-dichlorophenoxy)- 1 -(2-oxiran-2-ylethyl)piperidine
O
Amixtureof4-(3,4-dichlorophenoxy)piperidine(WO 0058305, WO 0177101) (2.00g), 2-(2-bromoethyl)oxirane (J. Am. Chem. Soc. 1981, 103, 7520-8) (1.36g) and potassium carbonate (2.2 g) in acetone (20 ml) was stirred at 50°C for 12h. The solvent was removed under vacuum. The residue was partitioned between water and ethyl acetate. The organic layer was washed with water, brine and dried over magnesium sulfate. The mixture was filtered and the solvent was evaporated to afford the sub-title compound as a yellow oil (2.50g) which was used without further purification in the next step.
MS (APCI) 316/318 (M+H)+
JH NMR 5 (CDC13) 7.31 (1H3 d), 7.00 (1H, d), 6.75 (1H, dd), 4.27 (1H, dquintet), 3.02-2.95 (1H, m), 2.78 (1H, t), 2.77-2.68 (2H, m), 2.57-2.49 (3H, m), 2.39-2.24 (2H, m), 2.03-1.94 (2H, m), 1.87-1.75 (2H, m), 1.77-1.72 (1H, m), 1.73-1.61 (1H, m).
Step 2: 1 -amino-4-[4-(3 ,4-dichlorophenoxy)piperidin- 1 -yl]butan-2-ol
(Figure Remove)
In a sealed metal tube, a solution of 4-(3 ,4-dichlorophenoxy)- l-(2-oxiran-2-ylethyl)piperidine (l.OOg) in 7N ammonia in methanol (25 ml) was heated at 70°C for 12h. The solvent was removed under vacuum and the residue purified on silicagel (0 to 1 0% 7N
ammonia in methanol/dichloromethane) to afford the title compound as a yellow oil (0.55g).
MS (APCI) 333/335 (M+H)+
'H NMR 5 (CDC13) 7.31 (IH, d), 6.99 (IH, d), 6.75 (IH, dd), 4.36-4.27 (IH, m), 3.79-3.70 (IH, m), 2.93-2.78 (IH, m), 2.76-2.59 (5H, m), 2.61-2.50 (IH, m), 2.37-2.27 (IH, m), 2.03-1.90 (2H, m), 1.89-1.76 (2H, m), 1.74-1.61 (IH, m), 1.54-1.46 (IH, m).
Preparation 4 (2R)- 1 - Amino-3-[4-(4-chlorophenoxy)piperidin- 1 -yl]propan-2-ol
(Figure Remove)
Prepared as described in Preparation 1 .
'HNMR 5 (CD3OD) 7.13 (2H, d), 6.80 (2H, d), 4.26 (IH, septet), 3.68-3.59 (IH, m), 2.77-2.65 (2H, m), 2.62 (IH, dd), 2.46 (IH, dd), 2.38-2.24 (4H, m), 1.95-1.85 (2H, m), 1.73-1.61(2H,m).
Preparation 5 (IK)-1 -Amino-3-[4-(4-chloro-3-f luorophenoxy)piperidin-1 -yl]propan-2-ol
OH
Prepared as described in Preparation 1.
MS (ESI) 303/305 (M+H)+
JH NMR 5 (CD3OD) 7.32 (IH, t), 6.86 (IH, dd), 6.77 (IH, ddd), 4.40 (IH, quintet), 3.74 (IH, ddd), 2.87-2.75 (2H, m), 2.72 (IH, dd), 2.56 (IH, dd), 2.50-2.37 (4H, m), 2.08-1.95 (2H, m), 1.85-1.72 (2H, m).
Preparation 6 (IS)-1 -Ajnino-3-[4-(3,4-difluoroprienoxy)piperidin-l -yl]propan-2-ol
OH
Prepared as described in Preparation 1. MS (ESI) 287 (M+H)+
'HNMR5 (CD3OD) 7.14 (1H, dt), 6.87 (1H, ddd), 6.75-6.69 (lH,m), 4.35 (1H, septet), 3.80-3.71 (1H, m), 2.88-2.75 (2H, m), 2.75 (1H, dd)3 2.58 (1H, dd), 2.51-2.34 (4H, m), 2.07-1.94 (2H, m), 1.85-1.71 (2H, m).
Preparation 7
2R)-1 -Amino-3-[4-(3,4-dichlorophenoxy)piperidin-1 -yl]propan-2-ol. Step 1: 4-(3J4-dichlorophenoxy)piperidine
4-Hydroxypiperidine (50g, 494mmol) was added portionwise to a stirred suspension of potassium tert-butoxide (110.9g, 990mmol) in THF (900ml) at room temperature and under nitrogen. The mixture was heated at reflux and l,2-dichloro-4-fluorobenzene (98g, 594mmol) added dropwise over 30 minutes. The mixture was stirred at reflux for another 1 hour then cooled down to room temperature, diluted with ethyl acetate (500ml) and washed with water (500ml). The organic phase was diluted further with ethyl acetate (500ml) and extracted with 1M hydrochloric acid (200ml). The aqueous extract was adjusted to pH>10 by addition of a solution of sodium hydroxide and extracted twice with te/t-butylmethyl ether (750ml). The organic extracts were dried over . magnesium sulfate, filtered and concentrated under vacuum to yield the sub-title compound as a dark oil which was used as such in the next step.
MS (ESI) 246/248 (M+H)+
JH NMR 6 (CDCla) 7.31 (1H, d), 7.00 (1H, d), 6.78 (1H, dd), 4.29-4.37 (1H, m), 3.15 (2H, dt), 2.75 (2H, td), 1.97-2.03 (2H, m), 1.60-1.70 (2H, m).
Alternative Step 1: 4-(3,4-dichlorophenoxy)piperidine
A thin slurry of 4-hydroxypiperidine (50g, 494mmol) in THF (200ml) was added to a stirred suspension of potassium tert-butoxide (110.9g, 990mmol) in THF (650ml) at room temperature and washed in with THF (50ml). The resultant mixture was stirred under nitrogen for 20 minutes. l,2-Dichloro-4-fluorobenzene (98g, 594mmol) was added and the resultant mixture heated at reflux for 90 minutes. The reaction mixture was cooled to room temperature and water (500ml) added. The layers were separated and the solvent removed from the organic fraction. The material was then partitioned between MTBE and 10% aqueous citric acid solution. The layers separated and the aqueous layer washed with further MTBE (2x250ml). The aqueous phase was basified to pH>10 by addition of ION NaOH solution and the product extracted with iso-propyl acetate C2x300mT). The oreanics
were washed with brine (300ml), dried over magnesium sulfate, filtered and concentrated under vacuum to yield the sub-title compound as a dark oil which was used as such in the next step (109.1g, 90%).
Step 2: (2S)-1 -azido-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]propan-2-ol

(2J?)-Oxiran-2-ylmethyl 3-nitrobenzenesulfonate (21.Ig, 81.3mmol) inDMF (300ml) was treated with triethylamine (22.6ml, 163.0mmol) followed by 4-(3,4-dichlorophenoxy)-piperidine (20g, 81.3mmol). The mixture was stirred overnight at 60°C. Sodium azide (16g, 243.9mmol) was added to the mixture and the reaction was stirred for a further 72h. The solution was carefully concentrated under vacuum and the residue was diluted with water (600ml), extracted with ethyl acetate (1500ml). The organic layer was washed twice with water (500ml), then brine (200ml) and concentrated under vacuum to afford an oil.
Step 3: (2R)-1 -Amino-3-[4-(3,4-dichlorophenoxy)piperidin-1 -yl]propan-2-ol
The resulting oil from Step 2 was dissolved in wet tetrahydrofuran (225ml) and was treated with triphenylphosphine (53.3g, 203mmol). The reaction was heated at 60°C and stirred for 4h. The solvent was removed under vacuum, the residue re-dissolved into 2N hydrochloric acid (1000ml) and the aqueous layer was extracted with ethyl acetate (3 times 700ml). The aqueous phase was basified with a 2N sodium hydroxide solution and extracted with dichloromethane (3 times 1000ml). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under vacuum. The crude material was purified by chromatography (8% 7N ammonia in methanol/DCM) to give the title compound as a yellow oil (17g). MS (APCI) 319/321 (M+H)+
!HNMR 6 (CDC13) 7.31 (1H, d), 7.00 (1H, d), 6.75 (1H, dd), 4.0 (1H, app. sept), 3.74-3.62 (1H, m), 2.94-2.84 (1H, m), 2.82 (1H3 d), 2.72-2.61 (1H, m), 2.65 (1H, d), 2.60-2.49 (1H, m), 2.46-2.21 (3H, m), 2.06-1.91 (2H, m), 1.90-1.72 (2H, m).
Preparation 8
(2R)-1 -Amino-3-[4-(3 34-dichlorophenoxy)piperidin-1 -yl]propan-2-ol Stepl: (25)-1 -Chloro-3-[4-(3,4-dichlorophenoxy)piperidin-1 -yl]propan-2-ol
ClxV^T'°V^xi OH ri-A^ k/N^^s^CI
L.I
(S)-(+)-Epichlorohydrin (3.50ml, 44.7mmol) was added to a stirred solution of 4-(3,4-dichlorophenoxy)piperidine (10.Og, 40.6mmol) in ethanol (50ml). After 20h, water (50ml) was added. The mixture stirred for a further 2h then the precipitated solid was collected by filtration, washed with water and dried under vacuum at 50°C for 2h to give the sub-title compound.
MS (ESI) 338/340/342/344 (M+H)+
'H NMR 5 (CDC13) 7.31 (IH, d), 7.00 (IH, d), 6.75 (IH, dd), 4.28-4.33 (IH, m), 3.89-3.96 (IH, m), 3.54-3.62 (3H, m), 2.84-2.92 (IH, m), 2.65-2.72 (IH, m), 2.45-2.59 (3H, m), 2.32-2.36 (IH, m), 1.90-2.01 (2H, m), 1.77-1.87 (2H, m).
Step 2: (2K)-1 -Amino-3-[4-(3,4-dichlorophenoxy)piperidin-1 -yl]propan-2-ol
A solution of sodium hydroxide (1.62g, 40.6mmol) in methanol. (200ml) was added to the product of the previous step and the mixture stirred for Ih whereupon all solid had dissolved. Aqueous ammonia solution (28%, 80ml) was added and stirring continued at ambient temperature for 3 days. The solution was concentrated in vacua to a volume of 100ml then dissolved in hydrochloric acid (0.5M, 800ml) and extracted with diethyl ether (2 x 200ml). The aqueous extract was filtered to remove insoluble impurities then made alkaline by addition of sodium hydroxide and extracted with dichloromethane (4 x 200ml) with filtration of the two-phase mixture to remove further insoluble impurities. Organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure to provide the title compound as an oil (10.6g).
MS (APCI) 319/321 (M+H)+
]H NMR 5 (CDC13) 7.31 (IH, d), 7.00 (IH, d), 6.75 (IH, dd), 4.0 (IH, app. sept.), 3.74-3.62 (IH, m), 2.94-2.84 (IH, m), 2.82 (IH, d), 2.72-2.61 (IH, m), 2.65 (IH, d), 2.60-2.49 (IH, m), 2.46-2.21 (3H, m), 2.06-1.91 (2H, m), 1.90-1.72 (2H, m).
Preparation 9 (2^-l-Amino-3-[4-(3)4-dichlorophenoxy)piperidin-l-yl]-2-methylpropan-2-ol



(Figure Remove)Prepared as described in Preparation 7 (Steps 2 and 3) using [(2R)-2-methyloxiran-2-yl]methyl-3-nitrobenzenesulfonate.
MS (APCI) 333/335 (M+H)+
'H NMR 8 (CDC13) 7.30 (IH, d), 6.99 (IH, d), 6.75 (IH, dd), 4.38-4.30 (IH, m), 3.48 (2H, s), 2.96-2.78 (2H, m), 2.62-2.30 (4H, m), 2.00-1.90 (2H, m), 1.85-1.72 (2H, m), 1.25(3H,s).
Preparation 10 (2R)-1 -Amino-3-[4-(4-chloro-2-methylphenoxy)-piperidin-1 -yl]propan-2-ol

Prepared as described in Preparation 7 (Steps 2 and 3) from 4-(4-chloro-2-methylphenoxy)-piperidine.
MS (ESI) 299/301 (M+H)+ .
'H NMR 5 (CD3OD) 7.12-7.05 (2H, m), 6.87 (IH, d), 4.39 (IH, septet), 3.77-3.70
(IH, m), 2.84-2.72 (2H, m), 2.71 (IH, dd), 2.55 (IH, dd), 2.50-2.39 (2H, m), 2.40 (IH, d), ^
2.39 (IH, d), 2.18 (3H, s), 2.04-1.95 (2H, m), 1.86-1.75 (2H, m).
® Preparation 11
6-({ 1 -[(2JR)-3-Amino-2-hydroxypropyl]piperidin-4-yl} oxy)-2,3-dichlorobenzamide
CONH,

Step 1: tert-Bntyl 4-[2-(aminocarbonyl)-3,4-dichlorophenoxy]piperidine-1 -carboxylate

ci

To a stirred solution of tert-butyl 4-[3,4-dichlorophenoxy]piperidine-l-carboxylate (7.0g, 20.3mmol) in dry THF (250ml) at -70°C under a nitrogen atmosphere was added dropwise sec-bntyl lithium (18ml, 1.3M ia cyclohexane). The solution was stirred a further 30min. at this temperature then treated with solid carbon dioxide pellets (excess). The cooling bath was removed and the mixture stirred vigorously whilst warming to room temperature over Ih. After a further Ih the solution was concentrated to ca 50ml volume then partitioned between aqueous sodium hydrogen carbonate solution and diethyl ether. The aqueous phase was further washed with diethyl ether (3 x), then acidified to pH 4 and extracted with dichloromethane (3 x). The combined extracts were dried (magnesium sulphate) and concentrated. Treatment of the crude carboxylic acid (2.5g, 6.4mmol) with carbonyl-l,l-diimidazolide (1.25g, 7.7mmol) in dichloromethane (50ml) at room temperature for 72h gave the crude imidazolide which was concentrated in vacua, redissolved in ethanol (20ml) and treated with 35% aqueous ammonia (20ml) in an autoclave at 100°C for 2h. The mixture was allowed to cool to room temperature slowly to allow crystallization of the title compound. The crystalline product was filtered and washed with water. Recrystallization from ethanol/water gave the sub-title compound (1.90g).
MS (APCI) 289/291 (M+H-BOC)"1"
'HNMR6 (CDC13) 7.40 (IH, d), 6.83 (IH, d), 5.91 (IH, s), 5.73 (IH, s), 4.52 (IH, m), 3.59 (2H, m), 3.41 (2H, m), 1.86 (4H, m), 1.43 (9H, s).
Step 2[ 2,3 -dichloro-6-(piperidin-4-yloxy)benzamide
(Figure Remove)
To a stirred solution of tert-butyl 4-[-[2~(aminocarbonyl)-3,4-
dichlorophenoxy]piperidine-l-carboxylate (1.8g, 4.6mmol) in dichloromethane (10ml) was added trifluoroacetic acid (10ml). After 30min at room temperature the solution was concentrated in vacua and partitioned between saturated aqueous sodium hydrogen carbonate solution and dichloromethane. The aqueous was re-extracted a further three times with dichloromethane and three tunes with ethy acetate. The combined organic extracts were dried (anhydrous potassium carbonate) and concentrated to afford the subtitle compound as a white solid (1.15g).

MS (APCI) 289/291 (M+H)+
'H NMR 8 (CD3OD) 7.49 (1H, d), 7.09 (1H, d), 4.65 (1H, M), 3.15 (2H, m), 2.84 (2H, m), 2.02 (2H, m), 1 .82 (2H, m).
Step 3: 6-({l-[(2J?)-3-amino-2-hydroxypropyl]piperidin-4-yl}oxy)-2,3-dichlorobenzamide Step a: To a stirred solution of 2,3-dichloro-6-(piperidin-4-yloxy)benzamide (l.lg, 3.8mmol) in dimethylformamide (10ml) was added triethylamine (1.06ml. 7.6mmol) and (2R)-glycidyl-3-nitrobenzenesulfonate (l.Og, 3.8mmol) and the mixture heated at 60°C for 3h. Sodium azide (l.Og, 15.2mmol) was added and the temperature maintained for a further 48h. The mixture was concentrated in vacua (blast shield) to almost dryness, and the product partitioned between dichloromethane and aqueous sodium hydrogen carbonate solution. The aqueous layer was reextracted with dichloromethane then with ethyl acetate. The combined organic extracts were dried (anhydrous potassium carbonate) and concentrated in vacua,
Step b: The product was redissolved in tetrahydrofuran (50ml) and treated with water (5ml) and triphenylphosphine (2.4g). The mixture was heated at 60°C for 4h, then concentrated in vacua. The product was partitioned between ethyl acetate and IN aqueous hydrochloric acid. The aqueous extracts were washed further with ethyl acetate then basified with 48% sodium hydroxide solution to pH 11. The aqueous layer was extracted with dichloromethane (3 x), and the combined organic extracts dried (anhydrous potassium carbonate) and concentrated in vacua to afford crude amine product which was used without any purification in the next step (See Example 132).
Preparation 12 (R)-l-[4-(3,4-DicUoro-phenoxy)-piperio!in-l-yl]-3-methylamino-propan-2-ol
A solution of 4-(3,4-dichlorophenoxy)-l-[(2Jl?)-oxiran-2-yhnethyl]piperidine (Ig, 3.3 Immol) and methylamine (2.56ml 40% in H2O, 33.1mmol) hi ethanol (15ml) was heated at 60°C in a sealed vessel for 16h. The solvent was evaporated at reduced pressure and the residue purified by flash column chromatography eluting with 8% 7M ammonia methanol in dichloromethane to give the title compound (875mg).
MS (APCI) 333/335 (M+H)+

]H NMR 5 (CDC13) 7.31 (IH, d), 6.99 (IH, d), 6.75 (IH, dd), 4.32-4.26 (IH, m), 3.86-3.80 (IH, m), 2.91-2.86 (IH, m), 2.71-2.65 (2H} m), 2.65 (IH, dd), 2.56-2.51 (2H, m), 2.54 (IH, dd), 2.48-2.42 (2H, m), 2.46 (3H, s), 2.38-2.27 (3H, m).
Preparation 13 (2R)- 1 -Amino-3-[4-(2,4-dichIoro-3-metliylplienoxy)piperidin- 1 -yl]propan-2-ol
ci


Prepared as described in Preparation 10 using 4-(2,4-dichloro-3-methylph.enoxy)-piperidine.
MS (APCI) 333/335 (M+H)+
'H NMR 5 (CD3OD) 7.25 (2H, d), 6.94 (2H, d), 4.54-4.37 (IH, m), 3.88-3.71 (IH, m), 3.35-3.24 (2H, m), 2.93-2.72 (4H, m), 2.72-2.57 (IH, m), 2.08-1.90 (2H, m), 1.92-1.75(2H,m).
Preparation 14 (2S)- 1 -Arnino-3 -[4-(3,4-dichlorophenoxy)piperidin- 1 -yl]propan-2-ol

H
Prepared as described in Preparation 7 using (2S)-oxiran-2-ylmethyl-3-nitrobenzenesulfonate .
MS (ESI) 319/321 (M+H)+
]H NMR 5 (CDC13) 7.30 (IH, d), 6.99 (IH, d), 6.75 (IH, dd), 4.36-4.24 (IH, m), 3.75-3.65 (IH, m), 2.94-2.78 (2H, m), 2.70-2.60 (2H, m), 2.59-2.51 (IH, m), 2.41-2.25 (3H, m), 2.03-1.93 (2H, m), 1.87-1.77 (2H, m).
Preparation 15
(2J?)-l-Amirio-2-methyl-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]propan-2-ol. Step 1: 2-[[(2R)-2-me%loxiranyl]methyl]- IS-isoindole- 1 ,3(2#)-dione.

Me
O

To a solution of (26')-(2-methyloxiran-2-yl)methyl 3-nitrobenzenesulphonate (1.913g, 7mmoles) in dry dimethylformamide (15ml), was added potassium phthahmide (1.304g, 7mmoles). The mixture was stirred at 50°C for 5h and then cooled to room temperature. The resulting mixture was partitioned between ethyl acetate and water. The aqueous phase was washed with ethyl acetate (2x100ml) and the combined organic extracts were washed with water (3x100ml), saturated brine solution, dried over sodium sulfate and concentrated in vacua to leave a crude orange wax. Purification by chromatography (silica, 20% ethyl acetate in z-so-hexane) afforded the subtitle compound as a white solid (0.864g).
MS(ESI)189(M-COy1'
'HNMRfi (CDC13) 7.90-7.85 (2H, m), 7.78-7.71 (2H, m), 4.02 (1H, d), 3.71 (1H, d), 2.82 (1H, d), 2.62 (1H, d), 1.39 (3H, s).
Step 2:
2-[(2^)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxy-2-methylpropyl]-Iff-isoindole-1,3(2#)-dione.

A solution of 4-(3,4-dichlorophenoxy)piperidine (0.985g, 4rnmoles), 2-[[(2J2)-2-methyloxiranyl]methyl]-lf/-woindole-l,3(2//)-dione (0.869g, 4mmoles) and triethylamine (0.809g, 1.12ml, Smmoles) in ethanol (20ml) was stirred at 50°C for 5h. The resulting solution was cooled to room temperature and concentrated in vacua to leave a crude yellow gum. Flash chromatography (silica, 2% of TATmethanolic ammonia in dichloromethane as eluant) afforded the subtitle compound as a yellow oil (1.24g).
MS (APC1) 463/465/467 (M+H)+
]HNMR 5 (CDC13) 7.89-7.85 (2H, m), 7.76-7.72 (2H, m), 7.30 (1H, d), 6.98 (1H, d), 6.78 (1H, dd), 4.27-4.21 (1H, m), 3.88 (lH,d), 3.70 (1H, d), 3.43 (1H, bd s), 2.96-2.81 (2H5 m), 2.60-2.42 (4H, m), 1.95-1.89 (2H, m), 1.80-1.70 (2H, m), 1.15 (3H, s).
Step 3:
(2R)-1 - Amino-2-methyl-3-[4-(3,4-dichlorophenoxy)piperidin-1 -yl]propan-2-ol.

To a solution of 2-[(21S}-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxy-2-methylpropyl]-l#-wouidole-l,3(2.#)-dione (278mg, 0.6mmoles) in ethanol (5ml) was added aqueous methylamine (40% wt. solution in water, 6ml). The mixture was stirred at room temperature for 24h and then concentrated in vacua to leave a crude yellow glass. This glass was dissolved in methanol (2ml), added to an Isolute Flash SCX cartridge (2g), washed with methanol (25ml) and 7N ammonia in methanol (25ml). The methanolic ammonia was concentrated in vacua to give the title compound as a yellow glass (165mg).
MS (ESI) 333/335/337 (M+H)+
1E NMR 5 (CDC13) 7.31 (1H, d), 6.99 (1H, d), 6.75 (1H, dd), 4.29-4.21 (1H, m), 2.96-2.80 (2H, m), 2.60-2.30 (4H, m), 2.00-1.90 (3H, m), 1.85-1.75 (3H, m), 1.13 (3H, s).
Preparation 16 7-(Chlorosulfonyl)-1 -oxo-1,2-dihydroisoquinoline-4-carboxylic acid
(Figure Remove)
l-Oxo-7-sulfo-l,2-dihydroisoquinoline-4-carboxylic acid (5g) was added to chlorosulphonic acid (25ml). The mixture was heated at 100°C for 84h and then slowly dripped onto ice with stirring. The mixture was filtered and the residue was washed with water and ether and dried to yield 7-(chlorosulfonyl)-l-oxo-l,2-dihydroisoquinoline-4-carboxylic acid as a buff solid (7.5g).
MS (APCI) 286 (M-H)'
'HNMRS (DMSO) n.si (m, d), 8.79 (m, d), 8.48 (m, d), 8.03 (m, d), 7.96 OH, dd).

7-(Chlorosulfonyl)-l-oxo-l,2-dihydroisoquinoline-4-carboxylic acid (Ig) was added to aqueous methylamine (60ml) and the mixture was stirred for 18h. Concentrated
Preparation 17 (Figure Remove)7-[(Methylamino)sulfonyl]-l -oxo-1,2-dihydroisoquinoline-4-carboxylic acid

hydrochloric acid was added to acidify the mixture, which was filtered to yield 7-
[(memylamino)siilfonyl]-l-oxo-l,2-dmydroisoquinoline-4-carboxylic acid as a buff solid (0.84g).
MS (APCI) 283 (M+H)+
'HNMR5 (DMSO) 12.93 (1H, s), 12.13 (1H, d), 9.03 (1H, d), 8.61 (1H, d), 8.16 (1H, d), 8.12 (1H, dd), 7.65 (1H, q), 2.43 (3H, d).
Preparation 18
1,2-Dihydro-7-[[(2-hydroxyethyl)amino]sulfonyl]-1 -oxo-4-isoquinolinecarboxylic acid

7-(Chlorosulfonyl)-l-oxo-l,2-dihydroisoquinoline-4-carboxylic acid (Ig) was added to ethanolamine(3ml) in tetrahydrofuran (3ml) and the mixture was stirred for 1 8h. Hydrochloric acid was added to acidify the mixture, which was filtered to yield 1,2-dihydro-7-[[(2-hydroxyethyl)anuno]sulfonyl]-l-oxo-4-isoquinoHnecarboxylic acid as a white solid.
MS(APCI)313(M+H)+
JH NMR 5 (DMSO) 12.92 (5H, s), 12.12 (5H, s), 9.01 (6H, d), 8.62 (6H, s), 8.16 (13H, d), 8.13 (13H, dd), 7.81 (6H, t), 4.67 (5H, s), 3.39-3.25 (84H, m), 2.81 (13H, q).
Preparation 19 7-[(Cyclopropylamino)sulfonyl]- 1 ,2-dihydro-l -oxo-4-isoquinolinecarboxylic acid

7-(Chlorosulfonyl)-l-oxo-l,2-dihydroisoqumohiie-4-carboxylic acid (Ig) was added to cyclopropylamine(3ml) in tetrahydrofuran (20ml) and the mixture was stirred for 18h. Hydrochloric acid was added to acidify the mixture which was filtered to yield 7-[(cyclopropylanimo)siilfonyl]-l,2-dmydro-l-oxo-4-isoq\mioUnecarboxylicacid as a white solid.

MS (APCI) 307 (M-H)'
!HNMR 6 (DMSO) 12.93 (IH, s), 12.13 (IH, d), 9.03 (IH, d), 8.65 (IH, d), 8.16 (IH, d), 8.14 (IH, dd), 8.08 (IH, d), 2.13 (IH, dsextet), 0.48 (2H, td), 0.39-0.34 (2H, m).
Preparation 20 7-(Azetidin-1 -ylsulfonyl)-1 -oxo-1,2-dihydroisoquinoUne-4-carboxylic acid

7-(Chlorosulfonyl)-l-oxo-l,2-dihydroisoquinoline-4-carboxylic acid (Ig) was added to azetidine (0.7ml) and diisopropylethylamine (0.4ml) in tetrahydrofuran (5ml) and acetonitrile (5ml) and the mixture was stirred for 72h then evaporated. The solid was crystallised from methanol then hydrochloric acid was added to acidify the mixture, which was filtered to yield 7-(azetidin-1-ylsulfonyl)-!-oxo-l,2-dihydroisoquinoKne-4-carboxylic acid as a white solid.
MS (APCI) 309 (M+H)+
'H NMR 5 (DMSO) 12.99 (1H, s), 12.21 (1H, d), 9.12 (1H, d), 8.54 (1H, d), 8.20 (1H, d), 8.16 (IH, dd), 3.70 (4H, t), 1.99 (2H, quintet).
Preparation 21 7-(Aminosulfonyl)-1 -oxo-1,2-dmydroisoquinoline-4-carboxylic acid

7-(Chlorosulfonyl)-l-oxo-l,2-dihydroisoquinoline-4-carboxylic acid (Ig) was added to 0.880 ammonia (60ml) and the mixture was stirred for 18h. Concentrated hydrochloric acid was added to acidify the mixture, which was filtered to yield 7-(aminosulfonyl)-l-oxo-l,2-dihydroisoquinoline-4-carboxylic acid as a white solid.
MS (APCI) 269 (M+H)+
'HNMR 5 (DMSO) 12.91 (in, s), 12.08 (IH, d), 8.99 (m, d), s.68 (in, d), s.i6
(1H, dd), 8.14 (IH, d), 7.53 (2H, s).


Preparation 22 7-[(Dmethylarnino)sulfonyl]-1 -oxo-1,2-dihydroisoquinoline-4-carboxylic acid
7-(Cnlorosulfonyl)-l-oxo-l32-dihydroisoquinolrne-4-carboxylic acid (O.Sg) was added to dimethylamine (15ml) and the mkture was stirred for 18h. The mixture was acidified with concentrated hydrochloric acid and then filtered to yield 7-[(dmetiiylammo)sulfonyl]-l-oxo-l,2-dmydroisoquinoline-4-carboxylic acid as a white solid.
MS (APCI) 295 (M-H)'
'HNMR6 (DMSO) 12.96 (1H, s), 12.19 (1H, d), 9.07 (1H, d), 8.50 (1H, d), 8.18 (1H, d), 8.11 (1H, dd), 2.65 (6H, s).
Preparation 23
7-[(3-Hydroxy-3-methylazetidin-l -yl)sulfonyl]-l -oxo-1,2-dihydroisoquinoline-4-carboxylic acid

7-(Chlorosulfonyl)-1 -oxo-1,2-dihydroisoquinoline-4-carboxylic acid (1 g), diisopropylethylamine (3ml) and 3-methylazetidin-3-ol hydrochloride (O.Sg) in tetrahydrofuran (8ml) were heated at 55°C for 3 days. The mixture was acidified with hydrochloric acid and then filtered to yield 7-[(3-hydroxy-3-methylazetidin-l-yl)sulfonyl]-l-oxo-l,2-dihydroisoquinolme-4-carboxyIic acid as a pale pink solid.
MS (ESI) 337 (M-H)~
*H NMR 5 (DMSO) 12.99 (1H, s), 12.22 (1H, d), 9.11 (1H, d), 8.53 (1H, s), 8.21 (1H, d), 8.16 (1H, dd), 3.61 (2H, d), 3.46 (2H, d)5 1.25 (3H, t).


Preparation 24 -[(2^)-3-Ammo-2-hydroxypropyl]piperidin-4-yl} oxy)-2-chlorobenzonitrile
Step 1: tert-Butyl 4-(3-chloro-4-cyanophenoxy)piperidine-l-carboxylate
Potassium terf-butoxide (5.57g, 49.68mmol) was added to a solution of tert-butyl 4-hydroxypiperidine-l-carboxylate (S.OOg, 24.84mmol) in glyme (100ml) and the mixture stirred for 30min. before addition of 2-chIoro-4-fluoro-benzonitrile (7.73g, 49.68mmol). The reaction was stirred at room temperature overnight and then partitioned between ethyl acetate (250ml) and water (200ml). The organic layer was separated, dried over magnesium sulfate and the solvent evaporated. The residue was purified by flash chromatography eluting with ethyl acetate:isohexane (4:1) to give the subtitle compound as a colourless solid (3.45g).
MS (ESI) 337 (M+H)+
'HNMR5 (CDC13) 1.47 (9H, s), 1.72-1.80 (2H, m), 1.90-1.97 (2H, m), 3.37 (2H3 ddd), 3.68 (2H, ddd), 4.54 (1H, dquintet), 6.86 (1H, dd), 7.01 (1H, d), 7.57 (1H, d).
Step 2: 4-({l-[(2J?)-3-Amino-2-hydroxypropyl]piperidin-4-yl}oxy)-2-chlorobenzonitriIe
To a solution of the tert-bntyl 4-(3-chloro-4-cyanophenoxy)piperidine-l-carboxylate (2.75g, 9.09mmol) in dichloromethane (20ml) was added trifluoroacetic acid (20ml) and the mixture stirred for 90 min.. The solvents were evaporated and the residue azeotroped with toluene (2x20rnl) before dissolving in water (30ml) and addition of sodium hydroxide to bring the solution to pH 11. The free base was extracted with DCM (5x100ml). The organics were combined, dried over sodium sulfate and the solvent removed under reduced pressure to give a thick oil which was dissolved in DMF (30ml) before addition of (2R)-oxiran-2-yhnethyl-3-nitrobenzenesulfonate (2.35g, 9.09mmol) and triethylamine (2.54ml, 18.18mmol). The mixture was heated at 60°C for 4h before addition of sodium azide (1.36g, 27.27mmol). Heating was continued at 60°C for a further 72h. The reaction mixture was cooled and partitioned between water (50ml) and ethyl acetate (100ml). The organic layer was separated and the solvent removed

under reduced pressure. The residue was dissolved in THF (20ml) and water (2ml) and triphenylphosphine (5.90g, 22.72mmol) added. The mixture was heated at 60°C for 16h before dilution with ethyl acetate (100ml). The solution was washed with IN HC1 (50ml) and the aqueous layer was separated and adjusted to pH 11 with sodium hydroxide. The product was extracted with DCM (4x100ml). The organics were combined and dried sodium over sulfate and the solvent removed under reduced pressure. The residue was purified by flash chromatography to give the title compound as a pale yellow solid (1.1 Og
MS(ESI)310(M+H)+
]H NMR 5 (CDC13) 7.56 (IH, d), 7.00 (IH, d), 6.85 (IH, dd), 4.42 (IH, septet), 3.73-3.67 (IH, m), 2.93-2.86 (IH, m), 2.86-2.78 (IH, m), 2.71-2.62 (2H, m), 2.61-2.55 (IH, m), 2.45-2.30 (3H, m), 2.06-1.96 (2H, m), 1.91-1.79 (2H, m).
Preparation 25 (2K)-1 -Amino-3-{4-[4-(methylsul.fonyl)phenoxy]piperidin-1 -yl }propan-2-ol.

Prepared as described in Preparation 24 starting from l-fluoro-4-(methylsulfonyl) benzene. Step 1: tert-Butyl 4-[4-(methylsulfonyl)phenoxy]piperidine-l-carboxylate

]HNMR5 (CDC13) 1.48 (9H, s), 1.74-1.82 (2H, m), 1.91-1.99 (2H, m), 3.04 (3H, s), 3.38 (2H, ddd), 3.69 (2H, ddd), 4.57-4.62 (IH, m), 7.02 (2H, d), 7.86 (2H, d).
Step 2: (2^)-l-Amino-3-{4-[4-(methylsulfonyl)phenoxy]piperidin-l-yl}propan-2-ol
MS (ESI) 329 (M+H)+
!H NMR 6 (CDC13) 7.85 (2H, d), 7.01 (2H, d), 4.47 (IH, septet), 3.73-3.67 (IH, m), 3.03 (3H, s), 2.95-2.88 (IH, m), 2.86-2.78 (IH, m), 2.72-2.62 (2H, m), 2.61-2.55 (IH, m), 2.45-2.30 (3H, m), 2.08-1.98 (2H, m), 1.92-1.81 (2H, m).


Preparation 26 4-({l-[(2^)-3-Amino-2-hydroxy]3ropyl]piperidiii-4-yl}oxy)benzonitrile
Prepared as described in Preparation 24 starting from 4-fluorobenzonitrile. Step 1 : /ert-Butyl 4-(4-cyanophenoxy)piperidine-l-carboxylate
MS (ESI) 303 (M+H)+
'H NMR5 (CDC13) 7.58 (2H, d), 6.95 (2H, d), 4.55 (1H, m), 3.69 (2H, ddd), 3.37 (2H, ddd), 1.97-1.90 (2H, m), 1.80-1.72 (2H, m), 1.47 (9H, s).
Step 2: 4-({ l-[(2J?)-3-Amino-2-hydroxypropyl]piperidin-4-yl}oxy)benzonitrile
MS (ESI) 276 (M+H)+
!H NMR 6 (CDC13) 7.57 (2H, d), 6.94 (2H, d), 4.46-4.41 (1H, m), 3.74-3.68 (1H, m), 2.94-2.88 (1H, m), 2.83 (1H, dd), 2.73-2.66 (1H, m), 2.64 (1H, dd), 2.61-2.55 (1H, m), 2.46-2.30 (3H, m), 2.07-1.97 (2H, m), 1.91-1.80 (2H, m).
Preparation 27 tert-Butyl 4-[4-chloro-2-(methoxycarbonyl)phenoxy]piperidine-1 -carboxylate

Diisopropylazodicarboxylate (5.2ml, 26.8mmol) was added dropwise to a solution of 5-chloro-2-hydroxy methylbenzoate (5.0g, 26.8mmol), /erf-butyl 4-hydroxypiperidine-1-carboxylate (5.4g, 26.8mmol) and triphenylphosphine (7.02g, 26.8mmol) in THF (200ml) at 0°C. The reaction mixture was allowed to warm to ambient temperature overnight. The solvent was removed under reduced pressure and the residue triturated with diethyl ether (200ml). The triphenylphosphineoxide was filtered off and the diethyl ether removed under reduced pressure. The residue was purified by flash column chromatography eluting with ethyl acetate:isohexane (1:9) to give the title compound as a brown oil (8.Ig).

MS (ESI) 370 (M+H)+
'H NMR 5 (DMSO) 1.47 (9H, s), 1.79-1.92 (4H, m), 3.45-3.54 (2H, m), 3.56-3.62 (2H, m), 3.89 (3H, s), 4.54-4.59 (1H, m), 6.92 (1H, d), 7.38 (1H, dd), 7.77 (1H, d).
Preparation 28 2-{[l-(^7-/-Butoxycarbonyl)piperidin-4-yl]oxy}-5-chlorobenzoic acid
Cl^^
An aqueous solution of 2N sodium hydroxide (20ml) was added to a solution of tert-butyl 4-[4-chloro-2-(methoxycarbonyl) phenoxy]piperidine-l-carboxylate (8.1g, 22.0mmol) in tetrahydrofuran (70ml) at 45°C. The mixture was stirred vigorously for 3h then adjusted to pH 2 with 2N hydrochloric acid. The product was extracted with ethyl acetate and the organic layer washed repeatedly with water until the washings were pH 6. The organic layer was dried over magnesium sulfate and evaporated. The residue was azeotroped with toluene to give the title compound as a colourless solid (7.5g).
MS (ESI) 356 (M+H)+
'H NMR 5 (DMSO) 1.47 (9H, s), 1.79-1.88 (2H, m), 2.03-2.11 (2H,m), 3.30 (2H, ddd), 3.77-3.85 (2H, m), 4.72 (1H, m), 7.02 (1H, d), 7.49 (1H, dd), 8.12 (1H, d), 10.91
Preparation 29
4-(4-Chloro-2-methylcarbamoyl-phenoxy)-piperidine-1 -carboxylic acid tert-butyl ester

Bromo-tris-pyrrolidinophosphonium hexafluorophosphate (1.57g, 3.37mxnol) was added to a vigorously stirred mixture of 2-{[l-(ter/-butoxycarbonyl)piperidtn-4-yl]oxy}-5 chlorobenzoic acid (l.OOg, 2.81mmol) and 40% aqmethylamine (2ml) in DCM (10ml). Stirring was continued for 30 min. before partitioning between IN hydrochloric acid (10ml) and dichloromethane (10ml). The organic layer was separated and washed with
saturated sodium bicarbonate solution (20ml) and water (20ml), then dried over sodium sulfate and the solvent removed under reduced pressure. The residue was purified by flash column chromatography eluting with ethyl acetatedsohexane (1:1) to give the title compound as a colourless solid (0.84g).
MS (ESI) 369 (M+H)+
'HNMR5 (CDC13) 8.17 (IH, d), 7.75 (IH, s), 7.35 (IH, dd), 6.91 (IH, d), 4.58 (IH, tt), 3.81-3.71 (2H, m), 3.29 (2H, ddd), 3.00 (3H, d), 2.08-1.98 (2H, m), 1.82-1.71 (2H, m), 1.48 (9H, s).
Preparation 30 tert-Butyl 4-[2-(aminocarbonyl)-4-chlorophenoxy]piperidine- 1 -carboxylate

Prepared as described in Preparation 29 using aqueous ammonia. MS (ESI) 355 (M+H)+ ]H NMR 5 (CDC13) 8.18 (IH, d), 7.67-7.61 (IH, m), 7.40 (IH, dd), 6.94 (IH, d),
5.83-5.76 (IH, m), 4.61 (IH, m), 3.84-3.76 (2H, m), 3.26 (2H, ddd), 2.09-2.01 (2H, m),
1. 82-1. 73 (2H,m), 1.47 (9H,s).
Preparation 31
Methyl 2-({ l-[(2J?)-3-amino-2-hydroxypropyl]piperidin-4-yl}oxy)-5-chlorobenzoate

Prepared as described in Preparation 24, Step 2 from tert-butyl 4-[4-chloro-2-(methoxycarbonyl)phenoxy]piperidine- 1 -carboxylate.
MS (ESI) 343 (M+H)*
'H NMR 8 (CDC13) 7.75 (IH, d), 7.37 (IH, dd), 6.92 (IH, d), 4.46-4.39 (IH, m), 3.89 (3H, s), 3.72-3.66 (IH, m), 2.93-2.87 (IH, m), 2.81 (IH, dd), 2.69-2.55 (2H, m), 2.63 (IH, dd), 2.43-2.31 (3H, m), 2.00-1.84 (2H, m), 1.67-1.46 (2H, m).
Preparation 32
2-({ 1 -[(2#)-3-Ammo-2-hydroxypropyl]piperidrn-4-yl} oxy)-5-chloro-.Af-methylbenzamide

cr
• Prepared as described in Preparation 24, Step 2 from 4-(4-chloro-2-methylcarbamoyl-phenoxy)-piperidine-l-carboxylic acid tert-butyl ester.
MS (ESI) 342 (M+H)+
JH NMR5 (CDC13) 8.18 (1H, d), 7.88 (1H, s), 7.34 (1H, dd), 6.91 (1H, d), 4.54-4.48 (1H, m), 3.73-3.67 (1H, m), 3.01 (3H, d), 2.89-2.83 (1H, m), 2.83 (1H, dd), 2.68-2.56 (2H, m), 2.63 (1H, dd), 2.44 (1H, dd), 2.39-2.33 (1H, m), 2.34 (1H, dd), 2.13-2.03 (2H, m), 1.94-1.83 (2H,m).
Preparation 33 2-({l-[(2^)-3-Amino-2-hydroxypropyl]piperidin-4-yl}oxy)-5-chlorobenzamide

cr
Prepared as described in Preparation 24, Step 2 from ter/-butyl 4-[2-(aminocarbonyl)-4-chlorophenoxy]piperidine-1 -carboxylate.
MS (ESI) 328 (M+H)+
3H NMR 5 (CDC13) 8.19 (1H, d), 7.75 (1H, s), 7.39 (1H, dd), 6.93 (1H, d), 5.85 (1H, s), 4.56-4.48 (1H, m), 3.73-3.67 (1H, m), 2.93-2.86 (1H, m), 2.83 (1H, dd), 2.73-2.66 (1H, m), 2.63 (1H, dd), 2.61-2.54 (1H, m), 2.44 (1H, dd), 2.37-2.30 (1H, m), 2.35 (1H, dd), 2.15-2.05 (2H, m), 1.90 (2H, did).
Preparation 34
terf-Butyl 4-{ 3 34-dichloro-2-[(cyclopropylamino)carbonyl]plienoxy}piperidine-1 -carboxylate

'A solution of/ert-butyl 4-[3J4-dichloro-2-(lH-imidazol-l-ylcarbonyl)phenoxy] piperidine-1-carboxylate (described in Preparation 11 step 1) (2.0g, 4.5mmol) in cyclopropylamine (12ml) was heated at 50°C for 14h. The solution was concentrated in vacua then partitioned between ethyl acetate and IN aqueous hydrochloric acid. The organics were dried over magnesium sulfate and concentrated in vacua. Crystallization from dichloromethanerisohexane gave the title compound as a white solid (0.64g).
MS (ESI) 429/431 (M+H)+
!H NMR 5 (DMSO) 8.46 (IH, d), 7.56 (IH, d), 7.17 (IH, d), 4.68 (IH, m), 3.42-3.27 (4H, m), 2.74 (IH, m), 1.78 (2H, m), 1.55 (2H, m), 0.68 (2H, m), 0.44 (2H, m).
Preparation 35
6-{ [1 -(3-Amino-2-hydroxypropyl)piperidin-4-yl]oxy}-2,3-dichloro-7V-cyclopropylbenzamide

Prepared as described in Preparation 24, Step 2 following Preparation 34.
MS (ESI) 402 (M+H)+
JH NMR 5 (CDC13) 7.35 (IH, d), 6.78 (IH, d), 5.82 (IH, s), 4.40-4.33 (IH, m), 3.68 (IH, tt), 2.92-2.85 (2H, m), 2.85-2.77 (2H, m), 2.81 (IH, dd), 2.62 (IH, dd), 2.42-2.29 (3H, m), 2.00-1.89 (2H, m), 1.88-1.79 (2H, m), 0.89 (2H, td), 0.66-0.62 (2H, m).
Preparation 36 tert-Butyl 4-[3 ,4-dichloro-2-(chlorosulfonyl)phenoxy]piperidine- 1 -carboxylate
so,ci


0
To a stirred solution of tert-butyl 4-[3,4-dichlorophenoxy]piperidine-l-carboxylate (lO.Og, 28.9mmol) in dry THF (400ml) at -70°C under a nitrogen atmosphere was added dropwjse sec-butyl lithium (26.7ml, 1.3M in cyclohexane). The solution was stirred a further 15min. at this temperature and then sulfur dioxide was bubbled through the mixture for lOmin. The cooling bath was removed and the mixture wanned to room temperature over Ih. N-Chlorosuccinimide (4.63g, 35mmol) was added and the mixture stirred at roorr temperature for 72h. The solution was concentrated in vacua and partitioned between ethyl acetate and IN aqueous hydrochloric acid. The organic extracts were dried (magnesium sulphate) and concentrated. Chromatography on silica (ethyl acetate: isohexane/l:3) gave the title compound (2.40g)
MS (ESI) 445 (M+H)+
JH NMR 5 (DMSO) 7.45 (IH, d), 7.03 (IH, d), 4.65 (IH, m), 3.59 (2H, m), 3.33 (3H, s), 1.66 (4H, m), 1.40 (9H? s).
Preparation 37 2,3-Dichloro-6-(piperidin-4-yloxy)benzenesulfonamide
SO
fer?-Butyl-4-[3,4-dichloro-2-(chlorosulfonyl)phenoxy]piperidine-l-carboxylate (O.SOg, 1 .Smmol) was dissolved in 7N ammonia in methanol and stirred at room temperature for 20min. The solution was concentrated in vacua and then azeotroped once with toluene. The residue was redissolved in dichloromethane:trifluoroacetic acid 71:1 (20ml) and stirred at room temperature for 15 minutes. The solution was concentrated in vacua, then partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate solution. The aqueous was reextracted with ethyl acetate (4 times), and the combined organics dried over anhydrous potassium carbonate. Concentration in varun afforded the title compound as a white powder (0.54g).
MS (ESI) 325/327 (M+H)+
!H NMR 5 (DMSO) 7.74 (1H, d), 7.34 (1H, d), 4.66 (1H, m), 2.96 (2H, m), 2.55 (2H, m), 1 .91 (2H3 m), 1 .63 (2H, m).
Preparation 38 2,3-Dichloro-A'-raethyl-6-(piperidin-4-yloxy)benzenesulfonamide
o=s=o

/erf-Butyl 4-[3 ,4-dichloro-2-(chlorosuIfonyl)phenoxy]piperidine- 1 -carboxylate (0.70g, l.Smmol) was dissolved in 40% aqueous methylamine in water (10ml) and methanol (10ml) and stirred at room temperature for 30min. The solution was concentrated in vacuo and then azeotroped with toluene (4 times). The residue was redissolved in dichloromethane/trifluoroacetic acid (1:1) (20ml) and stirred at room temperature for 1 5 minutes. The solution was concentrated in vacua, then partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate solution. The aqueous was reextracted with ethyl acetate (4 times), and the combined organics dried over anhydrous potassium carbonate. Concentration in vacua afforded the title compound as a white powder (0.69g).
MS (ESI) 339/341 (M+H)+
'H NMR 5 (DMSO) 7.76 (1H, d), 7.35 (1H, d), 4.64 (1H, m), 2.96 (2H, m), 2.54 3H, s), 2.54 (2H, m), 1.90 (2H, m), 1.61 (2H, m).
Preparation 39 2J3-r>ichloro-N-cyclopropyl-6-(piperidin-4-yloxy)benzenesulfonamide

tert-Butyl 4-[3,4-dichloro-2-(chlorosulfonyl)phenoxy]piperidine-1 -carboxylate (0.70g, l.Smmol) was dissolved in cyclopropylamine (8ml) and stirred at room temperature for 30mia. The solution was concentrated in vacua and then azeotroped with toluene (4 times). The residue was redissolved in dichloromethane: trifluoroacetic acid /
1:1 (20ml) and stirred at room temperature for 15min. The solution was concentrated in vacua, then partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate solution. The aqueous was reextracted with ethyl acetate (4 times), and the combined organics dried over anhydrous potassium carbonate. Concentration in vacua afforded the title compound as a white powder (0.70g).
MS (ESI) 365/367 (M+H)+
1E NMR 5 (DMSO) 7.78 (1H, d), 7.36 (1H, d), 4.65 (1H, m), 2.97 (2H, m), 2.55 (2H, m), 2.27 (1H, m), 1.89 (2H, m), 1.63 (2H, m), 0.49 (4H, m) ;
Preparation 40
6-({ 1 -[(2J?)-3-Amino-2-hydroxypropyl]piperidm-4-yl}oxy)-2,3-dichlorobenzenesulfonamide
NH2
o=s=o
-H
Prepared as described in Preparation 7 (Steps 2 and 3) following Preparation 37. MS (ESI) 398/400 (M+H)+
Preparation 41 6-({l-[(2^)-3-Amino-2-hydroxypropyl]piperidin-4-yl}oxy)-2,3-dichloro-A'-
methylbenzenesulfonamide
HN"" •o=s=o

Prepared as described in Preparation 7 (Steps 2 and 3) following Preparation 38. MS(ESI)412/414(M+H)+
Preparation 42
6-({l-[(2J?)-3-Amino-2-hydroxypropylJpiperidin-4-yl}oxy)-2,3-dichloro-A'-cyclopropylbenzenesulfonamide
HN
0=S=0 Ci

Prepared as described in Preparation 7 (Steps 2 and 3) following Preparation 39. MS (ESI) 438/440 (M+H)+
Preparation 43 7-(Methylsulfonyl)-1 -oxo-1,2-dihydroisoquinoline-4-carboxylic acid

To a solution of sodium bicarbonate (500mg) and sodium sulfite (353mg) in 4ml of water at 0°C was added portionwise the T-tchlorosulfony^-l-oxo-l^-dihydroisoquinoline-4-carboxylic acid (see Preparation 16) (400mg). The reaction was warmed to room temperature and then heated at 80°C for 2h. The reaction was cooled to 0°C and acidified to pH~l with concentrated hydrochloric acid. The suspension was diluted with 4ml of water and stirred for 15 minutes at 0°C then filtered under nitrogen. The soh'd was washed twice with water and was added to a degassed aqueous solution (3ml) of potassium hydrogen carbonate (280mg) at 45°C. Ethanol was then slowly added until the solution became slightly cloudy. lodomethane (262p.l) was then added and the reaction refluxed (45-50°C) for 5L The reaction was concentrated under vacuum, extracted with ethyl acetate and the aqueous phase acidified with concentrated hydrochloric acid. The reaction was stirred at 0°C for 30 min. and the soh'd collected by filtration then recrystallised from acetone to yield the title compound as a white solid (325mg),
MS (ESI) 266 (M-H)'
'H NMR 5 (DMSO) 12.97 (1H, bs), 12.19 (1H, d), 9.07 (1H, d), 8.70 (1H, d), 8.27 (1H, dd)5 8.19 (1H, d), 3.30 (3H, s).
6-(Methylsulphonyl)-l#-indole-3-carboxylicacid




Prepared as described in Preparation 43 following Preparation 16 using indole-3-carboxylic acid.
•MS(ESI)238(M-H)-
'HNMRS (DMSO) 12.34 (in, bds), 12.29 (m, vbds), 8.31 OH, s), 8.21 (IH,
8.03 (IH, d), 7.69 (IH, dd), 3.20 (IH, d).
Preparation 45
6-Fluoro- 1 -oxo- 1 ,2-dihydroisoquinoline-4-carboxylic acid Prepared following literature procedures: Liebigs Annalen der Chemie, 1981, 5, 819-27 and Chemical & Pharmaceutical Bulletin, 1983, 31, 1277-82.
Step 1 : Dimethyl [5-fluoro-2-(methoxycarbonyl)phenyl]malonate

F
(Prepared according to US 5 1 89 1 68)
To a rapidly stirred suspension of 2-bromo-4-fmorobenzoic acid (4.5g) and copper(I) bromide (175mg) in 25ml of dirnethylmalonate at 0°C was added portionwise sodium hydride (60% in mineral oil, L3g). After 10 min., the reaction warmed to room temperature and stirred for 30 minutes at room temperature then heated at 70°C for 2h. The solidified reaction was then diluted with water (80ml) and was extracted with diethyl ether (3x50ml). The aqueous layer was acidified with concentrated hydrochloric acid and extracted with ethyl acetate (3x100). The combined organic layers were dried over magnesium sulfate, filtered, concentrated under vacuum and the crude material recrystallised from diethyl ether/iyo-hexane to yield the sub-title compound as a white solid
]H NMR 5 (DMSO) 13.36 (1H, bs), 8.05 (1H, dd), 7.35 (1H, ddd), 7.14 (1H, dd), 5.08 (1H, s), 3.70 (6H, s).
Step 2: 2-(Carboxymethyl)-4-fluorobenzoic acid

F
A suspension of dimethyl [5-fluoro-2-(methoxycarbonyl)phenyl]malonate (l.SOg) in concentrated hydrochloric acid (25ml) was heated at 110°C for 48h. The reaction was cooled and the sub-title compound collected as a white solid by filtration (1.50g).
MS (ESI) 197 (M-H)-
'H NMR 5 (DMSO) 7.97 (1H, dd), 7.24 (1H, dd), 7.20 (1H, dd), 3.96 (2H, s).
Step 3: (42)-6-Fluoro-4-(methoxymethylene)-l#-isochromene-1,3(4H)-dione




2-(Carboxymethyl)-4-fluorobenzoic acid (1.40g) in a mixture of acetic acid (3ml) and trimemylorthoformate (1ml) was heated at 1 10°C for 3h. During this time the methyl acetate generated was distilled off. When finished, the reaction was cooled to 0°C. The white solid was collected by filtration and was washed with cold water and methanol (l-32g).
MS (ESI) 207 (M-Me)'
Step 4: Methyl 6-fluoro-l-oxo-l£r-isochromene-4-carboxylate

o
F
To a suspension of (42)-6-fiuoro-4-(methoxymethylene)-lJ:r-isochromene-l,3(4JH)-dione (1.30g) in methanol (20ml) was slowly added sulforic acid (1 .5ml). The mixture was heated at 40-50°C for 3h. As the reaction proceeded the sub-title compound crystallized
out. me reaction was cooled to room temperature and a white solid was collected by filtration and washed with cold methanol. MS (ESI) 222 (M+H)+
'H NMR 6 (DMSO) 8.49 (1H, s), 8.30 (1H, dd), 8.25 (1H, dd), 7.56 (1H, td), 3'.87 (3H, s).
Step 5: Methyl 6-fluoro-1 -oxo-1,2-dihydroisoqumoline-4-carboxylate

F
A mixture of methyl 6-fluoro-1-oxo-l#-isochromene-4-carboxylate (1.53g) and ammonium acetate (2.5g) in 4ml of glacial acetic acid was heated at 80°C for 16h. The reaction was cooled to 40°C, diluted with 8ml of water and the solid collected by filtration (l-38g).
MS (ESI) 220 (M-HT
JH NMR 5 (DMSO) 12.00 (1H, s), 8.46 (1H, dd), 8.32 (1H, dd), 8.10 (1H, s), 7.44 (1H, td), 3.83 (3H, s).
Step 6: 6-Fluoro-l-oxo-l,2-dihydroisoquinoline-4-carboxylic acid

To a solution of methyl 6-fluoro-1-oxo-l,2-dihydroisoquinoline-4-carboxylate (1.3g) in methanol (3ml) was added a aqueous solution (3ml) of sodium hydroxide. (Ig) and the reaction mixture was heated at 80°C for 3h. The reaction was cooled to 20°C and carefully acidified with concentrated hydrochloric acid. The white precipitate was isolated by filtration, washed with water and methanol to yield the title compound (1.16g)
MS (ESI) 206 (M-H)'
'H NMR 5 (DMSO) 12.85 (1H, s), 11.91 (1H, d), 8.58 (1H, dd)3 8.31 (1H, dd), 8.09 (1H, d), 7.41 (1H, td).

Preparation 46
7-FIuoro-l-oxo-l,2-dih3^droisoqumoline-4-carboxylic acid Prepared following literature procedures: Liebigs Annalen der Chemie, 1981, J, 819-27 and Chemical & Pharmaceutical Bulletin, 1983, 31, 1277-82.
Step 1: Dimethyl [4-fluoro-2-(methoxycarbonyl)phenyl]malonate

Prepared as described in Preparation 45, Stepl using 2-bromo-5-fluorobenzoic acid.
MS (ESI) 269/237 (M-H)'
!H NMR 5 (DMSO) 7.70 (IH, dd), 7.49 (IH, td), 7.39 (IH, dd), 5.71 (IH, s), 3.68 (6H,s).
Step 2: 2-(Carboxymethyl)-5-fluorobenzoic acid

Prepared as described in Preparation 45, Step 2 using dimethyl [4-fluoro-2-(methoxycarbonyl)phenyl]malonate.
MS (ESI) 197 (M-H)'
JHNMR 5 (DMSO) 7.81-7.74 (IH, m), 7.62 (IH, dd), 7.41-7.35 (IH, m), 3.92 (2H,s).
Step 3: Methyl 7-fluoro-l-oxo-ljy-isochromene-4-carboxylate

Prepared as described in Preparation 45, Steps 3 and 4 using 2-(carboxymethyl)-5-fluorobenzoic acid.
MS (ESI) 223 (M+H)+

'H NMR 5 (DMSO) 8.60 (1H, dd)3 8.42 (1H, s), 7.95 (1H, dd), 7.86 (1H, ddd), 3.87 (3H, s).
Step 4: Methyl 7-fluoro-l-oxo-l,2-dihydroisoqumoline-4-carboxylate

,o
0

Prepared as described in Preparation 45, Step 5 using methyl 7-fluoro-l-oxo-l.tf-is ochromene-4-carboxylate.
MS (ESI) 221 (M-HT
]H NMR 5 (DMSO) 12.04 (1H, s), 8.82 (1H, dd), 8.03 (1H, s), 7.91 (1H, dd), 7.73 (lH,td),3.83(3H,s).
Step 5: 7-Fluoro-l-oxo-l,2-dihydroisoquinoline-4-carboxylic acid

F
Prepared as described in Preparation 45, Step 6 using methyl 7-fluoro-l-oxo-l,2-dihydroisoquinoline-4-carboxylate.
MS (ESI) 206 (M-H)-
]H NMR 6 (DMSO) 12.81 (1H, s), 12.00 (1H, d), 8.93 (1H, dd), 8.02 (1H, d), 7.90 IK, dd), 7.71 (1H, td).
Preparation 47
6-(Methylsulfonyl)-1 -oxo-1,2-dihydroisoquinoline-4-carboxylic acid Prepared following literature procedures: Liebigs Annalen der Chemie, 1981,5,
819-27 and Chemical & Pharmaceutical Bulletin, 1983,31, 1277-82.
Step 1: 2-[2-Ethoxy-l-(ethoxycarbonyl)-2-oxoethyl]-4-(methylsulfonyl)benzoic acid




Prepared following literature procedure: Journal of Organic Chemistry, 1998, 63, 4116-4119.
To a very rapidly stirred suspension of 2-chloro-4-(methylsulfonyl)benzoic acid (lO.Og) and copper(l) bromide (l.Og) in 50ml of diethylmalonate at 20°C was added portionwise sodium ethoxide (lO.Og). The reaction was stirred for 30 min. at room temperature then heated at 90°C for 36h. The slurry was diluted with water (200ml), aqueous ammonia was added (3ml) and the mixture extracted with diethyl ether (3x100ml). The aqueous layer was acidified with concentrated hydrochloric acid and extracted with ethyl acetate (3x100ml). The combined organic layers were dried over magnesium sulfate, filtered and concentrated under vacuum. MS (ESI) 357/311 (M-H)-
'H NMR 5 (CD3OD) 8.28 (1H, d), 8.06 (1H, dd), 7.99 (1H, d), 5.78 (1H, s), 4.20 (4H,q), 3.19 (3H,s), 1.28 (6H, t).
Step 2: 2-(CarboxyrnethyI)-4-(methylsulfonyl)benzoic acid

Prepared following literature procedure: Journal of Organic Chemistty, 1998, 63, 4116-4119.
The crude material of Step 1 was dissolved in methanol (200ml) and a solution (200ml) of sodium hydroxide (13g) slowly added. The reaction was stirred at room temperature for 3h. The methanol was removed under vacuum. The aqueous layer was extracted with diethyl ether (3x100ml), acidified with concentrated hydrochloric acid, saturated with sodium chloride and extracted with ethyl acetate (3x100ml). The combined organic layers were dried over magnesium sulfate, filtered, concentrated to one third volume and heated at 65°C for 3h to complete decarboxylation. A solid formed which was collected by filtration (7. Ig).
MS (ESI) 257/213 (M-H)'
'HNMR 6 (DMSO) s.io (in, d), 7.95 (m, d), 7.93 (in, dd), 4.07 (2H, s), 3.28
(3H, s).

Step3:(42)-4



o=s=o
Prepared as described in Preparation 45, Step 3 using 2-(carboxymethyl)-4-(methylsulfonyl)benzoic acid.
MS (ESI) 267 (M-Me)'
]H NMR 5 (DMSO) 8.68 (1H, d), 8.32 (1H, d), 8.31 (1H, s), 7.98 (1H, dd), 4.36 (3H, s), 3.46 (3H3 s).
Step 4: Methyl 6-(methylsulfonyl)-l-oxo-l#-isochromene-4-carboxylate




Prepared as described in Preparation 45, Step 4 using (42)-4-(methoxymethylene)-6-(methylsulfonyl)-l#-isochromene-l,3(4//)-dione.
]HNMR 8 (DMSO) 9.08 (1H, d), 8.56 (1H, s), 8.44'(1H, d), 8.18 (1H, dd), 3.89 (3H, s), 3.34 (3H, s).
Step 5: Methyl 6-(methylsulfonyl)-l-oxo-l,2-dihydroisoquinoline-4-carboxylate

o=s=o
Prepared as described in Preparation 45, Step 5 using methyl 6-(methylsulfonyl)-l-oxo-l#-isochromene-4-carboxylate.
MS (ESI) 280 (M-H)~
'H NMR 5 (DMSO) 12.23 (1H, s), 9.35 (1H, d), 8.47 (1H, d), 8.17 (1H, s), 8.06 (1H, dd), 3.86 (3H, s), 3.78 (3H, s).

Step 6: 6-(Methylsulfonyl)-l-oxo-1,2-dihydroisoquinoline-4-carboxylic acid

o=s=o
Prepared as described in Preparation 45, Step 6 using methyl 6-(methylsulfonyl)-l-oxo-1,2-dihydroisoquinoline-4-carboxylate. • MS (ESI) 266 (M-H)'
'H NMR 5 (DMSO) 12.99 (1H, s), 12.14 (1H, d), 9.45 (1H, d), 8.46 (1H, d), 8.15 (1H, d), 8.04 (1H, dd), 3.30 (3H, s).
Preparation 48
(2R)-1 -Arnrno-3-{4-[3,4-dichloro-2-(methylsulfonyl)phenoxy]piperidin-l -yl}propan-2-ol
I o=s=o
Cl ^""'^ ^^ ^"^ ^"^ z
Step 1: tert-butyl 4-[3,4-dichloro-2-(methylsulfonyl)phenoxy]piperidine-l-carboxylate
I
0=5=0

cr
ii
o
To a stirred solution of tert-butyl 4-[3,4-dichlorophenoxy]piperidine-l-carboxylate (lO.Og, 28.9mmol) in dry THF (400ml) at -70°C under a nitrogen atmosphere was added dropwise sec-butyl lithium (26.7ml, 1.3M in cyclohexane). The solution was stirred a further 15min. at this temperature and then was treated with dimethyldisulfide (3.9ml, 43mmol). The solution was stirred at this temperature for 30 min. and then the cooling bath removed and the mixture stirred vigorously whilst warming to —30°C over 30 min. Saturated aqueous ammonium chloride solution (5ml) was added and the mixture concentrated to ca 30ml volume and partitioned between water and ethyl acetate. The organic extracts were dried over magnesium sulphate and concentrated. Treatment of the crude residue with meto-chloroperbenzoic acid (13.3g, 57-86%) in dichloromethane (200ml) at room temperature for 14h gave the crude sulfone. The solution was shaken with

sodium metabisulfite solution, then the organics dried over magnesium sulfate and concentrated in vacua . Chromatography on silica (ethyl acetate: isohexane) gave the subtitle compound (0.65g)
MS (ESI) 424/426 (M+H)+
JH NMR 6 (DMSO) 7.88 (1H, d), 7.42 (1H, d), 4.92 (1H, m), 3.52 (2H, m), 3.32 (3H, s), 3.36-3.27 (2H, m), 1.90 (2H, m), 1.69 (2H, m), 1.40 (9H, s).
Step 2: (2R}~ 1 -Amino-3-{4-[3,4-dichloro-2-(methylsulfonyl)phenoxy]piperidin- 1 -yl}propan-2-ol
Prepared as described in Preparation 24, Step 2 from ter/-butyl 4-[3,4-dichloro-2-(methylsulfonyl)phenoxy]piperidine- 1 -carboxylate .
MS (ESI) 397/399 (M+H)+
JH NMR 5 (CDC13) 7.60 (1H, d), 6.94 (1H, d), 4.60-4.53 (1H, m), 3.73-3.67 (1H, m), 3.33 (3H, s), 3.02-2.96 (1H, m), 2.81 (1H, dd), 2.79-2.73 (1H, m), 2.64-2.56 (1H, m), 2.63 (1H, dd), 2.43-2.32 (3H, m), 2.11-1.91 (4H, m)
Preparation 49
8-Fluoro- 1 -oxo- 1 ,2-dihydroisoquinoline-4-carboxylic acid Step 1 : 2-(Carboxymethyl)-6-fluorobenzoic acid
o OH

Prepared as described in Preparation 45, Step 1 and 2 using 2-bromo-6-fluorobenzoic acid.
MS (ESI) 197 (M-H)'
'HNMR 8 PMSO) 7.46 (1H, td), 7.20 (IH, dd), 7. 18 (1H, d), 3.77 (2H, s).

Prepared as described in Preparation 45, Step 3 using 2-(carboxymethyl)-6-fluorobenzoic acid.
Step 2: (42)-8-Fluoro-4-(methoxymethylene)-lff-isochromene-l ,3(4/f)-dione

MS (ESI) 207 (M-Me) Step 3: Methyl 8-fluoro-l-oxo-l#4sochromene-4-carboxylate




Prepared as described in Preparation 45, Step 4 using (4Z)-8-fluoro-4-(methoxymethylene)-1 H-isochromene-1,3 (4#)-dione.
MS (ESI) 222 (M+H)+
]H NMR5 (DMSO) 8.42 (1H, s), 8.34 (1H, d), 7.96 (IH, td), 7.50 (1H, dd), 3.86 (2H5 s).
Step 4: Methyl 8-fluoro-l-oxo-l,2-dihydrQisoquinoh'ne-4-carboxylate

o
Prepared as described in Preparation 45, Step 5 using methyl S-fluoro-l-oxo-lJ^-isochromene-4-carboxylate
MS (ESI) 220 (M-H)-
'HNMR5 (DMSO) 11.86 (1H, s), 8.57 (1H, d), 8.03 (1H, s), 7.80 (1H, td), 7.30 (1H, dd), 3.82 (3H, s).
Step 5: S-Fuoro-l-oxo-l^-dihydroisoquinoline^-carboxylic acid
N
* *

Prepared as described in Preparation 45, Step 6 using methyl 8-fluoro-l-oxo-l ,2-dihydroisoquinoline-4-carboxylate.
MS (ESI) 206 (M-H)"
JH NMR 5 (DMSO) 12.75 (19H, s), 11.76 (19H, d), 8.69 (22H, d), 8.02 (23H, d), 7.78 (24H, td), 7.29 (22H, dd).

Example 1
N-{ (lR)-3-[4-(3,4-Dichlorophenoxy)piperidin- 1 -ylJ-2-hydroxypropyl } -2-(rnethylsulfonyl)benzamide.


50=3=0

A mixture of 2-(methylsulphonyl)benzoic acid (0.063g), (2R)-l-amino-3-[4-(3,4-dichlor.ophenoxy)piperidin-l-yl]propan-2-ol (O.lg) and A^-diisopropylethylamine (O.lml) in dry dimethylformamide (3ml) was cooled to 0°C with stirring. 2-(lH-9-Azabenzotriazole-1 -yl)- 1 , 1 ,3,3-tetramemyluronium hexafluorophosphate (0. 1 3g) was added and the mixture was stirred at 0°C for l-2h. Saturated sodium bicarbonate solution (10ml) was added. The mixture was extracted with ethyl acetate. The organic layer was separated and washed with brine and dried over sodium sulphate. The mixture was filtered and the solvent was evaporated. The resulting oil was purified by normal phase chromatography using methanol/dichloromethane as eluent, and by reverse phase HPLC using acetonitrile and 0.1% aqueous ammonium acetate as eluent, to give the title compound as a white solid (0.055g).
MS (APCI) 501/503 (M+H)+
!HNMR 5 (DMSO) 8.57 (IH, t), 7.96 (IH, dd), 7.78 (IH, td), 7.69 (IH, td), 7.57 (IH, dd), 7.49 (IH, d), 7.25 (IH, d), 6.98 (IH, dd), 4.48-4.37 (IH, m), 3.85-3.74 (IH, m), 3.40-3.25 (IH, m), 3.37 (3H, s), 3.26-3.13 (IH, m), 2.83-2.69 (2H, m), 2.44 (IH, dd), 2.37-2.26 (3H, m), 1.95-1.84 (2H, m), 1.65-1.50 (2H, m).
Example 2
Ar-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-4-(methylsulfonyl)benzamide

o
Prepared as described in Example 1 from (2R)-l-amino-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]propan-2-ol (O.lg) and 4-(methylsulphonyl)ben2oic aci (0.063g). Title compound obtained as white solid (0.038g). MS (APCI) 501/503 (M+H)+

]HNMR 5 (DMSO) 8.69 (IH, t), 8.05 (4H, dd), 7.49 (IH, d), 7.25 (IH, d), 6.98 (IH, dd), 4.76 (IH, brs), 4.43 (IH, mult), 3.86-3.78 (IH, m), 3.43 (IH, dt), 3.26 (3H, s), 3.20 (IH, dd), 2.79-2.67 (2H, m), 2.41-2,24 (4H, m), 1.95-1.85 (2H, m), 1.66-1.54 (2H, m).
Example 3
2-Chloro-Ar-{(2/?)-3-[4-(3,4-dichloroplienoxy)piperidin-l-yl]-2-hydroxypropyl}-4-(methylsulfonyl)benzamide

.
Prepared as described in Example 1 using (2R)-l-amino-3-[4-(3,4-dichloropb.enoxy)piperidin-l-yl]propan-2-ol (O.lg) and 3-(methylsulfonyl)benzoic acid (0.074g). Title compound obtained as white solid (0.033g). MS (APCJ) 535/537 (M+Hf
JH NMR 5 (DMSO) 8.60 (IH, t), 8.03 (IH, d), 7.93 (IH, dd), 7.70 (IH, d), 7.49 (IH, d), 7.25 (IH, d), 6.98 (IH, dd), 4.70 (IH, brs), 4.47-4.39 (IH, m), 3.82-3.74 (IH, m), 3.41-3.31 (IH, m), 3.29 (3H, s), 3.23-3.15 (IH, m), 2.80-2.69 (2H, m), 2.44-2.25 (4H, m), 1.96-1.86 (2H, m), 1.65-1.54 (2H, m).
Example 4
4-Amino-Ar-{(2/?)-3-[4-(3,4-dicbJorophenoxy)piperidin-l-ylJ-2-hydroxypropyl}-3-methoxybenzamide

o
Prepared as described in Example 1 from (2R)-l-amino-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]propan-2-ol (O.lg) and 4-amino-3-methoxybenzoic acid (0.052g). Title compound obtained as white solid (0.053g). MS (APCI) 468/470 (M+H)+
'HNMR5 (DMSO) 8.05 (IH, t), 7.49 (IH, d), 7.31-7.27 (2H3 m), 7.25 (IH, d), 6.98 (IH, dd), 6.60 (IH, d), 5.23 (2H, s), 4.74 (IH, brs), 4.47-4.38 (IH, m), 3.80 (3H, s),

3.81-3.73 (IH, m), 3.38-3.30 (IH, m), 3.18-3.09 (IH, m), 2.80-2.65 (2H, m), 2.36 (2H, dd), 2.32-2.22 (2H, m), 1.95-1.86 (2H, m), 1.66-1.54 (2H, m).
Example 5
JV-{(2J?)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-3-(methylsulfonyl)benzamide

o Prepared as described in Example 1 from (2R)-l-amino-3-[4-(3,4-
dichlorophenoxy)piperidin-l-yl]propan-2-ol (O.lg) and 3-(methylsulfonyl)benzoic acid
(0.063g). Title compound obtained as white solid (0.017g). MS (APCI) 501/503 (M+H)+
'HNMR 5 (DMSO) 8.74 (m, t), 8.39 (m, t), s.is (m, dt), 8.07 (m, ddt), 7.76
(IH, t), 7.49 (IH, d), 7.25 (IH, d), 6.98 (IH, dd), 4.77 (IH, brs), 4.47-4.39 (IH, m), 3.86-3.78 (IH, m), 3.45 (IH, dt), 3.26 (3H, s), 3.24-3.14 (IH, m), 2.80-2.66 (2H, m), 2.41-2.24 (4H, m), 1.95-1.86 (2H, m), 1.65-1.54 (2H, m).
Example 6
JV-{(2JR)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-5-(methylsulfonyl)thiophene-2-carboxamide.
clNpY°Yx^ QH H rfV-s-
o
Prepared as described in Example 1 from (2R)-l-amino-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]propan-2-ol (O.lg) and 5-(methylsulfonyl)thiophene-2-carboxylic acid (0.065g). Title compound obtained as white solid (0.039g). MS (APCI) 507/509 (M+H)+
!HNMR6 (DMSO) 8.85 (IH, t), 7.84 (2H, dd), 7.49 (IH, d), 7.26 (IH, d), 6.98 (IH, dd), 4.80 (lH,brs), 4.47-4.39 (IH, m), 3.83-3.75 (IH, m), 3.45-3.38 (IH, m), 3.38 (3H, s), 3.18-3.09 (IH, m), 2.79-2.66 (2H, m), 2.37-2.22 (4H, m), 1.95-1.85 (2H, m), 1.6. 1.53(2H,m

Example 7
A^-{(2J?)-3-[4-(3,4-DicMorophenoxy)piperidiii-l-yl]-2-liydroxypropyl}quinolirie-6-carboxamide

o Prepared as described in Example from (2R)-l-amino-3-[4-(3,4-
dichlorophenoxy)piperidin-l-yl]propan-2-ol (O.lg) and quinoline-6-carboxylic acid
(0.054g). Title compound obtained as white solid (0.032g). MS (APCI) 474/476 (M+H)+ 1H NMR 5 (DMSO) 8.98 (IH, dd), 8.68 (IH, t), 8.52 (IH, d), 8.47 (IH, dd), 8.19
(IH, dd), 8.08 (IH, d), 7.61 (IH, dd), 7.49 (IH, d), 7.24 (IH, d), 6.97 (IH, dd), 4.78 (IH,
brs), 4.48-4.39 (IH, m), 3.90-3.82 (IH, m), 3.46 (IH, dt), 3.31-3.23 (IH, m), 2.82-2.70
(2H, m), 2.45-2.25 (4H, m), 1.96-1.87 (2H, m), 1.67-1.55 (2H, m).
Example 8
JV-{(2J?)-3-[4-(3,4-Dichlorophenoxy)piperidm-l-yl]-2-hydroxypropyl}-2-oxo-2,3-dihydro-l,3-benzothiazole-6-carboxamide acetate salt

Prepared as described in Example 1 from (2R)-l-amino-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]propan-2-ol (O.lg) and 2-oxo-2,3-dihydro-l,3-benzothiazole-6-carboxylic acid (0.06 Ig). Title compound obtained as acetate salt, a white solid (0.1 Og).
MS (APCI) 496/498 (M+H)+
'HNMR 8 (DMSO) 8.36 (m, t), s.os (m, d), 7.78 (IH, dd), 7.49 (m, d), 7.25
(IH, d), 7.15 (IH, d), 6.98 (IH, dd), 4.47-4.40 (IH, m), 3:80 (IH, quintet), 3.38 (IH, dt), 3.22-3.14 (IH, m), 2.80-2.67 (2H, m), 2.41-2.25 (4H, m), 1.95-1.86 (2H, m), 1.91 (3H, s), 1.66-1.54(2H,m).

Example 9
JV-{(2JK)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-6-fluoroimidazofl ,2-a]pyridine-2-carboxamide
F
Cl ^ N/V Y n
o
. Prepared as described in Example 1 from (2R)-l-amino-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]propan-2-ol (O.lg) and 6-fluoroimidazo[l,2-a]pyridine-2-carboxylic acid (0.056g). Title compound obtained as white solid (0.076g). MS (APCI) 481/482 (M+H)+
'HNMR8 (DMSO) 8.80-8.78 (IH, m), 8.63 (IH, t), 8.33 (IH, s), 7.68 (IH, dd), 7.50 (IH, d), 7.52-7.44 (IH, m), 7.28 (IH, d), 7.00 (IH, dd), 4.89 (IH, s), 4.52-4.44 (IH, m), 3.83-3.74 (IH, m), 3.44-3.28 (2H, m), 2.83-2.66 (2H, m), 2.44-2.23 (4H, m), 2.02-1.90 (2H,m), 1.82-1.72 (2H,m).
Example 10
A/-{(272)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-l-oxo-l,2-dihydroisoquinoline-4-carboxamide

Prepared as described in Example 1 from (2R)-l-amino-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]propan-2-ol (O.lg) and l-oxo-l,2-dihydroisoquinoline-4-carboxylic acid (0.059g). Title compound obtained as white solid (0.047g).
MS (APCI) 490/492 (M+H)+
]H NMR 5 (DMSO) 11.59 (IH, d), 8.33 (IH, t), 8.22 (2H, dd), 7.73 (IH, t), 7.54-7.48 (3H, m), 7.26 (IH, d), 6.98 (IH, dd), 4.79 (IH, s), 4.48-4.40 (IH, m), 3.85-3.76 (IH, m), 3.43-3.31 (IH, m), 3.14 (IH, quintet), 2.83-2.69 (2H, m), 2.45-2.25 (4H, m), 1.96-1.87 (2H,m), 1.67-1.55 (2H,m).

Example 11
N- {(2^)-3-[4-(3,4-Dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl} -1,3-benzothiazole-6-carboxamide




Prepared as described in Example 1 from (2R)-l-arnino-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]propan-2-ol (O.lg) and l,3-benzothiazole-6-carboxylic acid (0.056g). Title compound obtained as white solid (0.066g).
MS (APCI) 480/482 (M+H)+
]H NMR 5 (DMSO) 9.54 (IH, s), 8.67 (IH, d), 8.60 (IH, t), 8.15 (IH, d), 8.02 (IH, dd), 7.49 (IH, d), 7.25 (IH, d), 6.98 (IH, dd), 4.78 (IH, brs), 4.47-4.39 (IH, m), 3.87-3.79 (IH, m), 3.44 (IH, dt), 3.23 (IH, quintet), 2.82-2.68 (2H, m), 2.40 (IH, dd), 2.37-2.23 (3H, m), 1.96-1.86 (2H, m), 1.66-1.54 (2H, m).
Example 12
3-Cyano-7V-{(2JR)-3-|;4-(3,4-dicnlorophenoxy)piperidin-l-yl]-2-hydroxypropyl} benzamide
o Prepared as described in Example 1 from (2R)-l-amino-3-[4-(3,4-
dichlorophenoxy)piperidin-l-yl]propan-2-ol (0.2g) and 3-cyanobenzoic acid (0.092g).
Title compound obtained as white solid (0.050g). MS (APCI) 448/450 (M+H)+
'HNMR 5 (CDci3) s.io (m, s), 7.79 (IH, d), 7.58 (m, t), 7.31 (IH, d), 7.00 (in,
d), 6.80 (IH, t), 6.75 (IH, dd), 4.38-4.25 (IH, m), 4.00-3.87 (IH, rn), 3.81-3.68 (IH, m),
3.36 (IH, dt), 2.98-2.85 (IH, m), 2.75-2.63 (IH, m), 2.63-2.53 (IH, m), 2.48 (IH, dd),
2.36 (IH, d), 2.32 (2H, t), 2.07-1.90 (2H, m), 1.90-1.73 (2H, m).

Example 13
7V-{4-[4-(3,4-Diclilorophenoxy)piperidin-l-yl]-3-hydroxybiitvn-?. (methylsulfonyl)benzamide




Prepared as described in Example 1 from 4-amino-l-[4-(3,4-
dichlorophenoxy)piperidm-l-yl]butan-2-ol (0.26g) and 2-(methylsulphonyl)benzoic acid (0.156g). The title compound was obtained as a white solid (0.170g).
MS (APCI) 515/517 (M+H)+
'H NMR 5 (CDC13) 8.09 (IH, dd), 7.65 (IH, dd), 7.59 (IH, td), 7.53 (IH, dd), 7.31 (IH, d), 6.99 (IH, d), 6.74 (IH, dd), 6.74 (IH, dd), 4.32-4.23 (IH, m), 3.92-3.83 (IH, m), 3.83-3.74 (IH, m), 3.57-3.46 (IH, m), 3.37 (3H, s), 2.94-2.85 (IH, m), 2.70-2.60 (IH, m), 2.60-2.50 (IH, m), 2.40 (IH, dd), 2.35 (IH, dd), 2.32-2.23 (IH, m), 2.01-1.89 (2H, m), 1.88-1.69 (2H, m), 1.67-1.55 (2H, m).
Example 14
j\r-{4-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-3-hydroxybutyl}-2-oxo-2,3-dihydro-l,3-benzothiazole-6-carboxamide
OH o

Prepared as described in Example 1 from 4-amino-l-[4-(3,4-dichlorophenoxy)piperidin-l-yl]butan-2-ol (0.26g) and 2-oxo-2,3-dihydro-l,3-benzothiazole-6-carboxylic acid (0.152g). Title compound obtained as a white solid (0.105g).
MS (APCI) 510/512 (M+H)+
1E NMR 6 (CDC13) 7.88 (IH, d), 7.71 (IH, dd), 7.48-7.39 (IH, m), 7.31 (IH, d), 7.13 (IH, d), 7.00 (IH, d), 6.76 (IH, dd), 4.36-4.27 (IH, m), 3.93-3.83 (2H, m), 3.49-3.38 (IH, m), 2.97-2.87 (IH, m), 2.73-2.53 (2H, m), 2.46-2.32 (2H, m), 2.36-2.27 (IH, m), 2.06-1.91 (2H, m), 1.90-1.75 (3H, m), 1.66-1.53 (IH, m).

Example 15
4-Amino-7V-{4-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-3-Iiydroxybutyl}-3-methoxybenzamide
ci
Ck

Prepared as described in Example 1 from 4-arnino-l-[4-(3,4-
dichlorophenoxy)piperidin-l-yl]butan-2-ol (0.26g) and 4-amino-3-methoxybenzoic acid (0.130g). Title compound obtained as white solid (O.OSOg).
MS (APCI) 482/484 (M+H)+
]H NMR 5 (CDC13) 7.39 (IH, d), 7.31 (IH, d), 7.15 (IH, dd), 7.04 (IH, bs), 7.00 (IH, d), 6.75 (IH, dd), 6.65 (IH, d), 4.29 (IH, septet), 4.08 (2H, bs), 3.90 (3H, s), 3.89-3.75 (2H, m), 3.49-3.36 (IH, m), 2.96-2.85 (IH, m), 2.73-2.61 (IH, m), 2.61-2.50 (IH, m), 2.44-2.34 (2H, m), 2.35-2.23 (IH, m), 2.07-1.90 (2H, m), 1.90-1.71 (2H, m), 1.70-1.48(2H,m).
Example 16
N- {4-[4-(3,4-Dichlorophenoxy)piperidin-1 -yl]-2-hydroxybutyl} -2-(methylsulfonyl)benzamide

Prepared as described in Example 1 from l-arnino-4-[4-(3,4-
dicMorophenoxy)piperidin-l-yi]butan-2-ol (0.2g) and 2-(methylsulphonyl)benzoic acid (0.12g). Title compound obtained as white solid (0.090g).
MS (APCI) 515/517 (M+H)+
]H NMR 5 (CDC13) 8.10 (IH, d), 7.67 (IH, td), 7.61 (IH, td), 7.55 (IH, dd), 7.30 (lH,.d), 6.98 (IH, d), 6.73 (IH, dd), 6.61 (IH, t), 4.33-4.23 (IH, m), 4.06 (IH, octet), 3.70 (IH, ddd), 3.36-3.29 (IH, m), 3.37 (3H, s), 2.97-2.82 (IH, m), 2.78-2.68 (IH, m), 2.64 (IH, dt), 2.60-2.47 (2H, m), 2.38-2.22 (IH, m), 2.02-1.41 (6H, m).
The compounds of Examples 17 and 18 were prepared in a similar way to Example 1 following Preparation 13 starting from 4-(2,4-dichloro-3-methylphenoxy)piperidine

Example 17
N- {(2R)-3-[4-(2,4-Dichloro-3 -methylphenoxy)piperidin-1 -yl]-2-hydroxypropyl} -1 -oxo-1,2-dihydroisoquinoline-4-carboxamide




Prepared as described in Example 1 following Preparation 13.
MS (APCI) 504/506 (M+H)+
!H NMR 5 (DMSO) 11.58 (IH, s), 8.31 (IH, t), 8.22 (2H, d), 7.72 (IH, t), 7.56-7.48 (2H, m), 7.35 (IH, d), 7.10 (IH, d), 4.80-4.70 (IH, m), 4.53-4.44 (IH, m), 3.85-3.75 (IH, m), 3.39 (IH, dt), 3.15 (IH, quintet), 2.78-2.64 (2H, m), 2.40 (3H, s), 2.39-2.27 (4H, m), 1.96-1.83 (2H, m), 1.74-1.61 (2H, m).
Example IS N- {(2R)-3-[4-(2,4-Dichloro-3 -methylphenpxy)piperidin-1 -yl]-2-hydroxypropyl }-2-
(methylsulfonyl)benzamide
Prepared as described in Example 1 following Preparation 13.
MS (APCI) 515/517 (M+H)+
'HNMRS (CDC13) 8.10 (IH, dd), 7.67 (IH, t), 7.62 (IH, t), 7.54 (IH, dd), 7.19 (IH, d), 6.74 (IH, d), 6.55 (IH, t), 4.41- 4.27 (IH, m), 4.03-3.89 (IH, m), 3.68 (IH, ddd), 3.44 (IH, dt), 3.36 (3H, s), 3.00-2.87 (IH, m), 2.80-2.66 (IH, m), 2.63-2.51 (2H, m), 2.51-2.42 (IH, m), 2.47 (3H, s), 2.42-2.29 (IH, m), 2.03-1.76 (4H, m).
Example 19
Ar-{(21S)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-ylJ-2-hydroxypropyl}-2-(methylsulfonyl)b enzamide
Prepared as described in Example 1 following Preparation 14.
MS (APCI) 501/503 (M+H)+
1H NMR 8 (CDC13) 8.10 (IH, dd), 7.68 (IH, td), 7.62 (IH, td), 7.54 (IH, dd), 7.: (IH, d), 6.99 (IH, d), 6.75 (IH, dd), 6.53 (IH, t), 4.35-4.22 (IH, m), 4.04-3.91 (IH, m), 3.68 (IH, ddd), 3.45 (IH, dt), 3.36 (3H, s), 2.98-2.85 (IH, m), 2.80-2.66 (IH, m), 2.65-2.52 (2H, m), 2.46 (IH, dd), 2.41-2.28 (IH, m), 2.04-1.88 (2H, m), 1.87-1.67 (2H, m).
Example 20
A^-{(2y?)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-3-[(methylamino)sulfonyl]benzamide
CK/^OV-^ OH

o
Prepared as described in Example 1 following Preparation 7.
MS (APCI) 516/518 (M+H)+
1H NMR 5 (CDC13) 8.25 (IH, s), 7.99 (IH, d), 7.95 (IH, d), 7.55 (IH, t), 7.41 (IH, t), 7.31 (IH, d), 7.00 (IH, d), 6.75 (IH, dd), 4.95 (IH, s), 4.36-4.25 (IH, m), 4.16-4.05 (IH, m), 3.75 (IH, ddd), 3.31 (IH, ddd), 3.02-2.90 (IH, m), 2.74-2.56 (2H, m), 2.68 (3H, s), 2.51 (IH, dd), 2.37-2.26 (IH, m), 2.37 (IH, dd), 2.07-1.91 (2H, m), 1.91-1.72 (2H, m).
Example 2.1
3,5-Bis(acetylamino)-JV-{(2JS)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl} benzamide
NHAc
NHAc
Prepared as described in Example 1 following Preparation 7.
MS (APC1) 537/539 (M+H)+
!H NMR 5 (CDC13) 9.00 (2H, s), 7.86 (IH, s), 7.66 (2H, s), 7.50 (IH, s), 7.31 (IH, d), 6.99 (IH, d), 6.74 (IH, dd), 4.42-4.27 (IH, m), 4.19-4.03 (IH, m), 3.63-3.46 (IH, m), 3.42-3.26 (IH, m), 3.05-2.91 (IH, m), 2.91-2.74 (IH, m), 2.75-2.54 (4H, m), 2.17-1.96 (2H, m), 2.11 (6H, s), 1.97-1.79 (2H, m).
Example 22
3-(Acetylamino)-jV-{(2^)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl} benzamide
NHAc

o
Prepared as described in Example 1 following Preparation 7. MS (APCI) 480/482 (M+H)+
'H NMR 6 (CDC13) 7.88 (IH, s), 7.78 (IH, d), 7.55-7.45 (2H, m), 7.39 (IH, t), 7.31 (IH, d), 6.99 (IH, d), 6.82 (IH, t), 6.75 (IH, dd), 4.37-4.22 (IH, m), 3.99-3.85 (IH, m), 3.77-3.63 (IH, m), 3.38 (IH, quintet), 2.96-2.83 (IH, m), 2.75-2.63 (IH, m), 2.63-2.51 (IH, m), 2.52-2.24 (3H, m), 2.20 (3H, s), 2.08-1.90 (2H, m), 1.90-1.69 (2H, m).
Example 23
N- {(2K)-3-[4-(3,4-Dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl} - \H-pyrazole-4-carboxamide
f!l. ^ r\ ^ M

OH
H r NH
O
Prepared as described in Example 1 following Preparation 7.
MS (APCI) 413/415 (M+H)+
!H NMR 8 (CDC13) 8.02 (2H, s), 7.33 (IH, d), 7.00 (IH, s), 6.95 (IH, t), 6.76 (IH, d), 4.44-4.33 (IH, m), 4.07-3.98 (IH, m), 3.74-3.61 (IH, m), 3.40 (IH, td), 2.98 (IH, td), 2.89-2.77 (2H, m), 2.62 (2H, d), 2.68-2.56 (IH, m), 2.18-1.99 (2H, m), 1.98-1.82 (2H, m).
Example 24
2-(Acetylamino)-5-bromo-Ar-{(2J?)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl jbenzamide
Br

Prepared as described in Example 1 following Preparation 7.
MS (APCI) 558/460/562 (M+H)+
1R NMR 6 (CDC13) 10.98 (IH, s), 8.52 (IH, d), 7.66 (IH, s), 7.55 (IH, d), 7.32 (IH, d), 7.26 (IH, s), 7.16-7.05 (2H, m), 7.00 (IH, s), 6.76 (IH, d), 4.42-4.30 (IH, m), 4.06-3.94 (IH, m), 3.72-3.59 (2H, m), 3,43-3.29 (IH, m), 2.95 (IH, t), 2.75 (2H, t), 2.59-2.43 (3H, m), 2.19 (3H, s), 2.13-1.96 (5H, m), 1.96-1.78 (3H, m).
Example 25
Ar-{(2^)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-liydroxypropyl}-2-oxo-l,2-dihydropyridine-3 -carboxamide
0

Prepared as described in Example 1 following Preparation 7.
MS (APCI) 440/442 (M+H)+.
]H NMR 5 (CDC13) 9.86 (IH, t), 8.61 (IH, dd), 7.53 (IH, dd), 7.31 (IH, d), 6.99 (IH, d), 6.75 (IH, dd), 6.52 (IH, t), 4.33-4.24 (IH, m), 3.97-3.89 (IH, m), 3.70 (IH, ddd), 3.44 (IH, td), 2.94-2.85 (IH, m), 2.73-2.63 (IH, m), 2.59-2.50 (IH, m), 2.49-2.37 (2H, m), 2.30 (IH, t), 2.04-1.90 (2H, m), 1.87-1.72 (2H, m).
N- {(l/?)-3-[4-(3,4-Dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl} -1 -oxo-1,2-dihydroisoquinoline-5-carboxamide

Clvx^O^x. QH TT Tj ?H H
o
Prepared as described in Example 1 following Preparation 7. ' MS (APCI) 490/492 (M+H)+
'HNMR5 (DMSO) 11.34 (IH, d), 8.46 (IH, t), 8.28 (IH, d), 7.78 (IH, dd), 7.50 (IH, t), 7.49 (IH, d), 7.25 (IH, d), 7.23-7.16 (IH, m), 6.98 (IH, dd), 6.81 (IH, d), 4.72 (IH, d), 4.49-4.37 (IH, m), 3.87-3.76 (IH, m), 3.46-3.35 (IH, m), 3.30-3.16 (IH, m), 2.83-2.67 (2H, m), 2.47-2.23 (4H, m), 1.97-1.84 (2H, m), 1.68-1.50 (2H, m).
Example 27
N- {(2R)-3 -[4-(3,4-Dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl} quinoline-4-carboxamide




Prepared as described in Example 1 following Preparation 7.
MS (APCI) 474/476 (M+H)+
'HNMR8 (CD3OD) 1.69-1.79 (m, 2H), 1.90-2.00 (m, 2H), 2.53-2.65 (m, 4H), 2.84-2.94 (m, 2H), 3.39 (dd, IH), 3.54 (dd, IH), 3.99-4.05 (m, IH), 4.33-4.40 (m, IH), 6.81 (dd, IH), 7.03 (d, IH), 7.29 (d, IH), 7.52 (d, IH), 7.59 (t, IH), 7.73 (t, IH), 8.00 (d, IH), 8.15 (d, IH), 8.83 (d, IH).
Example 28
JV-{(2Jff)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-l//-indole-4-carboxamide

Y
o Prepared as described in Example 1 following Preparation 7

MS (APCI) 462/464 (M+H)+
'H NMR 5 (CD3OD) 1.82-1.91 (m, 2H), 2.00-2.13 (m, 2H), 2.63-2.76 (m, 4H), 2.96-3.05 (m, 2H), 3.44 (dd, IH), 3.54 (dd, IH), 4.04-4.11 (m, IH), 4.43-4.50 (m, IH), 5.50 (s, IH), 6.56 (d, IH), 6.90 (dd, IH), 7.12 (d, IH), 7.32 (d, IH), 7.38 (d, IH), 7.43 (d, !H),7.63(dd,lH),8.14(s, IH).
Example 29
2-(Acetylamino)-JV-{(2^)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypr opyl} b enzamide

Prepared as described in Example 1 following Preparation 7.
MS (APCI) 480/482 (M+H)+
'HNMRS (CDC13) 11.05 (IH, bds), 8.60 (IH, d), 7.52-7.46 (2H,m), 7.31 (IH, d), 7.08 (IH, t), 6.99 (IH, d), 6.81 (IH, bd s), 6.76 (IH, dd), 4.36-4.28 (IH, m), 3.96-3.90 (IH, m), 3.72-3.64 (IH, m), 3.40-3.32 (IH, m), 2.94-2.86 (2H, m), 2.72-2.58 (2H, m), 2.49-2.31 (3H, m), 2.20 (3H, s), 2.03-1.93 (2H, m), 1.89-1.79 (2H, m).
Example 30
2-(Acetylamino)-5-chloro-A7-{(27?)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}benzarnide .

Prepared as described in Example 1 following Preparation 7.
MS (APCI) 514/516/518 (M+H)+
!H NMR 6 (CDC13) 10.94 (IH, bd s), 8.59 (IH, d), 7.47 (IH, d), 7.43 (IH, dd), 7.32 (IH, d), 7.00 (IH, d), 6.87 (IH, bd s), 6.76 (IH, dd), 4.36-4.28 (IH, m), 3.97-3.90 (IH, m), 3.68-3.61 (IH, m), 3.38-3.32 (IH, m), 2.94-2.88 (IH, m), 2.72-2.58 (2H, m), 2.50-2.33 (3H, m), 2.19 (3H, s), 2.05-1.95 (2H, m), 1.90-1.80 (2H, m).

Example 31
2-(Acetylamino)-4-chloro-A^-{(2JR)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}benzarmde




Prepared as described in Example 1 following Preparation 7. ' MS (APCI) 514/516/518 (M+H)+
'H NMR 5 (CDC13) 11.19 (IH, bd s), 8.73 (IH, d), 7.42 (IH, d), 7.32 (IH, d), 7.05 (IH, d), 7.00 (IH, d), 6.78-6.74 (2H, m), 4.36-4.28 (IH, m), 3.96-3.88 (IH, m), 3.70-3.62 (IH, m), 3.38-3.30 (IH, m), 2.94-2.88 (IH, m), 2.70-2.58 (2H, m), 2.49-2.30 (3H, m), 2.20 (3H, s), 2.04-1.96 (2H, m), 1.90-1.78 (2H, m).
Example 32 5-Chloro-JV-{(2/?)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-2-
[(methylsulphonyl)amino]benz amide
O NHS02Me
ci CK /^ ,o, ^ QH

Prepared as described in Example 1 following Preparation 7.
MS (APCI) 550/552/554 (M+H)+
JH NMR 6 (CDC13) 7.69 (IH, d), 7.52 (IH, s), 7.45 (IH, d), 7.31 (IH, d), 7.00 (IH, d), 6.75 (IH, dd), 4.36-4.28 (IH, m), 3.96-3.90 (IH, m), 3.72-3.64 (IH, m), 3.36-3.30 (IH, m), 3.04 (3H, s), 2.95-2.89 (IH, m), 2.74-2.56 (2H, m), 2.50-2.30 (3H, m), 2.05-1.95 (2H, m), 1.90-1. 88 (2H,m).
Example 33 4-Chloro-JV-{('2JR)-3-[4-(3,4-dicWorophenoxy)piperidrn-l-yl]-2-hydroxypropyl}-2-

O NHS02Me
Prepared as described in Example 1 following Preparation 7.
[(methylsulphonyl)aminojbenzairiide

MS (APCI) 550/552/554 (M+Hf
]HNMR5 (CDC13) 7.75 (1H, d), 7.48 (1H, d), 7.31 (1H, d), 7.09 (1H, dd), 7.00 (1H, d), 6.75 (1H, dd), 4.38-4.28 (1H, m), 3.97-3.87 (1H, m), 3.72-3.66 (1H, m), 3.34-3.28 (1H, m), 3.08 (3H, s), 2.98-2.90 (1H, m), 2.76-2.58 (2H, m), 2.50-2.30 (3H, m), 2.10-1.94 (2H, m), 1.90-1.74 (2H,m).
Example 34
•2-Amino-4-chloro-^-{(2^)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl } benzamide

O NH2
Prepared as described in Example 1 following Preparation 7.
MS (APCI) 472/474/476 (M+H)+
'HNMRo- (CDC13) 7.31 (1H, d), 7.27 (1H, d), 6.99 (1H, d), 6.75 (1H, dd), 6.67 OH, d), 6.61 (1H, dd), 6.55 (1H, t), 5.64 (2H, bd s), 4.34-4.24 (1H, m), 3.92-3.82 (1H, m), 3.68-3.62 OH, m), 3.36-3.29 (1H, m), 2.94-2.86 (1H, m), 2.70-2.54 (2H, m), 2.47-2.29 (2H, m), 2.26-2.16 (1H, m), 2.04-1.94 (2H, m), 1.88-1.78 (2H, m).
Example 35
5-Chloro-JV-{(2^)-3-[4-(3,4-dichlorophenoxy)piperidui-l-yl]-6-oxo-l,6-dihydropyridine-3-carboxamide

O
To a solution of (2^)-l-amino-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]propan-2-ol (150 mg, 0.47 mmol) and triethylamine (48 mg, 66 [A, 0.47 mmol) in dichloromethane (20 ml) was added a solution of 5-chloro-6-hydroxynicotinyl chloride (90 mg, 0.47 mmol) in dichloromethane (10 ml). The mixture was stirred at room temperature for 3h and then the solution was concentrated in vacuo to leave a crude oil. Purification by reverse phase HPLC (Symmetry, 0.1% ammonium acetate / acetonitrile) afforded the title compound as a colourless glass (150 mg, 67%).
MS (APCI) 474/476/478 (M+H)+

'H NMR 5 (CDC13) 8.07 (IH, d), 8.04 (IH, d), 7.31 (IH, d), 7.09 (IH, bd s), 6.99 (IH, d), 6.75 (IH, dd), 4.36-4.26 (IH, m), 4.00-3.90 (IH, m), 3.68-3.58 (IH, m), 3.32-3.2: (IH, m), 2.96-2.86 (IH, m), 2.76-2.58 (2H, m), 2.51-2.35 (3H, m), 2.04-1.94 (2H, m), 1.88-1.76(2H,m).
Example 36
2-(Aminosulphonyl)-4-chloro-7\'-{(2J!?)-3-[4-(3,4-dichlorophenoxy)piperidm-l-yl]-2 -hydroxypropyl} benzamide

Prepared as described in Example 1 following Preparation 7.
MS (APCI) 536/538/540 (M+H)+
'H NMR 5 (CDC13) 8.39 (IH, d), 7.90 (IH, bd s), 7.78 (IH, dd), 7.45 (IH, d), 7.32 (IH, d), 7.00 (IH, d), 6.76 (IH, dd), 4.38-4.22 (2H, m), 3.76-3.62 (IH, m), 3.30-3.20 (IH, m), 3.10-3.00 (IH, m), 2.80-2.68 (2H, m), 2.60-2.40 (3H, m), 2.10-2.00 (2H, m), 1.96-1.86 (2H,m).
Example 37
JV-{(2/?)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-7//"-indazole-3-carboxamide

Prepared as described in Example 1 following Preparation 7.
MS (APCI) 463/465 (M+H)+
!H NMR 5 (CDC13) 8.43-8.33 (2H, m), 7.54 (IH, d), 7.43 (IH, t), 7.32 (IH, d), 6.9
Example 38
1 -tert-B\ityl-N- {(2R)-3 -[4-(3,4-dichloroplienoxy)piperidin-1 -ylj-2-hydroxYDrop vl) -S-methyl-y/f-pyrazole-S-carboxamide
Me
9H H H
O tBu
Prepared as described in Example 1 following Preparation 7.
MS (APCI) 483/485 (M+H)+
'H NMR 5 (CDC13) 7.31 (IH, d):, 6.99 (IH, d), 6.75 (IH, dd),'6.43 (IH, bd s), 6.21 (IH, s), 4.35-4.25 (IH, m), 3.92-3.82 (IH, m), 3.70-3.58 (IH, m), 3.38-3.28 (IH, m), 2.95-2.85 (2H, m), 2.70-2.50 (2H, m), 2.45-2.30 (3H, m), 2.24 (3H, s), 2.05-1.90 (2H, rn), 1.90-1.7S(2H,m), 1.67(9H,s).
Example 39
Ar-{(2JR)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-4,5,6,7-tetrahydro-2/jT-indazole-3 -carboxamide

Prepared as described in Example 1 following Preparation 7.
MS (APCI) 467/469 (M+H)+
'H NMR 5 (DMSO) 12.69 (IH, s), 7.83 (IH, bd s), 7.49 (IH, d), 7.25 (IH, d), 6.98 (IH, dd), 4.80 (IH, d), 4.43 (IH, quintet), 3.73 (IH, q), 3.39-3.16 (2H, m), 2.80-2.52 (6H, m), 2.38-2.23 (4H, m), 1.96-1.86 (2H, m), 1.78-1.58 (6H, m).
Example 40
Prepared as described in Example 1 following Preparation 7. MS (APCI) 481/483 (M+H)+
N- { (2R)-3 -[4-(3 ,4-Dichlorophenoxy)piperidin- 1 -yl j-2-hydroxypropyl } -3 -(trifluoromethyl)-7#-pyrazole-4-carboxajmde


'H NMR 6 (CDC13) 8.11 (IH, s), 7.32 (IH, d), 7.00 (IH, d), 6.75 (IH, dd), 6.70 (IH, bd s), 4.38-4.28 (IH, m), 4.00-3.90 (IH, m), 3.70-3.60 (IH, m), 3.42-3.32 (IH, m; 2.98-2.88 (IH, m), 2.75-2.58 (2H, m), 2.50-2.36 (3H, m), 2.10-1.96 (2H, m), 1.92-1.76 (2H, m).
Example 41
N- {(2^)-3-[4-(3,4-Dichlorophenoxy)piperidin-l -yl]-2-hydroxypropyl}-2-methylimida2o[l,2-a]pyridine-3-carboxainide
Prepared as described in Example 1 following Preparation 7. MS (APCI) 477/479 (M+H)+
'H NMR 6 (CDC13) 9.40 (IH, d), 7.58 (IH, d), 7.36-7.30 (2H, m), 7.00 (IH, d), 6.92 (IH, t), 6.76 (IH, dd), 6.35 (IH, bd s), 4.38-4.28 (IH, m), 4.01-3.93 (IH, m), 3.82-3.72 (IH, m), 3.48-3.40 (IH, m), 2.98-2.90 (IH, m), 2.75 (3H, s), 2.70-2.58 (IH, m), 2.5 2.30 (4H, s), 2.06-1.96 (2H, m), 1.94-1.76 (2H, m).
Example 42
A'r-{(2JR:)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-4-(;//-pyrazol-3-yl)benzamide

Prepared as described in Example 1 following Preparation 7.
MS (APCI) 489/491 (M+H)+
'H NMR 8 (CDC13) 7.84 (2H, d), 7.76 (2H, d), 7.64 (IH, d), 7.34-7.29 (2H, m), 7.00 (IH, d), 6.75 (IH, dd), 6.66 (IH, d), 4.45-4.35 (IH, m), 4.18-4.08 (IH, m), 3.78-3.61 (IH, m), 3.52-3.42 (IH, m), 3.06-2.96 (IH, m), 2.90-2.80 (2H, m), 2.75-2.63 (3H, m), 2.18-2.03 (2H, m), 2.00-1.80 (2H, m).
Example 43
Ar-{(27?)-3-[4-(3,4-DicMorophenoxy)piperidin-l-yl]-2-hydroxypropyl}ciimoliiie-4-carboxamide

o
Prepared as described in Example 1 following Preparation V. •MS (APCI) 475/477 (M+H)+
'HNMR 8 (CDci3) 9.41 (IH, s), s.ei (m, d), 8.38 (m, d), 7.94-7.82 (2H, m),
7.33 (IH, d), 7.20 (IH, bd s), 7.01 (IH, d), 6.76 (IH, dd), 4.46-4.36 (IH, m), 4.18-4.08 ;iH, m), 3.88-3.78 (IH, m), 3.56-3.46 (IH, m), 3.06-2.96 (IH, m), 2.94-2.78 (2H, m), '.70-2.60 (3H, m), 2.03-1.89 (4H, m).
Example 44
Ar-{(27?)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-2-oxo-l,2-.ihydroquinoline-4-carboxamide

Prepared as described in Example 1 following Preparation 7.
MS (APCI) 490/492 (M+H)+
!H NMR 5 (DMSO) 8.69 (IH, t), 7.74 (IH, d), 7.53 (IH, t), 7.49 (IH, d), 7.34 (IH, , 7.25 (IH, d), 7.18 (IH, t), 6.98 (IH, dd), 6.54 (IH, s), 4.50-4.40 (IH, m), 3.87-3.77 H, m), 3.48-3.40 (IH, m), 3.28-3.18 (IH, m), 2.82-2.70 (2H, m), 2.44-2.24 (4H, m), 57-1.87 (2H, m), 1.68-1.56 (2H, m).
Example 45 ^'.{3_[4_(3.i4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-2-oxo-2,3-
rydro-1 #-benzimidazole-1 -carboxamide

Prepared as described in Example 35, using 2-oxo-2,3-dihydro-l#-benzirnidazole-1-carbonyl chloride.
MS (APCI) 479/481 (M+H)+
'H NMR 6 (CDC13) 9.02 (IH, t), 8.17-8.14 (IH, d), 7.32 (IH, d), 7.18-7.12 (2H, m), 7.08-7.05 (IH, m), 7.00 (IH, d), 6.75 (IH, dd), 4.42-4.32 (IH, m), 4.16-4.06 (IH, m), 3.71-3.61 (IH, m), 3.49-3.39 (IH, m), 3.04-2.94 (IH, m), 2.85-2.75 (2H, m), 2.71-2.57 (3H, m), 2.16-1.98 (2H, m), 1.96-1.80 (2H, m).
Example 46
TV- {(2R~)-3> -[4-(3,4-Dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl} -4-oxo-3,4-dihydrophthalazine-1-carboxamide




Prepared as described in Example 1 following Preparation 7. . MS (APCI) 491/493/495 (M+H)+
'HNMRS (CDci3) 9.13 (IH, d), 8.43 (m, d), 7.91-75 (SH, m), 7.32 (IH, d), 7.00
(IH, d), 6.76 (IH, dd), 4.40-4.32 (IH, m), 4.08-3.98 (IH, m), 3.76-3.66 (IH, m), 3.46-3.38 (IH, m), 3.00-2.92 (IH, m), 2.80-2.66 (2H, m), 2.58-2.44 (3H, m), 2.14-1.98 (2H, m), 1.96-1.80 (2H,m).
Example 47 JV-{(2J2)-3-[4-(3,4-DicMorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-lJ:f-indole-
3-carboxamide

1
o
Prepared as described in Example 1 following Preparation 7. MS (APCI) 462/464/466 (M+H)+
JH NMR 6 (CDC13) 9.03 (IH, bd s), 8.07-8.04 (IH, d), 7.84 (IH, s), 7.45-7.41 (IH, m), 7.32 (IH, d), 7.28-7.22 (2H, m), 6.99 (IH, d), 6.82 (IE, t\ 6.74 f IH, dd), 4.44-4.34

(IH, m), 4.16-4.06 (IH, m), 3.78-3.68 (IH, m), 3.56-3.44 (IH, m), 3.04-2.94 (IH, m), 2.92-2.82 (2H, m), 2.77-2.65 (3H, m), 2.18-1.98 (2H, m), 1.98-1.78 (2H, m).
Example 48
Ar-{(lR)-3-[4-(4-Chloropb.enoxy)piperidin-l-yl]-2-hydroxypropyl}-2-(methylsulfonyl)benzamide
O '
^ n ^
OH
H
oo=s=o
Prepared as described in Example 1 following Preparation 4.
MS (APCI) 467/469 (M+H)*
]H NMR 5 (CD3OD) 8.08 (IH, d), 7.79 (IH, t), 7.71 (IH, t), 7.61 (IH, d), 7.26 (2H, 1), 6.95 (2H, d), 4.56-4.45 (IH, m), 4.21-4.08 (IH, m), 3.47 (2H, d), 3.35 (3H, s), 3.22-1.08 (2H, m), 3.01-2.77 (4H, m), 2.18-2.00 (2H, m)3 1.99-1.83 (2H, m).
Example 49
A/-{(2J?)-3-[4-(4-Chlorophenoxy)piperidin-l-yl]-2-liydroxypropyl}-l-oxo-l,2-ihydroisoquinoline-4-carboxamide

Prepared as described in Example 1 following Preparation 4.
MS (APCI) 466/468 (M+H)+
*H NMR 6 (DMSO) 11.57 (IH, d), 8.30 (IH, t), 8.22 (2H, d), 7.73 (IH, t), 7.58-45 (2H, m), 7.30 (2H, d), 6.97 (2H, d), 4.75 (IH, s), 4.41-4.29 (IH, m), 3.87-3.74 (IH, m), 3.46-3.26 (IH, m), 3.22-3.07 (IH, m), 2.85-2.67 (2H, m), 2.41-2.21 (4H, m), 2.00-1.84 (2H,m), 1.70-1.51 (2H,m).

Example 50
N- {(2R)-3 -[4-(4-Chloro-3-fluor ophenoxy)piperidin-1 -yl]-2-hydroxypropyl} -1 -oxo-,2-diliydroisoquinoline-4-carboxainide





Prepared as described in Example 1 following Preparation 5. . MS (APCI) 474/476 (M+H)+
]H NMR 6 (CD3OD) 8.25 (IH, d), 8.08 (IH, d), 7.67 (IH, ddd), 7.48 (2H, t), 7.21 (IH, t), 6.75 (IH, d), 6.66 (IH, ddd), 4.30 (IH, dq), 3.95-3.87 (IH, m), 3.45 (IH, dd), 3.29-3.24 (IH, m), 2.80-2.69 (2H, m), 2.45-2.31 (4H, m), 1.95-1.86 (2H, m), 1.73-1.62 (2H, m).
Example 51
N- {(2R)-3 -[4-(3,4-Difluorophenoxy)piperidin-1 -yl]-2-hydroxypropyl} -1 -oxo-1,2-dihydroisoquinoline-4-carboxamide

Prepared as described in Example 1 following Preparation 6.
MS (APCI) 458 (M+H)+
'H NMR 6 (CD3OD) 8.25 (IH, dd), 8.08 (IH, d), 7.67 (IH, ddd), 7.50-7.46 (2H, m), 7.03 (IH, dt), 6.76 (IH, ddd), 6.63-6.59 (IH, m), 4.24 (IH, dquintet),-3.94-3.87 (IH, m), 3.45 (IH, dd), 3.26 (IH, dd), 2.74 (2H, d), 2.45-2.30 (4H, m), 1.90 (2H, dt), 1.72-1.61 (2H,m).
Example 52

Prepared as described in Example 1 following Preparation 12. MS (APCI) 504/506 (M+H)+
N- { (2iS)-3-[4-(3 ,4-Dichlorophenoxy)piperidin- 1 -yl]-2-hydroxypropyl} -jV-methyl- 1 -oxo- 1 ,2-dihydroisoquinoline-4-carboxamide

'HNMR5 (DMSO) 1.25-1.42 (m, IH), 1.57-1.73 (m, 2H), 1.89-2.15 (m, 3H), 2.26-2.42 (m, 2H), 2.69-2.85 (m, IH), 2.90-3.15 (m, 4H), 3.63-3.77 (m, IH), 3.97-4.09 (m, IH), 4.26-4.49 (m, IH), 4.79-4.95 (m, IH), 6.91-7.01 (m, IH), 7.18-7.31 (m, 2H), 7.45-7.57 (m, 3H), 7.73 (t, IH), 8.23 (d, IH), 11.51 (s, IH).
Example 53
^-{(ZS)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-Ar-methyl-1 .ff-indazole-3 -carboxamide




Prepared as described in Example 1 following Preparation 12.
MS (APCT) 477/479 (M+H)+
JHNMR5 (DMSO) 1.36-1.51 (m, IH), 1.58-1.67 (m, IH), 1.72-1.81 (m, IH), 1.86-1.96 (in, IH), 2.04-2.21 (m, 2H), 2.26-2.39 (m, 2H), 2.71-2.81 (m, IH), 3.13 (s, 3H)3 3.49-3.57 (m, IH), 3.78-3.93 (m, IH), 3.98-4.06 (m, IH), 4.31-4.48 (m, IH), 4.71-4.83 (m, IH), 6.93-7.00 (m, IH), 7.16-7.25 (m, 2H), 7.34-7.43 (m, IH), 7.49 (d, IH), 7.58 (t, IH), 7.95 (dd, IH), 13.34-13.49 (m, IH).
Example 54 ^-{(25}-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-JV'-methyl-4-
oxo-3,4-dihydroph.thalazine-1 -carboxamide


c


Prepared as described in Example 1 following Preparation 12.
MS (APCI) 505/507 (M+H)+
'HNMR5 (CD3OD) 1.44-1.55 (m, IH), 1.69-1.80 (m, 2H), 1.93-2.02 (m, IH), 2.15-2.24 (m, IH), 2.19 (d, IH), 2.46-2.60 (m, 2H), 2.84-2.93 (m, IH), 3.20 (s, 3H), 3.42-3.51 (m, IH), 3.75 (dd, IH), 3.84 (qt, IH), 4.16-4.25 (m, IH), 4.35-4.41 (m, IH), 6.79 (ddd, IH), 7.00 (dd, IH), 7.28 (dd, IH), 7.72-7.89 (m, 3H), 8.31 (t, IH).

jaxample 55
Benzole acid, 3-[[2-[[(2£)-3-[4-(3,4-dichlorophenoxy)-l -piperidinyl]-2-hydroxypropyl]amino]-2-oxoethyl]amiiio]-, methyl ester


o " o
Prepared as described in Example 1 following Preparation 7. MS (APCI) 510/512 (M+H/
'HNMR5 (CDC13) 8.17 (IH, t), 7.95 (IH, dd), 7.38 (IH, t), 7.31 (IH, d), 6.98 d), 6.91 (IH, t), 6.78-6.68 (2H, m), 6.57 (IH, d), 4.32-4.20 (IH, m), 3.92 (2H, d), 3.89 (3E s), 3.80-3.69 (IH, m), 3.52-3.40 (IH, m), 3.26 (IH, dt), 2.87-2.74 (IH, m), 2.62-2.39 (2H, m), 2.32 (IH, dd), 2.28-2.14 (2H, m), 2.00-1.84 (2H, m), 1.83-1.66 (2H, m).
Example 56
Propanamide,JV-[2-[[2-[[(ZK)-3-[4-(3,4-dichlorophenoxy)-l-piperidinyl]-2-iydroxypropyl]amino]-2-oxoethyl]amind]phenyl]-
OH
cr
Prepared as described in Example 1 following Preparation 7.
MS (APCI) 523/525 (M+H)+
JH NMR 5 (CDC13) 7.48 (IH, t), 7.31 (IH, d), 7.23-7.11 (2H, m), 7.05 (IH, d), 6.98 2H, d), 6.83-6.71 (2H, m), 6.67 (IH, d), 4.54 (IH, t), 4.31-4.17 (IH, m), 3.92 (IH, d), .79-3.66 (IH, m), 3.45 (IH, td), 3.22 (IH, td), 2.78-2.66 (IH, m), 2.61-2.43 (IH, m), 2.49 IH, q), 2.37 (IH, t), 2.26-2.06 (3H, m), 1.98-1.82 (2H, m), 1.82-1.64 (2H, m), 1.29 (3H, t).
Example 57
Propanamide,jV-[2-[[2-[[(2J?)-3-[4-(3,4-dichlorophenoxy)-l-piperidinyl]-2-hydtoxypropyl]amino]-2-oxoethyl]amino]phenyl]-

Prepared as described in Example 1 following Preparation 7.
MS (APCI) 494/496 (M+H)+
'H NMR 8 (CDC13) 7.73 (2H, dd), 7.32 (IH, dd), 7.29-7.21 (2H, m), 7.02-6.97 (IH, m), 6.97-6.88 (IH, m), 6.80-6.71 (IH, m), 6.60-6.49 (IH, m), 4.36-4.23 (IH, m), 4.14 (2H, t), 3.89-3.75 (IH, m), 3.62-3.48 (IH, m), 3.31-3.17 (IH, m), 2.94-2.81 (IH, m), 2.72-2.59 (IH, m), 2.60-2.47 (IH, m), 2.43-2.22 (3H, m), 2.40 (3H, s), 2.05-1.89 (2H, m), 1.88-1.72 (2H,m).
Example 58
(2,S)-A'-{(2Je)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-2-hyroxy-2-phenylethanamide

Prepared as described in Example 1 following Preparation 7.
MS (APCI) 453/455/457 (M+H)+
]H NMR 5 (CDC13) 7.44-7.26 (6H, m), 6.98 (IH, d), 6.74 (IH, dd), 6.54 (IH, bd s), 5.06 (IH, s), 4.34-4.24 (IH, m), 3.83-3.73 (IH, m), 3.56-3.43 (IH, m), 3.32-3.20 (IH, m), 2.88-2.80 (IH, m), 2.62-2.52 (2H, m), 2.33-2.10 (3H, m), 2.02-1.90 (2H, m), 1.86-1.70 (2H,m).
Example 59
2-[2-({(2^)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}amino)-2-oxoethoxy]benzamide

Prepared as described in Example 1 following Preparation 7.
MS (APCI) 496/498 (M+H)+
'H NMR 5 (CDC13) 7.97 (IH, d), 7.48 (IH, t), 7.36-7.28 (2H, m), 7.17-7.07 (IH, m), 7.13 (2H, t), 6.99 (IH, s), 6.93 (IH, d), 6.75 (IH, d), 5.99 (IH, s), 4.68 (2H, s), 4.35-4.22 (IH, m), 3.89-3.77 (IH, m), 3.67-3.54 (IH, m), 3.22 (IH, quintet), 2.91-2.79 (IH, m), 2.68-2.46 (2H, m), 2.43-2.20 (3H, m), 2.04-1.88 (2H, m), 1.88-1.71 (2H, m).
Example 60
N-{ (2K)-3-[4-(3 54-Dichlorophenoxy)pip.eridin-l -yl]-2-hydroxypropyl}-2-(3-oxo-2,3-dmydro-4#-l,4-benzoxa2in-4-yl)acetainide
V^l OH ON k^NNX*SxNvJ
Cl
O
' Prepared as described in Example 1 following Preparation 7. MS (APCI) 508/510 (M+H)+
'HNMR5 (CDC13) 7.31 (1H, d), 7.08-7.01 (4H, m), 6.99 (1H, d), 6.74 (1H, dd), 6.53 (1H, bd s), 4.69 (2H, s), 4.56 (2H, q), 4.34-4.24 (1H, m), 3.80-3.72 (1H, m), 3.52-3.42 (1H, m), 3.28-3.18 (1H, m), 2.88-2.80 (1H, m), 2.63-2.45 (4H, m), 2.36-2.21 (3H, m), . 2.00-1.90 (2H, m), 1.86-1.70 (2H, m).
Further Examples of compounds of the invention which have been prepared as described in Example 1 following Preparation 7 are presented in the Table below.
Example Name (M+H)
61 N-{(2R)-3-[4-(354-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}- 452
2-methoxybenzamide
62 N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}- 451
2-(methylamino)benzamide
63 N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2- 423
hydroxypropyl}nicotinamide
64 N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2- 423
hydroxypropyl }isonicotinamide
65 N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}- 465
3-(dimethylamino)benzamide
66 N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}- 505
2-(l,3-dioxo-l,3-dihydro-2H-isoindol-2-yl)acetamide
67 N-{(2R)-3-[4-(3,4-dicnlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}- 439
6-hydroxynicotinamide
68 N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-liydroxypropyl}- 475
2-( lH-indol-3-yl)acetaraide
69 N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2- 448
hydroxypropyl}bicyclo[4.2.0]octa-l,3,5-triene-7-carboxamide
70 N-{(2R)-3-[4-(334-dichlorophenoxy)piperidin-l-yi]-2-hydroxypropyl}- 492
4,7-dimethylpyrazolo[531 -c] [ 1,2,4]triazine-3-carboxamide
71 N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2- 424
hydroxypropyl }pyrazine-2-carboxamide
72 N- {(2R)-3 -[4-(3,4-dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl} - 464
9H-purine-6-carboxamide
73 N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2- 473
hydroxypropyl}qumoline-6-carboxamide
74 N- {(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl}- 491
2,7-dimetttylpyrazolo[l35-a]pyrimidine-6-carboxainide
75 N- {(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1 -yl]-2-b.ydroxypropyl} - 470
2-(pyrimidin-2-ylthio)acetamide
76 N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}- 479
5-fluoro-1 H-indole-2-carboxamide
77 N-{(2R)-3-[4-(334-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}- 479
133-benzothiazole-6-carboxamide
78 N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}- 489
5-phenyl-l,3-oxazole-4-carboxainide
79 N-{(2R)-3-[4-(334-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}- 439
6-hydroxypyridine-2-carboxa.mide
80 N-{(2R)-3-[4-(334-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}- 493
3-oxo-3,4-dIhydro-2H-134-benzoxazine-7-carboxamide
81 N-{(2R)-3-[4-(334-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-. 439
3 -hydroxypyridine-2-carboxamide
82 N-{(2R)-3-[4-(3,4-dicblorophenoxy)piperidin-l-yl]-2-h.ydroxypropyl}- 462
1 H-benzimidazole-5-carboxamide
83 N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-liydroxypropyl}- 461
1 H-indole-5-carboxamide
84 N-{(2R)-3-[4-(334-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}- 475

1 -methyl -1 H-indole-2-carboxamide
85 N- {(2R)-3 -[4-(3,4-dichlorophenoxy)piperidin-1 -yl] -2-hydroxypropyl} - 412
1 H-imidazole-4-carboxamide
86 N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}- 461
lH-indole-6-carboxamide
87 N-{(2R)-3-[4-(3,4-dic]ilorophenoxy)piperidin-l-yl]-2-hydroxypropyl}- 475
1 -methyl-1 H-indole-3-carboxamide
88 N- {(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l -yl]-2-hydroxypropyl} - 461
1 H-indole-7-carboxamide
89 N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-liydroxypropyl}- 515
3-[(methylamiao)sulfonyl]benzamide
90 N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}- 578
3,4-bis(methylsulfonyl)benzamide
91 N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-liydroxypropyl}- 437
2-pyridin-3-ylacetamide
92 N-{ (2R)-3-[4-(3,4-dichlorophenoxy)piperidin- l-yl]-2-hydroxypropyl} - 477
5-hydroxy-1 H-indole-2-carboxamide
93 N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}- 440
1,5-dimethyl- lH-pyrazole-3-carboxamide
94 N- {(2R)-3 - [4-(3,4-dichlorophenoxy)piperidin-1 -yl] -2-hydroxypropyl} - 539
5-(methylsulfonyl)-lH-indole-2-carboxamide
95 N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2- 474
hydroxypropyl} quinoxalme-6-carboxamide
96 N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}- 474
l,8-naphthyridine-2-carboxamide
97 N-{(2R)-3-[4-(3)4-dichlorophenoxy)piperidin-l-yl]-2- 518
hydroxypropyl}imidazo[2,l-b][l,3]benzothiazole-2-carboxamide
98 N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}- 490
2,6-dimethylimidazo[l,2-a]pyridine-3-carboxamide
99 N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}- 478
3-oxo-2,3-dihydro-1 H-indazole-4-carboxamide
100 N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}- 478
3-oxo-2,3-dihydro-lH-indazole-6-carboxamide

101 N-{(2R)-3-[4-(3,4-diclilorophenoxy)piperidin-l-yl3-2-liydroxypropyl}- 480
3-(trifluoromethyl)-lH-pyrazole-4-carboxamide
102 2-(lH-benzimidazol-l-yl)-N-{(2R)-3-[4-(3,4- 476
dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl} acetamide
103 N-{(2R)-3-[4-(3,4-dicMorophenoxy)piperidin-l-yl3-2-liydroxypropyl}- 454
l-ethyl-3-methyl-lH-pyrazole-5-carboxamide
104 N-{(2R)-3-[4-(354-dichlorophenoxy)piperidin-l-yl]-2-liydroxypropyl}- 426
5-methyl-1 H-pyrazole-3 -carboxamide
105 N-{(2R)-3-[4-(3 J4-dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl}- 428
4-methyl-1,2,5-oxadiazole-3-carboxamide
106 6-chloro-N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2- 496
hydroxypropyl}iraidazo[l32-a]pyridine-2-carboxainide
107 N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}- 476
2-methylimidazo[l,2-a]pyridine-3-carboxamide
108 N-{(2R)-3-[4-(354-dichlorophenoxy)piperidin-l-yl]-2- 463
hydroxypropyl}imidazo[l ,2-a]pyrimidine-2-carboxamide
109 N-{(2R)-3-[4-(3J4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}- 484
2-[(4-methylpyrimidin-2-yl)tliio]acetamide
110 N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-liydroxypropyl}- 489
4-oxo-1,4-dihydroquiaoline-2-carboxamide
111 N-{(2R)-3-[4-(3,4-diclilorophenoxy)piperidiii-l-yl]-2- 473
hydroxypropyl}quinoline-8-carboxamide
112 N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}- 476
5-methylimidazo[ 1,2-a]pyridme-2-carboxamide
113 N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2- 462
hydroxypropyl} imidazof 1,2-a]pyridine-2-carboxamide
114 N-{(2R)-3-[4-(3J4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}- 474
1,6-naphthyridine-2-carboxaniide
115 N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-liydroxypropyl}- 480
2,1,3-benzoxadiazole-5-carboxamide 1 -oxide

Example 1 16
^V-{(2^)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-6-oxo-l,6-dihydropyridine-3-carboxamide
LJ

Prepared as described in Example 1 following Preparation 7. . MS (APCI) 440/442 (M+H)+
]H NMR 8 (CD3OD) 8.07 (IH, d), 7.99 (IH, dd), 7.39 (IH, d), 7.15 (IH, d), 6.92 (IH, dd), 6.53 (IH, d), 4.52 (IH, septet), 4.09-4.01 (IH, m), 3.49 (IH, dd), 3.34 (IH, d), 3.11-3.02 (2H, m), 2.86-2.67 (4H, m), 2.14-2.03 (2H, m), 1.95 (3H, s), 1.97-1.84 (2H, m).
Example 117
4-Chloro-A/- { (2K)-3 -[4-(3 ,4-dichlorophenoxy)piperidin- 1 -yl] -2-hydroxypropyl } -l/f-pyrazole-3-carboxamide
o ci
Prepared as described in Example 1 following Preparation 7.
MS (APCI) 447/449 (M+H)+
'H NMR 6 (CD3OD) 7.77 (IH, s), 7.37 (IH, d), 7.09 (IH, d), 6.88 (IH, dd), 4.39 (IH, t), 3.95 (IH, quintet), 3.49 (IH, dd), 3.40 (IH, dd), 2.86-2.77 (2H, m), 2.52-2.39 (2H, m), 2.49 (2H, d), 2.06-1.96 (2H, m), 1.85-1.74 (2H, m).
Example 118
Ar-{(2^)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-5-phenyl-1 ,3-oxazole-4-carboxamide

O
Prepared as described in Example 35 following Preparation 7 from 5-phenyl-l,3-oxazole-4-carbonyl chloride.

MS (APCI) 490/492 (M+H)+
*H NMR 6 (CD3OD) 8.12 (IH, s), 8.10-8.08 (2H, m), 7.40-7.35 (3H, m), 7.29 (IH, d), 7.04 (IH, d), 6.81 (IH, dd), 4.39 (IH, septet), 3.95 (IH, quintet), 3.44-3.33 (2H, m), 2.96-2.87 (2H, m), 2.67-2.55 (4H, m), 2.03-1.93 (2H, m), 1.85 (3H, s), 1.85-1.75 (2H, m).
Example 119
JV-{(2J?)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-3,5-dimethyl-1 £f-pyrazole-4-carboxamide


o
Prepared as described in Example 1 following Preparation 7.
MS (APCI) 441/443 (M+H)+
'HNMR 6 (CD3OD) 7.28 (IH, d), 7.00 (IH, d), 6.79 (IH, dd), 4.34-4.26 (IH, m), 3.86 (IH, quintet), 3.41 (IH, dd), 3.21 (IH, dd), 2.78-2.67 (2H, m), 2.41-2.30 (4H, m), 2.29 (6H, s), 1.95-1.86 (2H, m), 1.73-1.63 (2H, m).
Example 120 (2J?)-2-(Acetylarmno)-JV-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-
hydroxypropyl}-2-phenylethanamide
Q
Ql~~^ \xNxvx'5N^'N
O
Prepared as described in Example 1 following Prearation 7.
MS (APCI) 494/496 (M+H)+
'H NMR 8 (CD3OD) 7.34 (2H, d), 7.29-7.18 (4H, m), 6.99 (IH, t), 6.78 (IH, dd), 5.29 (IH, s), 4.27 (IH, septet), 3.76-3.65 (IH, m), 3.26-3.08 (2H, m), 2.65-2.49 (2H, m), 2.30-2.15 (4H, m), 1.91 (3H, s), 1.90-1.81 (2H, m), 1.69-1.58 (2H,m).

Example 121
JV-{(2S)-3-[4-(3,4-Dichloroplienoxy)piperidin-l-yl]-2-hydroxypropyl}-2-(2-hydroxyphenyl)acetarnide


cr

Prepared as described in Example 1 following Preparation 7.
MS (APCI) 453/455 (M+H)+
!H NMR 5 (CD3OD) 7.28 (IH, d), 7.05-6.97 (3H, m), 6.78 (IH, dd), 6.72-6.67 (2H, m), 4.27 (IH, dq), 3.72 (IH, quintet), 3.43 (2H, dd), 3.21-3.08 (2H, m), 2.68-2.57 (2H, m), 2.32-2.20 (4H, m), 1.90-1.81 (2H, m), 1.69-1.58 (2H, m).
Example 122
(lR)-A^-{(lR)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-2-[(methylsulfonyl)amuio]-2-phenylethanamide

Cl'

Prepared as described in Example 1 following Preparation 7.
MS (APCI) 530/532 (M+H)+
'H NMR 8 (CD3OD) 7.37 (2H, d), 7.31-7.21 (4H, m), 6.99 (IH, d), 6.78 (IH, dd), 4.96 (IH, s), 4.27 (IH, septet), 3.70 (IH, quintet), 3.24 (IH, dd), 3.13 (IH, dd), 2.72 (3H, s), 2.66-2.56 (2H, m), 2.32-2.18 (4H, m), 1.91-1.82 (2H, m), 1.70-1.59 (2H, m).
Example 123
(26)-2-(Acetylamino)-N-{ (2j?)-3-[4-(3,4-dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl}-2-ph.enylethanamide

l

Prepared as described in Example 1 following Preparation 7. MS (APCI) 494/496 (M+H)*

'HNMR5 (CD3OD) 7.34 (2H, d), 7.30-7.18 (4H, m), 6.99 (IH, dd), 6.78 (IH ddd), 5.29 (IH, s), 4.30-4.23 (IH, m), 3.76-3.65 (IH, m), 3.17-3.07 (2H, m), 2.65-2.41 (2H, m), 2.30-2.14 (4H, m), 1.92-1.80 (2H, m), 1.91 (3H, s), 1.68-1.57 (2H, in).
Example 124
(21S)-^-{(2J?)-3-[4-(3,4-Dichloroplienoxy)piperidin-l-yl]-2-hydroxypropyl}-2-[(methylsulfonyl)amino]-2-plienylethananude
(Figure Remove)
Prepared as described in Example 1 following Preparation 7.
MS (APCI) 530/5322 (M+H)+
1E NMR 5 (CD3OD) 7.47 (2H, d), 7.40-7.30 (4H, m), 7.08 (IH, d), 6.87 (IH, d 5.06 (IH, s), 4.39-4.32 (IH, m), 3.83 (IH, quintet), 3.27 (2H, d), 2.80 (3H, s), 2.73-2.5 (2H, m), 2.38-2.24 (2H, m), 2.28 (2H, d), 1.99-1.89 (2H, m), 1.78-1.67 (2H, m).
Example 125 1 - { (R)-3-[4-(3 }4-Dichlorophenoxy)piperidin- 1 -yl] -2-hydroxypropyl } -3 -o-tolyl-urea

A solution of o-tolylisocyanate (64ml, 0.51mmol) in dichloromethane (1ml) was added to a suspension of (2R)-l-amino-3--[4-(3,4-dichlorophenoxy)piperidin-l-yl]propan-2-ol (0,15g, 0.47mmol) in dichloromethane (3ml) over a five minute period. After Ih methanol (1ml) was added and the solvents removed under vacuum. The residue was purified by reverse phase chromatography (C8 Symmetry column) to give the title compound (87mg).
MS (APCI) 452/454 (M+H)+
'H NMR 5 (DMSO) 7.81 (IH, d), 7.78 (IH, s), 7.50 (IH, dd), 7.26 (IH, dd), 7.10 (IH, t), 7.05 (IH, s), 6.99 (IH, ddd), 6.86 (IH, t), 6.63 (IH, t), 4.74 (IH, d), 4.49-4.40 (IH, m), 3.72-3.63 (IH, m), 3.32-3.30 (IH, m), 2.99-2.90 (IH, m), 2.79-2.67 (2H, m), 2.35-2.24 (4H, m), 2.18 (3H, s), 1.97-1.88 (2H, m), 1.69-1.56 (2H, m).

Example 126 l-{(R)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-3-p-tolyl-urea
Prepared as described in Example 125 following Preparation 1.
MS (APCI) 452/454 (M+H)+
'H NMR 6 (DMSO) 8.52 (IH, s), 7.55 (IH, d), 7.31 (2H, d), 7.31 (IH, s), 7.07 (2H d), 7.03 (IH, d), 6.15 (IH, t), 4.82-4.76 (IH, m), 4.55-4.45 (IH, m), 3.76-3.67 (IH, m), 3.36-3.32 (IH, m), 3.03-2.95 (IH, m), 2.83-2.72 (2H, m), 2.40-2.31 (4H, m), 2.27 (3H, s), 2.03-1.92 (2H, m), 1.75-1.61 (2H, m).
Example 127
^-{(2,S)-3-[4-(3,4-DicMorophenoxy)piperidin-l-yl]-2-hydroxy-2-methylpropyl}-l-oxo-1,2-dmydroisoquinoline-4-carboxamide

Prepared as described in Example 1 following Preparation 9.
MS (APCI) 504/506/508 (M+H)+
'HNMR5 (CD3OD) 8.37 (IH, d), 8.18 (IH, d), 7.78 (IH, t), 7.59 (IH, s), 7.58 (IH, t), 7.37 (IH, d), 7.07 (lH,.d), 6.86 (IH, dd), 4.33-4.28 (IH, m), 3.60-3.45 (2H, m), 3.04-2.92 (2H, m), 2.60-2.45 (4H, m), 1.98-1.86 (2H, m), 1.72-1.60 (2H, m), 1.25 (3H, s).
Example 128

Prepared as described in Example 1 following Preparation 9. MS N-{ (2,S)-3 -[4-(3,4-DicMorophenoxy)piperidin-l -yl]-2-hydroxy-2-methylpropyl} -2-oxo-1,2-dihydroquinoline-4-carboxamide
(Figure Remove)
'H NMR 5 (CDC13) 7.93 (IH, d), 7.53 (IH, t), 7.34-7.20 (4H, m), 6.98 (IH, d), 6.75-6.69 (2H, m), 4.32-4.22 (IH, m), 3.68-3.40 (2H, m), 3.00-2.80 (2H, m), 2.70-2.48 (4H, m), 2.00-1.86 (2H, m), 1.84-1.72 (2H, m), 1.26 (3H, s).
Example 129
Ar-{(21S)-3-[4-(3,4-DicMoropheiioxy)piperidin-l-yl]-2-liydroxy-2-methylpropyl}-4-oxo-3,4-dmydrophthalazine-1 -carboxamide
Prepared as described in Example 1 following Preparation 9. MS (APCI) 505/507/509 (M+H)+
'HNMR s (CDCi3) 10.18 (IH, bs), 9.15 (m, d), 8.44 (IH, d), 8.06 (IH, bd s),
7.89 (IH, t), 7.81 (IH, t), 7.31 (IH, d), 7.01 (IH, d), 6.78 (IH, dd), 4.35-4.25 (IH, m), 3.58-3.37 (2H, m), 3.04-2.82 (2H, m), 2.66-2.46 (4H, m), 2.06-1.96 (2H, m), 1.94-1.80 (2H,m),1.23(3H,s).
Example 130
(2iS)-JV-{(21S)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxy-2-methylpropyl} -2-hydroxy-2-phenethanamide

Prepared as described in Example 1 following Preparation 9.
MS (APCI) 467/469/471 (M+H)+
'H NMR 8 (CDC13) 7.46-7.29 (6H, m), 6.98 (IH, d), 6.78 (IH, bd s), 6.75 (IH, dd), 5.08 (IH, s), 4.28-4.20 (IH, m), 3.71 (IH, bd s), 3.35-3.20 (2H, m), 2.86-2.69 (2H, m), 2.53-2.39 (2H, m), 2.31 (2H, s), 1.97-1.85 (2H, m), 1.82-1.70 (2H, m), 1.04 (3H, s).
Example 131
Air-{(2/2)-3-[4-(4-Chloro-2-methylphenoxy)piperidin-l-yl]-2-hydroxypropyl}-l-oxo- 1 ,2-dihydroisoq\iinoline-4-carboxamide

Prepared as described in Example 1 following Preparation 10. ' MS (APCI) 470/472 (M+H)+
'HNMR5 (CD3OD) 8.25 (IH, d), 8.08 (IH, d), 7.67 (IH, t), 7.48 (2H, t), 7.05-6.96 (2H, m), 6.77 (IH, d), 4.36-4.25 (IH, m), 3.98-3.87 (IH, m), 3.45 (IH, dd), 3.28 (IH, dd), 2.80-2.67 (2H, m), 2.49-2.34 (4H, m), 2.08 (3H, s), 1.98-1.84 (2H, m), 1.78-1.64 (2H, m).
Example 132
JV-((2/?)-3-{4-[2-(Aminocarbonyl)-3,4-dichlorophenoxy]piperidin-l-yl}-2-hydroxypropyl)- 1 -oxo-1 ,2-dihydroisoquinoline-4-carboxamide

The crude amine product obtained from Preparation 1 1 was redissolved in dichloromethane and treated with diisopropylethylamine (0.85ml) and 1 -oxo-1, 2-dihydroisoquinoline-4-carbonyl chloride (0.40g) at room temperature. The reaction was quenched with saturated aqueous sodium hydrogen carbonate solution and the mixture concentrated in vacua, azeotoping with toluene. Extraction of the solid residue into dichloromethahe/methanol, filtering solids and chromatography on silica (dichloromethane:7N ammonia in methanol/15:2) gave the target compound as a white solid (0.3 Ig).
MS (APCI) 533/535 (M+H)+
'H NMR 8 (CD3OD) 8.25 (IH, d), 8.12 (IH, d), 7.69 (IH, m), 7.55 (m, s), 7.49 (IH, m), 7.44 (IH, d), 7.05 (IH, d), 4.20 (IH, m), 3.55-2.96 (10H, m), 2.25-1.98 (4H, m).

Example 133
3-Cyano-7V-{(21S)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl }benzenesulfonamide

To a solution of (2J?)-l-arnino-3-{4-(3,4-dichlorophenoxy)piperidin-l-yl]propan-2-ol (0.200g, 0.63mmol) in 4ml of pyridine at 0°C was added 3-cyanobenzenesulfonyl chloride (0.127g, 0.63mmol). After 30 min, the reaction was allowed to warm to room temperature and was stirred for 2h. The reaction was concentrated under vacuum, and the residue partitioned between 10% aqueous sodium hydrogen carbonate and ethyl acetate. The organic layer was washed with water, then brine and dried over magnesium sulfate. The crude material was purified on silica gel (0 to 5% 7N ammonia in methanol/dichloromethane) to afford the title compound as a white foam (0.120g).
MS (ESI) 484/486 (M+H)+
JH NMR5 (DMSO) 8.22 (1H, d), 8.16-8.07 (2H, d), 7.82 (2H, t), 7.50 (1H, d), 7.25 (1H, d), 6.97 (1H, dd), 4.71 (d, 1H), 4.47-4.34 (1H, m), 3.63-3.51 (1H, m), 2.93 (1H, dd), 2.71 (1H, dd), 2.69-2.55 (2H, m), 2.32-2.12 (4H, m), 1.95-1.79 (2H, m), 1.65-1.45 (2H, m), 1.65-1.45 (2H,m).
Example 134
5-[({ (2»S)-3-[4-(3,4-DicMorophenoxy)piperidin-1 -yl]-2-hydroxypropyl} amino)-sulfonyl]-2-methoxybenzamide

Prepared as described in Example 133 following Preparation 7 using 3-(aminocarbonyl)-4-methoxybenzenesulfonyl chloride.
MS (APCI) 531/533 (M+H)+
!H NMR 6 (DMSO) 8.20 (1H, d), 7.87 (1H, dd), 7.73 (2H, s), 7.55 (1H, s), 7.49 (1H, d), 7.32 (1H, d), 7.25 (1H, d), 6.97 (1H, dd), 4.67 (1H, d), 4.41 (1H, septet), 3.96 (3H, s), 3.58 (1H, q), 2.82 (1H. dV 2.68-2.57 T3H. m\ 2.30-2.16 f4H. ml 1.91-1.82 Cm. mV 1.60-1.49(2H,m).

Example 135
J/V-{(21S)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-l-oxo-l52-dihydroisoquinoline-4-sulfonamide acetate salt

cu cr

' (2R)-l-Amino-3-[4-(3J4-dichlorophenoxy)piperidin-l-yl]propan-2-ol (0.15g) in pyridine (2ml) was treated with l-oxo-l,2-dihydroisoquinoline-4-sulfonyl chloride (O.llg) and the mixture was stirred at ambient temperature for 1 Sh. After further additions of the sulfonyl chloride (O.OSg) and stirring for 24h the solvent was evaporated. Purification by column chromatography and reverse phase HPLC (symmetry C8 column and acetonitrile/0.1% aqueous ammonium acetate) yielded the title compound as a white solid (0.06g).
MS (APCI) 526/528 (M+H)+

'H NMR 6 (DMSO) 8.39 (IH, d), 8.32 (IH, d), 7.95 (IH, s), 7.86 (IH, ddd), 7.64 (IH, t), 7.39 (IH, d), 7.11 (IH, d), 6.89 (IH, dd), 4.45-4.39 (IH, m), 3.82-3.75 (IH, m), 3.34 (IH, s), 2.97 (IH, dd), 2.92 (IH, dd), 2.81-2.72 (2H, m), 2.55-2.42 (2H, m), 2.02-1.92 (2H, m), 1.95 (3H, s, OAc), 1.82-1.72 (2H, m).
Example 136
iV-{(24S)-3-[4-(334-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-2,4-difluorobenzenesulfonamide


O' 'O

Prepared as described in Example 133 following Preparation 7 using 2,4-difluorobenzenesulfonyl chloride.
MS (APCI) 493/495 (M+H)+
!H NMR 5 (DMSO) 7.94 (IH/s), 7.86 (IH, td), 7.55 (IH, ddd), 7.49 (IH, d), 7.28 (IH, ddd), 7.25 (IH, d), 6.97 (IH, dd), 4.69 (IH, d), 4.42 (IH, septet), 3.60 (IH, sextet), 2.96 (IH, dd), 2.81 (IH, dd), 2.68-2.58 (2H, m), 2.34-2.16 (4H, m), 1.91-1.82 (2H, m), 1.60-1. 49 (2H,m).

Further Examples of compounds of the invention which have been prepared
according to Example 133 following Preparation 7 are now listed hi the following table.
Example Name (M+H)+
137 N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidni-l-yl]-2- 396
hydroxypropyl }methanesulfbnamide
138 N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2- 458
hydroxypropyl}benzenesiulfonamide
139 N-{(2S)-3-[4-(354-dichlorophenoxy)piperidm-l-yl]-2- 472
hydroxypropyl}-l-phenylmethanesulfonamide
140 N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidm-l-yl]-2- 488
hydroxypropyl} -4-methoxybenzenesulfonamide
141 N-({5-[({(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2- 597
hydroxypropyl} amino)sulfonyl] -2-thienyl} methyl)benzamide
142 4-cyano-N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2- 483
hydroxypropyl}benzenesulfonamide
143 N-{5-[({(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2- 536
hydroxypropyl}amino)sulfonyl]-4~methyl-l,3-thiazol-2-
yl}acetamide
144 N-{(2S)-3-[4-(354-dichlorophenoxy)piperidin-l-yl]-2- 464
hydroxypropyl}thiophene-2-sulfonamide
145 4-[({(2S)-3-[4-(334-dichlorophenoxy)piperidhi-l-yl]-2- 502
hydroxypropyl} amino)sulfonyl]benzoic acid
146 N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2- 518
hydroxypropyl} -2,5-dimethoxybenzenesulfonamide
147 N-{(2S)-3-[4-(354-dichlorophenoxy)piperidin-l-yl]-2- 604
hydroxypropyl}-4-(phenylsulfonyI)thiophene-2-sulfonamide
148 N-{(2S)-3-[4-(354-dichlorophenoxy)piperidin-l-yl]-2- 531
hydroxypropyl}-5-(l,3-oxazol-5-yl)thiophene-2-sulfonamide
149 N-{(2S)-3-[4-(3)4-dichlorophenoxy)piperidin-l-yl]-2- 612
hydroxypropyl} -5-[ 1 -methyI-5-(trifluoromethyl)- lH-pyrazol-3-
yl]thiophene-2-sulfonamide

150 N-{(2S)-3-[4-(3,4-dicMorophenoxy)piperidin-l-yl]-2- 541
hydroxypropyl} -5-(pyridin-2-yl)thiophene-2-sulfonamide
151 5-chloro-N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2- 510
hydroxypropyl} -1,3-dimethyl-l H-pyrazole-4-sulfonamide
152 N-{(2S)-3-[4-(3,4-dicMorophenoxy)piperidin-l-yl]-2- 477
hydroxypropyl}-3,5-dimethylisoxazole-4-siilfonainide
153 N-{(2S)-3-[4-(3J4-dichlorophenoxy)piperidin-l-yl]-2- 516
hydroxypropyl}-2,lJ3-benzothiadiazole-4-sulfonamide
154 N-{(2S)-3-[4-(3,4-dicWorophenoxy)piperidin-l-yl]-2- 462
hydroxypropyl} -1 -methyl-1 H-imidazole-4-sulfonamide
155 N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2- 500
hydroxypropyl} -2,1,3-benzoxadiazole-4-sulfonamide
156 N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2- 531
hydroxypropyl}-5-(isoxazol-3-yl)thiophene-2-sulfonamide
157 methyl 3-[({(2S)-3-[4-(3:I4-dichlorophenoxy)piperidin-l-yl]-2- 522
hydroxypropyl} amino)sulfonyl]thiophene-2-carboxylate
158 2,6-dichloro-N-{(2S)-3-[4-(3J4-dichlorophenoxy)piperidiri-l-yl]- 526
2-hydroxypropyl} benzenesulfonamide
159 N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2- 472
hydroxypropyl} -3 -me thy Ibenzenesulfonamide
160 3-chloro-N-{(2S)-3-[4-(3J4-dichlorophenoxy)piperidin-l-yl]-2- 492
hydroxypropyl}benzenesiilfonamide
161 N-{(2S)-3-[4-(334-dichlorophenoxy)piperidiri-l-yl]-2- 424
hydroxypropyl }propane-2-sulfonamide
162 N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2- 424
hydroxypropyl }propane-1 -sulfonamide
163 N-{(2S)-3-[4-(3J4-dichlorophenoxy)piperidhi-l-yl]-2- 538
hydroxypropyl} -5-methyl-1 -phenyl-1 H-pyrazole-4-sulfonamide
164 3-chloro-N-{(2S)-3-[4-(3;,4-dichlorophenoxy)piperidin-l-yl]-2- 506
hydroxypropyl}-2-methylbenzenesulfonamide
165 methyl 5-[({(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2- 520
hydroxypropyl}amino)sulfonyl]-2-memyl-3-furoate

166 methyl 5-[({(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2- 519
hydroxypropyl}amino)sulfonyl]-l-methyl-lH-pyrrole-2-
carboxylate
167 N-{(2S)-3-[4-(334-dicMorophenoxy)piperidin-l-yl]-2- 518
hydroxypropyl} -3,4-dimethoxybenzenesulfonamide
168 5-chloro-N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-l -yl]-2- 498
hydroxypropyl}thiophene-2-sulfonaniide
169 N-{(2S)-3-[4-(3J4-dichlorophenoxy)piperidin-l-yl]-2- 544
hydroxypropyl}-6-(morpholin-4-yl)pyridine-3-sulfonaniide
170 N-{2-chloro-4-[({(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-l- 549
yl]-2-hydroxypropyl} amino)sulfonyl]phenyl} acetamide
171 N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2- 542
hydroxypropyl}-2,3-dihydroxyquinoxaline-6-sulfonainide
172 N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2- 518
hydroxypropyl} -2,4-dimethoxybenzenesulfonamide
173 5-[({(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2- 531
hydroxypropyl} amino)sulfonyl] -2-methoxybenzamide
174 N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2- 472
hydroxypropyl} -2-methylbenzenesulfonamide
175 N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2- 493
hydroxypropyl} -2,4-dimethyl-1,3 -thiazole-5-sulfonamide
176 N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2- 526
hydroxypropyl} -2-hydroxyquinoxaline-6-sulfonamide
177 N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2- 529
hydroxypropyl}-4-methyl-3,4-dihydro-2H-lJ4-ben2oxazine-7-
sulfonamide
178 N-{(2S)-3-[4-(334-dichlorophenoxy)piperidin-l-yl]-2- 459
hydroxypropyl}pyridine-3-sulfonamide
179 4'-cyano-N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2- 559
hydroxypropyl}biphenyl-2-sulfonamide
180 N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2- 476
-1.2-dimethvl-l H-imidazole-4-sulfonamide

181 4-acetyl-N-{(2S)-3-[4-(3,4-dicMorophenoxy)piperidin-l-yl]-2- 500
hydroxypropyl}benzenesidfonarnide
182 N-{(2S)-3-[4-(3,4-dicHoropb.enoxy)piperidin-l-yl]-2- 536
hydroxypropyl}-4-(methylsulfonyl)benzenesulfonamide
183 2-cbloro-4-cyano-N-{(2S)-3-[4-(3,4-dichloroplienoxy)-piperidiQ- 517
1 -yl]-2-hydroxypropyl}benzenesulfonamide
184 N-{(2S)-3-[4-(3}4-dichlorophenoxy)piperidin-l-yl]-2- 490
hydroxypropyl}-l,3,5-triinethyl-lH-pyrazole-4-sulfonamide
Example 185
Ar-[(2R)-3-[4-(3,4-Dichlorophenoxy)-l-piperidinyl]-2-hydroxypropyl]-l,4-diliydro-4~oxo-3-quinolinecarboxainide
u

o o
Prepared as described in Example 1 following Preparation 7 using 4-oxo-l,4-dihydroquinoline-3-carboxylic acid.
MS (APCI) 490/492 (M+H)+
'H NMR 6 (DMSO) 10.21 (5H, t), 8.74 (6H, s), 8.26 (6H, dd), 7.74 (10H, ddd), 7.68 (8H, d), 7.49 (IIH, d), 7.48-7.44 (IIH, m), 7.25 (6H, d), 6.98 (6H, dd), 4.80 (4H, s), 4.44 (6H, septet), 3.75 (6H, s), 3.55 (7H, ddd), 3.26-3.19 (20H, m), 2.78-2.68 (12H, m), 2.34 (20H, d), 2.33-2.25 (24H, m), 1.96-1.88 (12H, m), 1.69-1.58 (12H, m).
Example 186
JV-{(21S)-3-[4-(4-Chloro-2-methylphenoxy)piperidin-l-yl]-2-liydroxypropyl}-l oxo-lJ2-dihydroisoquinoline-4-carboxamide acetate salt
A
Prepared as described in Example 35 following Preparation 10 using (2S)-oxiran-2-ylmethyl-3-nitrobenzenesulfonate and l-oxo-l,2-dihydroisoquinoline-4-carbonyl chloride. MS (APCI) 470/472 (M+H)+

•±f NMR5 (DMSO) 8.32 (IH, 1), 8.22 (2H, d), 7.73 (IH, td), 7.52 (IH, td), 7.52 (IH, s), 7.20 (IH, d), 7.14 (IH, dd), 6.98 (IH, d), 4.38 (IH, septet), 3.81 (IH, quintet), 3.43-3.36 (IH, m), 3,18-3.11 (IH, m), 2.75-2.63 (2H, m), 2.42-2.28 (4H, m), 2.14 (3H, s), 1.94-1.84 (2H, m), 1.88 (3H, s, OAc), 1.70-1.58' (2H, m).
Example 187
Ar-{(21S)-3-{4-(3,4-Dichlorophenoxy)piperidiii-l-yl]-2-hydroxypropyl}-l-oxo-l,2-dihydroisoqumoline-4-carboxarnide
M

Prepared as described in Example 35 following Preparation 14 using l-oxo-1,2-dihydroisoquinoline-4-carbonyl chloride.
MS (APCI) 490/492/494 (M+H)4
'HNMR5 (CD3OD) 8.40 (IH, d), 8.21 (IH, d), 7.74 (IH, t), 7.54 (IH, t), 7.50 (IH, 3), 7.32 (IH, d), 7.00 (IH, d), 6.76 (IH, dd), 4.36-4.24 (IH, m), 3.99-3.93 (IH, d), 3.73-3.68 (IH, d), 3.33-3.28 (IH, m), 2.96-2.84 (IH, m), 2.75-2.30 (5H, m), 2.04-1.94 (2H, m), 1.88-1.76 (2H,s).
Example 188
A^-{(2^)-3-{4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-l-oxo-l,2-lihydroisoqurnoline-4-carboxamide

Prepared as described in Example 35 following Preparation 15 using l-oxo-1,2-dihydrois oquinoline-4-carbonyl chloride.
MS (APCI) 504/506/508 (M+H)+
]H NMR 6 (CD3OD) 8.38 (lH,d), 8.19 (IH, d)7.80 (IH, t), 7.61 (IH, t), 7.60 (IH, t), 7.38 (IH, d), 7.09 (IH, d), 6.87 (IH, dd), 4.37-4.30 (IH, m), 3.64 (IH, d), 3.42 (IH, d), 3.03-2.83 (2H, m), 2.60-2.46 (4H, m), 1.96-1,86 (2H, m), 1.72-1.60(2H, m), 1.26 (3H, s).

7v-|(2A:j-3-L4-(3,4-Diclilorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-7-[(methylamino)sulfonyl
7-[(Methylamino)sulfonyl]-1 -oxo-1,2-dihydroisoquinoline-4-carboxylic acid (0.1 g) in dimethyl formamide (7ml) was treated with N,N-carbonyldiimidazole (0.06g) and the mixture was heated at 55°C for 45 min. (2R)-l-Amino-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]propan-2-ol (0.1 Ig) in dimethyl formamide (1ml) was added and the mixture was stirred at ambient temperature for 18h. 1 Drop of water was added and the solvent was evaporated. Purification using reverse phase HPLC (Symmetry C8 column) and acetonitrile/aqueous ammonium acetate as eluent yielded the title compound as a white solid (0.03g).
MS (APCI) 583/585 (M+H)*
1H NMR 5 (DMSO) 8.59 (1H, a), 8.44 (1H, d), 8.42 (1H, t), 8.04 (1H, dd), 7.73 (1H, s), 7.62 (1H, s), 7.49 (1H, d), 7.25 (1H, d), 6.98 (1H, dd), 4.79 (1H, s), 4.44 (1H, septet), 3.80 (1H, quintet), 3.45-3.37 (1H, m), 3.18-3.11 (1H, m), 2.81-2.69 (2H, m), 2.42 (3H, s), 2.39-2.25 (4H, m), 1.96-1.87 (2H, m), 1.66-1.55 (2H, m).
Example 190
JV-{(2J?)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-7-{[(2-hydroxyethyl)amino] sulfonyl} -1 -oxo-1 J2-dihydroisoquinoline-4-carboxamide acetate salt

Prepared as described in Example 189 following Preparation 7 using l,2-dihydro-7 [[(2-hydroxyethyl)amino]sulfonyl]-l-oxo-4-isoquinolinecarboxylicacid.
MS (APCI) 613/615 (M+H)+
]H NMR 6 (DMSO) 8.61 (1H, s), 8.42 (1H, d), 8.42 (1H, t), 8.07 (1H, dd), 7.71 (1H, s), 7.49 (1H, d), 7.25 (1H, d), 6.98 (1H, dd), 4.44 (1H, septet), 3.81 (1H, quintet),
3.46-3.37 (IH, m), 3.35 (2H, t), 3.18-3.10 (IH, m), 2.80-2.68 (2H, m), 2.80 (2H, t), 2.42-2.25 (4H, m), 1.96-1.87 (2H, m), 1.88 (3H, s, OAc), 1.66-1.55 (2H, m).
Example 191
7-[(Cyclopropylamino)sulfonyl]--^-{(lff)-3-[4-(3,4-dicMorophenoxy;piperiain-i-
ylj^-hydroxypropylj-l-oxo-l^-dihydroisoquinoline^-carboxainide
H

Prepared as described in Example 189 following Preparation 7 using 7-[(cyclopropylamino)sulfonyl]-1,2-dihydro-1 -oxo-4-isoquinoHnecarboxylic acid.
MS (APCT) 609/611 (M4-H)+
]H NMR 8 (DMSO) 8.64 (IH, s), 8.44 (IH, d), 8.41 (IH, t), 8.07 (IH, dd), 7.72 (IH, s), 7.49 (IH, d), 7.25 (IH, d), 6.98 (IH, dd), 4.78 (IH, s), 4.44 (IH, septet), 3.81 (IH, quintet), 3.45-3.38 (IH, m), 3.18-3.10 (IH, m), 2.81-2.69 (2H, m), 2.42-2.25 (4H, m), 2.15-2,09 (IH, m), 1.96-1.86 (2H, m), 1.66-1.54 (2H, m), 0.50-0.44 (2H, m), 0.38-0.32 (2H, m).
Example 192
7-(Azetidin-1 -ylsulfonyl)-W-{ (2R)-3 -[4-(3,4-dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl}-l-oxo-l,2-dihydroisoqumoline-4-carboxamide acetate salt


'Y^ OH
kx-N^A^N
O


Prepared as described in Example 189 following Preparation 7 using 7-(azetidin-l-ylsulfonyl)- 1 -oxo- 1 ,2-dihydroisoquinoline«4-carboxylic acid.
MS (APCI) 609/61 1 (M+H)+
'H NMR 8 (DMSO) 8.53 (IH, t), 8.52 (IH, d), 8.44 (IH, t), 8.09 (IH, dd), 7.77 (IH, s), 7.50 (IH, d), 7.25 (IH, d), 6.98 (IH, dd), 4.43 (IH, septet), 3.81 (IH, quintet), 3.69 (4H, t), 3.47-3.37 (IH, m), 3.21-3.10 (IH, m), 2.83-2.68 (2H, m), 2.40-2.24 (4H, m), 2.05-1.86 (2H, m), 1.97 (2H, quintet), 1.88 (3H, s, OAc), 1.68-1.53 (2H, m). -
Example 193
7-(Aminosulfonyl)-JV-{(2/?)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-l-oxo-l,2-dihydroisoquinoline-4-carboxamide




Prepared as described in Example 189 following Preparation 7 using 7-(aminosulfonyl)-l-oxo-l,2-diliydroisoquinoline-4-carboxylic acid.
MS (APCI) 569/571 (M+H)+
!H NMR 5 (DMSO) 8.65 (IH, s), 8.40 (IH, d), 8.39 (IH, t), 8.09 (IH, dd), 7.69 (IH, s), 7.49 (IH, d), 7.50 (2H, s), 7.25 (IH, d), 6.98 (IH, dd), 4.77 (IH, s), 4.44 (IH, septet), 3.85-3.77 (IH, m), 3.41 (IH, dt), 3.14 (IH, dt), 2.81-2.69 (2H, m), 2.41-2.25 (4E m), 1.96-1.86 (2H, m), 1.67-1.54 (2H, m).
Example 194
Ar-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}^7-[(dimethylamino)sulfonylj -1 -oxo-1,2-dihydroisoqumok"ne-4-carboxamide
ci
cu
Prepared as described in Example 189 following Preparation 7 using 7-[(dimemylaniino)siilfonyl]-l-oxo-l,2-dihydroisoquinoline-4-carboxylic acid.
MS (APCI) 597/599 (M+H)+
1H NMR 5 (DMSO) 8.49 (IH, s), 8.48 (IH, d), 8.43 (IH, t), 8.04 (IH, dd), 7.75 (IH, s), 7.49 (IH, d), 7.25 (IH, d), 6.98 (IH, dd), 4.44 (IH, septet), 3.81 (IH, quintet), 3.46-3.37 (IH, m), 3.18-3.11 (IH, m), 2.82-2.69 (2H, m), 2.64 (6H, s), 2.42-2.26 (4H, m), 1.95-1.86 (2H, m), 1.89 (3H, s, OAc), 1.60 (2H, dt).
Example 195
Ar-{(lK)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-7-[(3-hydroxy-3-methylazetidin-1 -yl)sulfonyl ]-1 -oxo-1,2-dihydroisoquinoline-4-carboxamide acetate salt




Prepared as described in Example 189 following Preparation 7 using 7-[(3-hydroxy-3-methylazetidin-1 -yl)sulfonylj-1 -oxo-1,2-dihydroisoquinoline-4-carboxylic acid.
MS (APC1) 639/641 (M-HH)+
]H NMR 5 (DMSO) 8.53 (IH, d), 8.51 (IH, d), 8.45 (IH, t), 8.08 (IH, dd), 7.77 (IH, s), 7.49 (IH, d), 7.25 (IH, d), 6.98 (IH, dd), 4.44 (IH, septet), 3.82 (IH, quintet), 3.60 (2H, d), 3.45 (2H, d), 3.45-3.40 (IH, m), 3.19-3.10 (IH, m), 2.81-2.69 (2H, m), 2.42-2.25 (4H, m), 1.96-1.84 (2H, m), 1.88 (3H, s, OAc), 1.66-1.55 (2H, m).
Example 196
A^-[(2J2)-3-(4-{3,4-DicWoro-2-[(cyclopropylamino)carbonyl]phenoxy}piperidiQ-l-yl)-2-hydroxypropyl]-l-oxo-l,2-dihydroisoquinoline-4-carboxamide acetate salt

o
Prepared as described in Example 35 following Preparation 35 using l-oxo-1,2-dihydroisoquinoline-4-carbonyl chloride.
MS (APCI) 573/575 (M+H)+
!H NMR 6 (CD3OD) 8.25 (IH, d), 8.09 (IH, d), 7.68 (IH, t), 7.49 (IH, s), 7.48 (IH, t), 7.38 (IH, d), 6.97 (IH, d), 4.54-4.48 (IH, m), 4.03-3.97 (IH, m), 3.44 (IH, dd), 3.30 (IH, dd), 2.90-2.79 (2H, m), 2.76-2.58 (5H, m), 1.98-1.89 (2H, m), 1.87-1.79 (2H,. m), 1.85 (3H, s, OAc), 0.70-0.65 (2H, m), 0.52-0.48 (2H, m).
Example 197
N-{(2R)-3-[4-(3 -CMoro-4-cyanophenoxy)piperidin-1 -ylj-2-hydroxypropyl}-1 -oxo-,2-dihydroisoquinoline-4-carboxarQide
o
Prepared as described in Example 35 following Preparation 24 using l-oxo-1,2-dihydroisoquinoline-4-carbonyl chloride.
MS(APCI)481(M+H)+
JH NMR 5 (CD3OD) 8.36 (IH, dd), 8.19 (IH, d), 7.86 (2H, d), 7.77-7.75 (2H, m), 7.57 (2H, td), 7.12 (2H, d), 4.62-4.56 (IH, m), 4.07-4.01 (IH, m), 3.57 (IH, dd), 3.38 (IH, dd), 3.08 (3H, s), 2.98-2.88 (2H, m), 2.66-2.55 (4H, m), 2.12-2.04 (2H, m), 1.92-1.83 (2H, m).
Example 198
7V-((2/?)-2-Hydroxy-3-{4-[4-(methylsulfonyl)phenoxy]piperidin-l-yl}propyl)-l-oxo-1,2-dihydroisoquinoline-4-carboxamide

Prepared as described in Example 35 following Preparation 25 using l-oxo-1,2-dihydroisoquinoline-4-carbonyl chloride.
MS (APCI) 500 (M+H)+
'H NMR 8 (CD3OD) 8.36 (IH, dd), 8.19 (IH, d), 7.86 (2H, d), 7.77-7.75 (2H, m), 7.57 (2H, td), 7.12 (2H, d), 4.62-4.56 (IH, m), 4.07-4.01 (IH, m), 3.57 (IH, dd), 3.38 (IH, dd), 3.08 (3H, s), 2.98-2.88 (2H, m), 2.66-2.55 (4H, m), 2.12-2.04 (2H, m), 1.92-1.83 (2H, m).

example
7V-{(2/?)-3-[4-(4-Cyanoplienoxy)piperidin-l-yl]-2-hydroxypropyl}-l-oxo-l,2-dihydroisoquinoline-4-carboxamide

Prepared as described in Example 35 following Preparation 26 using l-oxo-1,2-dihydroisoquinoline-4-carbonyl chloride.
MS (APCI) 447 (M+H)+
!H NMR 8 (DMSO) 8.31 (IH, t), 8.22 (2H, d), 7.75-7.71 (3H, m), 7.54-7.50 (2H, m), 7.12 (2H, d), 4.80-4.73 (IH, m), 4.56-4.49 (IH, m), 3.83-3.77 (IH, m), 3.42-3.35 (2H, m), 3.18-3.11 (lH,m), 2.81-2.71 (2H, m), 2.41-2.27 (4H, m), 1.98-1.91 (2H, m), 1.68-1.59 (2H, m).
Example 200
N-((2R)- 3 - {4-[2-(Aminocarbonyl )-4-chlorophenoxy]piperidin-1 -yl} -2-hydroxypropyl)-1 -oxo-1,2-dihydroisoquinoline-4-carboxamide

Prepared as described in Example 35 following Preparation 33 using 1-oxo-1,2-dihydroisoquinolme-4-carbonyl chloride.
MS (APCI) 499 (M+H)+
'HNMR5 (CD3OD) 8.25 (IH, d), 8.08 (IH, d), 7.78 (IH, d), 7.67 (IH, td), 7.48 (IH, t), 7.47 (IH, s), 7.35 (IH, dd), 7.08 (IH, d), 4.56-4.50 (IH, m), 3.94-3.89 (IH, m), 3.46 (IH, dd), 3.27 (IH, dd), 2.79-2.70 (2H, m), 2.46-2.36 (4H, m), 2.03-1.95 (2H, m), 1.82-1.73 (2H,m).

Example 201
7V-[(2^)-3-(4-{4-Chloro-2-[(methylamino)carbonyl]phenoxy}piperidin-l-vl)-2-hydroxypropyl]-l-oxo-l,2-dmydroisoqumolme-4-carboxamide




• Prepared as described in Example 35 following Preparation 32 using l-oxo-1,2-dihydroisoquinoline-4-carbonyl chloride.
MS(APCI)513(M+Hf
'HNMR 8 (CD3OD) 8.25 (IH, d), 8.09 (IH, d), 7.67 (IH, td), 7.63 (IH, d), 7.48 (IH, s), 7.48 (IH, td), 7.33 (IH, dd), 7.07 (IH, d), 4.59-4.51 (IH, m), 4.01-3.94 (IH, m), 3.46 (IH, dd), 3.28 (IH, dd), 2.91-2.80 (2H, m), 2.83 (3H, s), 2.66-2.54 (4H, m), 2.05-1.94 (2H,m), 1.90-1.79 (2H,m).
Example 202
Methyl 5-chloro-2-{[ 1 -((2#)-2-hydroxy-3- {[(1 -oxo-1,2-dihydroisoquinolin-4-yl)carbonyl]amino}propyl)piperidin-4-yl]oxy}benzoate acetate salt

o

„ NH O

Prepared as described in Example 35 following Preparation 31 using l-oxo-1,2-dihydroisoquinoline-4-carbonyl chloride.
MS (APCI) 513 (M+H)+
*H NMR 8 (CD3OD) 8.25 (IH, dd), 8.09 (IH, d), 7.67 (IH, td), 7.60 (IH, d), 7.49 (IH, s), 7.48 (IH, td), 7.38 (IH, dd), 7.06 (IH, d), 4.59-4.54 (IH, m), 4.05-3.99 (IH, m), 3.76 (3H, s), 3.45 (IH, dd), 3.30 (IH, dd), 3.03-2.92 (2H, m), 2.79-2.61 (4H, m), 2.00-1.86 (4H,m), 1.84(3H,s,OAc).

Example 203
A^((2^)-3-{4-[2-(Aminosulfonyl)-3,4-dichlorophenoxy]piperidin-1 -yl}-2-hydroxypropyl)-1 -oxo-1,2-dihydroisoquinoline-4-carboxamide trifluoroacetate sail

,o

_ NH 0

Prepared as described in Example 35 following Preparation 4U using l-oxo-1,2-dihydroisoquinolme-4-carbonyl chloride.
MS (APCI) 569/571 (M+H)+

]H NMR 6 (CD3OD) 8.26 (IH, d), 8.09 (IH, d), 7.71 (IH, t), 7.62 (IH, d), 7.52 (IH, s), 7.48 (IH, t), 7.18 (IH, d), 5.02 (IH, s), 4.23-4.15 (IH, m), 3.55 (IH, t), 3.46-3.33 (5H, m), 3.16-3.08 (2H, m), 2.26 (2H, t), 2.15-2.00 (2H, m).
Example 204
A^-[(2^)-3-(4-{3,4-DicWoro-2-[(methylammo)siilfonyl]phenoxy}piperidin-l-yl)-2-hydroxypropyl]-l-oxo-l,2-dihydroisoquinoline-4-carboxamide acetate salt
,o

„ NH O

Prepared as described in Example 35 following Preparation 41 using l-oxo-1,2-lihydroisoquinoline-4-carbonyl chloride,
MS (APCI) 583/585 (M+H)+
JHNMR5 (CD3OD) 8.25 (IH, d), 8.08 (IH, d), 7.69 (IH, td), 7.60 (IH, d), 7.49 (IH, s), 7.48 (IH, td), 7.16 (IH, d), 4.73-4.68 (IH, m), 4.05-3.99 (IH, m), 3.44 (IH, dd), 3.30 (IH, dd), 3.15-3.04 (2H, m), 2.78-2.63 (4H, m), 2.52 (3H, s), 2.07-1.93 (4H, m), 1.85 (3H, s, OAc).
Example 2Qj
^-[(ZR)-3-(4-{3,4-DicMoro-2-[(cyclopropylamino)sulfonyl]phenoxy}piperidin-yl)-2-hydroxypropyl]-l-oxo-l52-dihydToisoquinoline-4-carboxamide acetate salt




Prepared as described in Example 35 following Preparation 42 using l-oxo-1,2-dihydroisoquinoline-4-carbonyl chloride.
MS (APO) 609/611 (M+H)+
1E NMR 5 (CD3OD) 8.25 (IH, d), 8.08 (IH, d), 7.68 (IH, t), 7.61 (IH, d), 7.49 [IH, s), 7.47 (IH, t), 7.17 (IH, d), 4.72-4.65 (IH, m), 4.03-3.96 (IH, m), 3.44 (IH, dd), 3.30 (IH, dd), 3.11-2.99 (2H, m), 2.73-2.58 (4H, m), 2.19-2.13 (IH, m), 2.04-1.90 (4H, m), 1.83 (3H, s, OAc), 0.50-0.43 (4H, m).
Example 206
7V-{(2J?)-3-[4-(3-Chloro-4-cyanoplienoxy)piperidin-l-yl]-2-hydroxypropyl}-7-methylsulfonyl)-1 -oxo-1,2-dmydroisoqumoline-4-carboxarnide

,o

_NH O

Prepared as described in Example 189 following Preparation L , -—& , (methylsulfonyl)-l-oxo-1,2-dihydroisoquinoline-4-carboxylic acid.
MS (APCI) 559 (M+H)+
'HNMR5 (GD3OD) 8.78 (IH, d), 8.35 (IH, d), 8.14 (IH, dd), 7.68 (IH, s), 7.60 (IH, d), 7.12 (IH, d), 6.95 (IH, dd), 4.56-4.51 (IH, m), 4.01-3.95 (IH, m), 3.47 (IH, dd), 3.28 (IH, dd), 3.10 (3H, s), 2.94-2.85 (2H, m), 2.64-2.52 (4H, m), 2.04-1.95 (2H, m), 1.86 (3HjS), 1.83-1.74 (2H,m).
Example 207
Ar-{(2^)-3-{4-(4-Chloro-2-methylphenoxy)piperidin-l-yl]-2-hydroxy-2-methylpropylj-e-^ethylsulphony^-l^-indole^-carboxamide
Me
n ^
OH

Prepared as described in Example 189 following Preparation 10 using 6-(methylsulphonyl)-lJ:/-mdole-3-carboxylicacid.
MS (APCT) 520/522/524 (M+H)+
'H NMR 5 (CD3OD) 8.35 (IH, d), 8.19 (IH, s), 8.07 (IH, d), 7.69 (IH, dd), 7.1 1 (IH, d), 7.08 (IH, dd), 6.88 (IH, d), 4.56-4.48 (IH, m), 4.20-4.12 (IH, m), 3.57 (IH, dd), 3.43 (IH, dd), 3.19-3.12 (5H, s), 3.03-2.98 (2H, m), 2.94 (IH, dd), 2.85 (IH, m), 2.18 (3h, s), 2.16-2.08 (2H, m), 2.03-1.94 (2H, m).
Example 208
JV"-{(2^)-3-{4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-b.ydroxypropyl}-6-;methylsulphonyl)-l#-indole-3-carboxamide

o
Prepared as described in Example 189 following Preparation 8 using 6-vmethylsulphonyl)-ljtf-indole-3-carboxylic acid.
MS (APCT) 540/542/544 (M+H)+ .
'H NMR 5 (CD3OD) 8.35 (IH, d), 8.34 (IH, s), 8.06 (IH, d), 7.69 (IH, dd), 7.38 (IH, d), 7.09 (IH, d), 6.87 (IH, dd), 4.50-4.43 (IH, m), 4.12-4.06 (IH, m), 3.57 (IH, dd), 3.41 (IH, dd), 3.13 (3H, s), 3.07-2.99 (2H, m), 2.81-2.68 (4H, m), 2.12-2.04 (2H, m), 1.94-1.82(2H,m).
Example 209
N-{ (2£)-3-[4-(3,4-Dichlorophenoxy)piperidin-1 -yl] -2-hydroxypropyl} -7-fluoro-1 -oxo-1,2-dihydroisoquinoline-4-carboxamide

F
Prepared as described in Example 189 following Preparation 7 using 7-fluoro- 1-oxo- 1 ;2-dihydroisoquinoline-4-carboxylic acid.
MS (APCI) 508/510 (M+H)+
1E NMR 8 (DMSO) 11.73 (IH, s), 8.39-8.26 (2H, m), 7.88 (IH, dd), 7.64 (IH, td), 7.54 (IH, s), 7.49 (IH, d), 7.25 (IH, d), 6.98 (IH, dd), 4.79-4.71 (IH, m), 4.48-4.38 (IH, m), 3.85-3.75 (IH, m), 3.46-3.34 (IH, m), 3.19-3.09 (IH, m), 2.82-2.65 (2H, m), 2.43-2.23 (4H, m), 1.97-1.84 (2H, m), 1.67-1.53 (2H, m).
Example 210
J^-{(ZR)-3-[4-(4-Chloro-2-methylphenoxy)piperidin-l-yl]-2-hydroxypropyl}-7-fluoro-l-oxo-l,2-dihydroisoquinoline-4-carboxamide

Prepared as described in Example 189 following Preparation 10 using 7-fluoro- 1-oxo-1 ,2-dihydroisoquinoline-4-carboxylic acid.
MS (APCI) 488 (M+H)+
JH NMR 6 (DMSO) 8.42-8.28 (2H, m), 7.88 (IH, dd), 7.64 (IH, td), 7.55 (IH, s), 7.20 (IH, d), 7.14 (IH, dd), 6.98 (IH, d), 4.43-4.33 (IH, m), 3.85-3.75 (IH, m), 3.45-3.34 (IH, m), 3.20-3.08 (IH, m), 2.75-2.60 (2H, m), 2.42-2.25 (4H, m), 2.14 (3H, s), 1.94-1.81 (2H,m), 1.70-1. 56 (2H,m).
Example 211
N-{(2R)-3 -[4-(4-CMoro-2-methylphenoxy)piperidin-1 -yl]-2-hydroxypropyl} -6-(methylsulfonyl)-! -oxo-1,2-diliydroisoquinoline-4-carboxamide


o
o=s=o
Prepared as described in Example 189 following Preparation 10 using 6-(methylsulfonyl)-1 -oxo-1,2-dihydroisoquinoline-4-carboxylic acid.
MS (APO) 548 (M+H)+
]H NMR S (DMSO) 11.98 (IH, s), 8.89 (IH, d), 8,44 (IH, d), 8.42 (IH, t), 8.01 (IH, dd), 7.76-7.72 (IH, m), 7.20 (IH, d), 7.14 (IH, dd), 6.98 (IH, d), 4.77 (IH, d), 4.43-4.34 (IH, m), 3.86-3.77 (IH, m), 3.42 (IH, td), 3.28 (3H, s), 3.17 (IH, quintet), 2.77-2.63 (2H, m), 2.42-2.29 (4H, m), 2.14 (3H, s), 1.95-1.84 (2H, m), 1.71-1.58 (2H, m).
Example 212 7^-{(2J?)-3-[4-(2,4-Dichloro-3-methylphenoxy)piperidin-l-yl]-2-hydroxypropyl}-6-
(methylsulfonyl)-! -oxo-1,2-dihydroisoquinoline-4-carboxamide

c^f\^f°^f'^\ QH
Prepared as described in Example 189 following Preparation 13 using 6-(methylsulfonyl)-1 -oxo-1,2-dib.ydroisoquinoline-4-carboxylic acid.
MS (APCI) 581/583 (M+H)+
'H NMR 5 (DMSO) 11.97 (IH, d), 8.89 (IH, d), 8.44 (IH, d), 8.42 (IH, t), 8.01 (IH, dd), 7.76-7.72 (IH, m), 7.35 (IH, d), 7.10 (IH, d), 4.80-4.73 (IH, m), 4.53-4.44 (IH, m), 3.86-3.76 (IH, m), 3.42 (IH, td), 3.28 (3H, s), 3.21-3.12 (IH, m), 2.79-2.65 (2H, m), 2.40 (3H, s), 2.42-2.30 (4H. m), 1.95-1.85 f2H. m\ 1.74-1.61 (2H, m).
Example 213
N-{ (2J?)-3-[4-(3,4-DicMorophenoxy)piperidin-1 -yl]-2-hydroxypropyl}-7-3iethylsulfonyl)-l-oxo-l,2-dihydroisoquinoline-4-carboxamide acetate salt




Prepared as described in Example 189 following Preparation 7 using 7-(rnethylsulfonyl)-1 -oxo-1,2-dihydroisoquinoline-4-carboxylic acid.
MS (APCI) 568/566 (M+H)+
!H NMR 5 (DMSO) 8.70 (IH, s), 8.46 (IH, d), 8.16 (IH, dd), 8.10 (IH, t), 7.70 (IH, s), 7.45 (IH, d), 7.18 (IH, d), 6.94 (IH, dd), 4.39 (IH, septet), 3.82 (IH, quintet), 3.42 (IH, dt), 3.30-3.09 (IH, m), 3.22 (3H, s), 2.82-2.67 (2H, m), 2.45-2.27 (4H, m), 1.99-1.80 (2H, m), 1.89 (3H, s, OAc), 1.72-1.53 (2H, m).
Example 214
JV-{(lR)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-7-(meihylsulfonyl)-1 -oxo-1,2-dihydroisoquinoline-4-carboxamide acetate salt

O' "0
Prepared as described in Example 189 following Preparation 10 using 7-(methylsulfonyl)-1 -oxo-1,2-dihydroisoquinoline-4-carboxylic acid.
MS (APCI) 548/550 (M+H)+
]H NMR 5 (DMSO) 8.68 (IH, d), 8.48 (IH, d), 8.43 (IH, t), 8.20 (IH, dd), 7.76 (IH, s), 7.21 (IH, d), 7.15 (IH, dd), 6.98 (IH, d), 4.84-4.72 (IH, m), 4.46-4.31 (IH, m), 3.88-3.74 (IH, m), 3.49-3.34 (IH, m), 3.28 (3H, s), 3.22-3.08 (IH, m), 2.78-2.60 (2H, m), 2.44-2.24 (4H, m), 2.14 (3H, s), 1.98-1.79 (2H, m), 1.74-1.54 (2H, m).
Example 215
JV-{(2^)-3-[4-(2,4-Dichloro-3-methylphenoxy)piperidin-l-yl]-2-hydroxypropyl}-7-(methylsulfonyl)-1 -oxo-1,2-dihydroisoquinoline-4-carboxamide acetate salt
ci

•Prepared as described in Example 1 89 following Preparation 13 using 7-(metfaylsulfonyl)- 1 -oxo- 1 ,2-dihydroisoquinoline-4-carboxylic acid.
MS (APCI) 582/584 (M+H)+
JH NMR 6 (DMSO) 8.68 (IH, d), 8.47 (IH, d), 8.44 (IH, t), 8.20 (IH, dd), 7.76 (IH, s), 7.35 (IH, d), 7.10 (IH, d), 4.53-4.44 (IH, m), 3.81 (IH, quintet), 3.42 (IH, dt), 3.20-3.09 (IH, m), 2.77-2.65 (2H, m), 2.40 (3H, s), 2.39-2.28 (4H, m), 1.95-1.85 (2H, m), 1.87 (3H, s, OAc), 1.73-1.61 (2H, m).
Example 216
JV-{(2J?)-3-[4-(3J4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-6-(rnethylsulfonyl)- 1 -oxo-1 ,2-dihydroisoquinoline-4-carboxamide

Prepared as described in Example 189 following Preparation 7 using 6-(methylsulfonyl)- 1 -oxo-1 ,2-duiydroisoquinoline-4-carboxylic acid. MS (ESI) 568/570 (M+H)+
Example 217 A^{(2^)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-6-fluoro-l-
oxo- 1 ,2-dihydroisoquinoline-4-carboxamideescribed in Example 189 following Preparation 7 using 6-fluoro-l-oxo-l,2-dihydroisoquinoline-4-carboxylic acid.
MS (APCT) 508/510 (M+H)+
'H NMR 8 (DMSO) 11.70 (IH, d), 8.34 (IH, t), 8.28 (IH, dd), 8.03 (IH, dd), 7.64 (IH, d), 7.49 (IH, d), 7.38 (IH, td), 7,25 (IH, d), 6.98 (IH, dd), 4.80-4.70 (IH, m), 4.44 (IH, septet), 3.87-3.73 (IH, m), 3.45-3.36 (IH, m), 3.14 (IH, quintet), 2.84-2.66 (2H, m), 2.43-2.21 (4H, m)31.99-1.84 (2H, m), 1.69-1.51 (2H, m).
Example 218
JV"-{(2jR)-3-[4-(4-Chloro-2-methylphenoxy)piperidin-l-yl]-2-liydroxypropyl}-6-fluoro-1 -oxo-1,2-dihydroisoquinoline-4-carboxamide

0
F
Prepared as described in Example 189 following Preparation 10 using 6-fluoro-l->xo-1,2-dihydroisoquinoline-4-carboxylic acid. MS (ESI) 488/490 (M+H)+
Example 219
N- {(2JR)-3-[4-(4-Chloro-2-methylphenoxy)pipendm-1 -yi j-2-nydroxypropyl} -2-oxo-4-(trifluoromethyl)-1,2-dihydropyrimidine-5-carboxamide



ci

Prepared as described in Example 35 following Preparation 10 using 2-oxo-4-(trifluoromethyl)-l,2-dihydropyrimidine~5-carbonyl chloride. MS (ESI) 489/491 (M+H)+
Example 220
Ar-{(lR)-3-[4-(2,4-Dichloro-3-methylphenoxy)piperidin-l-yl]-2-hydroxypropyl}-oxo-4-(trifiuoromethyl)-l ,2-dihydropyriinidine-5-carboxainide


3
Prepared as described in Example 35 following Preparation 13 using 2-oxo-4-(trifluoromethyl)- 1 ,2-dihydropyrimidine-5-carbonyl chloride. MS (ESI) 523/525 (M+H)+
Example 221
7vr-((lR)-3-{4-[3,4-Dichloro-2-(methylsulfonyl)phenoxy]piperidiri-l-yl}-2-hydroxypropyl)-l-oxo-l,2-dihydroisoquinoline-4-carboxamide acetate


O
Prepared as described in Example 35 following Preparation 48 using l-oxo-1,2-dihydroisoquinoline-4-carbonyl chloride.
MS (APCT) 568/570 (M+H)+
!H NMR 8 (CD3OD) 8.35 (IH, d), 8.18 (IH, d), 7.78 (IH, t), 7.76 (IH, d), 7.58 (IH, s), 7.57 (IH, t), 7.28 (IH, d), 4.87-4.80 (IH, m), 4.13-4.07 (IH, m), 3.54 (IH, dd), 3.40 (IH, dd), 3.35 (3H, s), 3.16-3.06 (2H, m), 2.85-2.69 (4H, m), 2.16-2.00 (4H, m), 1.94 (3H, s).
Example 222 ?/-{(2JR)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-6-oxo-4-
(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide acetate salt

Prepared as described in Example 35 following Preparation 7 using 6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carbonyl chloride, which was prepared by

hydrolysis with sodium hydroxide followed by treatment with thionyl chloride of the commercially available 6-chloro-4-trifluoromethyl methyl nicotinoate).
MS (APC1) 508/510 (M+H)+
]H NMR8 (DMSO) 8.35 (IH, t), 7.77 (IH, s), 7.49 (IH, d), 7.25 (IH, d), 6.98 (IH, dd), 6.72 (IH, s), 4.43 (IH, septet), 3.71 (IH, quintet), 3.29 (IH, dt), 3.06 (IH, dt), 2,78 -2.66 (2H, m), 2.36-2.24 (4H, m), 1.95-1.86 (2H, m), 1.90 (3H, s), 1.65-1.54 (2H, m).
Example 223
JV-{(lR)-3-[4-(4-Chloro-2-methylphenoxy)piperidin-l-yl]-2-hydroxypropyl}-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxainide acetate salt


cr
ii

Prepared as described in Example 35 following Preparation 10 using 6-oxo-4-(trifluoromethyl)-1,6~dmydropyridine-3 -carbonyl chloride.
MS (APCI) 488/490 (M+H)+
'H NMR 5 (DMSO) 8.35 (IH, t), 7.77 (IH, s), 7.20 (IH, s), 7.15 (IH, dd), 6.98 (IH, d), 6.73 (IH, s), 4.42 - 4.34 (IH, m), 3.72 (IH, quintet), 3.33 - 3.27 (IH, m), 3.06 (IH, dt), 2.71 - 2.61 (2H, m), 2.37 - 2.25 (4H, m), 2.14 (3H, s), 1.93-1.84 (2H, m), 1.91 (3H,s), 1.69-1.58 (2H,m).
Example 224 ^-{(2JR)-3-[4-(2)4-Dichloro-3-methylphenoxy)piperidin-l-yl]-2-hydroxypropyl}-6-
oxo-4-(trifluoromethyl)-1,6-dihydropyridrne-3-carboxamide
ci


O CF3
N
Prepared as described in Example 35 following Preparation 13 using 6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carbonyl chloride. MS (APCI) 522/524 (M+H)+

!H NMR 5 (DMSO) 8.32 (1H, t), 7.79 (1H, s), 7.35 (1H, d), 7.10 (1H, d), 6.69 (1H, s), 4.49 (1H, septet), 3.72 (1H, quintet), 3.30 (1H, dt), 3.07 (1H, dt), 2.74 - 2.64 (2H5 m), 2.40 (3H, s), 2.37 - 2.25 (4H, m), 1.94 -1.84 (2H, m), 1.89 (3H, s), 1.71 -1.61 (2H, m).
Example 225
7V-{(ZR)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-2-(2-oxoquinoxalin-1 (lH)-yI)acetamide




^sf) k^N

Prepared as described in Example 1 following Preparation 7 using (2-oxoquinoxalin-l-(2/:/)-yl)acetic acid.
MS (APCI) 505/507 (M+H)+
'HNMR6 (CDC13) 8.37 (1H, s), 7.92 (1H, d), 7.61 (1H, t), 7.49 (1H, d), 7.40 (1H, t), 7.32 (1H, d), 6.99 (1H, d), 6.74 (1H, dd), 6.72 (1H, bd s), 4.91 (2H, m), 4.36-4.26 (1H, m), 3.86-3.76 (1H, m), 3.52-3.42 (1H, m), 3.26-3.18 (1H, m), 2.88-2.80 (1H, m), 2.63-2.53 (2H, m), 2.40-2.26 (3H, m), 2.06-1.92 (2H, m), 1.87-1.73 (2H, m).
Example 226 7^-{(l/?)-3-[4-(3J4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-3-oxo-3J4-
dihydroquinoxaline-1 (2#)-carboxamide
o -.

N 0
Prepared as described in Example 35 following Preparation 7 using 3-oxo-3,4-dihydroquinoxaline-l(2/0-carbonyl chloride. . MS (APCI) 505/507 (M+H)+
!H NMR 8 (CDC13) 8.26 (1H, s), 7.43 (1H, d), 7.31 (1H, d), 7.19-7.09 (1H, m), 6.99 (1H, d), 6.94 (1H, d), 6.75 (1H, dd), 5.72 (1H, t), 4.44 (2H, s), 4.30-4.22 (1H, m), 3.88-3.81 (1H, m), 3.58-3.52 (1H, m), 3.17-3.11 (1H, m), 2.93-2.85 (1H, m), 2.67-2.61 (1H, m), 2.57-2.53 (1H, m), 2.44-2.40 (1H, m), 2.36-2.29 (2H, m), 2.00-1.90 (2H, m), 1.80-1.70 (2H,m).
Example 227
//-{(2JR)-3-[4-(4-Chloro-2-methylphenoxy)piperidin-l-yl]-2-hydroxypropyl}-3-(trifluoromethyl)-l#-pyrazole-4-carboxamide




CF3
Prepared as described in Example 1 following Preparation 10 using 3-(trifluoromethyl)- 17?-pyrazole-4-carboxylic acid.
MS (APCI) 460/462 (M+H)+
'HNMR6 (DMSO) 8.41 (IH, s), 8.15 (IH, t), 7.20 (IH, d), 7.14 (IH, dd), 6.98 (IH, d), 4.42-4.36 (IH, m), 3.77-3.71 (IH, m), 3.39-3.33 (IH, m), 3.10-3.04 (IH, m), 2.73-2.63 (2H, m), 2.36-2.26 (4H, m), 2.14 (3H, s), 1.92-1.82 (2H, m), 1.70-1.60 (2H, m).
Example 228
JV-{(2JR)-3-[4-(2,4-dichloro-3-metliylphenoxy)piperidin-l-yl]-2-hydroxypropyl}-3-(trifluoromethyl)-l#-pyrazole-4-carboxarnide

ci

cr
O CF3
Prepared as described in Example 1 following Preparation 13 using using 3-(trifluoromethyl)-llf-pyrazole-4-carboxylic acid.
MS (APCI) 495/497 (M+H)+
!HNMR8 (DMSO) 8.41 (IH, s), 8.15 (IH, t), 7.34 (IH, d), 7.09 (IH, dd), 4.50-4.42 (IH, m), 3.77-3.71 (IH, m), 3.37-3.33 (IH, m), 3.10-3.04 (IH, m), 2.74-2.64 (2H, m), 2.39 (3H, s), 2.36-2.26 (4H, m), 1.96-1.86 (2H, m), 1.69-1.62 (2H, m).
Example 229
N- {(2R)-3-{ 4-(3,4-Dichlorophenoxy)piperidin-1 -yl} -2-hydroxypropyl}-1 -oxo-1,2-dihydro-2-methylisoquinoline-4-carboxamide




Prepared as described in Example 1 following Preparation 7 using 2-methyl-l-oxo-1 ,2-dihydroisoquinoline-4-carboxylic acid.
MS (APCI) 504/506/508 (M+H)+
]H NMR 8 (CDC13) 8.47 (IH, d), 8.14 (IH, d)5 7.70 (IH, t), 7.61 (IH, s), 7.53 (IH, t), 7.33 (IH, d), 7.00 (IH, d), 6.76 (IH, dd), 6.58 (IH, bdt), 4.42-4.32 (IH, m), 4.06-3.96 (IH, m), 3.80-3.70 (IH, m), 3.63 (3H, s), 3.44-3.34 (IH, m), 3.02-2.92 (IH, m), 2.78-2.68 (2H, m), 2.59- 2.45 (3H, m), 2.16-2.00 (2H, m), 1.96-1.80 (2H, m).
Example 230
TV- { (2R)-3-{ 4-(3,4-Dichlorophenoxy)piperidin- 1 -yl]-2-hydroxypropyl} -2-oxo- 1 ,2-dihydro- 1 -methyl quinoline-4-carboxamide

Prepared as described in Example 1 following Preparation 7 using l-methyl-2-oxo-l,2-dihydroquinoline-4-carboxylic acid.
MS (APCI) m/z 504/506/508 (M+H)+
!HNMR 5 (CDC13) 7.97 (IH, d), 7.62 (IH, t), 7.40 (IH, d), 7.32 (IH, d), 7.28 (IH, t), 7.00 (IH, d), 6.83 (IH, s), 6.76 (IH, dd), 6.72 (IH, t), 4.39-4.31 (IH, m), 4.04-3.94 (IH m), 3.78-3.70 (IH, m), 3.72 (3H, s), 3.47-3.37 (IH, m), 3.00-2.90 (IH, m), 2.75-2.67 (2H, m), 2.56-2.42 (3H, m), 2.10-1.94 (2H, m), 1.94-1.78 (2H, m).
Example 231
N- {(lR)-3-[4-(3,4-dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl} -8-fluoro-1 -oxo-l,2-dihydroisoquinoline-4-carboxamide

Prepared as described in Example 35 following Preparation 7 using 8-fluoro-l-oxo-1 ,2-dihydroisoquiaoline-4-carbonyl chlori.de. MS (APCI) 508/5 10 (M+H)+
Example 232
N- {(lR)-3-[4-(4-chloro-2-methylphenoxy)piperidin-1 -yl]-2-hydroxvproDvl 1-8-fluoro-1 -oxo- l,2-dihydroisoquinoline-4-carboxamide



Prepared as described in Example 35 following Preparation 10 using 8-fluoro-l-oxo-l,2-dihydroisoquinoline-4-carbonyl chloride. MS (APCT) 488/490 (M+H)+
Example 233
JV-{(2/?)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-2-oxo-4-(trifluoromethyl)-132-dihydropyrirnidirje-5-carboxarnide

-
Prepared as described in Example 35 following Preparation 7 using 2-oxo-4-(trifluoromethyl)- 1 ,2-dihydropyrimidine-5-carbonyl chloride. MS (EPCI) 509/51 1 (M+H)+
Example 234
J/Vr-{(2Jl?)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-4-methyl-2-oxo- 1 ,2-dihydropyrimidine-5-carboxarrjide

O
Prepared as described in Example 35 following Preparation 7 using 4-methyl-2-oxo-1 ,2-dmydropyrimidine-5-carbonyl chloride. MS (EPCI) 455/457 (M+H)+
bxampie 235
Pharmacological Analysis: Calcium flux [Ca2+]j assay Human eosinopbils
Human eosinophils were isolated from EDTA anticoagulated peripheral blood as previously described (Hansel et al., J. Immunol Methods, 1991,145.105-110). The cells were resuspended (5xl06 ml"1) and loaded with 5jj,M FLUO-3/AM + Pluronic F127 2.2u-l/ml (Molecular Probes) in low potassium solution (LKS; NaCl 118mM, MgSO4 O.SmM, glucose 5.5mM, Na2CO3 8.5mM, KC1 5mM, HEPES 20mM, CaCl2 l.SmM, ESA 0.1%, pH 7.4) for one hour at room temperature. After loading, cells were centrifuged at 200g for 5min and resuspended in LKS at 2.5x106 ml"1. The cells were then transferred to 96 well FLIPr plates (Poly-D-Lysine plates from Becton Dickinson pre-incubated with 5jiM fibronectin for twoh) at 25}il/well. The plate was centrifuged at 200g for 5min and the cells were washed twice with LKS (200ul; room temperature).
A compound of the Examples was pre-dissolved in DMSO. and added to a final concentration of 0.1%(v/v) DMSO. Assays were initiated by the addition of an ASO concentration of eotaxin and the transient increase in fluo-3 fluorescence (lEx = 490nm and Ifim = 520nm) monitored using a FLIPR (Fluorometric Imaging Plate Reader, Molecular Devices, Sunnyvale, U.S.A.).
Compounds of the Examples were found to be antagonists if the increase in fluorescence induced by eotaxin (a selective CCR3 agonist) was inhibited in a concentration dependent manner. The concentration of antagonist required to inhibit the fluorescence by 50% can be used to determine the ICso for the antagonist at the CCR3 receptor.
Example 236 Human eosinophil chemotaxis
Human eosinophils were isolated from EDTA anticoagulated peripheral blood as previously described (Hansel et al., J. Immunol. Methods, 1991,145.105-110). The cells were resuspended at lOxlO6 ml"1 in RPMI containing 200 lU/ml penicillin, 200 jig/ml streptomycin sulfate and supplemented with 10% HIFCS, at room temperature.
Eosinophils (700 ul) were pre-incubated for 15 mins at 37° C with 7 fil of either vehicle or compound (lOOx required final concentration in 10% DMSO). The chemotaxis
plate (ChemoTx, 3umpore, Neuroprobe) was loaded by adding 28jil of a concentration of eotaxin 0.1 to lOOnM (a selective CCR3 agonist over this concentration range) containing a concentration of a compound according to the Examples or solvent to the lower-wells of the chemotaxis plate. The filter was then placed over the wells and 25 ul of eosinophil suspension were added to the top of the filter. The plate was incubated for 1 hr at 37° C in a humidified incubator with a 95% air/5% CO2 atmosphere to allow chemotaxis.
The medium, containing cells that had not migrated, was carefully aspirated from above the filter and discarded. The filter was washed once with phosphate buffered saline (PBS) containing 5 mM EDTA to remove any adherent cells. Cells that had migrated through the filter were pelleted by centrifugation (SOOxg for 5 mins at room temperature) and the filter removed and the supernatant transferred to each well of a 96-well plate (Costar). The pelleted cells were lysed by the addition of 28 jj.1 of PBS containing 0.5% Triton xlOO followed by two cycles of freeze/thawing. The cell lysate was then added to the supernatant. The number of eosinophils migrating was quantified according to the method of Strath et al.5 J. Immunol. Methods, 1985, 83, 209 by measuring eosinophil peroxidase activity in the supernatant.
Example 237 Guinea-pig isolated trachea
(See for example, Harrison, R.W.S., Carswell, H. & Young, J.M. (1984) European J. Pharmacol, 106,405-409.)
Male albino Dunkin-Hartley guinea-pigs (250g) were killed by cervical dislocation and the whole trachea removed. After clearing the adherent connective tissue, the trachea was cut into six ring segments each three cartilage bands wide and then suspended in 20ml organ baths containing Krebs-Henseleit solution of the following composition (mM): NaCl 117.6, NaH2P04 0.9, NaHCO3 25.0, MgSO4 1.2, KC1 5.4, CaCl2 2.6 and glucose 11.1. The buffer was maintained at 37°C and gassed with 5% CO2 in oxygen. Indomethacin (2.8p.M) was added to the Krebs solution to prevent development of smooth muscle tone due to the synthesis of cyclo-oxygenase products. The tracheal rings were suspended between two parallel tungsten wire hooks, one attached to an Ormed beam isometric force transducer and the other to a stationary support in the organ bath. Changes in isometric force were recorded on 2-channel Sekonic flat bed chart recorders. Experimental protocols
At the beginning of each experiment a force of Ig was applied to the tissues and this was reinstated over a 60 minute equilibration period until a steady resting tone was achieved. Subsequently, a cumulative histamine concentration effect (E/[A]) curve was constructed at 0.5 logic unit increments, in each tissue. The tissues were then washed and approximately 30 minutes later, test compound or vehicle (20% DMSO) was added.
i-oliowing an incubation period of 60 minutes a second E/[A] curve was performed to bistamine.
Contraction responses were recorded as a percentage of the first curve maximum. Data analysis
Experimental E/[A] curve data were analysed for the purposes of estimating the potencies (p[Aso] values) of bistamine in the absence and presence of the test compound. Affinity (pA2) values of test compounds were subsequently calculated using the following equation:
log(r-l) = log[Bj + pA2
where r = [A]50 in presence of test compound/[A]5o in absence of antagonist and [B] is the concentration of test compound. Compounds of the Examples were found to be HI antagonists.
Example 238 .
Histamine HI receptor binding activity of compounds of the invention was assessed by competition displacement of InM [3H]-pyrilamine (Amersham, Bucks, Product code TRK 608, specific activity 30Ci/mmol) to 2ug membranes prepared from recombinant CHO-Kl cells expressing the human HI receptor (Euroscreen SA, Brussels, Belgium, product code ES-390-M) in assay buffer (50mM Tris pH 7.4 containing 2mM MgCl2l 250mM sucrose and lOOraM NaCl) for 1 hour at room temperature.

CLAIMS compound of:

XisCH2,0,S(0)2orNR10;
Y is a bond, CH2, NR35, CH2NH, CH2NHC(O), CH(OH), CH(NHC(0)R33),
CH(NHS(0)2R34), CH20 or CH2S;
Z is C(O), or when Y is a bond Z can also be S(O)2;
R! is optionally substituted aryl, optionally substituted heterocyclyl or C4_6
cycloalkyl fused to a benzene ring;
R4 is hydrogen, Ci-e alkyl (optionally substituted by €34 cycloalkyl) or €3.6
cycloalkyl;
R2, R3, R5, R6, R7 and R8 are, independently, hydrogen, CH> alkyl or C3^
cycloalkyl;
m and n are, independently, 0 or 1;
R9 is optionally substituted aryl or optionally substituted heterocyclyl; R10, R32 and R35 are, independently, hydrogen, C\^ alkyl or C3.6 cycloalkyl; R33 and R34 are Ci-6 alkyl or C3^ cycloalkyl;
wherein the foregoing aryl and heterocyclyl moieties are, where possible, optionally substituted by: halogen, cyano, nitro, hydroxy, oxo, S(O)kR12, OC(0)NR13R14, NRI5R16, NR17C(0)R18, NR19C(O)NR20R21, S(O)2NR22R23, NR24S(0)2R25, C(O)NR26R27, C(0)R28, CO2R29,NR30CO2R31, Cw alkyl (itself optionally mono-substituted by NHC(O)phenyl), Ci-6 haloalkyl, Ci-6 alkoxy(Ci.6)alkyl, C^ alkoxy, Ci^ haloalkoxy, Ci^ alkoxy(Ci-6)alkoxy, C\^ alkyltbio, C2^ alkenyl, C2^ alkynyl, Cj-io cycloalkyl, methylenedioxy, difluoromethylenedioxy, phenyl, phenyl(Ci. 4)alkyl, phenoxy, phenylthio, phenyl(Ci-4)alkoxy, morphoHnyl, heteroaryl, heteroaryl(CM)alkyl, heteroaryloxy or heteroaryl(Ci-4)alkoxy; wherein any of the immediately foregoing phenyl and heteroaryl moieties are optionally substituted with halogen, hydroxy, nitro, S(0)r(CM alkyl), S(0)2NH2, S(O)2NH(CM alkyl), S(0)2N(CM alkyl)2, cyano, CM alkyl, CM alkoxy, C(O)NH2, C(O)NH(CM alkyl),

C02H, C02(CM alkyl), NHC(O)(CM alkyl), NHS(O)2(CM alkyl), C(O)(CM alkyl; CF3 or OCF3;
k and r are, independently, 0,1 or 2;
R'3, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R26, R27, R29 and R30 are, independently, hydrogen, C\^ alkyl (optionally substituted by halogen, hydroxy or C3.io cycloalkyl), CH2(C2-6 alkenyl), C3-$ cycloalkyl, phenyl (itself optionally substituted by halogen, hydroxy,, nitro, NH2, NH(CM alkyl), NH(CM alkyl)2, •S(0)2(CM alkyl), S(O)3NH2, S(O)2NH(CM alkyl), S(O)2N(CM alkyl)2, cyano, CM alkyl, CM alkoxy, C(O)NH2, C(O)NH(CM alkyl), C(O)N(CM alkyl)2, CO2H, C02(CM alkyl), NHC(0)(CM alkyl), NHS(O)2(CM alkyl), C(O)(CM alkyl), CF3 or OCF3) or heterocyclyl (itself optionally substituted by halogen, hydroxy, nitro, NH2, NH(CM alkyl), N(CM alkyl)2> S(O)2(CM alkyl), S(O)2NH2, S(O)2NH(CM alkyl), S(0)2N(CM alkyl)2, cyano, CM alkyl, CM alkoxy, C(O)NH2, C(O)NH(CM alkyl), C(O)N(CM alkyl)2, C02H, C02(CM alkyl), NHC(O)(CM alkyl), NHS(0)2(CM alkyl), C(O)(Ci-4 alkyl), CF3 or OCF3);
alternatively NRI3RH, NR15R16, NR20R21, NR^R23, NR26R27, may, independently, form a 4-7 membered heterocyclic ring selected from the group: azetidine (itself optionally substituted by hydroxy or CM alkyl), pyrrolidine, piperidine, azepme, 1,4-morpholine or 1,4-piperazine, the latter optionally substituted by CM alkyl on the distal nitrogen;
R12, R25, R28 and R31 are, independently, d.fi alkyl (optionally substituted by halogen, hydroxy or C3.i0 cycloalkyl), CH2(C2.6 alkenyl), phenyl (itself optionally substituted by halogen, hydroxy, nitro, NH2, NH(CW alkyl), N(CM alkyl)2 (and these alkyl groups may join to form a ring as described for R13 and R14 above), S(0)2(Ci-4 alkyl), S(O)2NH2, S(O)2NH(CM alkyl), S(O)2N(Cj-4 alkyl)2 (and these alkyl groups may join to form a ring as described for R13 and R14 above), cyano, C\. 4 alkyl, CM alkoxy, C(O)NH2, C(O)NH(CM alkyl), C(0)N(CM alkyl)2 (and these alkyl groups may join to form a ring as described for R13 and R14 above), COaH, C02(CM alkyl), NHC(0)(CM alkyl), NHS(O)2(Ci_4 alkyl), C(O)(CM alkyl), CF3 or OCF3) or heterocycly! (itself optionally substituted by halogen, hydroxy, nitro, NH2, NH(CM alkyl), N(CM alkyl)2 (and these alkyl groups may join to form a ring as described for R13 and R14 above)., S(O)2(CM alkyl), S(0)2NH2, S(O)2NH(CM alkyl), S(O)2N(Ci-4 alkyl)2 (and these alkyl groups may join to form a ring as

described for R13 andR14 above), cyano, CM alkyl, CM alkoxy, C(O)NH2,
C(0)NH(CM alkyl), C(O)N(CM alkyl)2 (and these alkyl groups may join to form a
ring as described for R13 and R14 above), CO2H, CO2(CM alkyl), NHC(O)(CM
alkyl), NHS(0)2(CM alkyl), C(O)(CM alkyl), CF3 or OCF3);
provided that when X is CH2 and m and n are both 0 then Y is not NR35;
or an N-oxide thereof; or a phannaceutically acceptable salt, solvate or solvate of a
salt thereof.
A compound as claimed in claim 1 wherein: X is O; Y is a bond, CH2, NR35, CH2NH, CH(OH), CH(NHC(0)R33), CH(NHS(O)2R34) or CH2O; Z is C(O), or when Y is a bond Z can also be S(0)2; R1 is optionally substituted phenyl; R4 is hydrogen or C\.6 alkyl; R2, R3, R5, R6, R7 and R8 are, when present, all hydrogen; m and n are, independently, 0 or 1; R9 is optionally substituted aryl or optionally substituted heterocyclyl; R32 and R35 are, independently, hydrogen or C\^ alkyl; R33 and R34 are Ci^ alkyl; wherein the foregoing phenyl, aryl and heterocyclyl moieties are, where possible, optionally substituted by: halogen, cyano, hydroxy, oxo, S(0)2R12, NR15R16, NR17C(0)R18, S(0)2NR22R23, NR24S(O)2R25, C(O)NR26R27, CO2R29, Ci-e alkyl (itself optionally mono-substituted by NHC(O)phenyl), CF3, phenyl or heteroaryl; wherein any of the immediately foregoing phenyl and heteroaryl moieties are optionally substituted with halogen, CM alkyl, CM alkoxy or CF3; R15, R16, R17, R18, R22, R23, R24, R26, R27 and R29 are, independently, hydrogen, Ci.6 alkyl (optionally substituted by hydroxy) or C3.e cycloalkyl; alternatively NR22R23 may form an azetidine ring (itself optionally substituted by hydroxy or CM alkyl); R12 and R25 are, independently, C^ alkyl or phenyl; or a phannaceutically acceptable salt thereof.
A compound as claimed in claim 1 or 2 wherein R1 is phenyl optionally substituted by halogen, cyano, CM alkyl, CM alkoxy, S(0)2(CM alkyl), S(O)2NH2, .. S(O)2NH(CM alkyl), S(O)2NH(C3-6 cycloalkyl), C(O)2(CM alkyl), C(O)NH(CM alkyl) or C(0)NH2.
A compound as claimed in claim 1 or 3 wherein X is O.

5. A compound as claimed in claim 1, 2, 3 or 4 wherein Y is a bond.
6. A compound as claimed in claim 1, 2, 3,4 or 5 wherein Z is C(O).
7. A compound as claimed in any of the preceding claims wherein m and n are both 0.
8. A compound as claimed in any of the preceding claims wherein R2, R3, R4, R5, R6,
•R7 and R8 are, when present, all hydrogen.
9. A compound as claimed in any of the preceding claims wherein R9 is optionally
substituted heterocyclyl; wherein the heterocyclyl group is: thienyl, pyrrolyl,
thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, 1,2,5-oxadiazolyl, pyridinyl,
1,6-dihydropyridinyl, pyrimidinyl, indolyl, indazolyl., 2,3-dihydro-lH-indazolyl, an
imidazopyridinyl, 2,1,3-benzothiadiazolyl, quinoxalinyl, quinolinyl, 1,2-
dihydroquinohiiyl, 1,4-dihydroquinoUne, isoquinohiiyl, 1,2-dihydroisoquinolinyl,
cinnolinyl, 3,4-dihydrophthalazinyl, 2,3-dihydro-4H-l,4-benzoxazinyl, 3,4-
dihydro-2H-l,4-benzoxazinyl, l,3-dihydro-2H-isoindolyl, pyrazolotriazinyl,
pyrazolopyrimidinyl, imidazobenzothiazolyl, midazopyrimidinyl, or 2,1,3-
benzoxadiazolyl, 1,3-benzothiazole, 2,3-dihydro-l,3-benzothiazole, 4,5,6,7-
tetrahydroindazole or 2,3-dihydro-lH-benzimidazole; wherein the heterocyclyl is
unsubstituted or substituted by one or more of: oxo (where possible), halogen,
alkyl, CF3, CM alkoxy, S(O)2(CM alkyl), S(O)2NH2, S(O)2NH(CM alkyl),
alkyl)2 or OCF3.
10. A process for preparing a compound as claimed in claim 1, the process comprising reacting a compound of formula (IT):
wherein X, R], R2, R3, R4, R5, R6, R7, R8, R32, m and n are as defined above, with: (i) when Y is a bond, CH2, NR35, CH2NH, CH2NHC(O), CH(OH), CH(NHCOR33), CH(NHSO2R341, ClkO or CHoS. Z is CfOl T?35 is

hydrogen and, R33 and R34 are as defined above, a compound of formula (ffla):
L1—-CO—Y—R9 (Ilia)
wherein R is as defined above and L1 is a leaving group in the presence of a base, optionally in the presence of a coupling agent; (ii) when Y is NH and Z is C(O), a compound of formula (fflb):
wherein R9 is as defined above; or,
(iii) when Y is a bond and Z is S(O)2, a compound of formula (Hie):
U S(0)2 R9 (Illc)
wherein R9 is as defined above and L1 is a leaving group hi the presence of a base.
11. A pharmaceutical composition comprising a compound of formula (I), or a
phannaceutically acceptable salt thereof, or solvate thereof, or a solvate of a salt
thereof, as claimed in claim 1, and a pharmaceutically acceptable adjuvant, diluent
or carrier therefor.
12. A compound of the formula (I), or a pharmaceutically acceptable salt, solvate or
solvate of a salt thereof, as claimed in claim 1, for use hi therapy.
13. A compound of formula (I), or a pharmaceutically acceptable salt, solvate or
solvate of a salt thereof, as claimed in claim 1, in the manufacture of a medicament
for use in therapy.
14. A method of treating a chemokine mediated disease state in a mammal suffering
from, or at risk of, said disease, which comprises administering to a mammal in
need of such treatment a therapeutically effective amount of a compound of
formula (T), or a pharmaceutically acceptable salt, solvate or solvate of a salt
thereof, as claimed in claim 1.
15. A process for preparing 4-(3,4-dichlorophenoxy)piperidine comprising the steps of

a. reacting 4-hydroxypiperidine with a suitable base in a suitable solvent at room
temperature; and,
b. heating the mixture so produced and l,2-dichloro-4-fluorobenzene at a
temperature in the range 50-90°C, or at reflux of the solvent used.

Documents:

2041-DELNP-2004-Abstract-(12-11-2007).pdf

2041-delnp-2004-abstract.pdf

2041-DELNP-2004-Claims-(12-11-2007).pdf

2041-delnp-2004-claims.pdf

2041-DELNP-2004-Correspondence-Others-(12-11-2007).pdf

2041-delnp-2004-correspondence-others.pdf

2041-DELNP-2004-Description (Complete)-(12-11-2007).pdf

2041-delnp-2004-description (complete).pdf

2041-DELNP-2004-Form-1-(12-11-2007).pdf

2041-delnp-2004-form-1.pdf

2041-delnp-2004-form-18.pdf

2041-DELNP-2004-Form-2-(12-11-2007).pdf

2041-delnp-2004-form-2.pdf

2041-DELNP-2004-Form-3-(12-11-2007).pdf

2041-delnp-2004-form-3.pdf

2041-delnp-2004-form-5.pdf

2041-DELNP-2004-GPA-(12-11-2007).pdf

2041-delnp-2004-gpa.pdf

2041-delnp-2004-pct-409.pdf

2041-delnp-2004-pct-notificatian.pdf

2041-delnp-2004-pct-search report.pdf

2041-DELNP-2004-Petition-137-(12-11-2007).pdf

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Patent Number 219482
Indian Patent Application Number 2041/DELNP/2004
PG Journal Number 26/2008
Publication Date 27-Jun-2008
Grant Date 07-May-2008
Date of Filing 15-Jul-2004
Name of Patentee ASTRAZENECA AB
Applicant Address S-151 85 SODERTALJE, SWEDEN.
Inventors:
# Inventor's Name Inventor's Address
1 MARK PURDIE
2 BRIAN SPRINGTHORPE
3 MARK FURBER
4 LILIAN ALCARAZ
PCT International Classification Number C07D 211/52
PCT International Application Number PCT/SE03/00258
PCT International Filing date 2003-02-17
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 0200465-3 2002-02-18 Sweden
2 0202673-0 2002-09-09 Sweden