| Title of Invention | "AN ENANTIOMERICALLY PURE AMINOPYRIDINE COMPOUND OF FORMULA (I) " |
|---|---|
| Abstract | An enantiomerically pure compound of formula 1 wherein: Y is N or CR12; R1 is selected from hydrogen, halogen, C6-12 aryl, 5-12 membered heteroaryl, C3-12 cycloalkyl, 3- 12 membered heteroalicyclic, -O(CR6R7)nR4, -C(O)R4, -C(O)OR4, -CN, -NO2, -S(O)mR4, - SO2NR4R5, -C(O)NR4R5, -NR4C(O)R5, -C(=NR6)NR4R5, C1-8 alkyl, C2-8 alkenyl, and C2-8 alkynyl; and each hydrogen in R1 is optionally substituted by one or more R3 groups; R2 is hydrogen. |
| Full Text | The present invention relates to an enantiomerically pure compound of formula 1. Field of the Invention The invention relates generally to novel chemical compounds and methods. More particularly, the invention provides enantiomerically pure aminoheteroaryl compounds, particularly aminopyridines and aminopyrazines, having protein tyrosine kinase activity, and methods of synthesizing and using such compounds. Preferred compounds are c-Met inhibitors useful for the treatment of abnormal cell growth, such as cancers. Background The hepatocyle growth factor (HGF), receptor (o-MET or HGFR) receptor tyrosine kinase (RTK) has been shown in many human cancers to be involved in oncogenesis, tumor progression with enhanced cell motility and invasion, as well as metastasis (see, e.g., Ma, P.C., Maulik, G., Christensen, J. & Salgia, R. (2003b). Cancer Metastasis Rev, 22, 309-25; Maulik. G., Shrikhande. A., Kijima, T., Ma, P.C.. Morrison, P.T. & Salgia, R. (2002b). Cytokine Growth Factor Rev, 13, 41-59). c-MET (HGFR) can be activated through overexpression or mutations in various human cancers Including small cell lung cancer (SCLC) (Ma, P.C., Kijima, T.. Maulik, G., Fox. E.A., Sattler, M., Griffin, J.D., Johnson, B.E. & Salgia, R. (2003a). Cancer Res, 63, 6272-6281). c-MET is a receptor tyrosine kinase that is encoded by the Mel proto-oncogene and transduces the biological effects of hepatocyte growth factor (HGF), which is also referred to as scatter factor (SF). Jiang et al., Crit. Rev. Oncol. Hematol. 29. 209-24B (1999). c-MET and HGF are expressed in numerous tissues, although their expression is normally confined predominantly to cells of epithelial and mesenchymal origin, respectively. c-MET and HGF are required for norma! mammalian development and have been shown to be important in ceil migration, cell proliferation and survival, morphogenic differentiation, and organization of 3-dimensional tubular structures (e.g., renal tubular cells, gland formation, etc.). In addition to its effects on epithelial cells, HGF/SF has been reported to be an angiogenic factor, and c-MET signaling in endothelial cells can induce many of the cellular responses necessary for angiogenesis (proliferation, motility, invasion). The c-MET receptor has been shown to be expressed in a number of human cancers, c-Met and its ligand, HGF, have also been shown to be co-expressed at elevated levels In a variety of human cancers (particularly sarcomas). However, because the receptor and ligand are usually expressed by different cell types, c-MET signaling is mosl commonly regulated by tumor-strcma (tumor-host) interactions. Furthermore, c-MET gene amplification, mutation, and rearrangement have been observed in a subset of human cancers. Families with germline mutations that activate c-MET kinase are prone to multiple kidney tumors as well as tumors in other tissues. Numerous studies have correlated the expression of c-MET and/or HGF7SF with the state of disease progression of different types of cancer (Including lung, colon, breast, prostate, liver, pancreas, brain, kidney, ovaries, stomach, skin, and bone cancers). Furthermore, the overexpression of c-MET or HGF have been shown to correlate with poor prognosis and disease outcome in a number of major human cancers including lung, liver, gastric, and breast c-MET has also been directly implicated in cancers without a successful treatment regimen such as pancreatic cancer, glioma, and hepatocellular carcinoma. Examples of c-MET (HQFR) inhibitors, their synthesis and use, can be found in U.S. Patent Application Serial No. 10/786,610, entitled "Aminoheteroaryl Compounds as Protein Kinase Inhibitors', filed February 26, 2004, and corresponding international application PCT/US2004/005495 of the same title, filed February 26, 2004, the disclosures of which are incorporated herein by reference in their entireties. It would be desirable to have novel c-MET (HGFR) inhibitors and methods of using such inhibitors for the treatment of abnormal cell growth, such as cancer. Summary In one embodiment, the invention provides an enantiomericaHy pure compound of formula 1 Cl NHj R1 F wherein: Y is N or CR1S; R1 is selected from hydrogen, halogen, C*.u aryl, 5-12 membered heteroaryl, Cj.12 cyctoalkyl. 3-12 membered heteroalicyclic, -O(CR*R7)nR4, -C(O)rf. -C(O)OR\ -CN. -NOj, •S(O)mR4. -SOzNtfR*. R2 is hydrogen, halogen, d-w alkyl, QM? alkenyl. CMJ alkynyl, Cs-ia cycloalkyl, Cm aryl, 3-12 membered heteroalicyclic. 5-12 membered heteroaryl, -S(O)mR*. -SOzNR*R5, -S(O)2OR4, -NOj. -NR"R5. -(CR*R7)nOR4, -CN, -C(O)R4. each R3 Is Independently halogen, CM2 alkyl, C*,2 aJkenyi, C^2 alkynyl, C^^ cycloalkyl, €«.« aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -S(O)mR*, -SOzNR^, 4, -N02l -NR-'R8, -(CRPF^OR*, -CN, -CKOJR4. -OCtOR4. -OCCR'R^nR4, -NR*C(O)RS, -(CR*R7y3R4, -{CR*Rr)((C(0)NR4R5, -(CR*R\NCR4R5, -C{=NR8)NR4R5, 6, -NR*S(O)pR* or -CtOJNR^R8, each hydrogen in R3 is optionally substituted by fl*. and R3 groups on adjacent atoms may combine to form a C«.u aryl, 5-12 membered heteroaryl. C* ,z cycloalkyl or 3-12 membered heleroallcydic group; each R4, R5. ft6 and R7 is independently hydrogen, halogen, C,.,± alkyl, Cj.it alkenyl, Cj.,2 alkynyl, C^t cycloalkyl, Ce.12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl; or any two of R4, R5, R4 and R7 bound to the same nitrogen atom may, together with the nitrogen to which they are bound, be combined to form a 3 to 12 membered heteroalicyclic or 5-12 membered heteroaryl group optionally containing 1 to 3 additional heteroaloms selected from N, O, and S; or any two of R4, R9, R6 and R7 bound to the same carbon atom may be combined to form a cydoatkyl, C«.1? aryl, 3-12 membered heteroalicyclic or 5-12 membered heteroaryl group; and each hydrogen in R4, R!, R6 and R7 is optionally substituted by R8; each R8 is independently halogen, Cv« alkyl, CM? alkenyt, CMZ alkynyl, C>12 cycloalkyl, C$.12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -NHj, -CN, -OH, -O-C,.,2 alkyl, -O-(CH2)nC3.12 cycloalkyl, -C-(CHz)nCi.i2 aryl, -O-(CHj)n(3-12 membered hetaroallcydic) or •O-(CHa)45-i2 membered heteroaryl); and each hydrogen in R( is optionally substituted by R11; each R* and R10 is independently hydrogen, halogen, C,.i* aikyt, C^ cycloalkyl, Ce.l2 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -S(O)mR4. -SOjNR4R5, -SJOkOR4, -N0a, -NR4R5, -(CR6RT)nOR4. -CN, -C(0)R4, -OC(0)R*. -NR*C(O)R5, . -(CR*RT)nC(O)OR4, -{CRsR7)nNCR4R5, -NR'CCONR'R8, -NR4S(0)PRS or -C(0)NR4R8; R9 Or R10 may combine with a ring atom of A or a substituent of A to form a Ca.,2 cycloalkyl, 3-12 membered heteroalicyclic, CB-U aryl or 5-12 membered heteroaryl ring fused to A; and each hydrogen in R* and R10 is optionally substituted by R3; each R11 is independently halogen, CM: alkyl, C,.,2 alkoxy, C>iZ cycloalkyl, Ce.12 aryl, 3-12 membered heteroalcyclic, 5-12 membered heteroaryl, -O-Cvu alkyl, -O-(CH?)*C3.12 cydoatkyl, -O-(CH2).CG.i2 aryl, -0-(CH2)n(3-12 membered heteroaflcydlc), -0- each R13 is independently halogen, C,.t2 alkyl, C2.ia alkenyt, C2.12 alkynyl, €3.12 cycloalkyl, Cs.i2 aryl, 3-12 membered heteroallcyclic, 5-12 membered heteroaryl, -S(0)mFT*, -SO2NR4RS, -S(O)zOR4, -NO2, -NR^R*. -{CR8R7)nOR4, -CN, -CCOJR4, -OC(O)R4, -OCCR^R4, -NR*C(0)RS, -(CR*RT)nC(O)OR4, -(CR6R7)nOR4, -(CR6Hr)nqO)NR4Rs1 -{CR6R7)nNCR4Rs, -C(cNR6)NR4R5, -NR*C(O)NRSR*. -NtfSpJpR5, -CCOJNR'R8, -(CRV^S-^ membered heteroalicyclic), -(CR"R?)n(C3.,8 cycloalkyl), -{CR"R7)n(CV12 aryl), -(CR8R7)(1(5-12 membered heteroaryl), -(CR*R7)«C(O)NR4RS, of -(CR*R7)nC(O)R4, R13 groups on adjacent atoms may combine to form a C«. 12 aryl, 5-12 membered heteroaryl, C^z cycloalkyl or 3-12 membered heteroalicyclic group, and each hydrogen In R13 is optionally substituted by R3; each m is independently 0,1 or 2; each n is independently 0,1,2,3 or 4; each p is independently 1 or 2; or a pharmaceutically acceptable salt, hydrate or solvate thereof. In a particular aspect of this embodiment, R2 is hydrogen. In another particular aspect of this embodiment, Y Is N. In another particular aspect of this embodiment, Y is N and R2 is hydrogen. In another particular aspect of this embodiment, Y is CR12. In another particular aspect of this embodiment, Y is CR12 and R12 Is H. In another particular aspect of this embodiment, and in combination with any other particular aspect not inconsistent, R1 is a furan, thiopene, pyrrole, pyrrotine, pynroiidine, dkaolane, oxazole, thlazole, Imldazole, imidazoline, imldazotojine, pyrazole, pyrazoline, pyrazolidlne, isoxazole, isothiazole, oxadiazole, Iriazote. thiadiazote, pyran, pyridine, piperidine, dioxane. morpholine, dithiane, thiomorpholine, pyridazine, pyrimidine, pyrazine, piperazine, triazine, trithiane or phenyl group, and each hydrogen in R1 is optionally substituted by one or more R3 groups. In another particular aspect of this embodiment, and in combination with any other particular aspect not inconsistent, R1 is a fused ring heieroaryl group, and each hydrogen in R1 is optionally substituted by one or more R3 groups. In another particular aspect of this embodiment and in combination with any other particular aspect not inconsistent, R' is hydrogen. In another particular aspect of this embodiment, and in combination with any other particular aspect not inconsistent, R1 is a halogen. In another embodiment, the invention provides an enanttomerlcally pure compound of formula la. Y is N or CH; R1 is a furan, thiopene, pyrrole, pyrroline. pyrroHdine, dioxolane, oxazole, thiazole, imidazole, imidazoline, imldazoJidine, pyrazole, pyrazoline, pyrazolidine, isoxazole, isothiazole, oxadiazole, triazole, ihladiazote, pyran, pyridine, piperidine. dioxane, morpholine, dithiane, thiomorpholine, pyridazine, pyiimidine, pyrazine, piperazine, triazine, trithiane, azitidine or phenyl group; and each hydrogen in R1 is optionally substituted by R3; each R3 is independently halogen, CM2 alkyl, Cz-« alkenyl, CM* alkynyi, Cj.12 cydoalkyl, Cg.12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -SfO^R4, -SOZNR4R*. -S(O)2OR4, -NOa, -NR4R5, -(CtfR^OR4, -CN. -C(O)R4, -OC(O)R4, -O(CR°R7)nR4, -NtfCfOrf, -(Cfl*R7)nC(0)OR41 -(CR8R7)nOR4, -(CRaR7)»C(O)NR*Rs, -(CReRr)BNCR4Rs, -C(*NR6)NR4RS, -NR*C(O)NR*R6, -NR4S(O)PRS or -C(O)NR*RS, each hydrogen in R3 is optionally substituted by R8, and R3 groups on adjacent atoms may combine to form a Cg.12 aryl, 5-12 membered heteroaryl, Cj. 12 cydoalkyl or 3-12 membered heteroalicydic group; each R4, R5, fle and R7 Is independently hydrogen, halogen, C, 12 alkyl, €2.12 alkenyl, CM: alkynyi, Cs.12 cydoalkyl, Cs.i2 aryl, 3-12 membered heteroalicydic, 5-12 membered heteroaryl; or any two of R4, Rs, R* and R7 bound to the same nitrogen atom may, together with the nitrogen to which they are bound, be combined to form a 3 to 12 membered heteroalicydic or 5-12 membered heteroaryl group optionally containing 1 to 3 additional heteroatorns selected from N, O, and S; or any two of R4, R5. R° and R7 bound to the same carbon atom may be combined to form a 03.12 cycloalkyi. Cm aryl, 3-12 membered heteroalicyciic or 5-12 membered heleroaryl group; and each hydrogen in R4, Rs, R6 and R7 is optionally substituted by R8; each R0 is independently halogen, Ci.i2 alkyl, C2.ia alkenyl, C2.,2 alkynyl, Cg.,? cycloalkyt, Ce-12 aryl, 3-12 membered heteroalicyciic, 5-12 membered heteroaryl, -NHa, -CN, -OH, -O-C,.,2 alkyl, -O-tCHjJuCwj cycloalkyt, -O^CH^Ce-w aiyl. -O-{CH2)n(3-12 membered heteroalicyciic) or -0-(CHj)fl(5-12 membered heteroaryl); and each hydrogen in R8 is optionally substituted by R11; each R9 and R10 Is independently hydrogen, halogen, C,.,2 alkyl, C^z cycloalkyi, C*.12 aryl, 3-12 membered heteroalicyciic, 5-12 membered heteroaryl, -S(O)mR4, -SO2NR4R5, -S(O)2OR4, -N02, -NR4RS, -{CR6RT)nOR4, -CN, -C(O)R4, -OCIOJR4, -NR4C(O)R*, -(CR6R7)nC(O)OR4, •(CR*R7)nNCR4Rs, *NR4C(O)NRiRe1 •NR4S(0)PRS or -C(0)NR4R5; R8 or R10 may combine with a ring atom o1 A or a substktuent of A to form a GHZ cycloalkyi, 3-12 membered heteroalicyciic, C&tz aryl or 5-12 membered heteroaryl ring fused to A; and each hydrogen in R9 and R10 is optionally substituted by R3; • each R11 is independently halogen, Ci.i2 alkyl, CM2 alkoxy, C^ cycloalkyi, Cfr12 aryl, 3-12 membered heteroalicyciic, 5-12 membered heteroaryl, -O-C,.,2 alkyl, -0-(CH2)«C3-tz cycloalkyt, -O-(CH2)nCfrl2 aryl, -O-{CH2)n(3-12 membered heteroalicyciic), -O-{CHj)n(5-12 membered heteroaryl) or -ON, and each hydrogen in R11 is optionally substituted by halogen, -OH, -CN, -C,.12 alkyl which may be partially or fully halogenated, -0-Ci.i2 alkyl which may be partially or fully halogenated, •CO, -SO or -SO2; each R13 is independently halogen, C^2 alkyl, CMS alkenyl, Ca.12 alkynyl, C3.t2 cycloalkyi, C«.iZ aryl, 3-12 membered heteroalicyciic, 5-12 membered heteroaryl, -S(O)mR4, -SO2NR4RS, -StO^OR4. -NOz, -NR4R5. -(CrfR^OR4. -CN. -C(0)R4, OC(O)R4. -0(CR6R7)nR4, -NR4C(O)R5, -(CR*R7)nC(0)OR*. -(CR'R'^OR4, -(CR6R7)nC(O)NR4Rs, -(CR'R^nNCr^R*. -C^NR'jNRV, •NR4C(0)NR5R8. -NR4S(0)PRS, -C(O)NR4RS, -(CR8R7)n(3-12 membered heteroalicyciic), -(CR6RT)B(C3.,a cydoalkyl), -(CR^R^Ce.^ aryl), -(CR6R7)rt(5-i2 membered heteroaryl). -(CR8R7)nC(0}NR4R5. or -(CRaR7)nC{0)R4, R13 groups on adjacent atoms may combine to form a C* t2 aryl, 5-12 membered heteroaryl, C^ cycloalkyi or 3-12 membered heteroalicyciic group, and each hydrogen in R13 is optionally substituted by R3; each m is independently 0,1 or 2; each n is independently 0,1,2,3 or 4; each p is independently 1 or 2; or a pharmaceutically acceptable salt, hydrate or solvate thereof. In another embodiment, the invention provides an enantiomericajly pure compound selected from the group consisting oi 5-Bromo-3-[(R)-1-{2,6-dichloro-3-fkJoro-phenyl)-ethoxy]. pyrazin-2.ylamine; 5-iodo-3-[(R)1 - 3-[1(R)-(2.6-dlohloro-3-fluoro-phenyl)-elhoxy>pyridin-2-y1amlne; 4-{5-Amino-6-[(R)-1-(2,6-dichk>ro- 3-fluoro-phenyl)-ethoxy]-pyrazin-2-y phenyl)-ethoxy]-pvra2in-2-yl)-phenyO-piperaziri-1 -yl-methanone; 4-{4-{5-Amino-«-((R)-1 -{2,6- dichloro-3.fluoro-ph8nyl)-«thoxyh)yraz!n-2-yl}-benzov))-piperazine-1-carDoxylic acid tert-butyl ester; 3-[(1 R)-1 -(2,6- yl}phenyi)methanol; 4-{6-amlno-5-[(1 R}-1-(2,6-dichloro-3-fluorophenyl)ethoxy]pyridki-3-yl}-N-(3-(dimethylamino)propy1]-N-methyibenzamide; tert-butyl 4-(4-{6-amino-5-[(1 R)-1 -phenyl}-emoxyH>-(1 -piperidin-4-yl-1 H-pyrazol-4-yl)-pyridin-2-ylamiTie; or a pharmaceutically acceptable salt, solvate or hydrate thereof. In another embodiment, the invention provides a pharmaceutical composition comprising any of the compounds of the invention and a pharmaceutically acceptable carrier. Examples of such compositions are described below, Preferred compounds of the invention include those having c-MET inhibitory activity as defined by any one or more of ICjo, Kt, or percent inhibition (%l). One skilled in the art can readily determine if a compound has such activity by carrying out the appropriate assay, and descriptions of such assays are shown in the Examples section herein. In one embodiment, particularly preferred compounds have a c-MET Ki of less than 5 uM or less than 2 uM, or less than 1 uM, or less than 500 nM or less than 200 nM or less than 100 nM. In another embodiment, particularly preferred compounds have a c-MET inhibition at 1 MM of at least 10% or at least 20% or at least 30% or at least 40% or at least 50% or at least 60% or at least 70% or at least 80% or at least 90%. Methods for measuring c-MET/HGFR activity are described in the Examples herein. in another embodiment, the invention provides a method of treating abnormal oeR growth in a mammal, including a human, the method comprising administering to the mammal any of the pharmaceutical compositions of the invention. In a specific embodiment of any of the inventive methods described herein, the abnormal cell growth is cancer, including, but not limited to, lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the. anal region, stomach cancer, colon cancer, breast cancer, uterine cancer, carcinoma o1 the fallopian tubes, carcinoma of the endomatrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, lymphocyte lymphornas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS tymphoma, spina axis tumors, brain stem glioma, pituitary adenoma, or a combination of one or more of the foregoing cancers. In another embodiment of said method, said abnormal cell growth Is a benign proHferative disease, Including, but not limited to, psoriasis, benign prostatic hypertrophy or restinosis. In another embodiment, the invention provides a method of treating an HGFR mediated disorder in a mammal, including a human, the method comprising administering to the mammal any of the pharmaceutical compositions of the invention. In further specific embodiments of any of the inventive methods described herein, the method further comprises administering to the mammal an amount of one or more substances selected from anti-tumor agents, anti-angiogenesis agents, signal transduction inhibitors, and antiprdiferative agents, which amounts are together effective in treating said abnormal ceil growth. Such substances include those disclosed in PCT Publication Nos. WO 00/38715. wo 00/38716, WO 00/38717, WO 00/38718, WO 00/38719, WO 00/38730. WO 00/38665, WO 00/37107 and WO XJ/38786, the disclosures of which are incorporated herein by reference In their entireties. Examples of anti-tumor agents Include mitotic inhibitors, for example vinca alkaloid ierivatives such as vinblastine vinorelbine, vindescine and vincristine; coichlnes allochochine, lallchondrine, N-benzoyitrimelhyl-methyl ether colchicinic acid, dolastatin 10, maystanslne, rfiizoxine, axanea such as taxol (padrtaxel), docetaxel (Taxotere), 2*-N^3-(dimethylamino)propyl]glutaramate [taxol derivative), thiocholchicine, trityl cystetne, teniposide, methotrexate, azathioprine, fiuorouridl, cytocine arabinoslde, 2'2'-difluorodeoxycytidine (gemcitablne), adriamycin and mitamycin. Alkylating agents, for example cis-platin, carboplatin oxiplatin, iproplatin, Ethyl ester of N-acetyl-DL-sarcosyM.-leucine (Asaley or Asalex), 1,4-cyctohexadiene-1l4-dicarbamic add, 2,5 -t>is(1-a2irdinyi)-3,6-dioxo-, diethyl ester (diaziquone), 1,4-bis(methanesutfonyloxy)biitane (bisulfan or teucosulfan) chtorozotodn, ctomesone, cyanomorpholinodoxorubldn, cyctodisone, dianhydroglactitol, ttuorodopan, hepsulfam, mitomycin C, hycantheonemitomycin C, mitozolamide, 1-(2-chloroethyl)-4-(3-criloropropyl)-piperazlne dhydrochtoride, piperazinedione, pipobroman, porfiromydn, spirohydantoin mustard, teroxirone, tetraplatin, thiotepa, triethylenemelamine, uracil nitrogen mustard, bis(3-mesyloxypropyl)amlne hydrochloride, mitomycin, nitrosoureas agents such as cydohexyl-chloroethyinitrosourea, melhylcydohexyl-chloroethylnitrosourea 1 -(2-chloroethyl)-3-(2,6-dioxo-3-piperidyl)-1 -nitroso-urea, bis{2-chloroethyl)nitrosourea, procaroazine, dacarbazlne, nitrogen mustard-related compounds such as mechtoroethamine, cydophosphamide, ifosamide, melphalan, chlorambucil, estramustine sodium phosphate, strptozoin, and temozoiamide, DNA antt-metaboliles. for example 5-fiuorouradl, cytosine arabinoside, hydroxyurea, 2-[(3hydroxy-2-pyrinodinyl)methylenehhydrazinecarbothioamide, deoxyfluorouridine, 5-hydroxy-2-fomvtpyriding thiosemicarbazone, aipha-2'-daoxy-6-thioguanosJne, aphidicolin glycinate, 5-azadeoxycytldine, beta-thioguanine deoxyriboside, cydocytidine, guanazole, inosine glycodiaktehyde, macbedn II, pyrazoDmidazole. cladrtoine, perttostatin, thioguanine, mercaptopurine, bleomycin, 2-chlOfodeoxyadenosine, inhibitors of thymidylate synthase such as rartitrexed and pemetrexed disodium, dofarabine, floxuridine and fludarabine. DrWRNA antimetabolites, for example, L-alanosine, 5-azacytidJne, aavidn, aminopterin and derivatives thereof such as N-[2-chloro-5-fJ(2, 4-diamino-5-methyl-6-quinazoliny1)methyl]amino]benzoy1]-L-aspartic add, N-[4-[((2, 4-diamino-5^Biyl"6-qulnazolinyl)methyl]amino]benzoyl]-L-aspartic acid, N -[2-chloro-4-{((2, 4-diaminopteridlnyl)methyllaminoIbBnzoyl]-L-a8partic add, soluble Baker's antifol, dlchkxoallyl lawsone, brequinai, ftoraf, dihydro-5-azacytldlne, methotrexate, N-(phosphonoacetyl)-L-aspartic add tetfasodlum sad, pyrazoturan, tritnetrexate, plteamycin, actinomytin D, cryptophydn, and analogs such as cryp(ophycin-52 or. for example, one of the preferred anti-metabolites disclosed in European Patent Application No. 239362 such as N-(5-lM-(3,4-cllhy Examples of MMP inhibitors include AG-3340. RO 32-3555, RS 13-0830. and the following compounds: 3-({4-(4-fluoro-phenoxy)-benzenesulfonyl]-( 1 -hydroxycarbarnovt-cyclopentyl)-anriino]-propionic acid; 3-exo-3-l4-(4-fluoro-phenoxy)-oenzene3ulfonylamino]-8-oxa-bicycloI3.2.1]octane-3-carboxyllc acid hydroxyamide; (2R, 3R) l-[4-(2-chloro*4-fluoro-benzyloxy)-benzenesulfonyl]-3-hydroxy-3-methy)-piperidin«-2-carboxvlic acid hydroxyamide; 4-[4-{4-fluoro-phenoxy)* benzenesurfonytamino]-tetrahydro-pyran-4-carboxyiic acid hydroxyamide; 3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1 -hydroxycarbamoyl-cyclobutyl)-aminol-propionjc add; 4-[4-{4-chloro-phenoxy)-benzenesurfonylamino}-tetrahydro-pyran-4-carboxylic acid hydroxyamide; 3-[4-(4-chloro-phenoxy)-benzenesultonvlamino]-1etrahydro-pyran-3-carboxylic acid hydroxyamide; (2R, 3R) 1-(4-(4-fluoro-2-methyl-benzyloxy)-Denzenesulfonyll.3-hydroxy-3-methyl-piperidine-2-carboxylic add hydroxyamide; 3-[[4-(4-flijoro-phenoxy)-benzenesulfc>ny]]-(1-hyaYox^ ackl; 3-{{4-(4-fluoro-pheno)cy)-benzene3Ul1onyl)-(4-hydroxyc»rbamoyl-tetrahydro-pyran-4-y1)-amino]- propionic acid; 3-exo-3-(4-(4-chtora-phenoxy)-benzBnesulfonylamif»o]-8-oxa-bicyclo[3.2.1 ]octane-3- carboxylic acid hydroxyamide; 3-endo-3-[4-(4-fluwo-phenoxy)-benzenesulfonytamino]-8-oxa- bicydo{3.2.1]octane-3-carboxyilc add hydroxyamide; 3-(4-(4-fluoro-phenoxy)- benzenesuNonylaminoHetrahydro-furan-3-carboxylic acid hydroxyamide; and pharmaceuticatly acceptable salts, solvates and hydrates thereof. Examples of signal transduction inhibitors include agents that can inhibit EGFR (epidermal growth factor receptor) responses, such as EGFR antibodies, EGP antibodies, and molecules that are EGFR inhibitors; VEGF (vascular endothelial growth factor) inhibitors; and ert>82 receptor inhibitors, such as organic molecules or antibodies that bind to the ert>B2 receptor, for example, HERCEPTIN™ (Genentech, Inc. of South San Francisco, California, USA). EGFR inhibitors are described In, for example in WO 95/19970 (published July 27, 1995), WO 98/14451 (published April 9,1998), WO 98/02434 (published January 22.1998). and United States Patent 5,747,498 (issued May 5,1996). EGFR-inhibiting agents include, but are not limited to, the monoclonal antibodies C225 and antl-EGFR 22Mab (ImClone Systems Incorporated of New York, New York, USA), the compounds ZD-1839 (AstraZeneca), BIBX-1382 (Boehringer Ingelheim), MDX-447 (Medarex Inc. of Annandale, New Jersey, USA), and OLX-103 (Merck & Co. of Whitehouse Station, New Jersey. USA), VRCTC-310 (Ventech Research) and EGF fusion toxin (Seragen Inc. of Hopkinton, Massachusetts). VEGF inhibitors, for example SU-5416 and SU-6666 (Sugen Inc. of South San Francisco, California, USA), can also be combined or co-administered with the composition. VEGF inhibitors are described in, for example in WO 99/24440 (published May 20, 1999), PCT International Application PCT/1B99/00797 (filed May 3,1999), in WO 95/21613 (published August 17,1995), WO 99/61422 (published December 2, 1999), United States Patent 5,834,504 (issued November 10, 1998), WO 98/50356 (published November 12,1998), United States Patent 5,883,113 {issued March 16,1999), United States Patent 5,886.020 (issued March 23, 1999). United States Patent 5.792,783 (issued August 11, 1998). WO 99/10349 (published March 4, 1999), WO 97/32856 (published September 12,1997), WO 97/22596 (published June 26,1997), WO 98/54093 (published December 3,1998), WO 98/02438 (published January 22,1998), WO 99/16755 (published April 8, 1999), and WO 98/02437 (published January 22,1998), all of which are herein incorporated by reference in their entirety. Other examples of some specific VEGF Inhibitors are IM862 (Cytran Inc. of Kirkland, Washington, USA); anti-VEGF monoclonal antibody bevacizumab (Genentech, Inc. of South San Francisco, California); and angiozyme, a synthetic ribozyme from Rlbozyme (Boulder, Colorado) and Chiron (Emeryville. California). EfbB2 receptor inhibitors, such as GW-282974 (Glaxo Welcome pic), and the monoclonal antibodies AR-209 (Aronex Pharmaceuticals Inc. of The Woodlands, Texas, USA) and 2B-1 (Chiron), may be administered in combination with the composition. Such erbB2 inhibitors include those described in WO 98/02434 (published January 22,1998), WO 99/35146 (published July 15. 1999), WO 99/35132 (published July 15, 1999), WO 98/02437 (published January 22, 1998), WO 97/13760 (published April 17t 1997), WO 95/19970 (published July 27,1995), United States Patent 5,587,458 (issued December 24, 1996), and United States Patent 5,877,305 (issued March 2, 1999), each of which is herein Incorporated by reference in its entirety. ErbB2 receptor inhibitors useful in the present invention are also described in United States Provisional Application No. 60/117,341, filed January 27. 1999, and in United States Provisional Application No. 60/117,346, filed January 27,1999, both o1 which are herein incorporated by reference in their entirety. Other antiproliferative agents that may be used include inhibitors of the enzyme famesyl protein transferees and inhibitors of the receptor tyrosine kinase PDGFr, including the compounds disclosed and claimed in the following United States patent applications: 09/221946 (filed December 28, 1998); 09/454058 (filed December 2, 1999); 09/501163 (filed February 9, 2000); 09/539930 (filed March 31, 2000); Op/202796 (filed May 22. 1997); 09/384339 (filed August 26, 1999); and 09/383755 (filed August 26, 1999); and the compounds disclosed and clainwi in the following United States provisional patent applications: 60/168207 (filed November 30, 1999); 60/170119 (filed December 10, 1999); 60/177718 (filed January 21, 2000); 60/168217 (filed November 30,1999), and 60/200834 (filed May 1,2000). Each of the foregoing patent applications and provisional patent applications is herein incorporated by reference In their entirety. Compositions of the invention can also be used with other agents useful in treating abnormal eel growth or cancer, including, but not limited to, agents capable of enhancing antitumor immune responses, such as CTLA4 (cytotoxic lymphodte antigen 4) antibodies, and other agents capable of blocking CTLA4; and anti-proliferative agents such as other farnesyl protein transferase inhibitors. Specific CTLA4 antibodies that can be used in the present invention include those described in United States Provisional Application 60/113,647 (filed December 23, 1998) which is herein incorporated by reference in Its entirety. Definitions Unless otherwise stated, the following terms used in the specification and claims have the meanings discussed below. Variables defined in this section, such as R, X, n and the like, are for reference within this section only, and are not meant to have the save meaning as may be used outside of this definitions section. Further, many of the groups defined herein can be optionally substituted. The listing in this definitions section of typical substituents is exemplary and is not intended to limit the substituents defined elsewhere within this specification and claims. "Alkyl" refers to a saturated aliphatic hydrocarbon radical including straight chain and branched chain groups of 1 to 20 caibon atoms, preferably 1 to 12 carbon atoms, more preferably 1 to 8 caibon atoms, or 1 to 6 carbon atoms, or 1 to 4 carbon atoms. "Lower aikyl" refers specifically to an alky) group with 1 to 4 carbon atoms. Examples of alkyl groups include methyl, ethyl, propyl, 2-propyl, n-butyl, tec-butyl, tert-butyl, pentyl, and the tike. Atkyi may be substituted or unsubstituted. Typical substituent groups include cycloalkyl, aryl. heteroaryl, heteroaHcydic, hydroxy, alkoxy, aryloxy, mercapto. alkvlthio, arylthio, cyano, halo, caibonyt, thiocarbonyl, O-carbamyl, N-carbamyi, 0-thtocarbamyl, N-thiocarbamyl, C-amido, N-amido, C-carboxy, O-carboxy, nltro, silyl, amino and -NR*Ry, where R* and Ry are independently selected from the group consisting of hydrogen, alkyl, cydoalkyt, aryl, carbonyt, aoetyl, sulfonyl, tritluoromethanesulfonyl and, combined, a five- or six-member heteroallcyclic ring. "CydoalkyT refers to a 3 to 8 member all-carbon monocyclic ring, an all-carbon 5-member/6-member or 6-member/6-member fused bicydic ring, or a mullicyclic fused ring (a "fused" ring system means that each ring in the system shares an adjacent pair of carbon atoms with each other ring in the system) group wherein one or more of the rings may contain one or more double bonds but none of the rings has a completely conjugated pi-electron system. Examples, without limitation, of cycloalkyl groups are cyclopropane, cyclobutane, cyclopentane, cydopenlene, cyclohexane, cydohexadiene, adamantane, cydoheptane, cycloheptatriene, and the like. A cydoalkyi group may be substituted or unsubstituted. Typical substituent groups include atkyl, aryl, heteroaryl. heleroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkyltbio, arylthio, cyano, halo, carbonyl, thiocarbonyi, C-carboxy, O-carboxy, O-carbamyl, N-carbamyl, C-amldo, N-amido, nitro, amino and -NR'R', witti R* and Ry as defined above. Illustrative examples of cycloalkyl are derived from, but not limited to, the following: (Figure Remove) "Alkenyl" refers to an alkyl group, as defined herein, consisting of at least two carbon atoms and at least one carbon-carbon double bond. Representative examples Include, but are not limited to. ethenyl, 1-propenyl, 2-propenyl, 1>, 2-> or 3-butenyl. and the like. 'Alkynyf refers to an alkyl group, as defined herein, consisting of at least two carbon atoms and at least one carbon-carbon triple bond. Representative examples include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl, and the like, "Aryl' refers to an all-carbon monocydlc or fused-ring polycyclic groups of 6 to 12 carbon atoms having a completely conjugated pi-electron system. Examples, without limitation, of aryl groups are phenyl, naphthalenyl and anthracenyl. The aryl group may be substituted or unsubstltuted. Typical substituents include halo, trihaiomethyl, alkyl, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, nitro, carbonyl, thiocarbonyi, C-carboxy, O-carboxy, 0-carbamyl, N-carbamyt, O-lhiocarbamyt, N-thiocarbamyl, C-amido, N-amido, sulfinyi, suHonyl, amino and -NR*Ry, with R" and Ry as defined above. "Heteroaryt* refers to a monocyclic or fused ring group of 5 to 12 ring atoms containing one, two, three or four ring heteroatoms selected from N, 0, and S, the remaining ring atoms being C, and, in addition, having a completely conjugated pi-electron system. Examples, without limitation, of unsubstituted heteroaryl groups are pyrrole, turan, thiophene, imidazole, oxazote, thlazole, pyrazole, pyridine, pyrtmidlne. quinollne. teoquinoline, purine, tetrazde, triazine, and carbazole. The heteroaryl group may be substituted or unsubstltuted. Typical substituents include akyl, cycloalkyl, halo, trihaiomethyl, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, nitro, carbonyl, thiocarbonyi, sulfonamido, C-carboxy, O-carboxy, sulfinyl, suifonyl, O-carbamyl, N-carbamyl, O-thkwarbamyt, N-thiocarbamyl, C-amido, N-amWo, amino and -NR"RY with ff and RY as defined above. A pharmaceutteally acceptable heteroaryl is one that is sufficiently stable to be attached to a compound of the Invention, formulated into a pharmaceutical composition and subsequently administere limited 3,4-dihydro-2H-pyran 5,6-dihydro-2H-pyran 2H-pyran (3,4-dihydro-2H-pyranyl) (5,6-dihydro-2H-pyranyl) (2H-pyranyl) 1,2,3,4-tetrahydropyridine 1,2,5,6-tetrahydropyridine (1,2,3,4-tetrahydropyridinyl) (1,2,5,6-tetrahydropyridinyl) The heterocycle group is optionally substituted with one or two substituents Independently selected from halo, lower alkyl, lower alkyl substituted with carboxy, ester hydroxy, or mono or dlalkylamino. 'Hydroxy" refers to an -OH group. "APkoxy" refers to both an -O-(alkyl) or an -O-(unsubstituted cyctoalkyl) group. Representative examples include, but are not limited to. methoxy, ethoxy. propoxy, butoxy, eyclopropytoxy, cyclobutytoxy. cyclopenlyloxy, cyclohexyloxy, and the like. "Haloalkoxy1 refers to an -O-(haloalKyl) group. Representative examples include, but are not limited to, trifluoromethoxy, tribromomelhoxy, and the like. "Arytoxy* refers to an -0-aryl or an -0-heteroary! group, as defined herein. Representative examples include, but are not limited to, phenoxy, pyridinyloxy, furanyloxy, trrienytoxy, pyrimidinyloxy, pyrazlnyloxy, and the like, and derivatives thereof. 'Mercapto* refers to an -SH group. •Alkylthlo" refers to an -S-(alkyl) or an -S-(unsubstituted cyctoalkyl) group. Representative examples include, but are not limited to, methylthlo. ethyltrtio. propylthio, butylthio. cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, and the like. 'Arytthio* refers to an -S-aryl or an -S-heteroaryl group, as defined herein. Representative examples include, but are not limited to, phenyltnio, pyridinylthio, furanyltnio, thtenylthio, pyrimkttnylthio, and the like and derivatives thereof. *AcyT or "carbonyt" refers to a -C{O)R' group, where R" is selected from the group consisting of hydrogen, tower alkyl, trihalomethyl, unsubstituted cydoalkyl, aryl optionally substituted with one or more, preferably one, two, or three substituents selected from the group consisting of lower alkyl, trihalomethyl, lower alkoxy, halo and -NR'R" groups, heteroaryl (bonded through a ring carbon) optionally substituted with one or more, preferably one, two. or three substttutents selected from the group consisting of lower alkyl, trihaloalkyl, lower alkoxy, halo and -NR*Ry groups and hetaroalicyclic (bonded through a ring carbon) optionally substituted with one or more, preferably one, two, or three substituents selected from the group consisting of lower alkyl, trihaloalkyl, lower alkoxy, halo and -NlW groups. Representative acyl groups include, but are not limited to, acetyl, trifluoroacetyl, benzoyl, and the like 'Aldehyde' refers to an acyl group In which R" is hydrogen. Thioacyl" or "thiocarbonyl* refers to a -C(S)R" group, with R* as defined above. A •thiocarbonyT group refers to a -C(S)R" group, with R' as defined above. A "C-carboxy" group refers to a -C(0)OR" group, with R" as defined above. An 'O-carboxy* group refers to a -OC(O)R" group, with R' as defined above. •Ester' refers to a -C(0)OH" group with R" as defined herein except that R* cannot be hydrogen. "Acetyl* group refers to a -C(O)CH3 group. "Halo" group refers to fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine. Trihalomethyl* group refers to a methyl group having three halo substituents, such as a trifluoromethyl group. "Cyano* refers to a -CaN group. A 'sulfinyT group refers to a -S(0)R" group wherein, In addition to being as defined above, R" may also be a hydroxy group. A •sutfbnyt" group refers to a -S(0)2R" group wherein, in addition to being as defined above, R* may also be a hydroxy group. •S-sulfonamido" refers to a -S(0)JNRIRV group, with R* and Rr as defined above. "N-sulfonamldo1 refers to a -NR"S(O)zRy group, with R" and Ry as defined above. 'O-carbamyl" group refers to a -OC(O)NRXR* group with R' and R' as defined above. •N-carbamyT refers to an RyOC(O)NR*- group, with R* and Ry as defined above. "CMhiocarbamyr refers to a -OC(S)NRXR' group with R" and Ry as defined above. •N-thtocartoarnyT refers to a R"OC(S)NR*- group, with R' and R* as defined above. "Amino* raters to an -NR*Ry group, wherein R" and Ry are both hydrogen. •C-amido' refers to a -C(0)NR*Ry group with R* and Ry as defined above. "N-amido" refers to a R"C(0)NRy- group, with R* and Rv as defined above. •NitrO* refers to a -NOS group. "Haloafeyl" means an alkyl, preferably lower alkyl, that is substituted with one or more same or different halo atoms, e.g., -CH,CI. -CF3. -CH2CF3, -CH8ca3, and the like. "HydroxyalkyT means an alkyl, preferably lower alkyl, that is substituted with one, two, or three hydroxy groups; e.g., hydroxymethyl, 1 or 2-hydroxyethyl, 1,2-, 1.3-. or 2,3-dihydroxypropyl, and the like. •Aratkyi" means alkyl, preferably lower alky), that is substituted with an aryt group as defined above; e.g., -CHjphenyl, *(CH2hPhenyl, • •Dialkylamino" means a radical -NRR where each R is independently an alky! or unsubstituted cycloalkyl group; dlmethylamino, diethylarruno, (t-methyiethyl)-ethylamino, cyolohexylmethylamino, cyclopentyimethyiambio. and the like. "Optional* or 'optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, "heterocyde group optionally substituted with an alkyl group* means that the alkyl may but need not be present, and the description includes situations where the heterocycle group is substituted with an alkyl group and situations where the heterocycle group is not substituted with the alkyl group. A 'pharmaceutical composition" refers to a mixture of one or more of the compounds described herein, or physiologically/pharmaceuticatly acceptable salts, solvates. hydrates or prodrugs thereof, with other chemical components, such as physiologfcally/pharmaceutlcaKy acceptable carriers and exclpients. The purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism. As used herein, a •physiologically/pharmaceulically acceptable carrier* refers to a carrier or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound. A 'pharmaceutically acceptable exdpient' refers to an inert substance added to a pharmaceutical composition to further facilitate administration of a compound. Examples, without limitation, of exciptents include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols. As used herein, the term "pharmaceuttcalty acceptable salt" refers to those salts which retain the biological effectiveness and properties of the parent compound. Such salts include: (1) acid addition salts, which can be obtained by reaction of the free base of the parent compound with inorganic acids such as hydrochloric add, hydrobromic acid, nitric acid, phosphoric add. sulfuric acid, and perchloric add and the like, or with organic acids such as acetic add, oxalic acid, (D) or (L) malic add, malelc add, methanesulfonic acid, ethanesulfonic add, p-toluenesulfonic acid, salicylic acid, tartaric acid, dtric acid, succWc acid or matonic acid and the like; or (2) salts formed when an addle proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ton, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine. triethanolamine, tromethamine. N-methylglucaminfl, and the like. "PK" refers to receptor protein tyrosine kinase (RTKs), non-receptor or "cellular* tyrosine kinase (CTKs) and sertne-threonine klnases (STKs). "Modulation* or "modulating* refers to the alteration of the catalytic activity of RTKs, CTKs and STKs. In particular, modulating refers to the activation of the catalytic activity of RTKs, CTKs and STKs. preferably the activation or inhibition of the catalytic activity of RTKs, CTKs and STKs, depending on the concentration of the compound or salt to which the RTK, CTK or STK is exposed or, more preferably, the inhibition of the catalytic activity of RTKs. CTKs and STKs. •Catalytic activity* refers to the rate of phosphorylation of tyrosine under the influence, direct or indirect, of RTKs and/or CTKs or the phosphorylation of serine and threonine under the influence, direct or indirect, of STKs. 'Contacting" refers to bringing a compound of this invention and a target PK together in such a manner that the compound can affect the catalytic activity of the PK, either directly, i.e., by interacting with the kinase itsetf, or indirectly, i.e., by Interacting with another molecule on which the catalytic activity of the kinase is dependant. Such 'contacting* can be accomplished 'in vitro.' i.e., in a test tube, a petri dish or the like. In a test tube, contacting may involve only a compound and a PK of interest or It may Involve whole cells. Cells may also be maintained or grown in cell culture dishes and contacted with a compound in that environment. In this context, the ability of a particular compound to affect a PK related disorder, i.e., the ICa of the compound, defined below, can be determined before use of the compounds in vivo with more complex living organisms is attempted. For ceils outside the organism, multiple methods exist, and are well-known to those skilled in the art, to get the PKs in contact with the compounds including, but not limited to, direct cell microinjection and numerous transmembrane carrier techniques. "In vitrtf refers to procedures performed in an artificial environment such as, e.g., without limitation, in a test tube or culture medium. •In vivtf refers to procedures performed within a living organism such as, without limitation, a mouse, rat or rabbit. "PK related disorder," "PK driven disorder," and 'abnormal PK activity" all refer to a condition characterized by inappropriate, i.e., under or, more commonly, over, PK catalytic activity, where the particular PK can be an RTK, a CTK or an STK. Inappropriate catalytic activity can arise as the result of either (1) PK expression in cells which normally do not express PKs, (2) increased PK expression leading to unwanted cell proliferation, differentiation and/or growth, or, (3) decreased PK expression leading to unwanted reductions in cell proliferation, differentiation and/or growth. Over-activity of a PK refers to either amplification of the gene encoding a particular PK or production of a level of PK activity which can correlate with a cell proliferation, differentiation and/or growth disorder (that is, as the level of the PK increases, the severity of one or more of the symptoms of the cellular disorder increases). Under-adMty is, of course, the converse, wherein the severity of one or more symptoms of a cellular disorder increase as the level of the PK activity decreases. "Treat", "treating" and treatment" refer to a method of alleviating or abrogating a PK mediated cellular disorder and/or its attendant symptoms. With regard particularly to cancer, these terms simply mean that the life expectancy of an individual affected with a cancer will be increased or that one or more of the symptoms of the disease wlH be reduced. "Organism" refers to any Bving entity comprised of at least one cell. A living organism can be as simple as, for example, a single eukarfotic cell or as complex as a mammal, including a human being. "Therapeutically effective amount' refers to that amount of the compound being administered which will relieve to some extent one or more of the symptoms of the disorder being treated. In reference to the treatment of cancer, a therapeutically effective amount refers to that amount which has at least one of the following effects: (1) reducing the size of the tumor; (2) inhibiting (that is, slowing to some extent, preferably stopping) tumor metastasis; (3) inhibiting to some extent (that is, slowing to some extent, preferably stopping) tumor growth, and (4) relieving to some extent (or, preferably, eliminating) one or more symptoms associated with the cancer. "Monitoring" means observing or detecting the effect of contacting a compound with a cell expressing a particular PK. The observed or detected effect can be a change in cell phenotype, in the catalytic activity of a PK or a change in the Interaction of a PK with a natural binding partner. Techniques for observing or detecting such effects are well-known In the art. The effect is selected from a change or an absence of change in a cell phenolype. a change or absence of change in the catalytic activity of fiaid protein kinasa or a change or absence of change in the interaction of said protein kinase with a natural binding partner in a final aspect of this invention. "Cell phenotype* refers to the outward appearance of a ceil or tissue or the biological function of the cell or tissue. Examples, without limitation, of a cell phenotype are cell size, cell growth, cell proliferation, eel differentiation, cell survival, apoptosis, and nutrient uptake and use. Such phenotypic characteristics are measurable by techniques well-known m the art. •Natural binding partner* refers to a potypeptide that binds to a particular PK in a celf. Natural binding partners can play a role in propagating a signal in a PK-medialed signal transduction process. A change in tha interaction of the natural binding partner with the PK can manifest itself as an increased or decreased concentration of the PK/natural binding partner complex and, as a result, in an observable change in the ability of the PK to mediate signal transduction. As used herein, the terms 'optically pure,* 'enantiomericaHy pure," 'pure enantiomer,' and "optically pure enantiomer" mean a composition that comprises one enantiomer of a compound and is substantially free of the opposite enantiomer of the compound. A typical optically pure compound comprises greater than about 80% by weight of one enantiomer of the compound and less than about 20% by weight of the opposite enanfomer of the compound, more preferably greater than about 90% by weight of one enantiomer of the compound and less than about 10% by weight of the opposite enantiomer of the compound, even more preferably greater than about 96% by weight of one enantiomer of the compound and less than about 5% by weight of the opposite enantiomer of the compound, and most preferably greater than about 97% by weight of one enantiomer of the compound and less than about 3% by weight of the opposite enantiomer of me compound. Detailed Description General schemes for synthesizing the compounds of the invention can be found in the Examples section herein. Some of the general procedures are shown with reference to synthesis of compounds wherein the 1-(2,6-dichloro-3-fluorophenyl)-ethoxy moiety is the pure (R)-isomer, and some are shown with reference to compounds wherein said moiety is a racernic mixture. H should be understood that the procedures herein can be used to produce racemic compounds or enantiomerically pure (R) isomers by choosing the corresponding racemic or enantiomerically pure starting material. The procedures shown herein can be used to produce a wide variety of enantiomerically pure compounds by selection of the appropriate enantiomerically pure starting material In addition to the compounds shown herein, trie invention also provides enantiomerically pure compounds corresponding to the 3-[t-(2,8-dicNoro-3-fluoro-phcnyi)-ethoxy]-pyridin-2-ylamine and 3-[1-(2.6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2*ylamine compounds shown in U.S. Patent Application Serial No. 10/786,610 (PCT/US2004/005495); in U.S. Application Serial No. to be assigned, docketnumber PC 32546, filed August 26, 2004 and entitled. "Pyrazolo-Substiluted Aminoheteroaryl Compounds as Protein Kinase Inhibitors"; and in U.S. Application Serial No. to be assigned, docket number PC 32548, filed August 26, 2004 and entitled, "Aminoheteroaryl Compounds as Protein Kinase Inhibitors". The disclosures of these documents are incorporated herein by reference In their entireties. Unless indicated otherwise, all references herein to the inventive compounds include references to salts, solvates. hydrates and complexes thereof, and to solvates, hydrates and complexes of salts thereof, including polymorphs, stereoisomers, and isotopically labeled versions thereof. Pharmaceutically acceptable salts include acid addition and base salts (including disalts). Suitable acid addition sans are formed from adds which form non-toxic salts. Examples include the acetate, aspartate, banzoate, besylate, bicarbonate/carbonate, bisulphate/sulfate, borate, camsylate, citrate, edisylate, esylata, formate, fumarate, glucoptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodlde/iodide, isethionate, laoate, malate, maleate, malonate, mesylate, methytsulfate, naphthytate, 2-napsyfale, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphaJte/dihydrogen phosphate, saccharate, stearate. succinate, tartrate, tosylate and trifiuoroacetate salts. Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminum, arginine, benzathine, calcium, choline, dlethytamine, diolamine, glycine, lysine, magnesium, meQlumlne, olamine, potassium, sodium, tromethamine and zinc salts. For a review on suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH. Weinheim, Germany, 2002), the disclosure of which is incorporated herein by reference in its entirety. A pharmaceutically acceptable salt of the inventive compounds can be readily prepared by mixing together solutions of the compound and the desired acid or base, as appropriate. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization in the salt may vary from completely ionized to almost non-Ionized. The compounds of the invention may exist In both unsolvated and solvated forms. The term 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, tor example, ethanol. The term 'hydrate' is employed when the solvent is water. Pharmaceutically acceptable solvates in accordance with the invention include hydrates and solvates wherein the solvent of crystallization may be isotopically substituted, e.g. D2O, de-acetone, de-DMSO. Also included within the scope of the invention are complexes such as claihrates, drug-host inclusion complexes wherein, in contrast to the aforementioned solvates, the drug and host are present in atolchiometric or non-stoichlometric amounts. Also included are complexes of the drug containing two or more organic and/or inorganic components which may be in stoichiometfic or non-stolchlometrlc amounts. The resulting complexes may be ionized, partially ionized, or non-ionized, For a review of such complexes, see J Pharm 3d, g£ (8), 1269-1288 by HaleWian (August 1975), the disclosure of which is incorporated herein by reference in its entirety. Also within the scope of the Invention are polymorphs, prodrugs, and isomers (including optical, geometric and tautomeric isomers) of the inventive compounds Derivatives ol compounds of the invention which may have little or no pharmacological activity themselves but can, when administered to a patient, be converted into the inventive compounds, for example, by hydrolytic cleavage. Such derivatives are referred to as 'prodrugs'. Further information on the use of prodrugs may be found in 'Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T Higuchi and W Stella) and 'Bioreversible Carriers in Drug Design', Pergamon Press, 1987 (ed. E B Roche, American Pharmaceutical Association}, the disclosures of which are incorporated herein by reference in their entireties. Prodrugs in accordance with the Invention can, for example, be produced by replacing appropriate functionalities present in the inventive compounds with certain moieties known to those skilled In the art as 'pro-moieties' as described, for example, in "Design of Prodrugs' by H Bundgaard (Elsevier, 1985), the disclosure of which is incorporated herein by reference in its entirety. Some examples of prodrugs in accordance with the invention include: (i) where the compound contains a carboxylic acid functionality (-COOH), an ester thereof, for example, replacement of the hydrogen with (d-Ce)alkyl; (if) where the compound contains an alcohol functionality (-OH), an ether thereof, for example, replacement of the hydrogen with (C,-Cg)alkanoyloxymethyl; and (iii) where the compound contains a primary or secondary amino functionality (-NH2 or • NHR where R * H), an amide thereof, for example, replacement of one or both hydrogens with (Ci-C,0)alkanoyl. Further examples of replacement groups in accordance with the foregoing examples and examples of other prodrug types may be found in the aforementioned references. Finally, certain inventive compounds may themselves act as prodrugs o1 other of the inventive compounds. Compounds of the invention containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. Where a compound of the invention contains an alkenyl or alkenylene group, geometric cis/trans (or Z/E) isomers are possible. Where the compound contains, for example, a keto or oxime group or an aromatic moiety, tautomeric isomerism ('tautomerism') can occur. A tingle compound may exhibit more than one type of isomerism. Included within the scope of the Invention are all stereoisomers, geometric isomers and tautomeric forms of the inventive compounds. Including compounds exhibiting more than one type of Isomerism, and mixtures of one or more thereof. Also included are add addition or base salts wherein the counterton is optically active, for example, D-lactate or L-tysine, or racemic, for example, DL-tartrale or DL-arglnine. Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallization. Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound contains an acidic or basic moiety, an add or base such as tartaric acid or 1-phenytethylamine. The resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to one skilled in the art. Chlral compounds of the invention (and chiral precursors thereof) may be obtained in enantiomerfcally-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% isopropanol, typically from 2 to 20%, and from 0 to 5% of an alkylamkie, typically 0.1% diethvtamlne. Concentration of the efaate affords the enriched mixture. Stereoisomerte conglomerates may be separated by conventional techniques known to those skilled in the art; see, for example, "Stereochemistry of Organic Compounds" by E L Eltel (Wiley, New York, 1994). the disclosure of which is incorporated herein by reference in its entirety. The invention also includes isotopically-labeled compounds of the Invention, wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds of the invention Include isotopes of hydrogen, such as 2H and 3H, carbon, such as "C, 13C and "C, chlorine, such as *CI, fluorine, such as 1BF, iodine, such as m\ and t!sl, nitrogen, such as 13N and 15N, oxygen, such as 1SO. 17O and 18O, phosphorus, such as MP, and sulfur, such as KS. Certain isotopically-labeled compounds of the invention, for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, 3H, and carbon-14,14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with heavier Isotopes such as deuterium, 2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased In vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Substitution with positron emitting isotopes, such as 11C, 18F, "O and "N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent In place of the non-labeled reagent otherwise employed. Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopteally substituted, e.g. D2O, oVacetone, d6-OMSO. Compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products, or mixtures thereof. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose. The compounds can be administered alone or in combination with one or more other compounds of the invention, or in combination with one or more other drugs (or as any combinationthereof). Generally, they will be administered as a formulation In association with one or more pharmaceutically acceptable excipients. The term "excipienT is used herein to describe any ingredient other than the compound(s) of the invention. The choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipierrt on solubility and stability, and the nature of the dosage form. Pharmaceutical compositions suitable for the delivery of compounds of the invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation can be found, for example, In 'Remington's Pharmaceutical Sciences', 19th Edition (Mack Publishing Company, 1995), the disclosure of which is incorporated herein by reference in its entirety. Oral Administration The compounds of the invention may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth. Formulations suitable for oral administration Include solid formulations such as tablets capsules containing particulars, liquids, or powders, lozenges (including liquid-filled), chews, multl and nano-parUculates, gels, solid solution, liposome, films (including muco-adhesive), ovules sprays and liquid formulations. Liquid formulations Include suspensions, solutions, syrups and elixirs. Such formulation! may be used as fillers in soft or hard capsules and typically include a carrier, for example, water ethanol, polyethylene glycol, propytene gtycol. methytceKutose, or a suitable oil, and one or mori emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by th The compounds of the invention may also be used in fast-dissolving, fast-disintegratin For tablet dosage forms, depending on dose, the drug may make up from 1 wt% to 80 wf of the dosage form, more typically 1rom 5 wt% to 60 wt% of the dosage form. In addition to th drug, tablets generally contain a disiniegrant. Examples of disintegrates include sodium stare glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellos sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alky substituted hydroxypropyl cellulose, starch, pregelatinized starch and sodium alginate. General! the dislntegrant will comprise from 1 wt% to 25 wt%, preferably from 5 wt% to 20 wt% of tr dosage form. Binders are generally used to Impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalUne cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose and hydroxypropyl methylcettutose. Tablets may also contain diluents, such as lactose (monohydrate. spray-dried monohydrata, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate. Tablets may also optionally include surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present surface active agents are typically In amounts of from 0.2 wt% to 5 wt% of the tablet, and glidants typically from 0.2 wi% to 1 wt% of the'tablet. Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate. Lubricants generally are present in amounts from 0.25 wt% to 10 wt%, preferably from 0.5 wt% to 3 wt% of the tablet. Other conventional ingredients include anti-oxidants, colorants, flavoring agents, preservatives and taste-masking agents. Exemplary tablets contain up to about 80 wt% drug, from about 10 wt% to about 90 wt% binder, from about 0 wt% to about 85 wt% diluent, from about 2 wt% to about 10 wt% disintegrant, and from about 0.25 wt% to about 10 wt% lubricant. Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tablettng. The final formulation may include one or more layers and may be coated or uncoated; or encapsulated. The formulation of tablets is discussed in detail in 'Pharmaceutical Dosage Forms: Tablets, Vol. 1', by H. Lieberman and L. Lachman, Marcel Oekker, N.Y., N.Y., 1980 (ISBN 0-8247-691B-X), the disclosure of which is incorporated herein by reference in its entirety. Solid formulations for oral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained*, pulsed*, controlled-, targeted and programmed release. Suitable rnodified release formulations are described in U.S. Patent No. 6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles can be found in Verma etal, Pharmaceutical Technology On-line, 25(2), 1-14 (2001). The use of chewing gum to achieve controlled release is described in WO 00/35298. The disclosures of these references are incorporated herein by reference in their entireties. Paranteral Administration The compounds of the invention may also be administered directly Into the blood stream, into muscle, or Into an Internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal. intrathecal, intraventricular. intraurethral, intrastemal, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle (including micro needle) injectors, needle-free Injectors and infusion techniques. Parenteral formulations are typically aqueous solutions which may contain exdpients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, 1or some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water. The preparation of parenteral formulations under sterile conditions, for example, by lyophilization, may readily be accomplished using standard pharmaceutical techniques wen known to those skilled in trie art. The solubiity of compounds of the invention used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents. Formulations for parenteral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. Thus compounds of the invention may be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound. (Examples of such formulations include drug-coated stents and PGLA microspheres, Topical Administration The compounds of the Invention may also be administered topically to the skin or mucosa, that is, dermaHy or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Uposomes may also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propytene glycol. Penetration enhancers may be incorporated; see, for example, J Pharm Soi, §8 (10}, 955-958 by Finnln and Morgan (October 1999). Other means of topical administration include delivery by electroporation, iontophoresis, phonophoreste. sonophoresis and micro needle or needle-free (e.g. Powderject™, Bioject™. etc.) injection. The disclosures of these references are incorporated herein by reference in their entireties. Formulations for topical administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. Inhaled/lntranasal Administration The compounds of the invention can also be administered intranasally or by inhalation, typically In the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidytcholina) from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, spray, atomizer (preferably an atomizer using etectrohydrodynamics to produce a line mist), or nebulizer, with or without the use of a suitable propellent, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. For intranasal use, the powder may include a btoadhesive agent, tor example, chitosan or cyclodextrin. The pressurized container, pump, spray, atomizer, or nebulizer contains a solution or suspension of the compound(s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, sotubilizing, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, otete acid, or an oligolactic acid. Prior to use in a dry powder or suspension formulation, me drug product is micronized to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanopartlcles, high pressure homogenization, or spray drying. Capsules (made, for example, from gelatin or HPMC), blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as Aleutine, mannitol, or magnesium stearate. The lactose may be anhydrous or in the form of the rhonohydrate, preferably the latter. Other suitable excipienls include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose. A suitable solution formulation for use in an atomizer using electrohydrodynamics to produce a fine mist may contain from 1ug to 20mg of the compound of the invention per actuation and the actuation volume may vary from fuL to 100uL A typical formulation includes a compound of the invention, propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents which may be used instead of propylene glycol include grycerol and polyethylene glycol. Suitable flavors, such as menthol and lavomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the invention intended for inhaled/intranasal administration. Formulations for irthaled/intranasal administration may be formulated to be immediate and/or modified release using, for example, poly(DL-lactic-coglycolic add (PGLA). Modified release formulations Include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. In the case of dry powder inhalers and aerosols, the dosage unit is determined by means of a valve which delivers a metered amount. Units in accordance with the invention are typically arranged to administer a metered dose or "puff containing a desired mount of the compound of the invention. The overall dally dose may be administered in a single dose or, more usually, as divided doses throughout the day. Rectal/lniravaginal Administration Compounds of the invention may be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate. Formulations for rectal/vaginal administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. Ocular Administration Compounds of the invention may also be administered directly to the eye or ear, typically in the form of drops of a micronized suspension or solution in isotonic, pH-adjusted, sterile saline. Other formulations suitable for ocular and aural administration include ointments, biodegradable (e.g. absorbaWe gel sponges, collagen) and nort-btodegradabte (e.g. sUcone) implants, wafers, lenses and particular or vesicular systems, such as niosomes or liposomes. A polymer such as crossed-linked polyacrylic acid, polyvinytalcortot, hyaluronic acid, a callutosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethytcellulose, or methyl cellulose, or a heteroporysaccharlde polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride. Such formulations may also be delivered by Iontophoresis. Formulations for ocular/aural administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted, or programmed release. Other Technologies Compounds of the invention may be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers, in order lo improve their solubility, dissolution rate, taste-masking, bioavaHability and/or stability for use in any of the aforementioned modes of administration. Drug-cyclodextrin complexes, for example, are found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used. As an alternative to direct complexation with the drug, the cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent, or solubilizer. Most commonly used for these purposes are alpha-, beta- and gamma-cyclodextrins, examples of which may be found in PCT Publication Nos. WO 91/11172, WO 94/02518 and WO 98/55148, the disclosures of which are incorporated herein by reference in their entireties. The amount of the active compound administered will be dependent on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the discretion of the prescribing physician. However, an effective dosage is typically in the range of about 0.001 to about 100 mg per Kg body weight per day, preferably about 0.01 to about 35 mg/kg/day, In single or divided doses. For a 70 kg human, this would amount to about 0.07 to about 7000 mg/day, preferably about 0.7 to about 2500 mg/day. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while In other cases still larger doses may be used without causing any harmful side effect, with such larger doses typically divided into several smaller doses for administration throughout the day. Kit-of-Parts Inasmuch as it may desirable to administer a combination of active compounds, for example, for the purpose of treating a particular disease or condition, It is within the scope of the present Invention that two or more pharmaceutical compositions, at least one of which contains a compound in accordance with the invention, may conveniently be combined in Ihe form of a kit suitable for coadministration of the compositions. Thus the kit of the invention includes two or more separate pharmaceutical compositions, at least one of which contains a compound of the invention, and means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet. An example of such a kit is the familiar blister pack used for the packaging of tablets, capsules and the tike. The kit of the invention Is particularly suitable for administering different dosage forms, for example, oral and parenterai, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another. To assist compliance, the Kit typically includes directions for administration and may be provided with a memory aid. Exampjgj In the following examples, "El" means ethyl, "Ac* means acetyl, "Me" means methyl, "Ms" means methanesuHonyl (CHiSOj), "iPr" means isopropyl, "HATU" means 2-(7-Aza-1H-benzotrlazole-1-yl}-1,1,3,3-tetramethyluronium hexafluorophosphale, "Ph" means phenvl, "Boc" means tert-butoxycarbonyi, 'EtOAc* means ethyl aoetate, "HOAc" means acetic acid, "NEty or "Et9N" means triethylamine, THF means tetrahydrofuran, 'DIG' means diisopropylcarbodiimide, "HOBf means hydroxy benzotriazole, "MeOH" means methanol, "i-PrOAc" means isopropyl acetate, "KOAc" means potassium acetate. "DMSO" means dimethylsulfoxide. "AcCI" means acetyl chloride, "CDCb" means deuterated chloroform, "MTBE" means methyl t-butyl ether, *DMF" means dimethyl formamide, "AcjO" means acetic anhydride, "MeSSOP means trimethylsuffoxonlum iodide, "DMAP" means 4-dlmathylaminopyridine, 'dopf means diphenylphosphino ferrocene. "OWE" means ethytene glycol dimethyl ether, HOBT means 1-hydroxybenzotriazole. EDO means 1-Ethyl-3-(3-dimethylaminopropyl)-carbodiimide. The following examples are given to illustrate the present invention. It should be understood, however, that the invention is not to be limited to the specific conditions or details described in these examples. Reagents can be synthesized as shown herein, or are available from commercial sources (e.g., Aldrich, Milwaukee, Wl; Acros. Morris Plains, NJ; Biosynth International, Napervilte, IL; Frontier Scientific, Logan, UT; TCI America, Portland, OR; Combi-Blocks, San Diego, CA; Matrix Scientific, Columbia, SC; Acros, Morris Plains, NJ; Alfa Aesar, Ward Hill, MA; Apollo Scientific, UK; etc.) or can be synthesized by procedures known in the art. The synthesis of several specific reagents is shown In U.S. Patent Application Serial No. 10/786,610. entitled "Aminoheieroaryl Compounds as Protein Kinase Inhibitors", filed February 26, 2004. and corresponding international application PCT/US2004/Q05495 of the same title, filed February 26.2004. Other reagents can be synthesized by adapting the procedures therein, and one skilled in the art can readily adapt those procedures to produce the desired compounds. Further, these references contain general procedures and specific examples for the preparation of a large number of heteroarylamlno compounds, and one skilled in the art can readily adapt such procedures and examples to the preparation of compounds of the present invention. The disclosures of these references are Incorporated herein by reference in their entireties. When a general or exemplary synthetic procedure is referred to, one skilled in the art can readily determine the appropriate reagents, If not indicated, extrapolating from the general or exemplary procedures. Some of the general procedures are given as examples for preparing specific compounds. One skilled in the art can readily adapt such procedures to the synthesis of other compounds. It should be understood that R groups shown in the general procedures are meant to be generic and non-limiting, and do not correspond to definitions of R groups elsewhere In this document. Each such R group represents one or multiple chemical moieties that can be the same or different from other chemical moieties also represented by the same R symbol. One skilled, in the art can readily appreciate the range of R groups suitable in the exemplary syntheses. Moreover, representation of an unsubstltuted position in structures shown or referred to in the general procedures is lor convenience and does not preclude substitution as described elsewhere herein. For specific groups that can be present, either as R groups in the general procedures or as optional substituents not shown, refer to the descriptions in the remainder of this document, including the claims, summary and detailed description. Some of the general procedures are shown with reference to synthesis of compounds wherein the 1>{2,6-dichioro-3-(luorophenyi)-ethoxy moiety is the pure (R)-isomer, and some are shown with reference to compounds wherein said moiety Is a racsmic mixture. It should be understood that the procedures herein can be used to produce racemic compounds or enanttomertcally pure 5-bromo-3-f 1 -(2.6-dtch (Figure Remove) F 1. 2,6-Dichkxo-3-11uoroacetophanone (15 g, 0.072 mol) was stirred in THF (150 mL, 0.5M) at 0°C using an ice bath for 10 mln. Uthium aluminum hydride (2.75 g, 0.072mol) was slowly added. The reaction was stirred at ambient temperature for 3 hr. The reaction was cooled in ice bath, and water (3 ml) was added drop wisely followed by adding 15% NaOH (3 mL) slowly. The mixture was stirred at ambient temperature for 30 min. 15% NaOH (Q mL). MgSO4 were added and the mixture filtered to remove solids. The solids were washed with THF (50 mL) and the filtrate was concentrated to give 1-(2,6-dichloro-3-fluoro-phenyl)-ethanol (14.8 gm, 95% yield) as a yellow on. 'H NMR (400 MHz, DMSO-dg) 61.45 (d, 3H), 5.42 (m. 2H), 7.32 (m, 1H). 7.42 (m, 1H). 2. To a stirred solution of triphenyt phosphine (8.2 g, 0.03 mol) and DEAD (13.65 mL of a 40% solution in toluene) in THF (200 ml) at 0°C was added a solution of l-(2,6-dichloro-3-fluoro- phenyO-ethanol (4.55 g, 0.021 mol) and 3-hydroxy-nitropyridlne (3.35 g, 0.023 mol) in THF (200 ml). The resulting bright orange solution was stirred under a nitrogen atmosphere at ambient temperature for 4 hours at which point all starting materials had been consumed. The solvent was removed, and the crude material was dry loaded onto silica gel, and eluted with ethyl acetate- hexanes (20:80) to yield 3-(2,6-dichlofo-3-fluoro-benry1oxy)-2-nitro-pyrid!ne (6.21 g, 0.021 mol, 98%) as a pink solid. 1H NMR (CDCb. 300 MHz) 61.8-1.85 (d, 3H), 6.0-6.15 (q. 1H), 7.0-7.1 (t, 1 H), 7.2-7.21 (d, 1H), 7.25-7.5 {m. 2H), 8.0-8.05 (d, 1H). 3. To a stirred mixture of AcOH (650 ml) and EtOH (500 mL) was suspended 3-(2,6- d4chloro-3-1luorobenzyloxy)-2-n!tro-pyridine (9.43 g, 0.028 mol) and iron chips (15.7 g, 028 mot). The reaction was heated slowly to reflux and allowed to stir for 1 hr. The reaction was cooled to room temperature then diethyt ether (500 mL) and water (500 mL) was added. The solution was carefully neutralized by the addition of sodium carbonate. The combined organic extracts were washed with safd NaHCO3 (2 x 100 ml), H2O (2 x 100 mL) and brine (1 x 100 mL) then dried (Na?SOO, filtered and concentrated to dryness under vacuum to yield 3-(2,6-dichloro-3-fluoro-benzyloxy)-pyridin-2-yIamine (9.04 g. 0.027 .mol, 99%) as a light pink solid. 'H NMR (CDCI3. 300 MHz) $1.8-1.85 (d. 3H), 4.9-5.2 (brs, 2H). 6.7-6.84 (q. 1H), 7.0-7.1 (m. 1H). 7.2-7.3 (m. 1H), 7.6-7.7 (m, 1H). 4. A stirring solution of 3-(2,6-dichloro-3-fluoro-benryloxy)-pyridin-2-ylamine (9.07 g, 0.03 mol) in acetonitrtte was cooled to 0°C using art Ice bath. To this solution was added N-bromosuccinimide (NBS) (5.33 g, 0.03 mol) portionwise. The reaction was stirred at 0°C for 15 mln. The reaction was concentrated to dryness under vacuum. The. resulting dark oil was dissolved in ElOAc (500 mL), and purified via silica gel chromatography. The solvents were then removed in vacuo to yield 5-bromo-3-(2.6-dichloro-3'fluoro-benzyloxy)-pyridin-2*ylamine (5.8 g, 0.015 mol, 51%) as a white crystalline solid. 'H NMR (CDCI3.300 MHz) 61.85-1.95 (d, 3H), 4.7-5.0 (brs, 2H), 5.9-6.01 (q, 1H>, 6.8-6.95 (d, 1H), 7.01-7.2 (t, 1H), 7.4-7.45 (m, 1H), 7.8-7.85 (d. 1H). 5-|Qdo-3-ri-f2.6-dlehloro-3- 3-(1-(2,6-Oichloro-3-fIuoro-phenyl)-ethoxy]-pyridin-2-ylamine (10.0 g, 33.2 mmol) in acetonHrile (600 mL) and acetic acid (120 mL) was added N-todosucdnimlde (11.2 g, 49.8 mmol). The mixture was stirred at room temperature for 4 h and the reaction was quenched with Na2SzOs solution. After evaporation, the residue was partitioned between ethyl acetate and water. The organic layer was washed with 2N NaOH solution, brine, and dried over Na2SO4. The crude product was purified on a silica gel column to provide 5-iode~3-[1-(2,6-dichloro-3-fluoro-phenyl}-ethoxyl-pyridin-2-ytamlne (7.1 g, 50% yield).MS m£427 [M+1]. 'H NMR (400 MHz. DMSO-D6) 0 ppm 1.74 (d. ^6.57 Hz, 3 H) 5.91 - S.99 (m, 3 H) 6.82 (d, JM.26 Hz, 1 H) 7.46 (t, J=8.72 Hz, 1 H) 7.56 (dd. Jb8.97.4.93 Hz, 1 H) 7.62 (d, J=1.52 Hz. 1 H). i 6-bromo-3-H-(2.6-dlchloro-3-fluoro-Dhenvl^-ethoxvVpvrazin-2-vlamine(racematel: (Figure Remove) 1. 2,6-Dtehloro-3-iluoroacetophanone (15 g, 0.072 mol) was stirred In THF (150 mL, 0.5M) at 0°C using an ice bath for 10 min. Lithium aluminum hydride (from Aldrich, 2.75 g, 0.072 mol) was slowly added. The reaction was stirred at ambient temperature for 3 h. The reaction was cooled in ice bath, and water (3 mL) was added drop wisely followed by adding 15% NaOH (3 mL) slowly. The mixture was stirred at ambient temperature for 30 min. 15% NaOH (9 mL), MgSO« were added and the mixture filtered to remove solids. The solids were washed with THF (SO mL) and the filtrat was concentrated to give 1-(2,6-dichtoro-3- PLE is an enzyme produced by Roche and sold through Biocatalytics inc. as a crude esterase preparation from pig liver, commonly known as PLE-AS (purchased from Biocatalytics as ICR-123, sold as an ammonium sutfate suspension). The enzyme is classified in the CAS registry as a "carboxylic-ester hydrda.se, CAS no. 9016-18-6". The corresponding enzyme classification number is EC 3.1.1.1. The enzyme is known to have broad substrate specificity towards the hydrolysis of a wide range of esters. The lipase activity 1$ determined using a method based on hydrolysis of ethylbutyrate In a pH tttrator. 1 LU (llpase unit) Is the amount of enzyme which liberates 1 unto! titratable butyric acid per minute at 22°C, pH 8.2. The preparation reported herein (PLE-AS, as a suspension) is usually shipped as an opaque brown-green liquid with a declared activity of > 45 lU/mg (protein content around 40 mg/mL). M SV1 -(2.6-dichtofo-3-fluorophBr>v11athanol (lS)-1-(2,6-dich»oro-3-fluorophonyl)etrianol, shown as compound (S-1) in the schemes below, was prepared by a combination of enzymatic hydrolysis of racemic 1-(2.6-dichtoro-3-fkiorophenyl)ethyl acetate, esterification and chemical hydrolysis with inversion according to Scheme B. Racemic l-(2,6-dlchioro-3-fluorophenyl)ethyl acetate (compound A2) was prepared according to Scheme A. Scheme A ci Al F A2 1 -f2.6-dichloro-3-fluoroohenvltelhanot (A1): Sodium borohydride (90 mg, 2.4 mmol) was added to a solution of 2',6'-dichloro-3'-fiuoro-acetophenon9 (Aldrich, catalog # 52,294-5) (207 mg. 1 mmol) in 2 mL of anhydrous CH3OH. The reaction mixture was stirred at room temperature for 1 h then was evaporated to give a colorless oil residue. The residue was purified by flash chromatography (eluting with 0-vlO% EtOAc In hexanes) to give compound A1 as a colorless oil (180 mg; 0.88 mmol; 86.5% yield); MS (APCI) (M-H) 208; 1H NMR (400 MHz. chloroform-D) 6 ppm 1.84 (d. J!=6.82 Hz, 3 H) 3.02 (d. J=9.85 Hz, 1 H) 6.97 - 7.07 (m, 1 H) 7.19 - 7.33 (m. 1 H). 1-(2.6-dichloro-3.fluoroDh9nvltetrivl acetate (A2): Acetic anhydride (1.42 mL, 15 mmol) and pyridine (1.7 mL, 21 mmol) were added sequentially to a solution of compound A1 (2.2 g, 10.5 mmol) In 20 mL of CHjCI2. The reaction mixture was stirred at room temperature for 12h and then evaporated to give a yeNowish oil residue. The residue was purified by flash chromaiography (editing with 7-»9% EtOAc in hsxanes) to give compound A2 as a colorless OH (2.26 g; 9-0 mmol; 85.6% yiefd); 1H NMR (400 MHz, chtoroform-D) 5 ppm 1.88 (d, J=6.82 Hz, 3 H) 2.31 (s, 3 H) 6.62 (q, Jb6.82 Hz, 1 H) 7.25 (t. JtB.46 Hz, 1 H) 7.49 (dd, J=8.84, 5.05 Hz, 1 H). tlrrer and a base addition line (1M NaOH), was added 1.2 mL of 100 mM potassium phosphate buffer pH 7.0 and 0.13 mL of PIE AS suspension. Then, compound A2 (0.13 g. 0.5 mmol, 1.00 eq) was added dropwise and the resulting mixture was stirred at room temperature for 20 h, maintaining the pH of the reaction constant at 7.0 using 1 M NaOH. Both the conversion and ee's of the reaction were monitored by RP-HPLC, and stopped alter 50% starting material was consumed (approximately 17 hours under these conditions). The mixture was then extracted three times with 10 mL of ethyl acetate to recover both ester and alcohol as a mixture of R-1 and S*2. Methanesulfonyt chloride (0.06 mL, 0.6 mmol) was added to a solution of a mixture of R-1 and S-2 (0.48 mmol) In 4 mL of pyridine under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 3 h then evaporated to obtain an oil. Water (20 mL) was added to the mixture and then ElOAc (20 mL x 2) was added to extract the aqueous solution. The organic layers were combined, dried, filtered, and evaporated to give a mixture of R-3 and S-2. This mixture was used in the next step reaction without further purification. 'H NMR (400 MHz, chtoroform-D) D ppm 1.66 (d, J=7.1 Hz, 3 H) 1.84 (d, 0=7.1 Hz. 3 H) 2.09 (s. 3 H) 2.92 (s. 3 H) 6.39 (q, J=7.0 Hz, 1 H) 6.46 (q, J-6.8 Hz, 1 H) 6.98 - 7.07 (m, 1 H) 7.07 - 7.17 (m, 1 H) 7.23 - 7.30 (m, 1 H) 7.34 (dd, J*6.B, 4.80 Hz, 1 H Potassium acetate (0.027 g, 0.26 mmol) was added to a mixture of R-3 and 8-2 (0.48 mmol) In 4 mL of DMF under nitrogen atmosphere. The reaction mixture was heated to 100'C for 12 h. Water (20 ml) was added to the reaction mixture and EtOAc (20 ml x 2) was added to extract the aqueous solution. The combined organic layer was dried, filtered, and evaporated to give an oi of S-2 (72 mg, 61% yield in two steps). Chiralily ee: 97.6%. 1H NMR (400 MHz, chloroform-D) D ppm 1.66 (d, J.7.1 Hz, 3 H) 2.09 (s, 3 H) 6.39 (q, ^=8.8 Hz, 1 H) 7.02 (t. ^8.5 Hz, 1 H) 7.22 - 7.30 (m, 1 H). Sodium methoxide (19 mmol; 0.5 M in methanol) was added slowly to compound S-2 (4.64 g, 18.B rnmoi) under a nitrogen atmosphere at 0°C. The resulting mixture was stirred at room temperature for 4 hours. The solvent was evaporated and HaO (100 mL) was added. The cooled reaction mixture was neutralized with sodium acetate-acetic acid buffer solution to pH 7. Ethyl acetate (100 mL x 2) was added to extract the aqueous solution. The combined organic layers were dried over NaaSO4, filtered, and evaporated to obtain a white solid (4.36 g, 94.9% yield); SFC-MS: 97%ee. 'H NMR (400 MHz. chloroform-D) D ppm 1.65 (d, J*6.8 Hz. 3 H) 5.58 (q, J-6.9 Hz. 1 H) 6.96 - 7.10 (m, 1 H) 722 - 7.36 (m, 1 H). .2.6Hllehloro.3.fluoroDhenvl^thoxv1-2-nrtropvrldine 3-Hydroxy-2-nitropyridlne (175 mg, 1.21 mmol) and triphenylphosphine (440 mg, 1.65 mmol) were added sequentially to a stirred solution of (lS)-1-(2,6-olchlorc-3-fluorophenyl)elhanol (229.8 mg, 1.1 mmol) In THF (10 mL) under a nitrogen atmosphere. The reaction mixture was maintained at room temperature for 1 h and then dilsopropy) azo-dicarboxylate (0.34 ml, 1.65 mmol) was added at 0°C. The mixture was stirred for an additional 12 h. The reaction mixture was evaporated under vacuum to give an on. The residue was purified by flash chromatography (eluting with 20->25% EtOAc in hexanes) to give the title compound as a white solid (321.5 mg; 0.97 mmol; 88.3% yield); MS (APCI) (M+H)* 331; SFC-MS: 99.5%ee. 'H NMR (400 MHz, chloroform-D) 5 ppm 1.85 (d, Jb6.6 Hz, 3 H) 6.10 (q. J!=6.6 Hz, 1 H) 7.04 - 7.13 (m, 1 H) 7.21 (dd, J=8.5. 1.14 Hz, 1 H) 7.30 (dd, J=0.0. 4.9 Hz. 1 H) 7,37 (dd, «/=8.6, 4.6 Hz. 1 H) 8.04 (dd, Jt4.6,1.3 Hz. 1 H). 3-ff 1 flM -(2.6-dlchlCTO-3-nuoroDhenvltethoxvlPvridlrv2-amin6 Iron (365 mg) was added to a stirred solution of 3-[(1H)-1-(2,6-dichloro-3-fluoroprteny()ethoxy]-2-nrUopyr!dtne (321 mg, 0.97 mmol) in a mixture of EtOH (2 mL) and 2M HO (0.2 mL) at 0°C. The resulting solution was heated to 85*C for 2 h. Celite (0.5 g) was added to the cooled reaction mixture. This mixture was filtered over a bed of calite and evaporated to give the title compound as B dark oU. MS (APCI) (M+Hf 301. 5-bromo-3-t1(RW2.6-dichloro-3-flugro-phenvH-BthoxyJ-pyridin-2-ylaminB: Br NH2 Vvl The enantiomerically pure R isomer was prepared as described above for the racemate, but using the enantiomerically pure starting materials described above. 'H NMR (400 MHz, OMSO-d«) B 1.74 (d, 3H). 6.40 (m. 1H), 6.52 (br s, 2H), 7.30 (m, 1H), 7.48 (m. 1H), 7.56 (s. 1H); MS m/z 382 (M+1). S-todo-3-KRi1-(2.6-dtchlofO'3-fluoTo-DhenvlVe1hoxvl-DVridln-2-vlamine: I ^CCl Periodic acid (60 mg, 0.24 mmol). iodine (130 mg, 0.5 mmol), and sulluric acid (0.03 mL) were added sequentially to a stirred solution of 3-[(lfl)-i-(2,6-dichloro-3-fluorophenyl)ethoxy]pyrkJin-2-amine (0.97 nunol) In a mixture ol acetic acid (3 ml) and H2O (0.5 mL). The resulting solution was heated to 80°C for 5 rt. The cooled reaction mixture was quenched with Na,SO3 (80 mg) and basicfad with saturated Na2CO3 (2 x 100 mL) » pH 7. CH2CI2 (2 x 50 mL) was added to extract the aqueous solution. The combined organic layers were dried over NajSO4 then filtered and concentrated under vacuum. The residue was purified by flash chromatography (eluting with 35-440% EtOAc in hexanes) to give the title compound as a yellow oil (254 mg; 0.6 mmol; 61.6% yield); MS (APCI) (M+H)* 426. 'H NMR (400 MHz, chloroform-D) 8 ppm 1.81 (d, J=6.8 Hz, 3 H) 4.86 (s, 2 H) 5.98 (q. vfc6.57 Hz, 1 H) 6.96 (d, JM.5 Hz, 1 H) 7.08 (dd. J=9.0,8.0 Hz, 1 H) 7.31 (dd, 0=8.8,4.8 Hz, 1 H) 7.78 (d, .M.8 Hz, 1 H). S-bromo-3-r(RM-f2.6-dlchloro-3- (Figure Remove) l F The title compound was prepared according to procedure 2. from (1S)-1-(2.6-dichloro-3-fluorophenyl)ethanol. 'H NMR (400 MHz. DMSO-d6) fi 7.53(s, 1H). 7.48(m, 1H). 7.39(1, 1H), 6.48 (s, 2H), 6.41 (q, 1H), 1.74(d. 3H); LCMS: 381 (M+1); c-Met Ki; 0.796 \tM. Genaral Scheme I for the Synthesis of 5-Ary!-3-(Substituted-Berayloxy).Pyridiiv2-ylamine (6): (Figure Remove) NBSCHsCNBenzyloxy)-Pyridin-2-v1amin8 (5): 1. Preparation of 3-(substrtuted-benzyloxy)-2-nitro-pyrldine (3): To a stirred solution of C&2CO3 (1.0 molar equivalent)) in DMF (0.2 M) under a N2 atmosphere containing 3-hydroxy-4- nitro-pyridine (Aldrich, 1.0 molar equivalent) is added substituted benzyl bromide (1.0 molar equivalent). The mixture Is stirred for 6 h at ambient temperature. The reaction is then diluted with EtOAc , and partitioned with HjO. The aqueous layer is extracted with EtOAc twice. The organic layers are then combined, washed with HSO and brine, dried over Na2SO4, filtered, and concentrated to dryness under vacuum to yield 3-(substituted-benzyioxy) 2-nitro-pyridine (3) as a solid. 2. Preparation of 3-(substituted-benzyloxy)-pyridin-2-ylamine (4): To a stirred mixture of AcOH and EtOH (1.3:1) is suspended Msubstituted-benzyloxy-2-nitro-pyridine (1.0 molar equivalent, 1 M) and iron chips (1.0 molar equivalent). The reaction Is heated slowly to reflux and alowed to stir for 1 hr. The reaction is cooled to room temperature then filtered through a pad of celite. The resulting filtrate is neutralized with cone. NH4OH, and then extracted with EtOAc for three times. The combined organic extracts are washed with saturated NaHCO3, HZ0, and brine, dried over NaaSO benzytoxy)-pyrklin-2-ylamine (4) as a solid. 3. Preparation of 5-bromo-3-(substituted benzyloxy)-pyridin-2-ylamine (5): A stirring solution of 3-{substituted-benzyloxy)-pyridin-2-ylamine (4) (1.0 molar equivalent) in acetonitrile is cooled to 0 °C using an ice bath. To this solution is added N-bromcsuccinimide (Aldrich, 1.0 molar equivalent) poitonwtee. The reaction is stirred at 0°C tor 15 min. The reaction is concentrated to dryness under vacuum. The resulting dark oil is dissolved in EtOAc and partitioned with H2O. The organic Is then washed with saturated NaHCO3 twice and brine once. Activated charcoal is added to tie organic layer and warmed to reflux. The solution is then cooled to room temperature and filtered through a pad of celite. The organic is then concentrated to dryness under vacuum to one third the original volume. The solids are then filtered off to yield 5-bromo-3-(substiluted ben2yloxy)-pyrtdirv2-ylamin8 (5) as a solid. General Scheme II for the Synthesis of 5-Aryl-3-(Substituted-Benzyloxy)-Pyrazln-2-ylamine General Procedure 2 for the Synthesis of 5-Bromo-3-(Substrtuted-Beiizyioxy}-Pyrazin-2-ylami(Figure Remove) ne. To an ice cooled solution of substituted benzyl alcohol (1.0 molar equivalent) and anhydrous telrahydrofuran (0.14 M) was added sodium hydride (1.0 molar equivalent) slowly under nitrogen atmosphere. After stirring for 30 minutes, 3,5-dlbromopyrazin-2-ylamme (1 .0 molar equivalent) in tetrahydrofuran (0.56 M) was added via an addition funnel at a fast dropwise rate. Once the addition was complete the ice bath was removed and the reaction was refluxed under nitrogen and monitored by reversed phase HPLC. After 18 hr HPLC showed that the majority of the starting 3,5-dibromopyrazln-2-ylamine had been consumed and the reaction was allowed to cool to room temperature. The reaction mixture was concentrated, diluted with ethyl acetate, and washed with brine. The organic layer was dried over anhydrous magnesium suifate and concentrated in vacuum. The crude product 'was purified using a silica gel eluting with 1:1 ethyl acetata/dichloromethane to yield the 5-bromo-3-(sub8tituted-benzytoxy)-pyrazin-2-ylamine as a white solid in 60-90% yield. General Procedure 3 for the Synthesis of S-Aryi-3-(Substituted-Benzyloxy)-Pyridin-2-ylamine and 5-Aryl-3-(Substituted-Benzyloxy)-Pyrazin-2-ylamine. DMBNajCO^HjO 80-c lHa Y:CH«N A mixture of 5-bromo-3-(substituted-benzyloxy)-pyridin-2-ylamine or 5-bromo-3-(substituted-benzyloxy)-pyrazin-2-ylamine (1 molar equivalent), aryl boronic acid or ester (1.2 molar equivalent), bis(triphenylphosphine) palladium II chloride (0.03 molar equivalent) and sodium carbonate (3.0 molar equivalent.) in ethylene glycol dimethyl ether and water (10:0.5, 0.03 M) is de-gassed and charged with nitrogen for three times, and then heated to reflux under nitrogen for overnight The reaction is cooled to ambient temperature and diluted with ethyl acetate. The mixture is washed with water, brine, dried over Na2SO4. and purified on a siica gel column to afford 5-aryl-3> (substituted-benzyloxy)-pyridin-2-ylamine, or5-aryl-3-(substituted-b8nzyloxy)-pyrazin'2-ylamIne. General Procedure 4 for Amidation Reaction of 6-amino-5-(substituted-benzyloxy)-pvridm-3-yl]-benzoic acid: To a solution of 6-amino-5-(substituted-benzyloxy)-pyridin-3-yl]-benzoic acid (1 molar equivalent), 1-hydroxybenzotriazote hydrate (HOBT, 1,2 molar equivalent), and 1-(3-dimethylamlnopropyl)-3-ethylcarbodtirnide hydrochlorlde (EDC, 1.2 molar equivalent) in DMF (0.2 M) is added amine (1.2 molar equivalent). The reaction solution is stirred at room temperature for overnight, then diluted with EtOAc, and partitioned with HjO. The organic is separated and the aqueous is extracted with EtOAc. The organic layers are combined, washed with saturated NaHCO3, and concentrated to dryness under vacuum. The material is purified using column chromatography (silica gel, 99:1 to 95:5 CHzClj/MeOH). The fractions containing product are concentrated under vacuum to yield the amide product. General procedure 5 for the preparation of 3-(substrtuted-benzyloxy)-5-(3-dialkylaminomethyl-1Af lndol-5-yl)-pyridin-2-ylamine: FWNH To a solution of benzotriazote (1.0 molar equivalent) in dichlorometriane (0.2 M) Is added amine (1.0 molar equivalent). The reaction Is stirred for 5 minutes at room temperature after which formaldehyde (37 % by wt, 1.0 molar equivalent) Is added and the reaction capped and stirred at room temperature for 3 h. Once IXC (10 % ethyl acetate: dichloromethane) shows the consumption of starting benzotriazole the reaction is dried with anhydrous magnesium sulfate (10 g), filtered and concentrated in vacuo. The crude product is purified with a silica gel column editing with 1:1 ethyl acetate: dichloromethane to yield the desired product as a white solid. To a solution of the amlnomethylbenzotriazole intermediate (1.0 molar equivalent) in dichloromethane (0.43 M) Is added aluminum chloride (2.0 molar equivalent) followed by 3-(2,6-dichloro-benzykwy}-5-(1W-indoi-5-y))- pyridine-2-ylamin (1.1 molar equivalent). The reaction is capped and heated with stirring to 40°C for 3-4 h. The reaction is then removed from the heat and allowed to cool to room temperature. The reaction mixture is diluted with sodium hydroxide (0.2 M) and chloroform, recapped and vigorously stirred at room temperature to dissolve the residue in the vial. The chloroform is extracted away from the aqueous, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product is purified with a silica get column, first eluting with 1:1, ethyl acetate: dichloromethane, to elute the less polar impurities and then eluting the product with 90:9:1, chtoroform:methanol:animonlum hydroxide. (Yields 10-67%.) General Procedure 6 for the synthesis of 3-(Subs*Med-t>enzyloxy)-5-phenyt-pyridin-2-ylamine using 3-(3-metrtoxy-benzyloxy)-5-phenyl-pyridin -2-ylarnine: (Figure Remove) To a solution of 3-benzyloxy-5-phenyl-pyridin-2-ylamine (Example 1-87, 3.27g, 11.8mmol) in methanol (30mL) was added Pd(OH)s (2.5g, 2.37mmol). The mixture was degassed and charged with hydrogen three times, and then stirred under hydrogen balloon for 5 h. The reaction was filtered through a celite pad, washed with methanol, and condensed. After high vacuum dry. 2-amino-S-phenyt-pyrklin-3-ol was obtained (2.04g, 93% yield). MS m£187 [M+1]. To a solution of 2-amino-5-phenyl-pyridin-3-ol (2.04 g. 10.95 mmol) In THF (anhydrous, 30 ml) was added NaH (1.31 g, 32.85 mmol) slowly. The mixture was stirred under nitrogen for 20 minutes, and then trityi chloride (3.66 g, 13.14 mmol) was added. The reaction was stirred at room temperature for over night under nitrogen. The solvent was evaporated, and the residue was dissolved in dichloromethane, washed with water, and dried over Na2S04. After filtration and condensation, the crude product was purified on a silica gel column eluting with EtOAc-Hexane (1:10) to provide 5-phenyl-2- General Procedure 7 for the Synthesis of 3-(Substituted-benzyloxy)-5-Aryl-pyridin-2-ylamlne using 5-[4-(2-morpholln-4-yl-ethoxy)-phenyl]-3-(3-nitro-bet>ryloxy)-pyridirt-2-ylamine: NO, To a solution of 2-amino-5-I4-(2-morpholin-4-yl-ethoxy)-phenyl]-pyridin-3-ol (prepared according to the procedures for 2-amino-5-phenyl-pyridin-3-ol in Example 1-88 of U.S. Patent Application Serial No. 10/786.610 (PCT/US2004/005495) (45.5 mg, 0.14 mmol) in DMP (3 mL) at 0°C was added NaH (60% in oil) (5.6 mg, 0.14 mmol) and the mixture was stirred at 0°C for 20 min. Then 1-bromomethyi-3-nitro-benzene was added and the mixture was stirred at 0°C for 1 hr and at room temperature for 2hr. Cold 1 N aqueous HCI (0.1 mL) was added and the solvent was removed under reduced pressure. The residue was purified with silica gel chromatography (CHjCferMeOhtNimOH = 100:3:0,3) to give 5-{4-(2-morpholln-4-yl-ethoxy)-phef>yl]-3-{3-nitro-benzy!oxy)-pyridin-2-ylamine as yellow solid (44 mg, 68%), General Procedure 8 for the Synthesis of {4-[6-Amino-5-(substituted-benzyloxy)-pyridin-3-yl]-phenyl)-[(2fl}-2-pyrrolidin-1 -ylmethyl-pyiTolldin-1 -yTJ-methanone using {4-[6-amino-5-(4-f Iuoro-2-trifljcromethvl^nzyloxy)-pyridin-3-yl)-phenylH(2fl)-2-pyrroMn-1-ytmerhyl-pyn-olidirv1-yl]-mettianone: (Figure Remove) 1. 6-Amino-5-benzyloxy-nicotinic acid was prepared according to procedure 3 from 3- benzyloxy-S-brcmo-pyridJn-2-ylamlne and 4-(4,4.5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-t)enzolc acid. MS m/z321 (M+1). 2. (4-(6-amino-5-benryloxy-pyridin-3-vl)-phenylH(2fl)-2-pyrrolidin-1 -ylmethyl-pyrrollclin-1 - ylj-methanone was prepared following procedure 4 using 6-amino-5-benzyloxy-nicotinlc add and (2H)-pyrrolidin-1-ylmethyl-pyrrolidir»e (prepared In Example I-39 of U.S. Patent Application Serial No. 10/786.610 (PCT/US2004/005495)). MS m/z457 (M-t-1). 3. To a solution of [4-(6-amino-5-benzyloxy-pyridin^-yl)-phenyl]-[(2n)-pyrrolidln-1-ylmethyl- pyrrolidin-1-yl]-metrianone (2.28 g. 5.00 mmol) in methanol (25 mL) was added 10% Pd/C (100 mg). The mixture was degassed and charged with hydrogen for three times, and then stirred under hydrogen balloon overnight. The reaction was filtered through a cellte pad, washed with methanol, and condensed. After high vacuum dry, [4-{6-amino-5-hydroxy-pvridin-3-yl)-phenyl]-[(2R)-2- pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone was obtained (1.74 g, 95% yield). 'H NMR(400 MHz, DMSO-d«) 6 7.79 (s. 1H). 7.54 (m, 3H), 7.46 (m. 2H). 7.14 (s, 1H). 5.68 (s, 2H), 4.22 (m, 1H), 3.45 (m, 2H), 2.66 (m, 1H), 2.52 (m. 4H), 1.96 (m, 2H), 1.84 (m. 3H), 1.64 (m, 4H); MS rrvi 367 (M+1). 4. To a stirred solution of [4-(6-amino-5-hydroxy-pyrldln-3-yl)-phenylH(2fl)-2-pyrrolidln-l- ylmethyl-pyrrolidin-l-ytymethanone (100 mg, 0.27mmol) in anhydrous DMF(15 mL) under a N} atmosphere containing, at O'C, sodium hydride ($0% dispersion in mineral oil, 11 mg, 0.49mmol) was added . The mixture was allowed to stir at 0°C for 30 min. 1-(Bromomethyl)-4-fluoro-2- (trlfluoromethyl)ben2ene (0.046 mL. 0,27mmol) was added. The mixture was stirred at room temperature for 2hr.The reaction was diluted with BOAc, and partitioned with H2O. The aqueous layer was extracted with EtOAc (2 x 25 mL). The organic layers were combined, washed with HjO (1 x l5mL), brine (1 x 15mL), dried over MgSO4, filtered, concentrated, and purified on a siica gel column to yield {4.[6-amino-5-(4-fluoro-2-trrfluororrwthyl-benzyloxy)^yridln^yl3-phenylJ-[(2fl)-2- pyrroWin-1-ylmethvl-pyrrolidirv1-yll-methanone as off-white crystals. General Procedure 9 for the Synthesis 2-Dlalkylamlno-ethanesultonic add [6-amlno-5-(substituted-benzvtoxy)-pyridin-3-yl}-phenyl-amide using 2-tJiethylamino-ethanesuHonic add {4-[6-amlno-5-(2-chloro-3,6- (Figure Remove) 1. To a solution of 4-(4.4,5,5-Tetramethy)-[1,3.2]dloxaborolan-2-vl)-phenylamine (5 g, 22.8 mmol) in dichtoromethane (120 mL ) was added W-methyl morpholine (7.5 mL, 68.4 mmol). This mixture was cooled to 0"C under nitrogen atmosphere. 2-Chtoroethanesuifonyl chloride (2.5 mL, 23.9 mmol) in dlchloromethane (60 mL) was then added drop wise with stirring. Once the addition was complete the flask was stirred at 0°C for 1 hr and then at room temperature while monitoring by TLC (1:1 ethyl acetate:hexanes) and staining with ninhydrin. After 4 h stirring some starting boronic ester still remained and an additional 0.2 equivalents (0.5 mL) of 2-chloroethanesulfonyl chloride in dichloromathane (25 mL) was added drop wise at room temperature. After 1 hr the boronic ester had been consumed as shown by TLC and the total reaction volume was reduced by one-haH via rotary evaporation. The contents were diluted with ethyl acetate (200 ml), washed wrth 50% brine (2 x 100 mL), dried over anhydrous sodium sulfate and concentrated in vacuum. The crude product was purified using silica gel (120 g) and eluting with 10% ethyl acetate. dichloromethane to yield ethenesulfonic add [4-(4,4,5,5-tetramethvKl,3.2]dioxaborolan-2-yl)-phenyl]-amidea as a white solid (6.2 g. 20.2 mmol, 89% yield). 'H NMR (CDCI3, 300 MHz), 6 7.76 (d, J = 8.4, 2H), 7.12 (d. J • 8.45, 2H) 6.65 (s. 1H), 6.55 (dd, J = 9.77,6.7, 1H), 6.31 (d, J » 16.54, 1 H), 5.96 (d, J « 9.8.1 H), 1.33 (s. 12H). 2. To a solution of ethenesulfonic acid l4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-v1}- pher»yl]-amide (0.500 g, 1.6 mmol) in methanol (5 mL) was added dlethylamine (0.707 g, 4.0 mmol) in methanol (S ml), and the reaction was stirred at room temperature and monitored by TLC (1:1 Ethyl acetate: hexanes). After 2 hr the reaction was concentrated in vacuum and the residue partitioned between ethyl acetate (50 mL) and water (50 mL). The ethyl acetate was then washed with 50% brine (1 x 50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. Crude product was purified using a 10 g prepacked silica gel column, etutlng with 1:1 ethyl acetate: dichloromethane to provide 2-diethyiamino-ethanesulfonic acid (4-(4,4,5,6- tetramethyHi,3,2]dtoxaborolan-2-vt)-prttnyl]-amtde as a white solid (0.346 g, 0.90 mmol, 56%). 1H NMR (CDCIs, 300 MHz) fi 7.78 (d, J • 6.85, 2H) 7.15 (d. J « 6.66. 2H). 3.20 3. 2-diethylamino-ethanesulfonlc acid [4-[6-amino-5-(2-chloro-3.6-dlfluoro-benzyloxy)- pyrldin-3-ylJ-phenyiJ-amide was prepared following the general Suzuki coupling procedure 3 from 5- bromo-3-(2-chloro-3,6-dlfluoro-benzyloxy)-pyrldin-2-y1amine and 2-dlethylamino-elhanesulfonic acid [4-(4,4,5.5-tetramethyl-[1,3.2)dloxaborolan-2-yl)-pheny1].amide prepared in part 2 as a white solid in 60% yield. General Procedure 10: 1: 4-(4,4,5.5-tetramethyl 1,3,2 dloxaboralan-2-yl) aniline (3 g, 0.013 mol) was dissolved in dichtoromeihan* (350 mL) to which pyridine (1.02 g, 0.013 mol) and 4-nrtrophenyl chtoroformate was added. The reaction was stirred for 13 hr where TLC analysis showed consumption of all starting materials. The solution was washed with saturated NaHCO3 (3 x 50 mL), water (3 x 50 ml) and brine (3 x 50 mL). The organic layer was dried over Na2SO4 and solvent removed to yield a white crystalline solid {4.(4,4,5.5-Tetramelhyl-[1,3,2]dioxaborolarh2-yt)-phenyl]-carbamic acid phanyl ester, 4.45 g, 91%. 'H NMR (CDCI3 300 MHz; 6 1.4 (s, 12H), 7.1 (brs, 1H), 7.3 (d, 2H), 7.5 (d, 2^,7.8(^2^, 8.3 (d.2H). 2: [4-(4,4,5,&-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyt]-caifaamic acid phenyl ester (500 mg, 1.3 mmol) was dissolved in anhydrous dichloromethane (0.5 mL) and triethylamine (0.187 mL, 1.3 mmol). To this stirred solution was added 1-methyl piperazine (or any other amine) (0.144 mL, 1.3 mmol). The solution turned yellow instantly, and tic analysis showed consumption of aN starting material. The reaction was washed with water (3 x 500 mL), saturated sodium bicarbonate (2 x 200 mL) and dried prior to removal of solvents in vacuo. The boronic esters were used without purification. 3: To a mixture of 2.1 mL of DME and 2.8 mL of 2N Na2CO3 was added 100 mg of the bromide scaffold. 1 equivalent of the boronic acid, and 5 mot % of PdfPPha)* The reaction was stirred and heated at 80"C overnight in a two dram vial. The crude mixture was filtered through ceolite and extracted with EtOAc (2 x 100 mL). The combined extracts were washed with NaHCO3 (1 x 100 mL), followed by water (1 x 100 mL), and then saturated brine (1x 100mL). The resulting mixture was concentrated In vacuum. The residue was dissolved in hexane and purified via column chromatography. General Procedure 11: (Figure Remove) , 1: To a solution of 3-[1-(2,6-Dichloro-3-fluoro-phenyl}-«thoxy]-pyridin-2-ylamine (10.0 g, 33.2 mmol) in acetonrtrHe (600 ml) and acetic acid (120. ml) was added N-iodosuccinimide (11.2 g. 49.8 mmol). The mixture was stirred at room temperature for 4 hr and the reaction was quenched with NajSjOs solution. After evaporation, the residue was partitioned between ethyl acetate and water. The organic layer was washed with 2N NaOH solution, brine, and dried over NajSO«. The crude product was purified on a silica gel column to provide 3-[l-(2,6-dichtoro-3-fluoro-phenyl)-ethoxy)-5-iodo-pyridin-2-ylamine (7.1 g, 50% yield).MS /n&427 [M+1] 2: To a solution of 3-(1-(2,6-DichlOro-3-fkJoro-phenyl)-ethoxy]-5-iodo-pyridin-2-ylamine (7.1 g, 16.8 mmol) and prop-2-ynyl-caifoamic acid tert-butyt ester (3.1 g, 20.0 mmot) In THF (60 mL) and et3N (60 mL) was added Cul (63 mg, 0.3 mmol} and Pd(PPh3)4 (384 mg. 0.3 mmol). The mixture was stirred under nitrogen and monitored by TLC until the reaction waa complete. The mixture was extracted with EtOAc and washed by water. The crude product was purified on a silica gel column eluting with 20-40% EtOAc in hexanes to provide (3-{6-Amtno-5-(1-(2,6-dichtoro-3-fluoro-pherryl)-ethoxyl*pyridln-3-yl}-prop-2-ynyl)-carbamic acid tart-butyl ester (2.2 g. 29% yield). 3: The solution of (3-{6-Amino-5-[1-(2,6-dlchloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-y1}-prop-2-ynyl)-carbamic acid tert-butyl ester in 25% TFA in dchloromethane was stirred for 2 hr, then washed by 2N NaOH, water twice, brine, dried over Na^O* After filtration and evaporation, S-(3-amino-prop-1-ynyl)-3-[1-(2,6-dichlorQ-3-fluoro-pher»yl)-«thO)cy]-pyridif>-2-vlamine was obtained in 93% yield. 4: To a solution of 5-(3-amirw-prop-l-ynyl)-3-[1-(2,6Hliohloro-3-fluoro^henyi)-einoxy]' pyridtn-2-ylamlne (0.282 mmol, 1 eq) and 4-nitrophenyt chloroiormate (1 eq) in anhydrous dtehtoromethane (10 nil) was added pyridine (1 eq). The reaction was stirred for 4 hr under nitrogen, and then the selected amine (1 eq) and triethvtamine (1 eq) were added. The mixture was refluxed for 5 minutes and cooled to room temperature. The reaction mixture was washed with water. The organic layer was evaporated and purified on a silica gel column eluting with 0-20% methanol in dtchtoromethane on prepacked silica columns. Final yields varied between 24% and 71%. General Procedure 12: (Figure Remove) 1: To a solution o» 5^3-arftirK>prev-1'ynyl)-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-yiamine (prepared in procedure 11) (400 mg, 1.1 mmol) in dichloromethane (17 ml) was added chloroacetyl chloride (153 mg, 1.4 mmol). The reaction was stirred at room temperature with TLC monitor of the completion of the reaction. After the completion, the solvent was evaporated to get the crude product. 2: To a solution of N-{3-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridiiv3-yO-prop-2-ynyl)-2-chloro-acetamide (1 eq) in acetortitrlle (5 eq) was added tha individual amine (5 eq). The mixture was refluxing under nitrogen overnight After evaporation of solvent, the residue was purified on a silica gel column eluting with 1-10% methanol in dichloromethane to provide the product with yields varied between 47% to 97%. (Figure Remove) (Figure Remove) (Figure Remove) vGeneral Procedure 13: 1. To a stirred solution of 2-amino-3-benzyloxvpyridine (42.0 g, 0.21 mol) in CH3CN (600 mL) at 0*C was added N-bromosuccinim'»ds (37.1 g, 0.21 mot) over 30 minutes. The mixture was stirred for 0.5 hr, after which the reaction was then diluted with EtOAc (900 mL) and partitioned with HgO (900 ml). The organic layer was washed with brine and dried {NaaS04). filtered and concentrated to dryness under vacuum to yield 3-benzyloxy-5-bromo-pyridin-2-ylamine (31.0 g, 0.11 mol. 53%). 'H NMR (CDCI3. 300 MHz) 8 4.63-4.78 (bi*. 2H). 5.04 (s, 2H), 7.07 (d, 1H, J, 1.8 Hz), 7.33-7.42 (m, 5H), 7.73 (d, 1K, J, t .8 Hz). 2. To a stirred mixture of 3-benzyloxy-5-bromo-pyridin-2-ylamine (31.0 g. 0.11 mol) in a mixture of DME (600 mL) and H2O (600 ml) was added 4-cartaoxymethylboronic acid (29.9 g, 0.11 mol), Pd(PPh3)4 (6.4 g, 5.55 mmol). and NajCOs (82.0 g. 0.78 mol). The reaction was heated slowly to reflux and allowed to stir for 3 hr. The reaction was cooled to room temperature, then diluted with CH2CI2 (1.5 L) and partitioned with HZO (700 mL). The organic layer was washed with saturated NaHCOa (700 mL), dried (NazSO*), filtered, and concentrated in vacuo. The crude material was purified by column chromatography (silica gel, 1:1 to 4:1 EtOAc:hexanes) and the fractions containing product were combined and concentrated in vacuo to yield 4-{6-amino-5- benzytoxy-pyridin-3-yl)-banzoic acid methyl ester (29.4 g, 0.086 mol, 79%). 1H NMR (CDCI3, 300 MHz) t> 3.92 (8, 3H), 4.82-4.94 (brs, 2H). 5.15 (S, 2H). 7.22 (d, 1H, J, 1.8 Hz), 7.33-7.42 (m. 5H), 7.54 (d, 2H. J, 8.6), 7.98 (d. 1H. J, 1.8 Hz), 8.06(d, 2H. J, 8.6 Hz). 3. To a stirring solution of 4-(6-amino-5-benzyloxy-pyridin-3-yl)-benzoic acid methyl ester (10.0 g. 0.03 mol) in EtOH:H2O (95:5, 600 mL) was added Pd/C (15.9 g, 0.015 mol) (the reaction was de-gassed under vacuum). The solution was allowed to stir under an HZ atmosphere for 22 hr. The solution was filtered through wet cetite and the celite washed with EtOH. The filtrate was conoentrated under vacuum to yield 4-(6-Amino-5-hydroxy-pyridin-3-yl)-tonzoic acid methyl ester (2.3 g, 9.3 mmol, 31%). 'H NMR (MeOO, 300 MHz) B 3.90 (s, 3H), 7.21 (d, 1H, J, 1.9 Hz), 7.62 (d, 2H. J, 8.5 Hz). 7.76 (d. 1H. J, 1.9 Hz). 8.04(d, 2H. J, 8.5 Hz). 4. To a stirring solution of 4-(6-amino-5-hydroxy-pyridin-3-vl)-benzoic acid methyl ester (2.3 g. 9.3 mmol) in CHjClj (180 mL) was added N.N-diisopropvlethvlamine (32 mL, 0.019 mol), 4- methyi-benzenesuHonyi chloride (2.66 g. 0.014 mol), and PS-DMAP (catalytic amount). The reaction was stirred at ambient temperature for 6 hr then filtered to remove the resin. The resin was washed with CHjCfe (3 x 20 ml), and the combined fractions were washed with 10% citric acid (100 ml), saturated Nad (100 mL), dried (NaaSO«) and filtered and concentrated in vacua The resulting crude material was purified by column chromatography (silica gel, 100% CH2CI2 to 95:5 CHjCI^MeOH) and the fractions containing the desired product were combined and concentrated in vacuo to yield 4-(6-Amino-5*(toluene-4-sulfonyloxy)-pyridin-3-yl}-benzoic acid methyl ester (3.3 g. 8.2 mmol, 88%). 1H NMR (COCIa, 300 MHz) 6 2.47 (s, 3H), 3.93 (S, 3H). 4.81-4.86 (brs, 2H). 7.36-7.44 (m, 5H), 7.81 (d, 2H, J, 8.3 Hz). 8.05 reaction was allowed to stir for 0.5 hr. A solution of 4-t6-Amino-5-(k5luene-4-sutfony!oxy)-pyrWitv3- yl]-toen20ic acid methyl ester (3.8 g, 9.6 mmol) in anhydrous DMF (30 mL) was added to the reaction mixture which was allowed to come to ambient temperature slowly and stirred for 21 hr at this temperature. The reaction was diluted with EtOAc (500 ml) and HjO (100 mL). The organic layer was separated off and the aqueous was further extracted with EtOAc (1 x 200 mL). The organic layers were combined and washed with brine (1 x 100 mL), dried with Na2S04 and concentrated 10 dryness under vacuum. The crude mixture was purified by column chromatography (slice gel, 40:60 to 70:30 EtOAc:hexanes) and the fractions containing product were combined and concentrated in vacuo to yield 4-{6-amino-5-[1-(3-fluoro-2-trifluoromethyl- phenyl)-ethoxy]-pyrldin-3-yl}-benzoic acid methyf ester (1.4 g. 3.2 mmol, 34%). 'H NMR (CDCI3, 300 MHz) fi 1.73 (d, 3H, J, 6.2 Hz), 3.91 (s. 3H), 4.87-4.64 (brs, 2H), 5.81 (q, 1H. J, 6.1. 6.3 Hz), 6.92 (d, 1H, J, 1.8 Hz), 7.38 (d, 2H, J, 8.6 Hz), 7.46-7.66 (m, 3H), 7.93 (d, 1H, J, 1.8 Hz), 8.02 (d, 2H, J, 8.5 Hz). 6. To a stirred solution of 4-{6-amlno-5-(1-(3-fluoro-2-trHluoromethyl-phenyl)-etnoxy]- pyridin-3-yl}-benzoic acid methyl ester (1.4 g, 3.2 mmol) in warm IPA (72 mL) was added HjO (38 mL) containing LJOH (0.68 g, 16.2 mmol). The reaction was heated to reflux for 3.5 hr. The reaction was neutralized and diluted with EtOAc (200 ml) and extracted upon cooling. The organic layer was washed with brine (50 mL), dried over Na2S04 and concentrated under vacuum to yield 4-i6-Amino-5-[1-(3-fluoro-2-lrifluoromethyt-phenyl)-ethoxy)-pyridin-3-yl)-benzoic acid (1.2 g, 2.8 mmol, 86%). 'H NMR (MeOD. 300 MHz) 1.8 Hz). 7.39 (d, 2H, J, 8.3 Hz). 7.52-7.67 (m. 3H), 7.80 (d, 1H. J, 1.8 Hz). 7.97 (d, 2H, J, 8.3 Hz). 7. Preparation of amide compounds: A stirring solution of 4-{6-Amino-5-[l-(3-fluoro-2- trilluoromethyl-phenyl)-ethoxy]-pyridin.3.yl}-benzolc acid (50 mg, 0.12 mmol). EDO (27.0 mg, 0.13 mmol) and HOBt (18.0 mg, 0.13 mmol) in DMF (2 mL) was added to a two dram vial containing NHR,Rz(0.12 mmol). The reaction was stirred at room temperature for 18 hr. The reaction was then diluted with CHjClj (3 mL) and partitioned with Hzo. The organic was separated washed with saturated NaCI (1x2 mL) and saturated NaHCO3 (1x2 mL). The organic was concentrated to dryness under vacuum. The material was purified using column chromatography (silica gel, 99:1 to 95:5 CHjClj/MeOH). The fractions containing product were concentrated under vacuum to yield amide compounds. General Procedure 14: 1: To a mixture of 1-(2-chloroethyl)pyrrolidine hydrochloride (200 mg, 1.18rrvnol) and 4-[4-(4,4,5,5-TetramethyK1)3,2]dk)xaborolan-2-yl)-phenyl]-1H.pyrazole (229 mg, 1.19 mmof) in DMF (6 mL) was added C*jCO3. The mixture was stirred at room temperature overnight. Water {10 mL) was then added to the mixture. The product was extracted with EtOAc (3 x 10 mL). The combined extracts were then washed with brine (5x10 mL) to remove the OMF, then dried over Na2SO 2: To a mixture of 3-[1-(2,6-Dichloro-3-fluoro-phenyl)-etnoxy)-5-iodo-pyridin-2-ylamine (200 mg, 0.468 mmol}, pinacol taoronfc ester (1.2 eq), Na2CO3 (149 mg, 1.41 mmol) in water (1.25 mL). and dimethyl ethyl gtycol (3.75 mL, 0.1 M) was added Pd(PPh3)2Clz (16 mg, 0.020 mmol) in a microwave reaction vessel. The system was degassed and charged with nitrogen. The mixture was stirred at 160°C in a microwave apparatus for 15 minutes. The mixture was cooled to room temperature followed by tie addition of water (10 mL). The product was extracted with EtOAc (3 x 20 mL), dried over Na2SO4, and concentrated. The crude product was purified by reverse phase HPLC with o. 1 % TFA In water and acetonitrite. General Procedure IS: ACN/AoOH -NH O 1: To a solution of 3«-oxazolo(4.5-b]pyridin-2-one (13.6 g, 100 mmol) in acetonitrile (600 mL) and acetic add (120 mL) was added N-bromosuccinimide (21.4 g, 120 mmol). The mixture was stirred at room temperature for 4 hr and the reaction was quenched with NajSjOs solution. After evaporation, the residue was partitioned between ethyl acetate and water. The organic layer was washed with 2N NaOH solution, brine, and dried over Na2SO«. The crude product was purified on a silica gel column to provide 6-bromo-3Hoxazolo[4l5-b]pyridin-2-one (11.5 g, 55% yield). 2: e-Bromc-SH-oxazolo^.S-bjpyridin-S-one (21.5 g, 100 mmol) was suspended in NaOH solution (2N, 250 mL, 500 mmol). The mixture was refluxed overnight and a clear solution was obtained. After cooling to room temperature, the reaction solution was neutralized to pH -7. A lot of COj was released and also precipitate was observed. The product was filtered, washed with water, and dried under high vacuum to provide 2-amino-5-bromc-pyridirt-3-ol as an off-white solid (17.8 g, 98% yield). 3: To a solution of 2-amino-5-bnomopyridin-3-ol (356 mg, 1.89 mmol) in DMF (8 mL) was added CsjCOs (620 mg, 1.89 mmol). The mixture was stirred at room temperature under nitrogen for 1 hr. To the reaction mixture was added bromo-compound (0.9 eq) in DMF (5 mi.) slowly. The reaction solution was stirred under nitrogen for five hr, and then partitioned between water and ethyl acetate. The organic layer was washed with brine for three times, dried over MgSO«. The crude product was purified on a silica gel column eluting with hexane-ethyl acetate (4:1) to provide the product with 70%-80% yield. Generai Procedure 16 using Example 1*488 of U.S. Patent Application Serial No. 10/786,610 (PCT/US2004/0054B5): 1. To a solution of 3-benzylaxy-5-bromo-pyridln-2-ylarnlne (1 g, 3.58 mmol) in dtmethylsLitfoxide (7 ml) was added sequentially bis(pinacolato)dtoorane (1.0 g, 3.94 mmol), potassium acetate (1.05 g. 10.7 mmol) [1,1'-bis(dlphenylphosphino)ferroclne]d!chloropailaoium (II). complex wilh dichloromethane (1:1) (146 mg, 0.18 mmol). The mixture was heated to 80°C for 16 hr and then cooled to room temperature. The reaction mixture was diluted with ethyl acetate (50 mL) and filtered. The filtrate was washed with water (2X50 mL) and dried over magnesium sulfate. Concentration In vacuo yielded the crude boronate as a brown solid (1.13 g, 97%). 1H NMR (CDCI3) 8 1.32 ($, 12 H), 5.08 (s, 2H), 5.44 (brs, 2H), 7.33-7.42 (m, 6H), 8.03 (s, 1H). 2. An 18 mL reaction vessel was charged with the crude 3-benzytoxy-5-(4,4,5,5- tatramethyt-[1,3,2]dtoxaboro!an-2-yl)-pyridin-2-vlamine (161 mg, 0.49 mmol), dimethoxvethane (3 mL) and 2-bromopyridine (117 mg, 0.74 mmol). To this solution was added [1.V- bis(diphenylprio3phino)ferroclne)dichloropalladlum (II), complex with dichloromethane (1:1) (20 mg, 0.05 mmol) and a 2 M solution of cesium carbonate in water (0.75 mL, 1.5 mmol). The reactor was warmed to 80"C for 66 hr under a nitrogen atmosphere, then cooled to room temperature. The reaction mixture was partitioned between ethyl acetate (5 mL) and water (5 mL). The organic layer was washed with additional water (5 mL) and diluted wHh dimethylformamide (5 mL). Polymer- bound sullonic add (0.5 g, 2.1 mmol) was added to the organic solution, and the resulting mixture was gently agitated for 2 hr. The resin was filtered and washed with dimethylformamide, methanol and mathylene chloride (3X5 mL each solvent). Then the polymer was reacted with 2 M ammonia in methanoi for 1 hr. The resin was filtered and washed with additional 2 M ammonia in methanol (2X5 mL). and the combined filtrates were concentrated in vacuo. Purification of the crude product by flash column chromatography yielded 52.2 mg of product as a tan solid (38% yield). General Procedure 17: 1. To the solution of 3-(2-ChlorO'3,6-difluoro-benzyloxy)-5-(414,5)5-t8tramethyi- [1,3,2]dioxaborolan-2-yl)-pyridin-2-ylafnine (procedure 16) (10.0 g. 24.3 mmol) in f-butyl alcohol (50 ml) was added boc anhydride (5.83 g. 26.7 mmol) and reaction stirred at room temperature overnight. Additional boc anhydride (2.25 g, 10.3 mmol) was added and reaction stirred overnight again. Material was concentrated to a viscous black oil and used as-is. 2. The crude boronic ester (24.3 mmol theoretical) in THF (150 mL) was added to a solution of sodium bicarbonate (16.3 g, 194 mmot) in water (150 mL) and acetone (23 mL). The mixture was cooled to 2"C and oxone (13.5 g, 21.9 mmol) added slowly, keeping temperature below 8°C. Upon completion of addition, reaction was stirred fro 5 minutes then quenched with sodium bisulfite (14.2 g) in water (28 mL). Ethyl acetate was added (200 mL) and layers separated. Aqueous layer was neutralized with 6N HCI and extracted with ethyl acetate (2x200 ml). Combined organics were washed with watar (250 mL) and brine (250 mL), dried (Na2SOr) and concentrated to a crude black oil. Silica gel chromatography (ethyl acetate/hexane) gave the product as a light brown foam (4.78 g, 49.0 %). *H NMA (CDCIJ 5 1.48 (s, 9H), 1 .74 (d, 3H), 5.75 (q, 1H). 6.61 (d, 1H). 76.89 (dt, 1H), 6.94-7.04 (m, 2H), 7.26(d, 1H), 8.19 (bs, 1H). MS mfr 401 3. To cesium carbonate in a 2 dram vial was added [3-(2-Chloro-3,6-difluoro-benzyloxy)-5-hydroxy-pyridln-2-vl]-carbamic acid ten-butyl ester (100 mg, 0.25 mmol) in anhydrous DMF (1 mL) followed by benzyl bromide (89.2 uL, 0.75 mmol). The vial was capped and stirred at 90°C overnight. Reaction was filtered through a 5 mL Chem-Elut lube pre-wetted with water (3.5 mL) and eluted with 1:1 ethyl acetatermethylene chloride. After partial concentration, 4N HCI in dioxane (1-2 mL) was added and solution concentrated. Reverse phase chromatography (water.acetonitrHe, 0.05% TFA) followed by lyophilizatton, gave the desired product as an off white amorphous solid (25.3 mg, 20.0 %) and the bis-addWon product as a tan amorphous solid (35.2 mg,23.7%). General Ppjcedure 18: n(Figure Remove)dium borohydride (1.5 molar equivalent) is added to solution of ketone {3.89 mmol) in 10 mL of ethanol under a nitrogen atmosphere. The resulting mixture is stirred at room temperature for 12 hr. The mixture is then put in an ice bath and quenched with dilute aqueous HCI. The ethanol is evaporated and EtOAc is added to extract the aqueous solution. The EtOAc layer is dried over Na;S04. The NazS04 is filtered off and the filtrate evaporated to give a oil residue, compound A5. The residue is used without further purification. 3-Hydroxy-2-nitropyridine (1.1 molar equivalent) and triphenylphosphine (1.5 molar equivalent) are added to a solution of compound AS (1.1 mmol) in 10 mL of THF. The reaction mixture is then put in an ice bath and diisopropyl azodtcarboxytate (1.5 molar equivalent) is added. The ice bath is removed and the mixture stirred at room temperature for 12 hr. The solvent is evaporated to give a yellow oil residue. The residue is purified by silica gel chromatography (editing EtOAc in hexanes) to give compound A1. 2 M HCI (0.2 mL) is added to solution of compound A1 (0.97 mmol) in 2 ml of ethanol. The mixture is then put in an ice bath and Fe powder (365 mg) is added slowly. The reaction is heated to 85'C for 1 hr and cooled to room temperature. Celite (0.5 g) is added to stir and the resulting mixture is filtered through a bed of cetite and rinsed with ethanol. The filtrated is evaporated to give a brown oil residue, compound A2. The residue is used without further purification. Periodic acid (0.25 molar equivalent), iodine (0.5 molar equivalent), H2O (0.5 ml), and concentrate sutfuric acid (0.03 ml) are added to a solution of compound A2 In 3 mL of acetic acid. The reaction mixture is heated to B5°C for 5 hr. The reaction mixture is then cooled in an ice bath and basifled with saturated aq. Na,C03 to a pH of 3-4. Ethyl acetate is added to extract the aqueous solution. Dry EtOAc layer over Na2SO4. The NajSO* is filtered off and the filtrated evaporated to give a brown oil residue. The residue is purified by silica gel chromatography (eluting with EtOAc and hexanes) to give desired product, compound A3. General Procedure 19: NHj Rj A3 Boronic ester or boronic acid (1.3 molar equivalent) Is added to a solution of compound A3 (0.47 mmol) in 5 mL of DME. The mixture was purged with nitrogen several times and then dichlorobis(triprwnytphosphlno) palladium (II) (0.05 molar equivalent) is added. Sodium carbonate (3 molar equivalent) in 1 mL of HjO is added to the reaction mixture and the resulting solution heated to B5°C for 12 hr. Water is added to the reaction mixture to quench the reaction. EtOAc is then added to extract the aqueous solution. Dry EtOAc layer over Na2SO4. The NazS04 is tittered off and the filtrated evaporated to give a dark brown oil residue. The residue is purified by silica gel chromatography (eluting with CH3OH, CH2CI2, EtOAc, and hexanes) to give desired product, compound A4. llowish to white solid. General Procedure 22: AS AID A11 Compound Ad is prepared using general procedure 19. Di-te/t-butyJ dicarbonate (3 molar equivalent) and 4-(dimethylamino)pyridine (0.14 molar equivalent) are added to a solution of compound A9 (3 mmol) in 20 mL of DMF. The reaction mixture is stirred at room temperature tor 12 hr. Water Is added to the reaction mixture to quench the reaction. EtOAc is then added to extract the aqueous solution. Dry EtOAc layer over NazSO*. The Na2SO4 is filtered off and the filtrated evaporated to give a brown yellow oil residue. The residue is purified by silica gel chromatography (etuting with 25-+30 % EtOAc in hexanes) to give desired product, compound A10 as a yellowish oil (87.8% yield). Ozone Is bubbled through a solution of compound A10 In 50 ml of CHjCls at -78°C and dimethyl sulfide is added to quench the reaction. Saturated sodium chloride is added to the reaction mixture and EtOAc is added to extract the aqueous solution. Combined EtOAc layer is dried over Na?SO4. The NajSO4 is filtered off and the filtrated is evaporated to give a yellow oil residue. The residue is purified by silica gel chromatography {eliring with 35-+40 % EtOAc in hexanes) to give desired product, compound A11 as a yellowish oil (58.4% yietd). General Procedure 23: Reductive Amination NHZ A12 A13 Amlne nydrochtoride salt (1.2 molar equivalent), sodium acetate (2 molar equivalent to the amine hydrochloride salt) are added to a solution of compound A11 (0.45 mmol) in 4 ml of CH3OH under a nitrogen atmosphere. Molecular sieve (O.S g) is added to the reaction mixture and then sodium cyanoborohydride (2 molar equivalent) is added. The resulting mixture is stirred at room temperature for 12 hr under a nitrogen atmosphere. The reaction mixture is filtered through a bed of celtte and the filtrate is evaporated and purified by silica gel chromatography (elating CH3OH, EtOAc, and CH2CL2) to give desired product, compound A12 as an oM (52.6% yield). Add (16 molar equivalent or less) is added to compound At 2 (0.17 mmol) at room temperature. The resulting solution is stirred at room temperature or heated to 60°C for 12 hr. The reaction mixture is evaporated and the residue was purified by silica gel chromatography (eluting with CHaOH, EtOAc and CHzCla) to give desired product, compound A13. General Procedure 24: NH2 A11 AH A15 Ofihenyldiamines (1.2 molar equivalent) and sodium bisulfite (2.1 molar equivalent) are added to a solution of compound A11 (0.41 mmol) in 5 mL of DMA. The resulting solution is heated to 110°C for 12 hr. Water is added to the reaction mixture to quench the reaction. EtOAc is then added to extract the aqueous solution. Dry EtOAc layer over Na2SO4. The Na2SO4 is filtered off and the filtrated is evaporated to give a brown yellow oil residue. The residue is purified by silica gel chromatography (editing with EtOAc in hexanes) to give desired product, compound A14. Acid (16 molar equivalent or less) is added to compound A14 (0.16 mmol) at room temperature. The resulling solution is stirred at room temperature or heated to 60°C for 12 hr. The reaction mixture is evaporated and the residue is purified by silica gel chromatography (etuting with CH3OH, EtOAc and CHzClj) to give desired amide product, compound A15. General Procedure 25: (Figure Remove) NH2 Di-tert-buty! dicarbonate (3 molar equivalent). 4-(dimctriy1amlno)pyrldine (O.U molar equivalent) are added to a solution of compound A3b (2 mmol) in 10 ml of DMF. The reaction mixture is stirred at room temperature for 12 hr. Water is added to the reaction mixture to quench the reaction. EtOAc la then added to extract the aqueous solution. Dry EtOAc layer over Na{S04. The Na2SO4 Is filtered off and the filtrated is evaporated to give a brown yellow ol residue (compound a18). The residue Is used without further purification. Bis(pinacolato)diboron (1.2 molar equivalent) and potassium acetate (3.4 molar equivalent) are added to a solution of compound a16 in 4 ml of DMSO. The mixture is purged with nitrogen several times and then dichlorobie(trlphenylphosphino) palladium (II) (0.05 molar equivalent) is added. The resulting solution is heated to 80°C for 12 hr. Water is added to the reaction mixture to quench the reaction. EtOAc is then added to extract the aqueous solution. Dry EtOAc layer over NajSO*. The Na3S04 is filtered off and the filtrated is evaporated to give a dark brown oil residue. The residue is perilled by silica gei chromatography (eluttng with 30% EtOAc in hexanes) to give desired product, compound A17 (76% yield). HCI (5 molar equivalent) is added to a solution of compound A17 (0.43 mmol) in 4 mL of CHjClj. The resulting mixture Is heated to SO'C for 12 hr. Saturated NaHCOa is added to (he reaction mixture to neutralize the reaction. EtOAc is then added to extract the aqueous solution. Dry EtOAc layer over NajSO4. The Na2S04 is filtered off and the filtrated is evaporated to give the desired product (compound A18) as a yellow solid (75% yield). To a mixture of 4-|4-(6-Amino-5-hydroxy-pyric»n-3-y1)-t)en2oyl)-2,6-dimethyl-pipera2ine-l-cart)oxy1ic acid tert-butyl ester (50 mg, 0.12mmol) and 1-(1-bromoethyl)-2-trifluoromethyl-benzene (32 mg, 0.12 mmol} in DMF (2 ml) was added 2 M CszC03 (0.18 ml, 0.35 mmol), followed by water (0.5 ..mL). the mixture was stirred overnight then heated at 70°C for 6 hr, LCMS showed that the reaction was completed. The DMF and water were removed. TPA (2 mL was added to the residue and stirred at room temperature for 3 hr. The TFA was removed, followed by addition of methanol. The residue was purified by prep-HPLC to afford (4-{6-amino-5-[l-(2-trifluorometr)yl-phenyl)-eihoxyJ-pyridin-3-yJ}-phanyl)-(3,5-dimethyl-pipera2Fn-1-yl)-methanone (20 mg, yield 34.2%). General Procedure 34: using {4^&'Amino-5-(2-met^yl-ben2yloxy)-pyri(an•3•y1]•phe^yl}-(3,5-dlmethyl-piperazin-1-y1)-methanone M»C. 0 HjC Br HO Inttai To a mixture of (2R,6S)^-[4-(6-Amirx>5-hyaroxy-pvridin-3-yl)-benzoyl]-2,6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (100 mg, 0.23 mmol) and 1-bromomethyl-2-methyl-benzene (47 mg. 0.25 mmol) in DMF(2 ml) was added 2 M CsjCOa (0.35 mL, 0.7 mmol) folowed by water (0,5 mL). The mixture was stirred at room temperature overnight. LCMS showed the reaction was completed, DMF was removed, followed by addition of 4 N HCI in dioxane (2 mL) and the. reaction was stirred at room temperature for 3 hr. The volatiles were removed followed by addition of methanol. This solution was purified by prep-HPLC to afford {4-l6-Amino-5-(2-methyl-benzyloxy)-pyridin-3-ylJ-ph«nyl)-(3,5-dimethyl-piperazin-1-yl}-methanone (47 mg, yield 46.6%). General Procedure 35: using (6-amino-3-aza-blcyclo[3.1.0]hex-3-yl)-(4-{6-amino-5-[1-(2,6-dichloro 3-fluoro-phenyl)-ethoxy>pyridin-3-yl)-phenyl)-methanone OME2) To a mixture of [3-{4-lodo-Denzoy()-3-aza-bicyc!o[3.1.0]hex-6-yl]-carbamic acid tert-butyt ester (10 mg, 0.234 mmol) and 3-[1-(2,6-dlctiloro-3-fiuoro-phenyl)-€trioxyl-5-(4,4,5,5-tetoame1hy [1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine (100 mg. 0.234 mmol) in DME (2 mL) was adde Pd(dppf)2CI2.CH2Cl2 (10 mg, 0.012mmol) and CsjCOa (351 mg, 0.702 mmol). The mixture was bubbled with nitrogen for 10 min then microwaved at 150'C for 30 rnln. LCMS checked that the reaction was completed. The crude reaction mixture was diluted with ethyl acetate followed by washings with water and brine. The solution was dried over MgSO«. Purification by prep-HPLC afforded a solid. The solid was stirred with 4 N HCI/dioxane (3 mL) for 3 hr at room temperature. Removal of the volatiles led to a residue that was purified by prep-HPLC to afford (6-amino-3-aza General Procedure 36: using ethoxy)-[3,3']bipyridir>yl-6-ylamine 5-[1-(2.6-Dictiloro-3-fluoro-phenvl)-ethoxy]-6'-(2-morpholin-4-yl- NH, To a mixture of 6'-amino-5'-11-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-[3,31]bipyrtdinyl-6-ol (78 mg, 0.20 mmol), trlphenylphosphine (63 mg, 0.24 mmol) and 2-morpholin-4-yl-ethanol (0.026 mL, 0.22 mmol) was added DEAD (0.034 mL, 0.22 mmol). After stirring overnight more PPfa (63 mg, 0.24 mmol) and more DEAD (0.034 ml, 0.22 mmol) were added. After several hours, more alcohol (0.026 mL, 0.22 mmol) was added. After several more hours, more PPha (63 mg, 024 mmol) and more DEAD (0.034 ml, 0.22 mmol) were added After stirring overnight, the mixture was partitioned between dicNoromethane and half-saturated brine. The phases were separated and the aqueous phase was extracted with dichtoromethane. The combined organic phases were dried over Na2SO-etrtoxyl-6'-(2-morpholin-4-yl-ethoxy)-l3,3']bipyridinyl-6-ylamine (53 mg. 53%). General Procedure 37: using Example I-650 of U.S. Patent Application Serial No. 10/786,610 (PCT/US2004/005495) 3-(2,6-Dichloro-3-fliJoro-benzytoxy)-5^hiazol-2-yl-pyridin-2-ylamine: To a microwave tube equipped with a stir bar was added the iodo-pyridyl starting material (300 mg, 0.702 mmol), tetrakis(triphenylphosphine) palladium (0) (40 mg, 5 mol%) and tetrahydraluran (anhydrous, 6 mL). The vial was capped and purged with nitrogen for 5 minutes. 2-Thiazolylzinc bromide (0.5 M in THF, 1.4 mmol, 2.8 mL) was then added via syringe. The vial was heated to 120°C in the microwave for 10 minutes. TLC (1:1 ethyl acetetate-.methylene chloride) showed a large amount of starting material remaining. Additional 2-«hiazolyl2inc bromide (0.5 M in THF, 500 \>L) was added and the vial was heated to 120"C in the microwave for 20 minutes. TLC (1:1 ethyl actetate:methylene chloride) showed a large amount ol starting material still remaining. Additional 2-thiazolylzinc bromide (0.5 M hi THF, 500 jiL) was added and the vial was heated to 120°C in me microwave for 60 minutes. TLC (1:1 ethyl actetateimethylene chloride) still showed a large amount of starting material stitl remaining but also had become very messy. The vial contents were poured into a sat. NHjCI solution (10 ml) and this solution extracted with ethyl acetate (2 x 30 mL). The combined ethyl acetate layers were dried over NajSO4, filtered and concentrated in vacuo. The crude product was loaded onto a 10 g prepacked silica gel column and 1:1 ethyl acetate:methylene chloride used to elute the desired product. (40 mg, 15%). General Procedure 36: using Example 1-652 of U.S. Patent Application Serial No. 10/786,610 (PCT/US2004/005495) NH, F 3-[1 -(2,6-Dichloro-3'fluoro-phenyl)-emoxy]-5-(1 -methyl-1 H-imidazol-2-yl)-pyridln-2-ylamine: N General Procedure 39: using Example I-657 of U.S. Patent Application Serial No. 10/786,610 (PCT/US2004/005495) f M«NH2 MeOH To 6-Amlnc>-5-t1-(2,6^ich1oro-3-fluoro-pheny1) B3 (Figure Remove) 1. e-Nrtro-S-hydroxynicotinic add (B2): To a solution of 5-hydroxynicotinic acid (B1) (7.0 g, 50 mmol) In concentrated HZSO« was added 9 ml of fuming HN03 (90%) (9 ml). The reaction mixture was stirred at 55-60°C in a sealed tube tor four days. The mixture was then poured into ice and the pH was adjusted to 3 with 50% NaOH. MgSO4 was added to saturate the aqueous mixture, which was then extracted with isopropyl alcohol (4x45 ml). After the removal of isopropyl alcohol under reduced pressure, 5.93 g (64% yield) of B2 was obtained as a yellow solid. MB (ARCi), (M+H)* 185. 'HNMR (DMSo-dejo 6.01 (d, IH, AT-H), 8.41 (d, IH, Ar-H). 2. 2,e-Dichtorobenzyt-6-nitro-5^(2,6-dichloroben2y1)oxy]nicotinate (83): 6-nitro-5- hydroxynlcotinic acid (B2) (3.4 g. 18.5 mmol), 2,6-dlchtoroberoyl bromide (8.88 g, 37 mmol), DIPEA (5.5 g, 42.5 mmol) were dissolved in DMP (25 ml) in a 250 mL round bottomed flask and the reaction was stirred at room temperature for 4.5 hr and then concentrated under reduced pressure. The resulting mixture was poured into ice and the filtered. The solid collected was dried under reduced pressure to give 4.25 g (46% yield) of B3. MS (APCI) (M+H)* 503. 1HNMR (DMSO-d6) 0 5.47 (s, 2H, ArCHaO), 5-71 (s, 2K. ArCHjO), 7.24-7.43 (rr», 6H, Ar-H). 8.26(d. 1H, Ar-H), 8.66(d, 1H, Ar-H). 3. 2,6-Dichlorobenzyl-6-amino-5-[(2,6-dichlorobenzyl)oxy]nicotinate (84): A mixture of 2,6- dichlofoben2yl-e-nitro-5-[(2,6-dichlorobenzyl)oxy]nicotinate (B3) (5.5 g, 10.96 mmol), iron powder (0.92 g, 16.43 mmol), glacial acetic add (20 mL) and methanol (17mL) was stirred at 85*C for three hr. The reaction mixture was concentrated to near dryness, and ammonium hydroxide (30%) was added to neutralize the mixture. Minimum amount of DMF was added to dissolve the reaction mixture, which was purified by flash column chromatograph (eluent: EtOAc-EtOH, 9:1) to give 4.5 g (87%) of 84 as a pale yellow solid. MS (APCI) (M+Hf 473. 4. 6-Amino-S4(2,6-dlchtorobenzyl)oxy]niootinic acid (B5): A mixture of 2,6-dlchloroberzyl-5-amino-5-I(2,6-dichlorobenzytXixy]nicotinate (B4) (3.5 g, 7.4 rnmol), lithium hydroxide (0.41 g, 17 mmol), water (22 ml) and metnanol (30 ml) was stirred and reflux at 85°C for 5 hr. The mixture was concentrated to dryness under reduced pressure. The resulting residue was dissolved in water, extracted with a mixture of EtgO/hexane (1:1, 4x25 ml), neutralized with 1N HCI to form white precipitation, which was filtered and dried under reduced pressure to provide 1.83 grams (79%) of B5 as a white solid. MS (APCI) (M+H)* 313. 'HNMR (DMSO-d6) 0 5.26 (s, 2H, ArCHzO). 6.37 (S,2H. NHz), 7.43-7.48 (t, 1H. Ar-H), 7.54 (s, 2H, Ar-H), 7.56 (S, 1H, Ar-H), 8.18 (S, 1H, Ar-H). HATU, DMF, 70°C,2hr R'R"NH NH2 f To an array of 400 iiL of 0.2 M solution of different amines in DMF in a 96-well plate was added 400 UL (0.2 M in DMF) of 4-[6-amino-5-(2,6-dichloro-3-fluoro-benzyioxy)-pyridin-3-yl]-benzoic add, 80 pL. of triethylamine (1M in DMF) and 160 uL of HATU (O.S M in DMF) and the reactions were stirred at 70"C for 2 hr. The solvent was removed using the SpeedVac apparatus and the crude reaction mixtures were redissolved in DMSO and transferred using a iquid handler to a 1mL 96-well plate to give a final theoretical concentration of - 10 mM. The reactions were analyzed and positive product Identification was made using LC/MS. The mother stock solution was diluted to 50 nM and assayed for percent inhibition of c-MET at 50nM. General Procedure 41: HATU, DMF. Cl To an array of 400 DL of 0.2 M solution of different amines in DMF in a 96-well plate was added 400 OL (0.2 M in DMF) of 6-Amino-6-[(2,6- To a solution of 4-{4,4,5,5-tetramethyl-[1(3.2]dioxaborolan-2-yl)-lH-pyrazole (5 g, 25.77 mmol) and 2-bromo-2-methyl-propionic acid methyl ester (12.6 g, 27.06 mmol} in DMF (85 mL), was added CsjCQi (12.6 g, 36.65 mmol). The reaction mixture was heated to 90°C in an oil bath overnight. The reaction solution was cooled to room temperature, and partitioned between water and ethyl acetate. The combined ethyt acetate solution was washed with water five times, dried over Na2SO4, and concentrated to give the product 2-methyl-2-[4-{4,4,5,5-t8trameihyl-[1,3,2]dk>xaborolan-2-yl}-pyrazol-1-yt] propionlc add methyl ester (4.776 g. 63% yield). To a solution of 3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy3-5-iodo-pyridin-2-ylamine (6.363 g, 14.901 mmol) and 2-methyl-2-[4'(4,4l5l5-tetrainethyl-[1,3,2}clioxaborolan-2 To a solution of 2^4.{6-arnino-5-{1-(2,6-dlchtoro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-pyrazol-t-yl)-2-methyl-proDionic add (1.00 g, 2.20 mmol} in DMF (5.5 ml) were added HOBT (300mg, 2.20 mmol), EDO (633 mg, 3.30 mmol). and W,W-dimethyJ-propane-1,3-diamine (225 mg, 2.20 mmol). The reaction was stirred overnight at room temperature. The reaction was then purified by reversed phase 0-18 prep HPLC elating with acetonitrile/water with 0.1% acetic acid to afford 2-{4*{6-am!no-5-[1 -(2,6-dichloro-3-1luoro-phenyl)-ethoxy]-pyridin-3-yt)-pyra2ol-l -yl)-/V-(3-dimethylamino-propvl)-isobutyramide (170 mg, 14% yield). General Procedure 43 using 3-(1-(2.6-dfchloro-3-fluoro-phenyf)-ethoxy]-5-(3-methyl-pyrazol-1-yl)-pyrldin-2-ylamine NH, To a stirred solution of 3-(1-(2.6-dichlofO-3-fluoro-phenyl)^trioxy]-5-iodo-pyridin-2-ylamir>e (100 mg, 0.23 mmol) and 3-methyMH-pyrazole (59 mg, 0.70 mmol)in DMSO (1 ml was added KaPO« (101 mg, 0.47 mmol), dodecane (0.015 ml, 0.05 mmol), cyclohexanediamine (0.009 ml, 0.07 mmol) and copper iodide (Cul) (14 mg, 0.07 mmol). The solution was bubbled with nitrogen for 5 minutes, then radiated with microwave at 150°C for 2 hours, LCMS checked that the reaction was completed, the mixture was purified by prep-HPLC to leave 3-[1-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-5"(3-methyl-pyra2ol-1-yl)-pyridin-2-ylamlr»e (30 mg), yield 34.2% General Procedure 44 (Figure Remove) 2,5-dibromopyridine (1 molar eq.) was dissolved in anhydrous toluene (0.085 M) and cooled to -78°C. n-BuLJ (1.2 molar eq.) was slowly added over 5 minutes and then the resulting mixture allowed to stir at -78°C. After 2 h, R,CORj (1.3 molar eq.) was added and the solution kept at -78*C. After 1 h. saturated aqueous NH N X To a solution of 3-{1-(2,B-dichloro-3-fluoro^henyl)-ethoxy}-pyricfin-2-ylamine (1.8 g, 6.04 mmol), zinc cyanide. 98% (2.07 g, 12.07 mmol) and 1.1'-bis(dlpheny1pho$phino}-ferrocene, 97% (0.4 g, 0.712 mmol) in DMF (48 ml) was added [1 ,1'-bis(dlphenylpho8phino)-ferrocene)dichloropalladlum(ll) complex with dichloromethane(1:1) (0.25 g, 0.30 mmol). The reaction mixture was heated to 150°C for overnight under nitrogen atmosphere. The reaction was diluted with EtOAc (50 ml), washed with 4:1 :4 saturated NH4O/28% NH,OH/H.jO (2 x 28 ml), dried over NajSO4. The crude mixture was purified with a silica gel column eluting with a linear gradient of 25%-50% (EtOAc/hexanes) to provide 2-{1.(2-amir»-pyridln-3-yloxy)-ethyl)-3-chloro-4-dimethylamlno-benzonitrile as a yellow solid (37%yield) and 2-[1-(2-aminc-pyridln-3-yloxy)-ethylH-dimethylamino-isophthalonitrile as a dark brown solid (33% yield). General Procedure 46 KOH.K2COg B^NBr OCM To a mixture of 4-bromo-imWazole (995 mg. 6.77 mmol), potassium hydroxide (380 mg. 6.77 mmol), potassium carbonate (936 mg. 6.77 mmol) and tetra-n-butyl ammonium bromide (109 mg, 0.339 mmol) in dichloromethane (7 ml) was added tort-butyl bromo acetate (0.50 mL, 3.4 mmol). After stirring overnight the reaction was filtered. The filtrate was dried over sodium sulphate, filtered and concentrated by rotary evaporation. The residue was purified by silica gel chromatography using gradient elution of dichloromethane, ethyl acetate to afford (4-Bromo-imidazol-1-yl)-acetic acid tert-butyl ester (696 mg, 79%). General Procedure 47 Nj HO V 4 M solution of hydrochloric acid in dioxane (0.22 mL, 0.89 mmol) was added to a solution of (4-;6-Amino-5-[1-(2,6- H-a N-/ DMF A mixture of 4-bromi>-imidazole (217 mg, 1.48 mmol) and cesium carbonate (875 mg, 2.89 mmol) in dimethyrlformainide (5 mL) was stirred for 30 minutes. 4-(2-Chk>ro-ethyl)-morpholine hydrochloride (250 mg, 1.34 mmol) was added and the mixture was heated to 50°C. After heating overnight the reaction was concentrated by rotary evaporation. The residue was suspended in a mixture of dichtoromethane and methanol and filtered. The filtrate was concentrated by rotary evaporation. The residue was purified by silica gel chromatography using gradient elution ol dichloromethane, methanol to afford 4-[2-(4-Bromo-lmidazol-1-yl>-ethyll-morpholine (148 mg, 42%). General Procedure 4ft I Isoxazole (0.64 ml, 10 mmol} was added to a solution of N-iodosuccinimide (2.3 g, 10 mmol) ir trlfluoroacetic acid (20 ml). After stirring overnight, water (50 mL), hexanes (50 mL) and sodiurr bisuHite were added to the reaction. The phases were separated and the organic phase was driea over Na2SO4, filtered and concentrated by rotary evaporation to give 4-iodo-isoxazole (218 mg, 11%). General Procedure SC H2N"^ DIPEA Br NMP Br A tube was charged with 2,5-dibromopyridine (0.24 g, 1.0 mmd), 4-Amino-piperidine-1 -carboxylic acid tert-butyl ester (0.22 g, 1.1 mmol), di-isopropylethylamine (0.19 ml, 1.1 rnnxH) and N-methylpyrrolidinone (1.0 ml). The tube was sealed and the mixture was heated at 80°C overnight. The temperature was increased to 120°C and heated overnight. The reaction was partitioned between ethyl acetate and water. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over MgSO4 and concentrated by rotary evaporation. The residue was purified by silica gel chromatography using gradient elution of ethyl acetate and hexanes to afford 4-(5-bromo-pvridin-2-ylamirw)-piperidine-l-carboxylic acid tert-butyl ester (36 mg, 10%). General Procedure 53 F | Q| ^ ° NaOEt r«#Vw O Cl N1C'I Ot-Bu N N " ' Ot-Bu 4-(4^6-Amino-5-[l-(2,6-dichloro-3^lhoxy-phenylHthoxy]-pyridin-3-ylJ*en2cyl)-piperazine-1-carboxylic add tert-butyl ester: To 4 ml of DMSO was added 0.124 ml ethanol followed by 32 mg NaH. After stirring for 30 minutes 250 mg of 250 mg 4-(4-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyI)-ethoxy}-pvridln-3-yl}-benzoyl)- piperazine-1 -carboxylic acid tert-butyl ester was added and the reaction was heated to 40°C. After three hours the reaction was cooled and poured into water to precipitate. After neutralization to pH 6,200 mg of a tan solid was isolated. 77%. General Procedure 54 OMe ^OM. HO ta£7£S« &*" ° TTAyEijSiH to- TT r*V*N*v1 *f(4-{6-Amino-5-[l-(2,6-dichloro-3-hydroxy-phenyl)- ethoxyhpyridin-3-yl}-phenyl)'piperazin'1-yl-methanone: To 140 mg 4-[4-(6-Amino-5-{H2l6'dichloro-3-(2,4l6-trimethoxy-benzyloxy)-phenyr]-ethoxy)-pyridin-3-yl)- benzoyl]-piperazine-1-carboxylic acid tert-butyl ester (from general procedure S3) was added 1 mlTFA, the solution turned reddish immediately followed by addition of 100 uL trielhyi silane 3 seconds later. The solution turned to yellow. After stirring for four hours 5 mL of toluene were added arid the solvent was removed in vacuo. Chromatography with 10% MeOH/CHjClj, to 0.5% to 1 % NH.OH/9,5 to 9% MeOH/90% CH2CI2 led to 55 mg of a white solid. 62 % yield. General Procedure 55 BjCO 2-(4-bromc-2-methoxvDhenoxyjethanol (Ba): Potassium carbonate (1.4 g, 10 mmol) was added to a solution of ethyiene carbonate (1.8 g, 20 mmol) and 4>bromo-2-rnethoxyphenol (1.05 g, 5 mmol) in 5 ml of toluene under an Inert atmosphere. The reaction was heated at 115°C tor 12 h. Water (50 ml) and ethyl acetate (2 x 100 mL) were added to the reaction mixture to stir. The organic layers were combined, dried, filtered, and evaporated to get a yellow oil residue. The residue was purified by flash chromatography (eluting with 40-+45% EtOAc in hexanes) to give compound 8a as a light brown yellow oil (1 g; 4.13 mmol; 82.6% yield); MS (APCI) (M+H)4 246. 1H NMR (400 MHz, chloroform-D) 0 ppm 2.83 (t, J-6.3 Hz. 1 H) 3.84 (s. 3 H) 3.89 - 4.01 (m. 2 H) 4.03 - 4.13 (m, 2 H) 6.78 (d, Jfe=8.3 Hz, 1 H) 6.99 (d, 1 H) 7.02 (d, 1 H). 4-brom()-1-fg'chlorQethoxv^-2-methoKvbenzene (8b>: Thtony! chloride (0.3 mL) was added to solution of compound 1 in 1 mL of pyridine in an ice bath. The reaction was stirred in the ice bath for 10 minutes then heated to 100°C for 2 h. The reaction was cooled to room temperature and neutralized with dilute HCI (1 M). CHjClj (2 x 100 mL) was added to extract the aqueous solution. The combined organic layers were dried over NajSO4 then concentrated under vacuum. The residue was purified by Nash chromatography (eluting with 10—15% EtOAc in hexanes) to give compound 8b as a colorless oil (485 mg; 1.84 mmol; 50.3% yield); MS (APCI) (M+H)* 264. *H NMR (400 MHz, chloroform-D) 0 ppm 3.81 (t, J*6.2 Hz, 2 H) 3.85 (s. 3 H) 4.23 (t, J*6.2 Hz, 2 H) 6.78 (d. J=8.6 HZ. 1 H). Compound 9: Compounds of formula 9 can be formed by the following exemplary procedure: Compound A1B (1.3 molar equivalent) is added to a solution of aryl halide (0.51 mmol) in 7 mL of OME. The mixture is purged with nitrogen several times and then dichlorobis(tripheny!phsophino) palladium (II) (0.05 molar equivalent) is added. Sodium carbonate (3 molar equivalent) in 1.5 mL of HjO is added to the reaction mixture and the resulting solution is heated to 85 "C for 12 h. Water (20 mL) is added to the reaction mixture to quench the reaction. EtOAc (50 mL x 2) Is then added to extract the aqueous solution. Dry ErOAc layer over Na2SO«. The Na2SO4 is filtered off and the filtrated is evaporated to give a dark brown oil residue. The residue is purified by silica gel chromatography (eluting with CH3OH, CH^d?, EtOAc, and hexanes) to give desired product, compound 9. Compound 10: Compounds of formula 10 can be formed by the following exemplary procedure: Amine (7 molar equivalent) is added to a solution of compound 9 (0.17 mmol) In 3 mL of 2-methoxyethanol The resulting solution is heated to 85°C for 12 tv Water (20 ml) is added to the reaction mixture to quench the reaction. EtOAc (50 ml x 2) is then added to extract the aqueous solution. The EtOAc layer is dried over Na2S04. The NazSO« is filtered off and the filtrated is evaporated to give a light brown oil residue. The residue is purified by silica gel chromatography (eluting with CHaOH, CHjClj, EtOAc, and hexanes) to give desired product, compound 10. General Procedure 56 :l , 13 Comoound 14: Compounds of formula 14 can be formed by the following exemplary procedure: Lithium hexamethyldisilazide (1.2 molar equivalent; 1M in THF) is added to a solution of alcohol (1 mmol) in 2 mL of THF. The mixture is stirred at room temperature under a nitrogen atmosphere for 30 min and then 5-bromo-2-chloropyrimidine (1 molar equivalent) is added. The resulting solution is heated to 75 °C for 12 h. Water (20 mL) is added to the reaction mixture to quench the reaction. EtOAc (50 mL x 2) is then added to extract the aqueous solution. Dry EtOAc layer over NazSO4. The Na2SO4 is filtered off and the filtrated is evaporated to give an oil residue. The residue is purrfied by silica gel chromatography (eluting with EtOAc in hexanes) to give desired product, compound 14. Comoound IV. Compound A1S (1.3 molar equivalent) is added to a solution of 5-bromo-2-chloropyrimldine or compound 14 (1 mmol) in 24 mL of DME. The mixture is purged with nitrogen several times and then dichlorobis(triphenylphosphino) palladium (li) (0.05 molar equivalent) is added. Sodium carbonate (3 molar equivalent) in 3 mL of HjO is added to the reaction mixture and the resulting solution is heated to 85°C for 12 h. Water (50 mL) is added to the reaction mixture to quench the reaction. EtOAc (100 ml x 2) is then added to extract the aqueous solution. Dry EtOAc layer over Na2SO Compound 12: Amine (2 molar equivalent) is added to a solution of compound 11 in 3 ml of n-butanol. The reaction mixture Is irradiated in microwave at 120"C for 30 min. The resulting mixture is poured into a mixture of H20 and EtOAc (100 mU v:v: 1:1). The organic layer is dried, filtered, and evaporated to give a light brown oil residue. The residue is purified by silica gel chromatography (editing with CHSOH, CH2CI2, EtOAc, and hexanes) to give desired product, compound 12. Compound 1$: Acid (16 molar equivalent or less) is added to compound 12 (0.14 mmol) at room temperature. The resulting solution is stirred at room temperature or heated to 60°C for 12 h. The reaction mixture is evaporated and the residue is purified by silica gel chromatography (elutirtg with CHaOH, EtOAc and CHjCIa) to give desired amide product, compound 13, as a yellowish to white solid. General Procedure 57 Compound 15: Sodium hydride (1.3 molar equivalent) and RX (1.1 molar equivalent) were added to a solution of 2-amino-5-bromopyridine (0.84 mmol) in 3 ml of DMF. The reaction mixture is irradiated in microwave at 100*0 for 20 min. The resulting mixture is poured into a mixture of H2O and EtOAc (100 ml; v:v; 1:1). The organic layer is dried, filtered, and evaporated to give a light brown oil residue- The residue Is purified by silica gel chromatography (elutlng with CH3OH, j, EtOAc. and hexanes) to give desired product, compound 15. Qpmpound 16: Compound A18 (1.3 molar equivalent) is added to a solution of compound 15 (0.25 mmol) in 5 mL of DME. The mixture is purged with nitrogen several times and then dlchlorobis(triphenylphosphino) palladium (II) (0.05 molar equivalent) is added. Sodium carbonate (3 molar equivalent) in 0.8 mL of HZ0 is added to the reaction mixture and the resulting solution is heated to 85°C lor 12 h. Water (50 mL) Is added to the reaction mixture to quench the reaction. EtOAc (100 mL x 2) Is then added to extract the aqueous solution. Dry EtOAc layer over Na2SO*. The Na2SO, is filtered off and the filtrated is evaporated to give a dark brown oil residue. The residue is purified by flash chromatography (elutlng with CHjOH, CHjClj,, EtOAc, and hexanes) to give desired product, compound 16. Comgnund 17: Acid (16 molar equivalent or less) is added to compound 16 (0.114 mmol) at room temperature. The resulting solution is stirred at room temperature or heated to 60°C for 12 h. The reaction mixture is evaporated and the residue is purified by silica gel chromatography (eluting with CH3OH, EtOAc and ChfeCy to give desired amide product, compound 17. as a yellowish to white Solid. General Procedure 58 13 1-to i-n 1-(f-butoxycart)0nyl)azetidine-3.carboxyllc acid (Vt}(AXL016917. 1000 mg, 4.97 mmol} was dissolved in MeOH (5 ml_}/Toluene (20 mL) and then cooled to 0°C. TMSCHNN (trimethylsilyldiazomethane) (7.45 mmol) was then added drop-wise over 15 minutes with some bubbling observed. The color started dear and slowly turned yellow. The solution was stirred for 10 minutes at 0°C and then warmed to room temperature over 30 minutes. The solution was then concentrated and pumped on to remove toluene to afford 1.055 g of 1-f-butyJ 3-methyi azetidine-1,3-dicarboxylate (|-2t that was used directly in the next step without being purified (99% crude yield). 1-tert-butyl 3-methyl azetidine-1.3-dlcarboxylate (1055 mg, 4.90 mmol) was dissolved in THF (17 ml) and then cooled to 0°C. MeOH (0.397 ml, 9.60 mmol) and LJBH4 (14.7 mmol) were added sequentially. The reaction was warmed to room temperature over 3 h. Then 10% aqueous potassium sodium tartrate tetrahydrate (RocheUe's Salt) (30 ml) and EtOAc (30 mL) were added and the solution stirred at room temperature over 30 minutes. The organic layer was separated and then dried (NasS04) and concentrated to afford 674 mg of t-butyl 3-(hydroxymethyt)azetidine>1-carboxytate (1-3) as a crude product (dear oil). The product was used directly in the next step without purification. t-butyl 3-(hydroxymethyl)azetidine-l-carboxylate (674 mg, 3.60 mmol) was dissolved in CHgC)2 03 mL> 0.25M) and then EtsN (1.0 mL, 7.20 'mmol), DMAP (44 mg, 0.360 mmol), andmethanesuttonyi chloride (0.31 mL. 3.96 mmol) were added sequentially at 0°C with the MsCI addition being done slowly. The solution was warmed to rt over 1 h. After 15 h, saturated aqueous NaHCO3 (50 ml} was added and then the product was extracted with CHzClj (2 x 50 mL) and the combined organic extracts were washed with brine (50 ml), dried (NajS04), concentrated, and purified by flash chromatography (Biotage Horizon - 10%EtOAc/hexanes • 100% EtOAc) to afford 962 mg of (1-41 as an oil (quantitative). NaH (95%, 96 mg, 3.99 mmol) was combined in DMF (10 ml) under N2 at rt. 4-Bromopyrazole (533 mg, 3.63 mmol) was then added and the mixture stirred at rt. After 30 minutes (H) was added and the solution heated to 95°C. After 2 h, saturated aqueous NH«Ci (50 mL) was added and then EtOAc (50 mL). The organic extract was dried (NazSO4) and concentrated, and then run through a short pad of silica gel with 50% EtOAc/Hexanes to afford 846 mg of crude MJ51 that was used directly in the next step (74% crude yield). (1-S1 (846 mg, 2.68 mmol), (1-6> (815 mg, 3.21 mmol). l1.V-bis(diphenytphosphino)-ferrocene)dfchloropalladlum (108 mg, 0.133 mmol), and KOAc (893 mg, 9.10 mmoQ were combined in DMSO (10 ml, purged with Nj for 10 minutes) and then the solution was warmed to 80°C. After 16 h, the solution was filtered through Celite and then H20 (50 mL) and EtOAc (50 mL) was added. The organic phase was extracted and dried (Na^O*), concentrated, and then passed through a silica plug with 50% EtOAc/Hexane. The solvent was concentrated to afford 1.22 g of crude (1-7) used directly In the next step. The boronic ester (1-71 (4144 mg, 11.4 mmol), M-81 (2890 mg, 7.60 mmol), dichlorobis(triphenylphosphine)palladlum(ll) (534 mg, 0.760 mmol). DME (40 mL, De-gassed for 30 minutes with N2), and 1N Na2CO3 (40 mL, De-gassed for 30 minutes with Nfe) were combined and heated to 80°C. After 16 h. the reaction was cooled to rt and EtOAc (80 mL) was added. The solution was filtered through celite and then water (80 mL) was added. The organic layer was separated, dried (Na2SO4), and concentrated. The product was purified by flash chromatography to afford 1466 mg of (1-91 as a tan solid (36 %). 1 gram of DOWEX SOWX2-400 ion-exchange resin was prepared by washing it with. HaO (500 mL), 1:1 HzO/MeOH, MeOH (5X 250 mL), CHjCfe (500 mL), and hexanes (500 mL}. The DOWEX was then dried in a vacuum oven at 40"C for 1 day. (1-9) was dissolved in MeOH and then DOWEX (588 mg. 1.096 mmol) was added. The solution was stirred at rt for 2 h. The solution was then filtered and the resin was washed with MeOH (3X 200 mL) and the wash was discarded. The resin was then washed with 3.5M NH^MeOH and collected. The solution was then concentrated to afford 374 mg of (1-101 as a gummy solid (78%). To form compounds of formula (1-11). the following exemplary procedure can be followed. 1 molar equivalent of (1-10) is dissolved in DMF or CH2CI2 and then base (3 molar equivalents) and/or coupling reagent (1.5 molar equivalents) is added. To the solution is added X-R (1.1 molar equivalent), where X is, for example, Cl, Br, i, OMs, COCI. CO, COOH, ethylene or carbonate and R is a desired group such as those shown in the examples herein or similar groups. The resultant solution is stirred at rt for 4 h. HjO and EtOAc are added and the organic phase extracted, dried (NasSO4), and concentrated. The crude product can purified by purified by preparative HPLC or other methods well known In the art to afford the product (1-111. 3-Azetidinol (2i): A reaction mixture of N-benzhydrylazetidin-3-o) HO salt (2.76 g, 10.0 mmol) wrtti palladium hydroxide, 20% Pd (dry base) on C (400 mg) in 50 ml of MeOH was rtydrogenated at 55 psl for 48 h. The reaction mixture was filtered through Cellte pad and washed well with MeOH. The filtrate was concentrated under vacuum at room temperature water bath. The residue was treated with ether (3x30ml) and the solvent is decanted. The solid was air dried to give 571 mg of HCI salt product &g) as white solid (52% yield). 'H NMR (400 MHz, DMSO-D6) 6 ppm 3.33 (s. 1 H) 3.63 - 3.80 (m, 2 H) 3.93 - 4.09 (m, 2 H) 4.40 - 4.58 (m, 1 H) 6.18 (d, J-6.32 Hz, 1 H). 3-Hydroxy-a2etidine-1-carboxic acid tert-butyl ester (3-3): To a cold (0°C bath) stirred solution of compound (&£) (570 mg, 5.20 mmol) in 10ml of EtOH was added Et3N (1.8 ml, 13.0 mmol) and di-tert-butytdlcarbonate (1.702 g, 7.38 mmol). The resulting mixture of clear solution was stirred at room temperature overnight The reaction mixture was concentrated by vacuum. The residue was portioned between EtOAc (200mL) and 0.5N citric add solution (30mL; brine (30mL). The organic layer was dried (NajSOO, then concentrated by vacuum to give 899 mg (2»3) as dear oil (52%). 'H NMR (400 MHz, chlorofbrm-0) o ppm 1.42 (s, 9 H) 3.78 (dd, Jb9.47, 4.42 Hz, 2 H) 4.13 (dd. J=9.35.6.57 Hz, 2 H) 4.49 - 4.63 (m. 1 H). 3-Methanesulfonyloxy-azetidlne-1-carboxytlc acid tert-butyl ester (2-4): To a solution of compound (g-3) (466 mg; 2.69 mmol) with EtaN (0.75 ml; 5.38 mmol) and 4-(dimethytamino)-pyrtdhie (33 mg, 0.269 mmol) In 10 ml of CH2CI2 at 0°C was added methanesulfonyl chloride (0.25 mL 3.23 mmol). The resulting mixture of brown color solution was stirred at 0°C to room temperature for overnight, The reaction mixture was quenched with NaHCOs. then partitioned between CHZCIZ (200 ml) and saturated NaHC03 solution (50 ml). The organic layer was dried (NazS04). than filtered through silica gel pad, etuted with hexane: EtOAc/1:1; the filtrate was concentrated fay vacuum to give S14mg (2-4^ as yellow oil (91%yield). 'H NMR (400 MHz, chloroform-D) 6 pprn 1.43 {s, 9 H) 3.05 (s. 3 H) 4.08 (dd, JM0.36.4.29 Hz. 2 H) 4.26 (dd, JM0.36, 6.82 Hz. 2 H) 5.11 - 5.26 (m. 1 H). 1-(3-AzeHdine-1-carboxyfic acid tert-butyl ester)-4-bromoprazole(2jg): A 5 mL microwave tube was charge with compound (g-4) (304 mg. 1.21 mmol); 4-bromopyrazole (2-5. 178 mg, 1.21 mmol) and NaH 60% in mineral oil (73 mg, 1.82 mmol.) with 2 mL of OMF. The resulting mixture was microwaved at 110°C for 30 minutes. The reaction mixture was partitioned between EtOAc (200 ml) and saturated NaHCOs solution (2 x 50 mL);brine (50 ml). The organic layer was dried (NazSO4), then concentrated by vacuum to afford 360 mg of (2-6) as yellow oil (98%). 1H NMR (400 MHz, DMSO-D6) 6 ppm 1.36 -1.43 (m, 9 H) 4.08 (s, 2 H) 4.18 - 4.31 (m, 2 H) 5-12 - 5.22 (m. 1 H) 7.67(s,1 H) 8.14(s,1 H). toff Butyl 3-|4-(4,4,5,5-tetramethyl-1,3-dtoxoborolan.2-yl)-1 H-pyrazol-1 -yl]azetidine-l -caiboxylate (2JD: A reaction mixture of compound (££) (225 mg, 0.74 mmol) and bis(pinacolate)diboron (2-7. 227 mg. 0.69 mmol) with KOAc (247 mg, 2.52 mmol) in 3mL of DMSO was purged with N, for 15 minutes, then PdCl2(dppf)2CHjClz (30 mg, 2.52 mmol) was added. The resulting mixture was stirred at 80°C under N2 for overnight. After it cooled down to room temperature, the mixture was filtered through CeRte pad and washed well with EtOAc. The filtrate was extracted with HjO (2 x 50 ml), brine (50 ml). The organic layer was dried (NaaSO«), then concentrated by vacuum. The residue was then filtered through silica gel pad, eluted with hexane:EtOAc/3:2. The nitrate was concentrated by vacuum to give 250 mg of (g-6j as a dear oil (97% yield). *H NMR (400 MHz. chtorofomvD) 6 ppm 1.18 -1.27 (m, 9 H) 1.28 -1.34 (m, 6 H) 1.41 -1.49 (m, 6 H) 4.22 - 4.33 (m.2 H) 4.36 (t, J*8.59 Hz, 2 H) 4.98-5.13 (m, 1 H) 7.83 (s. 2 H). fart-Butyl 3-(4-{6-amino-5-[1 -(2,6"dichloro-3-1luorophenyl)ethoxy]pyridin-3-yl}-1 H-pyrazoM -yl)azetidine-l-carDOxylate (2-10): A reaction mixture of compound (2-B) (459 mg; 1.31 mmol) and 3-(1-(2,6-dichlora-3-fuoroph«nyl)ethoxy]-5-iodopyr!dln-2-amine (2-9) (374 mg; 0.88 mmol) in 13 ml of ethylene glycol dlmethytether, anhydrous (DME) was purged with N2 for 15 minutes, then PdOIMPPhj^Clu (46 mg, 0.07 mmol) was added and continued to purge with N2 (or another 15 minutes. Another t.O N Na2CO3 solution (3.9 mL; 3.9 mmol) was added after purging with N2 for 15 minutes. The resulting mixture was stirred at 85"C under Nj for overnight. The reaction mixture was filtered through Celite pad and washed well with MeOH. The filtrate was concentrated by vacuum. The residue was partitioned between EtOAc (200 mL) and saturated NaHCO3 solution (2 x 50 mL); brine (50 mL). The organic layer was dried (NajSO4), then concentrated by vacuum. The residue was purified by Biotage system (25 M. 100% CHjCI* 100% CHjClj to 90% CH2Cla with 10% MeOH) to collect the desired fraction to afford 421 mg of (2-10) as a brown color grease (92% yield). 'H NMR (400 MHz. chloroform-D) 5 ppm 1.17 -1.26 (m, 9 H) 1.80 -1.87 (m, 3 H) 4.04 - 4.18 (m. 2 H) 4.20 - 4.33 (m, 2 H) 4.34 - 4.41 (m. 1 H) 4.79 (s, 2 H) 5.02 (d. J=7.58 Hz. 1 H) 7.04 (t. ^=8.46 Hz. 1 H) 7.33 - 7.41 (m, 1 H) 7.44 • 7.52 (m. 1 H) 7.53 - 7.58 (m, 1 H) 7.59 - 7.65 (m, 1 H) 7.72 - 7.78 (m, 1 H); LCMS calcd for C24H2tCI2FNjOi (M+H) 523. found 523. S-(1 -Azetidln-3-yl-1 H-pyrazol-4-yl)-3-[1 -(2,6-dicNoro-3-fluorophenyl)ethoxy] yridin-2-amine (2-11): A reaction mixture of compound (2-10) (421 mg; 0.81 mmol) with 4.0 M HCI in dioxane (2.0mL; 8.1 mmol) in 5mL of CHzCiz was stirred at room temperature for 2.0 hours. The reaction mixture was concentrated by vacuum. The residue was treated with EtOAc. The precipitated solid was filtered off and washed well with EtOAc, hexane, then dried under vacuum to give 275 mg of (2-11) as a sand color solid of HCI salt (81% yield). 'H NMR (400 MHz, DMSO-D6) 5 ppm 1.79 -i .89 (m, 3 H) 3.56 (s, 1 H) 4.35 (s, 4 H) 5.40 (s. 1 H) 6-23 (d, Jt6.57 Hz. 2 H) 7.09 (s, 1 H) 7.40 -7.54 (m. 1 H) 7.59 {dd. J=8.84, 5.0S Hz. 1 H) 7.73 - 7.83 (m, 1 H) 7.86 {S, 1 H) 8.12 (s, 1 H) 9.20 (s. 1 H). LCMS calcd for Ci8H,6CljFN5O (M+H) 423, found 423. Compounds of formula 2-12 can be prepared by the following exemplary procedure: To a reaction mixture ol compound (2-1-11 (1.0 eq.) with EtjN (2.0 eq;) in 2.0 mL oi DMF at room temperature is added alkyl bromide (1.1 eq.). The resulting mixture is stirred under N2 at room temperature for overnight. The reaction mixture is partitioned between EtOAc (200 ml) and saturated NaHC03 solution (2 x 50 ml); brine (50 ml). The organic layer is dried (NajSO,). then concentrated by vacuum. The residue is purified by Oionex system (5% to 95% MeCN:H20 w 0.1% HOAc buffer) to collect the desired fraction to afford (2J2J. Alternatively, compounds of formula g-12 can be prepared by the following exemplary procedure: To a reaction solution of alkyl amine (1.0 eq.) with iPr2EtN (diisopropylethylamine} (3.0 eq.) in 2.0 mL of DMF is added HATU (1.5 eq.). After stirring for 30 minutes, compound (2*111 (1.0 eq.) is added. The resulting mixture is stirred at room temperature for overnight. The reaction mixture is partitioned between EtOAc (200 mL) and saturated NaHCO3 solution (2 x 50 mL) and brine (50 mL). The organic layer is dried (Na8S04) and concentrated by vacuum. The residue is purified by Oionex System (5% to 95% McCN:H20 w 0.1% HOAc) to collect the desired product to afford (2-12). General Procedure 6 iert-Butyl 1-oxa-6-azaspiro[2.5^ctane-6-carboxyfato (3-2): A solution of dimethytsulfoxonium methylide was prepared under N8 from NaH 60% dispersion in mineral oil (440 mo/, 11.0 mmol) and trlmethylsulfoxonium iodide (2.421 g; 11.0 mmol) in 5 ml of anhydrous DMSO. Another solution of 1-Boc-4-oxo-1-piperidincarboxy1ate (3-1.1.993 g; 10.0 mmol) in 5 mL of DMSO was added dropwise. The resulting mixture was stirred at 55°C for 6 hours. The cooled reaction mixture was poured into ice-HjO and extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with HjO (50 mL); brine (5 OmL) and then dried (NazSO*), then concentrated by vacuum to give 1.4791 g of (3-2) as a yellow oil (69% yield). 'H NMR (400 MHz, chloroform-D) 6 ppm 1.37 -1.52 (m, 11 H) 1.71 - 1.84 (m, 2 H) 2.63 - 2.72 (m, 2 H) 3.35 - 3.49 (m, 2 H) 3.62 - 3.78 (m. 2 H). tert-Butyl 4-hydroxy-4-{[4.(4,4.5,5-tetrametriy1-1,3,2-dioxaborolan-2-yl)-1 H-pyrazoM - yl]methy)}piperidine-1-carboxylate (3-4): A reaction mixture of compound (3-2) (214 mg; 1.0 mmol) and 4-(4(4,5.5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (3-3.194 mg; 1.0 mmol) with NaH 60% dispersion in mineral oil (60 mg; 1.5 mmol) in 3mL of DMF was stirred at 90°C for 3 hours. The reaction mixture was partitioned between EtOAc (200 mL) and saturated NaHCO3 solution (50 mL) and brine (50 mL). The organic layer was dried (Na^O*) and concentrated by vacuum to give 361 mg of (3-4) as a yellow grease (89% yield). 'H NMR (400 MHz, chloroform-D) 6 ppm 1,21 • 1.34 (m, 12 H) 1.39 - 1.50 (m, 9 H) 1.56 • 1.78 (m. 4 H) 3.14 (s, 2 H) 3-72 - 3.91 (m, J-32.34 Hz. 2 H) 4.05 (9. 2 H) 7.65 (a, 1 H) 7.80 (s, 1 H) 8.00 (s. 1 H). LCMS calcd for CaH^BNaOs (M+H) 408, found 408. HPLC purity 85%. /art-Butyl 4-[(4-(S-amino-5-[1 -(2,6-dichloro-3-fluorophenyl)ethoxy]pyridin-3-yl}-1 H-pyrazol-1 -yl)methyl]-4-hydroxypiperidine-1-carboxytate (3-6): A reaction mixture of compound (3-4) (361 mg; 0.89 mmol) and 3-{1-(2,6 4-[(4-{6-amino-5-{1-(2,6-dichloro-3-fluorophenyl)etftoxy]pyridin-3-yl}-lHi)yrazol-1-yl)methyl]piperidin-4-ol (3-7): A reaction mixture of compound (3-6) (145 mg; 0.25 mmol) with 4.0 M HCI in dioxane (2.0 mL; 8.1 mmol) in 5mL of CHjClj was stirred at room temperature for 2.0 hours. The reaction mixture was concentrated by vacuum. The residue was purified by Dionex system (5% to 95% MeCN:HjO w 0.1% HOAc buffer) to collect the desired fraction to afford 76 mg of (£7) as a yellow grease (63% yield). 'H NMR (400 MHz, DMSO-D6) 5 ppm 1.41 • 1.55 (m, 2 H) 1.59 - 1.71 (m. 2 H) 1.81 (d, J=6.57 Hz, 3 H) 2.88 - 3.00 (m, 2 H) 3.02 - 3.14 (m, 2 H) 4.08 (s, 2 H) 5.17 (s, 2 H) 6.14 - 6.27 (m, J-6.57 Hz, 1 H) 7.05 (s. 1 H) 7.40 - 7.49 (m, J=*8.72, 8.72 Hz, 1 H) 7.51 - 7.60 (m, J=9.09. 4,80 Hz, 1 H) 7.63 (s. 1 H) 7.76 (s, 1 H) 7.91 (s, 1 H) 8.51 (s. 1 H) 8.81 (s. 1 H). LCMS calcd for CaHwCljFNsOj (M+H) 481. found 481. HPLC purity 98%. Anal. (C2aHj4a2FNsOjX2.2HOAcx2.3H2O) C, H. N. General Procedure 61: Ei,N/DMAP CHjClj {2)NaH/DMF/ 90°C KOAc/DMSCWWPe Ethyl 2-[(4-bromo-lH-pyrazoH-yl)methyl]cyclopropanecarboxylate (4-3): To a reaction solution of ethyl 2-(hydroxymethyl)cydopropanecartx)xy1ate (4-t) (577 mg; 4.0 mmol) with EfeN (1.1 ml; 8.0 mmol) and DMAP (49 mg; 0.4 mmol) in l2mL of CH2CI2 at 0°C was added methanesuKonyl chloride (0.4 ml; 4.8 mmol). The resulting mixture of brown color suspension was stirred at 0*C to room temperature under N? for overnight. The reaction mixture was quenched with NaHCOa, then partitioned between CH2Clj (200 ml) and saturated NaHCO3 solution (50 mL); brine (50 ml). The organic layer was dried (Na^O*). then filtered through aiica gel pad. eluted with hexane:EtOAc/1:1. Trie filtrate was concentrated by vacuum to give 880 mg ot ethyl 2-{[(methylsuHonyl)oxy]methyl)cyclopropanecart>oxylate as a yellow oil (99% yield). 'H NMR (400 MHz. chloroform-D) 6 ppm 0.91 • 1.02 (m, 1 H) 1.26 (q, J=6.99 Hz, 3 H) 1.29 • 1.36 (m, 1 H) 1.63 -1.74 (m. 1 H) 1.79 -1.92 (m. 1 H) 3.02 (s, 3 H) 3.99 - 454 (m, 4 H). A reaction mixture of ethyl 2-{((methyl$ulfonyl)oxylmethy1}cycloproparwcarboxylate (880 mg; 4.0 mmol). 4-bromopyrazole (4-2.588 mg, 4.0 mmol) and NaH 60% In mineral oil (240 mg, 6.0 mmol) with 3.0 ml of DMF was formed. The resulting mixture was stirred at 90°C under Nj for four hours. The reaction mixture was partitioned between EtOAc (200 mL) and saturated NaHCO3 solution (2 x SO mL); brine (50 mL). The organic layer was dried (Na2SO..; ihen concentrated by vacuum to afford 812 mg of (4-3) as a yellow oil (74%). 'H NMR (400 MHz, chloroform-D) 5 pom 0.85 (dd. J=7.96, 3.16 Hz, 1 H) 0.88 - 0.98 (rn, 1 H) 1.18 -1.29 (m, 3 H) 1.56 -1.71 (m, 1 H) 1,79 -1.94 (m, 1 H) 3.96 - 4.08 (m. 2 H) 4.07 - 4.17 (m, 2 H) 7.45 (d, J=3.7Q Hz, 2 H). LCMS calcd for CtoH^BrNzOa (M+H) 274, found 274. HPLC purity 95%. Ethyl 2-{(4-(4.4,5.5-tetramethyM,3-dioxoborolan-2-yl)-1 H-pyrazoM-yt]methylJ cyclopropanecarboxytate (4-4): A reaction mixture of compound (4-3) (812 mg, 2.97 mmol) and bis(pinacolate)dlboron (906 mg, 3.57mmol) with KOAc (991 mg, 10.10 mmol) in 10.0 mL of DMSO was purged with N2 for 15 minutes, then Pdd2(dppf)2CH2CI2 (122 mg, 0.15 mmol) was added. The resulting mixture was stirred at 80*0 under N2 for overnight After cooling down to room temperature, the mixture was filtered through Ceflte pad and washed well with EtOAc. The filtrate was extracted with HjO (2 x 50 mL), brine (50 mL). The organic layer was dried (Na^O*), then concentrated by vacuum. The residue was then filtered through silica gel pad, and eluted with hexane:ErOAc/3:i. The filtrate was concentrated by vacuum to give 945 mg of (4-4> as a yellow oil (98% yield). 1H NMR (400 MHz, chloroform-D) 6 ppm 0.85 (dd. J=7.83, 3.03 Hz. 1 H) 0.90 - 0.96 (m, 1 H) 1.20 • 1.24 (m, 3 H) 1.29 -1-34 (m, 12 H) 1.62-1.71 (m, 1 H) 1.84 -1.97 (m, 1 H) 3.96 • 4.07 (m, 1 H) 4.08 - 4.14 (m, 2 H) 4.15 - 4.23 (m. ^=14.27.6.44 Hz, 1 H) 7.73 (s, 1 H) 7.77 (s. 1 H). Ethyl 2-[(4-{6-amino-5Hl -(2,6-dichtoro-3.fluorophenvl)ethoxy]pyridin-3-yi}-1 H-pyrazol-1 -yl)methyl)cydopropanacarboxyla1e (£6): A reaction mixture of compound (4-41 (643 mg; 2.01 mmol) and 3-[1-(2.6-dichtoro-3-tluorophenyl)ethoxy)-5-kxlopyridin-2-amine (££) (572 mg; 1.34 mmol) in 20.0 mL of ethylene glycoi dimethylether, anhydrous (DME) was purged with N2 for 15 minutes, then Pd(ll)(PPh3)2CI2 (71 mg, 0.1 mmol) was added and continued to purge wfth-N2 for another 15 minutes. Another 1.0 N Na8COs solution (6.0 mL; 6.0 mmol) was added after purging with Ms for 15 minutes. The resulting mixture was stirred at fl5°C under N2 for overnight. The reaction mixture was filtered through Celite pad and washed well with MeOH. The filtrate was concentrated by vacuum. The residue was partitioned between EtOAc (200 mL) and saturated NaHCOj solution (2 x 50 mL); brine (SO mL). The organic layer was dried (Na2SO«), then concentrated by vacuum. The residue was purified by Biotage system (25 M CH2CIZ100%; CHjClj 100% to 90% CH2CI2:10% MeOH) to collect the desired fraction to afford 600 mg of (£§) as a brown color grease (91% yield). *H NMR (400 MHz, DMSO-D6) 0 ppm 0.96 -1.10 (m, 2 H) 1.15 (t J=7.07 Hz. 2 H) 1.74 (s, 3 H) 1.79 (d, Jb6.57 Hz, 3 H) 3.95 - 4.14 (m, 4 H) 5.66 (s, 2 H) 6.08 (d, Jb6.57 Hz. 1 H) 6.88 (S, 1 H) 7.43 (t. J=8.72 Hz, 1 H) 7.49 - 7.62 (m, 2 H) 7.73 (S. 1 H) 7.88 (s, 1 H). LCMS calcct for G^H^CIjFN.Oa (M+H) 494, found 494. HPLC purity 95%. 2-l(4^6-amino-5-(1-(2,6xlichloro-3-fluoropherryl)ethoxy]pyridln-3-yl}-l^pvrazol-l-yl)methyl)cydopropanecarboxylic acid (4-7): To a reaction solution of compound (4-6) (377 mg, 0.76 mmol) in 5.0 mL of MeOH at room temperature under N2 was added another solution of 2.0 N NaOH (2) (1.5 mL, 3.04 mmol). The resulting mixture was stirred at 80°C for 3 hours. The reaction mixture was concentrated by vacuum to remove most of the MeOH and acidified by 2 M HCI to pH 4.0. The mixture was extracted with CHjClj (2 x 200 mL); the organic layers were washed with brine (50 mL), and dried (Na:SO 2-[(4-(6-amirtt-5-[1 -(2,6 General Procedure 62: NH2 'CI To a solution of 5-bromo-3-((fl)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxyJ-pyridln-2-ylamine (12.83 g, 33.76 mmol) in anhydrous DMF (100 mL) was added di-(Figure Remove) rt-butyl dicarbonate (21.25 g. 97.35 mmol) and 4-dimethyteminopyridine (0.793 g. 6.49 mmol). The reaction was stirred at ambient temperature for 18 hours under nitrogen. To the mixture was added saturated NaHCO'j solution (300 ml), and extracted with EtQAc (3x250 ml). The combined extracts were washed with water (5x100 ml), sat NaHCO3. and brine, then dried over NasS04. After filtration, evaporation, and high vacuum drying, di-boc protected 5-bromo-3-[(fl)-1-(2,6-clJchloro-3- To a solution of di-boc protected 3-[(fl)-1-(2,6-dichk)ro-3-fluoro-phenyl)-ethoxy]-5-(4I4,5,5- tetramethy)-[1l3,a)dioxaboro4an-2-yl)-pyr1din-2-ylamine (20.34 g, 32.42 mmol) In CH2CI2 (80 mL) was added a solution d dry HCl in dioxane (4N, 40.5 mL, 162 mmol). The reaction solution was stirred at 40°C oil bath under nitrogen for 12 hours. The reaction mixture was cooled to ambient temperature, diluted with EtOAc (400 ml), then washed carefully but quickly with saturated NaHCO3 until the water layer was basic (pH>8>. The organic layer was washed with brine, and dried over Na!SO4. After filtration, evaporation, and high vacuum drying, 3-[(fl)r1-{2,6-dichlorc-3- fluoro^rtenyi)^tr«xyl-5-(4l4.53-tetramethyi-[l,3,2]dioxaborolan-2-yl>-pvrldin-2-ylamine was obtained as an off-white foam sold (13.48 g, 97% yield). 1H NMR (DMSO-de, 400 MHz) S 8.01 (d, 1H), 7.27 (dd, 1H), 7.17 (d. 1H), 7.03 (t. 1H)P 6.12 (q, 1H), 5.08 (bs, 2H), 1.81 (d, 3H). 1.30 (s, 6H). 1.28(S,6H). To a stirred solution of 3-[(fl)-1-(2.6-dichloro-3-fluoro-phenvl)-ethoxy]-5-(4,4,5,5-tetramethyl-[1,3,2)dtoxaborolan-2-y!)-pyridin-2-ylamine (4.2711 g, 10.0 mmol) and 4-(4-bromo-pyrazol-1-y1)-piperidlne-1-carboxylic acid tert-outyi ester (see procedure 11) (3.9628 g, 12.0 mmol) in DME (40 mL) was added a solution of Na2COa (3.1787 g, 30.0 mmol) in water (10 mL). The solution was degassed and charged wJth nitrogen three times. To the solution was added Pd(PPh3)2Clj (351 mg, 0.50 mmol). The reaction solution was degassed and charged with nitrogen again three times. The reaction solution was stirred at 87°C oil bath for about 16 hours (or until consumption of the borane pinacol ester), cooled to ambient temperature and diluted with EtOAc (200 mL). The reaction mixture was filtered through a pad of celite and washed with EtOAc. The EtOAc solution was washed with brine, dried over Na2SO4, and concentrated. The crude product BH^FatO-C 2. aq.6.0NHCI/H;O/MeOH M A 100 ml of llask with a stir bar was dried in an oven and cooled in a dry nitrogen atmosphere. The flask was equipped with a rubber syringe cap. The flask was immersed in an ice-water bath under nitrogen, and 1.6 ml (1.6 mmol) of 1.0 M borane solution in THF was introduced. Then 2-(4-{5-Amino^[1-(2.6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-pyrazol-1-yl)-2-rnethyl-propionlc acid (procedure 5) (0.1 g, 0.221 mmol) in anhydrous THF (1.0 mL) was introduced. The resulting mixture was stirred at ambient temperature under nitrogen for 5 hours, and 6 N HCI (1.1 ml) was added slowly, and then H-.O (1.1 mL) and MeOH (7.4 mL) were introduced. The reaction mixture was stirred continually overnight. Most of solvents were evaporated in vacuo. and then a 1 N NaOH solution was used to adjust pH to 11. Water was added, and the solution was extracted with EtOAc (3x30mL) and dried over NaaSO4. After filtration and concentration, the crude product was purified with a reverse phase preparative HPLC eluting with acetonrtrlle/water containing 0.1% acetic acid from 10% to 60%. After lyophilization of the pure fractions, 2-(4-{6-amino-5-{1-(2,6-dichloro-3-fluoro-phenyl)-«thoxy]-pyridin-3-yl}-pyrBZol-1 -yl)-2-meti yl-propan-1 -of acetate was obtained as a white solid (21 mg, 22% yield). General Procedure 65: To a stirred solution of 4-hydroxy-piperidlne-l-carboxyllc acid tort-butyl ester (7.94 g, 39.45 mmol) in CHjClj (100 mL), cooled to 0°C, was slowly added NEt3 (5.54 mL, 39.45 mmol) folowed by methane sulfonyl chloride (3.06 mL. 39.45 mmol) and DMAP (48 mg, 0.39 mmol). The mixture was stirred at room temperature overnight. To the mixture was added water (30 mL). Extraction with CH2CI? (3 x 30 mL) followed by drying (NajSO*) and removal of the solvent in vacuo afforded 4-methanesu!tonyioxy-piperidine-1-carboxylic acid tert-butyl ester as a white solid (11.00 g, >99% yield). 'H NMR (CDCI0.400 MHz) 54.89 (m, 1H), 3.69 (m, 2H), 3.31 (m, 2H). 3.04 (a, 3H). 1.95 (m. 2H). 1.83 (m.2H), 1.46(s, 9H). To a stirred solution of 4-bromo-pyrazole (10.44 g, 71.03 mmol) in anhydrous DMF (96 ml), cooled to 0°C, was slowly added NaH (60% in mineral oil) (3.13 g, 78.133 mmol). The solution was stirred for 1 hour at 0*C. 4-MethanesuHonyloxy-piperidine-1-carDoxylic add tert-butyl ester (19.82 g , 71.03 mmol) was added slowly and the reaction was heated to 100°C overnight or until consumption of the pyrazde by NMR. The reaction was cooled to room temperature and water added (20 mL) followed by extraction with EtOAc. The combined extracts were washed with saturated aqueous NaCI (4 x 20 mL), dried with Na2SO To a solution of 4-(4-bromo-pyrazoM-yl)-piperidlne~1-carboxylic acid tert-butyl ester (500 mg, 1.515 mmol) in CH2CIZ (3 mL) was added TFA (3 mL). The reaction was stirred at room temperature until LCMS indicated completion of the reaction. The solvents were removed in vacuo, and the residue was dissolved in MeOH (15 mL). The pH of the solution was adjusted to 9 with hydroxide resin to afford 4-(4-bromo-pyrazol-1-yt)-piperidine. To a solution of 4-{4-bromo-pyrazol-1-yl)-piperidine (375 mg, 1.63 mmot) in DMF (3.26 mL) was added NEtg (230 uL. 1.63 mmol) and stirred for 5 minutes. Methyliodide (Mel) (1.63 mL, 1M Mel hi DMF, freshly made) was added and the reaction was stirred overnight at room temperature. Water was added and the solution was extracted with EtOAc (4 x 10 mL). The organic solution was washed with brine, dried with Na?S04, concentrated, and dried in vacuo to afford 4-(4-bromo-pyra2oM-yl)-1-methyl'piperldine (251 mg, 63% yield). To a solution of 3-[(fl)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy}-5-(1H-pyrazol-4-yl}-pyrazin-2-ylamine (295 mg, 0.80 mmol) in anhydrous DMF (4 mL) was added NaH (60% in mineral oil, 30.7 General Procedure 66: mg, 0.80 mmol). The mixture was stirred at ambient temperature under nitrogen for 0.5 h, and then 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (223.5 mg, 0.80 mmol) was introduced. The reaction mixture was heated to 90°C oil bath for 0.5 h under nitrogen, and cooled to ambient temperature. Water was added slowly to the mixture, which was extracted with EtOAc, washed with brine, and dried over Na2SO4. The crude product was purified on a silica gel column to provide 4-(4-{5-8mino-6-[(R)"1-{2,6-dichtoro-3-f1uoro-phenvl)-ethoxy]-pyrazin-2-yl)-pyra2ol-1-y1)-piperidine-1-carboxylic acid tert-butyl ester as a white solid (265 mg, 59% yield). To a solution of 4-(4.{5-amino-6-[1-(2,6-dichloro-3-fluoro-pnenyl)-ethoxy]-pyraiin-2-yl}-pyrazol-1-y!)-piperidine-1 -carboxylic add tert-butyl ester (265 mg, 0.48 mmol) in Cl-feCfe was added 4N HCI/dioxane (4 mL). The mixture was stirred at ambient temperature for one hour. After evaporation, the residue was dissolved in methanol (2.5 mL), and was purified on a reverse phase C-18 reparative HPLC eluting with aoeton'rtrile/water containing 0.1% acetic add with a linear gradient of 10%-40%. After lyopWIIzatton, 3-[(R)-1.(2,6-dichloro-3-fkJoro-phenyl)-ethoxy]-5-(1-piperidin-4-yl-lH-pyra2ol-4-y1)-pyrazin-2-ylflmine acetate was obtained as a white solid (125 mg, 51% yield). General Procedure 87: 0-(7-azabenzotriazol-l-yl)-N,N,N1,N'"tetramethyluronium phosphorus pentafluoride (HATU) (66 mg, 0.17 mmol) was added to a solution of 2-(4-{6-Amino-5-t1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-pyrazol-1-yl)-propionic add (69 mg, 0.16 mmol), triethylamine (0.024 mL, 0.17 mmol) and 3-dimethylamino-propylamine (0.022 mL, 0.17 mmol) In 1.6 mL of DMF. After stirring for 3 hours, the reaction was concentrated by rotary evaporation. The residua was purified by silica gel chromatography using gradient elutioh of dichloromethane. methanol, ammonium hydroxide to afford 2-(4-{6-Amino-5-[1 -(2r6-dichlorO'3-fluoro-phenyl)-ethoxy]-pyridin-3-y1}-pyrazol-1 -yl)-N-(3-dimethylamino-propyi)-propionamide. (41 mg. 50%). General Procedure 68: H3C n M „ N-NH /N~Boc DEAD Br THF Diethylazodksarboxytate (0.48 mL, 3.1 mmol) was added to a Q°C solution of triphenylphoaphine (0.80 g, 3.1 mmol) in THF (20 mL). After stirring for 5 minutes, 4-bromo-pyrazole (0.30 mg, 2.0 mmol) was added. After another 5 minutes of stirring, (2-hydroxyethyl)-methyl-carbamlc acid tert-butyl ester (0.45 g, 2.6 mmol) was added. The reaction was allowed to warm to room temperature and stir overnight. The reaction was cooled to 0°C and filtered. The filtrate was concentrated by rotary evaporation. The residue was purified by slica gel chromatography using gradient elution of dichloromethane, ethyl acetate to afford [2-(4-bromo-pyrazol-1-yl)-ethyl]-methyl-carbamic add tert-butyl ester (541 mg, 87%). General Procedure 69: H3C P N-NH .4^1 II f*t • - >«CHa Br a- DMF Br Sodium hydride (0.12 g, 4.9 mmol) was added to a solution of 4-bromo-4H-pyrazole (0.60 g, 4.1 mmol) in DMF (10 ml). After stirring for 10 minutes, a solution of 2-chloro-propionic acid methyl ester in DMF (4 mL) was added. After stirring for 4 hours, (he reaction was partitioned between ethyl acetate and water. The phases were separated and the aqueous phase was extracted with ethyl aoetate. The combined organic phases were dried over MgSO4 and concentrated by rotary evaporation. The residue was purified by silica gel chromatography using gradient elution of ethyl acetate and hexanes to afford 2-(4-bromo-pyrazol-1-yl)-propionic acid methyl eater (733 mg, 77%), General Procedure 70 MeOH, THF Cl CH3 ^^vX^n A solution of LIOH (34 mg, 1A mmol) in water (0.4 ml) was added to a solution of 2-(4-{6-Amino-5-(1 -(2.6-dJch!oro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-pyrazol-1 -yl)-propionic acid methyl ester (70 mg, 0.15 mmol) In a mixture THF (1.5 ml) and MeOH (0.4 mL). After stirring overnight, the reaction was partitioned between dichloromethane and half-saturated brine. A small amount of ethanoi was added and the pH was adjusted to 7 with 1 M HCI. The phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over NazSO*. filtered and concentrated by rotary evaporation to give 2-(4-{6-amino-5-[1-(2,6-dlcWoro-3-fluoro-phenyl)-ethoxy|-pyridin-3-yl)-pyra2ol-1-yl)-propionic acid (69 mg, 100%). General Procedure 71: o a stirred solution of 4^3^6-Amino-5-[1-(2,6-dichloro-3-fIuoro-pheriy1)-ethoxy]-pyrKJfn-3-yl)-pyrazol-1-yl)-pyrroJWine-2-carboxylic add methyl ester (105 mg, 0.21 mmol) in THF (5 mL) was added 2 M CH3NHj In THF (1.06 ml_ 2.12 mmol}, the mixture was stirred and heated at 55°C for 18 hours, LCMS checked that the reaction was completed, remove THF, the residue was purified by prep-HPLC to leave 4-(4^6-amlncH5-J1-(2,6^i General Procedure 72: ,Boc N-N XsBr.t L.Br.OMs tort-butyl 4-(4>4l5,5-tetramettnyl-1l3(2- Compound 21-3. shown with the specific example of 3-{1-(2.6-dichloro-3-thJorophenyl)ethoxy]-5-(1 H-pyrazol-4-yl)pyrklin-2-amine (21-3a): N-NH Compound 21-1 (1.0 molar equivalent) was added to a solution of compound 21-2a (Compound 21-2. with R substituents to give 2,6-dichloro-3-fluorophenyl) (1.92 mmol) in 20 ml of DME. The mixture was stirred at room temperature under a nitrogen atmosphere .for 30 minutes and then dichlorobis(triphenviphosphino) palladium (II) (0.05 molar equivalent) was added. Sodium carbonate (3 motar equivalent) in 4 ml of HjO was added to the reaction mixture and the resulting solution was heated to 85°C for 12 h. Alternative bases used were CsF and CsjCQj in with 1 or 2 equivalents of boronic ester, and al room temperature (CsF) or 80°C (all). Water was added to the reaction mixture to quench the reaction. EtOAc (150 ml x 2) was then added to extract the aqueous solution. Dry EtOAc layer over NasSO*. The NajSO* was filtered off and the filtrated was evaporated to give a dark brown oil residue. The residue was purified by silica gel chromatography (eluting with eluting with 0-+10 % MeOH in ethyl acetate) to give the desired product compound 21^33 (2.05 g. 53.6% yield). 1H NMR (400 MHz, chloroform-D) 6 ppm 1.60 (s, 1 H) 1.S4 (d, J=6.57 Hz, 3 H) 5.07 (s, 2 H) 6.06 (q, >6.57 Hz, 1 H) &89 (d, J-1.77 Hz, 1 H) 6.96 - 7.06 (m, 1 H> 7.22 -7.33 (m. 1 H) 7.67 (3,2 H) 7.80 (d. J=~\ .52 HZ, 1 H). To make compounds of formula 21-4, the following exemplary procedure can be used: sodium hydride (1.2 molar equivalent) is added to a solution of compound 21-3 (0.87 mmol) in 10 mL of DMF. The mixture is stirred at room temperature under a nitrogen atmosphere for 30 min and then compound 21-6 (1 molar equivalent) is added. The resulting solution ifi heated to 85-90°C for 12 h. Water (20 mL) is added to the reaction mixture to quench the reaction. EtOAc (50 mL x 2) is then added to extract the aqueous solution. Dry EtOAc layer over NazS04. The Na^Cv is filtered off and the filtrate is evaporated. The residue is purified by silica gel chromatography (eluting with EtOAc in hexanes) to gfve the desired product, compound 21d (20-50% yield). General Procedure 73: L « Br, Cl, COOH, COCI, OMs, ethylene carbonate, aldehyde Compounds of formula 22-3 can be prepared by the following exemplary procedure: Compound 22-2 (1.2 molar equivalent) is added to a solution of compound 2^1 (0.24 mmol) and base (3-5 molar equivalent) and/or coupling reagent (1 molar equivalent) in 5 mL of DMF. The mixture is stirred under a nitrogen atmosphere for 12 h. Water (20 mL) is added to the reaction mixture to quench the reaction. EtOAc (SO mL x 2) is then added to extract the aqueous solution. Dry EtOAc layer over NasSO+. The NazSO, is littered off and trie filtrate evaporated. The residue is purified by silica gel chromatography (eluting with CHjOH, CH*CI2, EtOAc, and hexanes) to give the desired product, compound 22d2. General Procedure 74: The following procedure can be used to prepare piperidine-pyrazote-2-aminopyridine derivatives. X = Sr, I R"-L' L1 * Br, d. COOH, COCl. OMs, ethytene carbonate, aldehyde 23-7a frrt-butvl 4-(4-iodo-iffpyrazol-i-vtiPiperidintt.i-cart)oxv>ate (23-1 at NaH (1.2 eq., 0.68 mmol) was added portonwlse to a stirred solution of 4-iodopyrazole (0.57 mmol) in OMF (2 L) at 4°C. The resulting mixture was stirred for 1 hour at 4'C and compound 23^4 (1.1 eq., 0.63 mmol) was then added. The resulting mixture was heated to 100°C for 12 h. The reaction was quenched with HjO and extracted with EtOAc several times. The combined organic layers were dried, filtered, and concentrated to afford an orange oil. The residue was purified fay silica gel chromatography (eluting with 5% EtOAc in pentane) to give compound gfl-lq as a white solid (140 g, 66%). Bis(pinacolato)diboron (1.4 eq.. 134 g. 0.52 mot) and potassium acetate (4 eq., 145 g. 1.48 mol) were added sequentially to a solution of compound 23-1a (uo g, 0.37 mol) in 1. 5 L of DMSO. The mixture was purged with nitrogen several times and dichlorobis(triphenylphosphino) paBadium (II) (0.05 eq., 12.9 g, 0.018 mol) was then added. The resulting mixture was heated at 80°C for 2 h. The reaction mixture was cooled to room temperature and filtered through a bed of celfte and washed with EtOAc. The filtrate was washed with saturated NaCI (500 ml x 2), dried over NajSO4, filtered and concentrated. The residue was purified by silica gel chromatography (eluting with 5% EtOAc in hexanes) to give compound 23-1 fr as a white solid (55 g, 40%). Compound 23-2 (1.0 molar equivalent) was added to a solution of compound 23-1 b (1.3 molar equivalent) in 15 ml of DME. The mixture was purged with nitrogen several times and then dichlorobis(triphenylphosphino) palladium (II) (0.05 molar equivalent) was added. Cesium carbonate (3 molar equivalent) in 4 mL of H20 was added to the reaction mixture and the resulting solution was heated to 85"C for 12 h. Water (10 mL) was added to the reaction mixture to quench the reaction. EtOAc (150 ml x 2) was then added to extract the aqueous solution. Dry EtOAc layer over NajS04. The NaaSO, was filtered off and the filtrated was evaporated to give a dark brown oil residue. The residue was purified by silica gel chromatography (elutlng with eluting with 75-* 100 % EtOAc in hexanes) to give compound 23-3a (61% yield). Hydrochloride (19 eq., 12 mmol) was added to a solution of compound 23-3a (0.63 mmol) in MeOH (4 mL). The mixture was stirred at room temperature lor 12 h. The solvent was evaporated and HjO (10 ml) was added. Saturated NaHCO3(aq) was added to neutralize the solution to pH 7. Ethyl acetate (100 mL x 2) was added to extract the aqueous solution. The combined organic layer was dried over NajSO Compounds of formula 23-7 can be formed according to the following general procedure: Compound 23-f (1.2 molar equivalent) is added to a solution of compound 23-Sa (0.24 mmol) and base (3-5 molar equivalent) and/or coupling reagent (1 molar equivalent) in 5 mL of DMF. The mixture is stirred under a nitrogen atmosphere for 12 h. Water (20 mL) is added to the reaction mixture to quench the reaction. EtOAc (50 mL x 2) is then added to extract the aqueous solution. Dry EtOAc layer over NazSO*. The NazS04 is filtered off and the filtrated Is evaporated to give an oil residue. The residue is purified by silica gel chromatography (eluting with CH3OH, CH2CI2, EtOAc. and hexanes) to give the desired product, compound 23-7a. General Procedure 75: HCO. N-NH 3-methoxy compounds can be prepared from the corresponding 3-fluoro compounds by the following general procedure. To 4 mL of DMSO is added 0.124 mL ethanol followed by 32 mg NaH. After stirring for 30 minutes 250 mg of 24-1 is added and the reaction heated to 40°C. After three hours the reaction is cooled and poured into water to precipitate. After neutralization to pH 6, the product 24-2 is isolated. General Procedure 76: TFA. H20 THF To a stirred solution of 3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy)-5-[1-(2l2-dimethyl-[1,3]dtoxolan-4-vlmethyl)-1H-pyrazol-4-yl].pyridln-2-ylamlne (150 mg, O.31 mmol) in THF (3 mL) and H20 (2 ml) was added TFA (2 mL) at 0°C, the mixture was stirred and warmed to room temperature, then heated at 50°C for 5 hours, LCMS checked that the reaction was completed, remove THF, the residue was purified by prep-HPLC to leave 3-(4-{6-amino-5-f1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-pvrazol-1-yl)-propane-1,2-diol (102 mg), yield 742%. General Procedure 77: H 0 NaH 9 4. r >=o > M 0 DMF ^ To a stirred solution of 4-bromo-1H-pyrazote in DMF was added sodium hydride at room temperature. The mixture was stirred for 30 minutes. [l,3]dioxolan-2-one was added, the mixture was stirred and slowly warmed to room temperature. The reaction was monitored by TLC. After the reaction was done, EtOAc was added, washed with saturated NaHCO3, water and brine, dried with NazSO4, filtered and concentrated- The residue was purified by silica gel, eluants EtOAc and DCM 10%, to give 2>(4-Bromo-pyrazol-1-yl)-ethanol 0.22 g, yield 34%. *H NMR (400 MHz, chloroform-D) 0 ppm 7.49 (s, 1 H) 7.46 (s. 1 H) 4,18 - 4.23 (m, 2 H) 3.93 - 3.98 (m, 2 H) 3.09 (s, 1 H). Example 1:5-Bromo-3-[(R)-l -{2,6-dlchioro-3-f luoro-pherryl)-ethoxyH>yraz!n-2-yiamine AcOH The tide compound was prepared according to procedure 2, from (lS)-l-(2,6-dichloro-3-fluorophenyl)ethanol. 'H NMR (400 MHz, DMSO-d6) o 7.53(S, 1H), 7.48(m, 1H), 7.39(t, 1H), 6.48 (s, 2H). 6.41 (q, 1 H), 1 J4(d, 3H); LCMS: 381 [M+1 ]; c-Met Ki: 0.796 pM. Example 2: 4-[5-AminQ-6-Kfll-1-(2.6-dichloro-3-1tuoro-phenvn-BthQxy]-pyra2in-2-yl)-benzQic acid The title compound was prepared according to procedure 3. 'H NMR (400 MHz, DMSO-d6) 6 8.16(8. 1H). 7.84(d, 2H). 7.77(d, 2H). 7.53(m. 1H), 7.37(t, 1H), 6.64 (s, 2H), 6.53(q, 1H). 1.78(d, 3H); LCMS: 422 [M+1]; c-Met Ki: 0.154 |JM. Example 3: (445-Amino-6-l(R)-l-(2,6-di(*iloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-piperazin-1 -yl-methanone AcOH NH, The title compound was prepared according to procedure 4. 'H NMR (400 MHz, DMSO-46) 8 8.11(s, 1H), 7.73(d, 2H), 7.53^, 1H). 7.37(t, 1H), 7.31(d, 2H), 6.55 (m. 3H), 3.51(br. 2H), 3.32(br, 2H), 2.67{br, 4H), 1.77(d, 3H); LCMS: 490 JM+IJ; c-Met Ki: 0.027 pM. Example 4: 4"(4-{5-Amir».6-[(R)-H2,6^ichle»ro-3-IIuorc^pheriyl)-ethoxy)-pyrazin-2-yl]-t>enzoyl)-piperazine-1-carboxylic add tert-butyt ester IH, The title compound was prepared according to procedure 16 followed by 20. 'H NMR (400 MHz, DMSO-d6) 6 8.1 2($, IH). 7.72(d, 2H), 7-50(m, 1H}. 7.33(t, 3H), 6.55 (m, 3H). 3.51 (br, 2H), 3.39(m, 3H), 3.32(br. 3H), 1.77(d, 3H), 1.40(s, 9H); LCMS: 590 tMtl); C-Met Ki: 0.335 pM. Example 5: 3-[(1 R)-1 -(2,6-dichloro-3-fluorophenyl)ethoxy]-&-[4-(plpera2in-1 -ylcarbor»yl)phenyl] pyridln-2-amlne l)s1hoxy]pyridin-3-yl}-N-I2- (dimethylamino)ethyl]-N-methylbanzainide The tide compound was prepared according to procedure 20. 'H NMR (400 MHz, DMSO-D6) 5 ppm 1.80 (d, J=6.82 Hz, 3 H) 1.97 (s. 3 H) 2.19 (9, 3 H) 2.30 - 2.42 (m, J=1.77 Hz, 2 H) 2.93 (s. 3 H) 3.22 - 3.29 (m. 1 H) 3.44 - 3.61 (m, 1 H) 5.95 (s. 2 H) 6.14 (q, J=6.57 Hz, 1 H) 6.98 (d, J»1.01 Hz. 1 H) 7.30 - 7.39 (m, 2 H) 7.40 - 7.47 (m. 3 H) 7.51 - 7.62 (m, 1 H) 7.87 (d, J=1.77 Hz, 1 H); LCMS: 506 [M+1]; c-Met Ki: 0.01 pM. Example?: (4-{6-amino-5-{(1 R}-1 -(2,6-cKchloro-3-fluorophenyl)ethoxy]pyridin-3-yl}phenyl)methanol (Figure Remove) The title compound was prepared according to procedure 27. 'H NMR (400 MHz, DMSO-D6) 5 ppm 1.84 (d. J=6.57 Hz, 3 H) 4.49 (d. J-5.B1 Hz. 2 H) 5.20 (t, Ja5.81 Hz, 1 H) 6.25 (q. J-6.57 Hz, 1 H) 6.46 - 6.88 (m, 2 H) 7.04 (d, J-1.52 Hz, 1 H) 7.34 (s, 4 H) 7.46 (t, J=8.72 Hz, 1 H) 7.59 (dd, J.8.97.4.93 Hz, 1 H) 7.76 (d, J»1.52 Hz, 1 H); LCMS: 408 [M+1]; c-Mct M: 0.051 uM. Example Ji: 4-{6-amino-5-((1R)-1-(2,6-dich!oro-3-fluorophen^}elhoxy]pyridin-3-yl)-N-[3-(dimethylamino)propyl]-N-methylbenzamide r- The title compound was prepared according to procedure 27. 'H NMR (400 MHz, DMSOD6) 3 ppm 1.60 -1.73 (m, 2 H) 1.80 (d, J=6.57 Hz, 3 H) 1.94 (S, 3 H) 2.13 (s, 3 H} 2.20 - 2.29 (m. 2 H) 2.92 (8. 3 H) 3.36 - 3.50 (m, 2 H) 5.96 (s. 2 H) 6,14 (q, J*6.57 Kz, 1 H) 6.98 (8, 1 H) 7.37 (s. 2 H) 7.40 - 7.51 (m, 3 H) 7.55 (dd, J=8.84,4.80 Hz, 1 H) 7.86 (d, J=1.77 Hz, 1 H); LCMS: 520 [M+1]; c-MetKi:O.Ol pM. Example 9: tart-butyl 4-(4-{6-arrrinc-5-{(1R)-1-(2.6-dichk>ro-3-1luorophenyl)ethoxy]pyridin-3-y1]benzoyl)piperazine-1 -carboxylate The title compound was prepared according to procedure 20. 1H NMR (400 MHz, chloroform-D) 6 ppm 1.46 (S, 9 H) 1.86 (d, J=6.82 Hz. 3 H) 3.30 - 3.89 (m, 6 H) 4.90 (s, 2 H) 6.11 (q, J=6.57 Hz, 1 H) 6.98 (d, J*1.52 Hz, 1 H) 7.01 - 7.10 (m. 1 H) 7.30 (dd, J=8.97, 4.93 Hz. 1 H) 7.35 - 7.43 (fn, 4 H) 7.88 (d, J=1.77 Hz, 1 H); LCMS: 590 [M+1]; c-Met Kh 0.03 yM. Example 10: 3-l(R)-1 -(2.6-Dichloro-3'fluoro-phenyl)"ethoxy]-5-[1 -(1 -methyl-piperidin-4-yl)-1 H-pyrazol-4-ytl-pyridin-2-ylamine The title compound was prepared according to procedure 62 using 3-[(fl)-1-(2,6-dichloro-3-r1uoro-ph8nyi}-ethoxy]-5-(4,4,5,5-t6lramethy(-[1.3,2]ciioxaborolan-2-yt)-pyTi(fln-2-ylamine and 4-(4-bromo-pyrazoM -yt)-i-methy-piperidlrte {prepared according to general procedure 11. 1H NMR (400MHz, CDdj) fl 7.65 (s. 1H), 7.55 (s. 1H), 7.50 (s, 1H), 7.31 (m,1H), 7.06 (m, 1H), 6.87 (s. 1H), 6.08 (m, 1H). 5.50 (bs, 2H), 4.18 (m, 1H), 3.11 (m, 2H), 2.40 (s, 3H), 2.30 (m, 2H), 2.20 (m, 4H), 2.07 (s. 3H), 1.86 (d, J B Hz. 3H); LCMS: 464 [M+1]; C-Met Kl: 0.01 \M. Example 11: 1 -[4-(4-{6-Amino-5-[(R)-1 -(2,6-dichloro-3-1luoro-phenyl)-ethoxy]-pyridin-3-yl}-pyrazol-1 -yl)-pipcridin-i -yl)-2-hydroxy-ethanone The title compound was prepared according to procedure 63. 'H NMR (400MHz, CDCI3) 6 7.72 (s, 1 H), 7.57 (s, 1H), 7.47 (s, 1H), 7.31 (m, 1H), 7.06 (m. 1H), 6.86 (s. 1H), 6.08 (m, 1H). 5.00 (bfi, 2H). 4.70 (m, 1H), 4.36 (m, 1H). 421 (s, 1H), 3.70 (m, 1H). 3.18 (m, 1H). 3.00 (m, 1H), 2.223 (m, 2H), 2.01 (m, 2H), 1.86 (d, J 8 Hz. 3H); LCMS: 508 [M+1]; C-Met Ki: 0.004 uM. Example 12: 3-[(R)-1-(2,6-Dlchloro-3-fluoro-Dhenyl)-ethoxy]-5-(l -piperidln-4-yM H-pyrazoM-yT)-pyridtn-2-ylamine rhe title compound was prepared according to procedure 62 using 3-[(R)-1-(2,6-dichloro-3-fluoro-)heny|)-ethoxy]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-y1)-pyridin-2-ylamine and 4-(4-bromo->yrazol-l-yl)"i-cyctopentyl-piperidine (prepared according to general procedure 11 using >romocyck>pentane as alkylatlon reagent). 1H NMR {400MHz, CDd3) 6 7.73 (s. 1H). 7.55 (s. 1H), M8 (s, 1H). 7.31 (m, 1H), 7.07 (m, 1H), 6.88 (s, 1H), 6.08 (m, 1H), 4.64 (m, 1H), 2.04 (m, 2H), 1.98 (m, 2H). 1.86 (d, J 8 Hz, 3H), 1,73 (m, 2H); LCMS: 435 [M+1]; c-Met Kl: 0.02 uM. Example 13: 3-[{R)-1-(2,6-D«chloro-3-fluoro-pheiiyl)-ethoxy]-5-(1-piperlcBn-4-y1-1H-pyTa2ol-4-yl)-3yridin-2-ytamine The title compound was prepared according to procedure 62. 'H NMR (400MHz, CDCI3) 6 7.69 (s. 1H), 7.56 (s, 1H), 7.50 (B, 1H), 7.32 (m, 1H). 7.07 {m. 1H), 6.87 (m, 1H), 6.07 (m, 1H), 5.25 (bs, 2H), 4.30 (m, 1H), 3.41 (m, 2H), 2.96 (m, 2H), 2.26 (m, 2H), 2.12 (m, 2H). 1.86 (d, J 8 Hz, 3H); LCMS: 450 [M+1]; c-Met Ki: 0.003 uM. Example 14: 3-[(R)-1-(2,6-Dtchloro-3-1kJOro-phenyI)-ethoxy]-5-(1-piperidln-4-yl-1H-pyrazol-4-yl)-pyrazJn-2-ylamine zoM-y1)-pyrazin-2-ylamine IHa The title compound was prepared according to procedure 3 using 5-bromo-3-[(fl)-1-(2,6-dichloro-3-nuoro-phcnyt)-ethoxy]-pyrazin-2-y)amlne and 4-(4,4,S,5-Tetramethyl-[1,3,2}dioxaborolan-2-yl)-pyrazote-l-carboxyHc acid tert-butyl aster. 'H NMR (400 MHz, DMSO-d6) 6 12.81(s, 1H), 7.79 (s, 1H)( 7.48(m, 1H). 7.36(t. 1H), 6.48 (q, 1H), 6.12{s, 2H), 1.75(d, 3H); LCMS: 368 [M+1]; c-Met KI: 0.065 pM. pxamote 16: 1-[4-(4^5-Aminc^[(R)-l-(2,6-dic^toro-3-fluoro-phenyt)-ethoxy]-pyra2ln-2-yl)-pyra20l-1 -yt)-piperldin-1 -yl]-2-hydroxy-ethanone (Figure Remove) AcOH The title compound was prepared according to procedures 62 and 63. using 5-bromo-3-[(R)-1-{2,6-dicWoro.3.fluoro-phenyl)-ethoxy]-pyra2irv2.ylamine as the starting material. 'H NMR (400 MHz, DMSO-d6) 6 7.91 (s. 1H}, 7.76(8, 1H), 7.64(s, 1H). 7.49(m. 1H), 7.36(t, 1H). 6.46 (q, 1H), 6.15(8, 2H), 4.57(br. 1H), 4.40(m, 2H). 4.12(br. 2H). 3.77(m. 1H). 3.35(m. 2H), 3.43(m. 1H). 3,16(m, 2H), 1.75(d, 3H); LCMS: 509 IM+1); c-Met Ki: 0.015 MM. Example 17: 3-[(R)-1 -(2,6-Dichloro-3-fluoro-pnenyl)-ethoxyj-5-[1 -(1 -methyl-piperidin-4-yl)-1 H-pyrazol-4-yll-pyrazin-2-y1amine AaOH The title compound was prepared according to procedure 62 using 5-bromo-3-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-y1amine and 4-(4-bromo-pyrazol-1-yl)-1-metriy-piperidine (prepared according to general procedure 11). 'H NMR (400 MHz, DMSO-d6) 6 7.88 (s, 1H), 7.76(8, 1H). 7,64(8, 1H). 7.49(m, 1H), 7.36(t, 1H), 6.46 (q, 1H). 6.15(s. 2H), 4.02(m, 1H), 2.84(m. 2H), 2.19(s. 3H), 2.00{m, 4H), 1.85(m, 3H). 175(d, 3H); LCMS: 465 [M+1]; c-Mct Ki: Q.03 pM. Example 1S: 1 -[4-(4-{5-Amino-6-[(R)-1 -(2,6-dichloro-3-fluoro-pheryyl).etho)cy]-pyra2in-2-yl>-pyra2oJ-1 -yl)-piperidin-1 -yl]-2-dimethylamino-athanone The title compound was prepared according to procedure 63 using 3-[(ff)-l-(2,6 HOAc The title compound was prepared according to procedure 62 using 5-bromo-3-[(fl)-1-(2-chloro-3,6-drfluoro-phervyl)-etrioxy]-pyridin-2-y)amine as starting material (according to the methods for the synthesis of 5-bromo-3-[1-(2,6-dichloro-3-tlJoro-phenyt)-ethoxy]-pyridir»-2-ylamine from (S)-1-(2-chloro-3,6-drtluoro-phenyl)-ethanol. obtained from SynChem, Inc.). 'H NMR (400MHz, DMSO-d6) 6 7.88 (s, 1H), 7.70 (s, 1H), 7.50 (S, 1H). 7.38 (m, 1H). 7.25 (m. 1H), 6.99 (s, 1H), 5.88 (m, 1H), 5.48 (bs, 2H). 4.08 (m, 1H), 2.96 (m, 2H), 2.53 (m, 1H), 2.45 (m, 1H), 1.89 (m, 1H), 1.80 (m, 4H), 1.67 (m. 4H); LCMS: 434 [M-t-1]; c-Met Ki: 0.09 uM. Biological Eyamoles It will be appreciated that, in any given series of compounds, a range of biological activities witt be observed. In its presently preferred aspects, this invention relates to novel compounds capable of modulating, regulating and/or inhibiting protein kirtase activity. The following assays may be employed to select those compounds demonstrating the optimal degree of the desired activity. Assay Procedures The following in vitro assay may be used to determine the level of activity and effect of the different compounds of the present invention on one or more of the PKs. Similar assays can be designed along the same lines for any PK using techniques well known in the art A literature reference is provided (Technikova-Dobrova Z, Sardanelll AM, Papa S FE8S Lett. 1991 Nov 4; 292: 69-72). The general procedure is as follows: compounds and kinase assay reagents are introduced into test wells. The assay is initiated by addition of the kinase enzyme. Enzyme inhibitors reduce the measured activity of the enzyme. In the continuous-coupled spectrophotometric assay the time-dependent production of ADP by the kinase is determined by analysis of the rate of consumption of NADH by measurement of the decrease in absorbance at 340 nm. As the PK produces ADP it is re-converted to ATP by reaction with phosphoenol pyruvate and pyruvate kinase. Pyruvate is also produced in this reaction. Pyruvate is subsequently converted to lactata by reaction with lactate dehydrogenase, which simultaneously converts NADH to NAD. NADH has a measurable absorbance at 340 nm whereas NAD does not. The presently preferred protocol for conducting the continuous-coupled spectrophotometric experiments for specific PKs Is provided below. However, adaptation of this protocol for determining the activity of compounds against other RTKs, as well as for CTKs and STKs, is well within the scope of knowledge of those skilled in the art. HQFR Continuous-coupled Spectrophotometric Assay This assay analyzes the tyrosine kinase activity of HGFR on the Met-2 substrate peptide, a peptkJe derived from the activation loop of the HQFR. Material* and Reagents: 1. HQFR enzyme from Upstate (Met, active) Cat. # 14-526 2. Met-2 Peptide (HGFR Activation Loop) Ac-ARDMYDKEYYSVHNK (MW = 1960). Dissolve up in 200 mM HEPES, pH 7.5 aUO mM stock. 3. 1 M PEP (phospho-enol-pyruvate) In 200 mM HEPES. pH 7.5 4. 100 mM NADH (B-Nfcotinamide Adenine Dlnucleotide, Reduced Form) in 200mM HEPES, pH7J3 5. 4 M MgClj (Magnesium Chloride) in ddHzO 6. 1 M on (DitWothreitol) in 200 mM HEPES, pH 7.5 7. 15 Unfts/mLLDH (lactic Dehydrogenase} 8. 15 Units/mL PK (Pyruvate Kinase) 9. 5M NaCI dissolved in ddHzO 1 o. Tweer>-20 (Protein Grade) 10% soiuoon 11. 1 M HEPES buffer (N-[2-Hydroxethyl]piperazinB-N-{2-ethanesutfonic acid]) Sodium Salt Dissolve in ddH2O, adjust pH to 7.5, bring volume to 1 L. Fitter at 0.1 um. 12. HPLC Grade Water; Burdick and Jackson #365-4,1 X 4 liters (or equivalent) 13. 100% DMSO (SIGMA) 14. Cosier * 3880 - black dear flat bottom half area plates for K determination and % inhibition 15. Costar tf 3359 - 96 weH polypropylene plates, round bottom for serial dilutions 16. Costar« 3635 - UV-plate clear flat bottom plates for % inhibition 17. BeokmanDU-650w/ micro cell holders 18. Beckman 4-position micro cell cuvette Procedure: Prep Dilution Buffer (DB) for Enzyme (For 30 ml prep) 1. DB final concentration is 2 mM DTT, 25 mM NaCI4, 5 mM MgCfe, 0.01% Tween-20, and 50 mM HEPES buffer, pH 7.5. 2. Make up 50 mM HEPES by adding 1.5 ml 1 M HEPES into 28.1 mi. of ddH2O. Add rest of the reagents. Into 50 ml conical vial, add 60 uL of 1M DTT, 150 uL 5M NaClj, 150 nL 1M MgCJ2, and 30 uL of 10% Tween-20 to give total volume of 30 mL. 3. Vortex for 5-10 seconds. 4. Aliquot out DB at 1 ml/tube and label tubes as 'DB HGFR" 5. Note: This can be prepared and stored ahead of time. 6. Freeze un-used aliqgots in microcentrifuge tubes at -20°C freezer. Prep Compounds 1. For compound dilution plate, add 4 uL of 10 mM stock into column 1 of plate, and bring volume to 100 uL with 100% DMSO. 2. Set up the Precision 2000 dilution method. A final concentration of 200 jiM compound in 50% DMSO, 100 mM HEPES (12 serial dilution). Prep Coupled Enzymatic Buffer: 1. Final concentration in assay: Reagent (Stock Cone.) Final Cone. In Assay a. PEP(1M) imM b. NADH(IOOmM) 300 uM c. MgClz(4M) 20 mM d. DTT(1M) 2mM e. ATP (500 mM) 300 uM f. HEPES 200 mM (pH 7.5) 100 mM g. Pyruvate Kinase (PK) 15unlts/mL h. Lactic Dehydrogenase (LDH) 15units/mL i. Met-2 peptide (10 mM) 0.500 mM j. HGFR 50 nM 2. For a 10 ml reaction buffer add 10 uL of 1M PEP, 33 uL of 100 mM NADH, 50 uL of 4M MgClj. 20 jiL of 1M DTT, 6 uL of 500 mM ATP. and 500 uL of 10 mM Met-2 peptide into 100 mM HEPES buffer pH 7.5 and vortex/mix. 3. Add coupling enzymes, LDH and PK, into reaction mix. Mix by gentle inversion. Running samples 1. Spectrophotometer settings: i. Absorbance wavelength (A): 340 nm ii. Incubation time: 10 min Hi. Runtime: 10min iv. Temperature: 37°C 2. Add 85 nU of CE reaction mix into each well of assay plate. 3. Add 5 uL of diluted compound into a well of the assay plate. 4. Add 5 uL of 50% DMSO for negative control into last column of assay plate. 5. Mix with multi-channel pipettor or orbital shaker. 6. Pre-incubate for 10 minutes at 37°C. 7. Add 10 ML of 500 nM HGFR to each well of assay plate; the final HGFR concentration is SO nM in a total final volume of 100 uL 8. Measure activity for 10 minutes at A = 340 nm and 37°C. The following in vitro assays may be used to determine the level of activity and effect of the ifferent compounds of the present invention on one or more of the PKs. Similar assays can be esigned along the same lines for any PK using techniques wed known in the art Several of the assays described herein are performed in an ELJSA (Enzyme-Linked Immunosorbent Sandwich Assay) format (Volter, et al., 1980, "Enzyme-Linked Immunosorbent Assay.* Manual of Clinical Immunology, 2d ed.. Rose and Friedman, Am. Soc. Of Microbiology, Washington, D.C., pp. 359-371). General procedure is as follows: a compound is introduced to cells expressing the test kinase, either naturally or recombinantly, for a selected period of time after which, If the test krnase is a receptor, a ligand known to activate the receptor is added. The cells are lysed and the lysate is transferred to the wells of an ELISA plate previously coated with a specific antibody recognizing the substrate of the enzymatic phosphorylation reaction. Non-substrate components of the cell lysate are washed away and the amount of phosphorylation on the substrate is detected with an antibody specifically recognizing phosphotyrosine compared with control cells that were not contacted with a test compound. The presently preferred protocols for conducting the ELISA experiments for specific PKs is provided below. However, adaptation of these protocols for determining the activity of compounds against other RTKs, as well as for CTKs and STKs, is well within the scope of knowledge of those skilled in me art. Other assays described herein measure the amount ol DMA made in response to activation of a test kinase, which is a general measure of a proliferative response. General procedure for this assay is as follows: a compound is introduced to cells expressing the test kinase, either naturally or recombinantly, for a selected period of time after which, if the test kinase is a receptor, a ligand known to activate the receptor is added. After Incubation at least overnight, a DMA labeling reagent such as S-bromodeoxyuridlne (BrdU) or Hs-thymidlne is added. The amount of labeled DNA is detected with either an anti-Brdll antibody or by measuring radioactivity and is compared to control cells not contacted with a test compound. MET Transohosphorvlation Assay This assay is used to measure phosphotyroslne levels on a poly(glutamic acid: ryrosine, 4:1) substrate as a means for identifying agonists/antagonists of met transphosphorylalion of the substrate. Materials and Reagents: 1. Coming 96-well EUSA plates, Coming Catalog # 25805-96. 2. Poly(glu-tyr), 4:1, Sigma, Cat. No; P 0275. 3. PBS, Gibco Catalog #450-1300EB 4. 50 mM HEPES 5. Blocking Buffer: Dissolve 25 g Bovine Serum Albumin, Sigma Cat No A-7888. in 500 ml PBS, filter through a 4 um filter. 6. Purified GST fusion protein containing the Met kinase domain, SUGEN, Inc. 7. TBST Buffer. 8. 10% aqueous (MilliQue HjO) DMSCv 9. 10 mM aqueous (dH2O) Adenosine-S'-triphosphate, Sigma Cat No. A-5394. 10. 2X Kinase Dilution Buffer: for 100 mL, mix 10 mL 1M HEPES at pH 7.5 with 0.4 ml 5% BSA/PBS, 0.2 mL 0.1 M sodium orthovanadate and 1 ml 5M sodium chloride in 88.4 ml dHjO. 11. 4X ATP Reaction Mixture: for 10 ml, mix 0.4 ml 1 M manganese chloride and 0.02 ml 0.1 MATPin9.56mLdHzO. 12. 4X Negative Controls Mixture: for 10 mL, mix 0.4 mL 1 M manganese chloride in 9.6 mL dHjO. 13. NUNC 96-weK V bottom polypropylene plates, Applied Scientific Catalog # S-72092 14. SOOmMEDTA. 15. Antibody Dilution Buffer: for 100 mL. mix 10 mL 5% BSA/PBS, 0.5 mL 5% Carnation9 Instant Milk in PBS and 0.1 ml 0.1 M sodium orthovanadate in 88.4 ml TBST. 16. Rabbit polydonal antophoephotyrosine antibody, SUGEN, Inc. 17. Goat anti-rabbit horseradish peroxidase conjugated antibody, Biosource, Inc. 18. ABTS Solution: tor 1 L mix 19.21 g citric acid, 35.49 g Na8HP04 and 500 mg ABTS with sufficient dH2O to make 1 L. 19. ABTS/HzOj: mix 15 mL ABST solution with 2ul H2O2 five minutes before use. 20. 0.2 M HCI Procedure: 1. Coat ELISA plates with 2 ug Poly(Glu-Tyr) in 100 uL PBS. hold overnight at 4«C. 2. Block plate with 150 uL of 5% BSA/PBS for 60 min. 3. Wash plate twice with PBS then once with 50 mMHepes buffer pH 7.4. 4. Add 50 uL of the diluted kinase to all wells. (Purified kinase is diluted with Kinase Dilution Buffer. Final concentration should be 10 ng/well.) 5. Add 25 pL of the test compound (In 4% DMSO) or DMSO alone (4% In dH2O) for controls to plate. 6. incubate the kinase/compound mixture for 15 minutes. 7. Add 25 uL of 40 mM MnCla to the negative control wells. 8. Add 25 uL ATP/ MnClz mixture to the all other wells (except the negative controls). Incubate for 5 min. 9. Add 25 uL. 500 mM EDTA to stop reaction. 10. Wash plate 3x with TEST. 11. Add 100 \A. rabbit potyclona! anti-Ptyr diluted 1:10,000 in Antibody Dilution Buffer to each well. Incubate, with shaking, at room temperature for one hour. 12. Wash plate 3x with TBST. 13. Dilute Biosource HRP conjugated anti-rabbit antibody 1: 6,000 in Antibody Dilution buffer. Add 100 uL per well and incubate at room temperature, with shaking, for one hour. 14. Wash plate 1X with PBS, 15. Add 100 til Off ABTS/H;>OZ solution to each well. | 16. If necessary, stop the development reaction with the addition of 100 uL of 0.2M HCI per well. 17. Read plate on Dynatech MR7000 ELISA reader with the test filter at 410 nM and the reference filter at 630 nM. BrdU INCORPORATION ASSAYS The following assays use cells engineered to express a selected receptor and then evaluate the effect of a compound of interest on the activity of Sgand-induced DNA synthesis by determining BrdU Incorporation into the DNA. The following materials, reagents and procedure are general to each of the following BrdU incorporation assays. Variances in specific assays are noted. General Materials and Reagents: 1. The appropriate ligand. 2. The appropriate engineered cells. 3. BrdU Labeling Reagent: 10 mM. in PBS, pH7.4(Roche Molecular Biochemicals, Indianapolis, IN). 4. FIxDenat fixation solution (Roche Molecular Biochemicals, Indianapolis. IN). 5. Anti-BrdU-POD: mouse monoclonal antibody conjugated with peroxidase (Chemicon, Temecula, CA). 6. TMB Substrata Solution: tetramethylbenzidine (TMB, ready to use, Roche Molecular Biochemicals. Indianapolis, IN). 7. PBS Washing Solution : 1X PBS, pH 7.4. 8. Albumin, Bovine (BSA), fraction V powder (Sigma Chemical Co., USA). General Procedure: 1. Cells are seeded at 8000 cells/well in 10% CS, 2mM Gin in DMEM, in a 96 well plate. Cells are incubated overnight at 37°C in 5% CO2- 2. After 24 hours, the cells are washed with PBS, and then are serum-starved in serum free medium (0%CS DMEM with 0.1% BSA) for 24 hours. 3. On day 3. the appropriate llgand and the test compound are added to the ceHs simultaneously. The negative control wells receive serum free DMEM with 0.1% BSA only; the positive control cells receive the ligand but no test compound. Test compounds are prepared in serum free DMEM with ligand in a 96 well plate, and serially diluted for 7 test concentrations. 4. After 18 hours of ligand activation, diluted-BrdU labeling reagent (1:100 in DMEM, 0.1% BSA) is added and the cells are incubated with BrdU (final concentration is 10 uM) for 1.5 hours. 5. After incubation with labeling reagent, the medium is removed by decanting and tapping the inverted plate on a paper towel. FixOenat solution is added (SO pi/Well} and the plates are incubated at room temperature for 45 minutes on a plate shaker. _6. The FixOenat solution is removed by decanting and tapping the inverted plate on a paper towel. Milk Is added (5% dehydrated milk in PBS, 200 uUwell) as a blocking solution and the plate is incubated for 30 minutes at room temperature on a plate shaker. 7. The blocking solution is removed by decanting and the wells are washed once with PBS. Anti-BrdU-POD solution is added (1:200 dilution in PBS, 1% BSA, 50 uLAvell) and the plate is Incubated for 90 minutes at room temperature on a plate shaker. 8. The antibody conjugate is removed by decanting and rinsing the wells 5 times with PBS, and the plate is dried by inverting and tapping on a paper towel. 9. TMB substrate solution Is added (100 pi/well) and incubated for 20 minutes at room temperature on a plate shaker until color development is sufficient (or photometric detection. 10. The absorbance of the samples are measured at 410 nm (in "dual wavelength" mode with a filter reading at 490 nm, as a reference wavelength) on a Dynatech ELISA plate reader. HGF-lnduced BrdU Incorporation Assay Materials and Reagents: 1. Recombinant human HGF (Cat. No. 249-HG. R&D Systems, Inc. USA). 2. BxPC-3 cells (ATCC CRL-1687). Remaining Materials and Reagents, as above. Procedure: 1. Cells are seeded at 9000 cells/well in RPMI 10% FBS in a 96 well plate. Cells are incubated overnight at 37*C in 5% COr 2. After 24 hours, the cells are washed with PBS, and then are serum starved in 100 U.L serum-free medium (RPMI with 0.1 % BSA) for.24 hours. 3. On day 3,25 jiL containing ligand (prepared at 1 ug/mL in RPMI with 0.1 % BSA; final HGF cone, is 200 ng/mL) and test compounds are added to the cells. The negative control wells receive 25 U.L serum-free RPMI with 0.1% BSA only, the positive control cells receive the ligand (HGF) but no test compound. Test compounds are prepared at 5 tmes their final concentration in serum-free RPMI with ligand in a 96 well plate, and serially diluted to give 7 test concentrations. Typically, the highest final concentration of test compound is 100 jiM, and 1:3 dilutions are used (i.e. final test compound concentration range is 0.137-100 jiM). 4. After 18 hours of ligand activation, 12.5 uL of diluted BrdU labeling reagent (1:100 in RPMI, 0.1% BSA) is added to each well and the cells are incubated with BrdU (final concentration is 10 uM) for 1 hour. 5. Same as General Procedure. 6. Same as General Procedure. 7. The blocking solution 'is removed by decanting and the wetls are washed once with PBS. Anti-BrdU-POD solution (1:100 dilution in PBS, 1% BSA) is added (100 tit/well) and the plate is incubated for 90 minutes at room temperature on a plate shaker. 8. Same as General Procedure. 9. Same as General Procedure. 10. Same as General Procedure. Cellular HGFR AutoohosDhorvlatlon Assay A549 celts (ATCC) were used in this assay. Cells were seeded in the growth media (RPMI 4 10%FBS) into 96 well plates and cultured overnight at 37 "C for attachment Cells were exposed to the starvation media (RPMI + 0.05% BSA). Dilutions of the inhibitors were added to the plates and Incubated at 37 °C for 1 hour. Cells were then stimulated by adding 40 ng/mL HGF for 15 minutes. Cells were washed once with 1 mM Na3VO« in HBSS and then lysed. The lysates were diluted with 1mM Na3VO4 in HBSS and transferred to a 96 well goat ant-rabbit coated plate (Pierce) which was pre-coaled with antl-HGFR antibody (Zymed Laboratories). The plates were incubated overnight at 4 *C and washed with 1% Tween 20 In PBS for seven times. HRP-PY20 (Santa Cruz) was diluted and added to the plates for 30 minutes incubation. Plates were then washed again and 1MB peroxidase substrate (Kirkegaard & Perry) was added and incubated lor 10 minutes. The reaction was then stopped by adding 0.09N HjSO,. Plates were measured at OD-450 nm using a spectrophotometar. ICso values were calculated by curve lilting using a four-parameter analysis. Compounds of the invention were measured for HGFR inhibition activity; the data are shown in each Example. Ki data were obtained using the HGFR Continuous-Coupled Spectrophotometric Assay, and ICso data were obtained using the Cellular HGFR Autophosphorytation Assay, both of which are described above. White tie invention has been illustrated by reference to specific and preferred embodiments, those skilled in the art will recognize that variations and modifications may be made through routine experimentation and practice of the invention. Thus, the invention is intended not to be limited by the foregoing description, but to be defined by the appended claims and their equivalents. AD references cited herein, including any priority documents, are hereby incorporated by reference in their entireties. We Claim: 1. An enantiomerically pure aminopyridine compound of formula 1 (Formula Removed) wherein: Y is N or CR12; R1 is selected from hydrogen, halogen, C6-12 aryl, 5-12 membered heteroaryl, C3-12 cycloalkyl, 3-12 membered heteroalicyclic, -O(CR6R7)R4, -C(O)R4, -C(O)OR4, -CN, -NO2, -S(O)R4, -SO2NR4R5, -C(O)NR4R5, -NR4C(O)R5, -C(=NR6)NR4R5, C1-8 alkyl, C2-8 alkenyl, and C2-8 alkynyl; and each hydrogen in R1 is optionally substituted by one or more R3 groups; R2 is hydrogen; each R3 is independently halogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -S(O)mR4, -SO2NR4R5, -S(O)2OR4, -NO2, -NR4R5, -(CR6R7)nOR4, -CN, -C(O)R4 -OC(O)R4, -O(CR6R7)nR4, -NR4C(O)R5, -(CR6R7)nC(O)OR4, -(CR6R7)nOR4, -(CR6R7)nC(O)NR4R5, -(CR6R7)nNCR4R5, -C(=NR6)NR4R5, -NR4C(O)NR5R6, -NR4S(O)pR5 or -C(O)NR4R5, each hydrogen in R3 is optionally substituted by R8, and R3 groups on adjacent atoms may combine to form a C6-12 aryl, 5-12 membered heteroaryl, C3-12 cycloalkyl or 3-12 membered heteroalicyclic group; each R4, R5, R6 and R7 is independently hydrogen, halogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl; or any two of R4, R5, R6 and R7 bound to the same nitrogen atom may, together with the nitrogen to which they are bound, be combined to form a 3 to 12 membered heteroalicyclic or 5-12 membered heteroaryl group optionally containing 1 to 3 additional heteroatoms selected from N, O, and S; or any two of R4, R5, R6 and R7 bound to the same carbon atom may be combined to form a C3-12 cycloalkyl, C6-12 aryl, 3- 12 membered heteroalicyclic or 5-12 membered heteroaryl group; and each hydrogen in R4, R5, R6 and R7 is optionally substituted by R8; each R8 is independently halogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyi, C6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -NH2, -CN, - OH, -O-C1-12 alkyl, -O-(CH2)nC3-12 cycloalkyi, -O-(CH2)nC6-12 aryl, -O-(CH2)n(3-12 membered heteroalicyclic) or -O-(CH2)n(5-12 membered heteroaryl); and each hydrogen in R8 is optionally substituted by R11; each R9 and R10 is independently hydrogen, halogen, C1-12 alkyl, C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic, 5-12 memebered heteroaryl, -S(O)mR4, -SO2NR4R5, -S(O)2OR4, -NO2, -NR4R5, -(CR6R7)nOR4, -CN, -C(O)R4, -CO(O)R4, -NR4C(O)R5, -(CR6R7)nC(O)OR4, -(CR6R7)nNCR4R5, -NR4C(O)NR5R6, -NR4S(O)pR5 or-C(O)NR4R5; R9 and R10 may combine with a ring atom of A or a substituted of A to form a C3.12 cycloalkyl, 3-12 memberbed heteroalicyclic, C6-12 aryl or 5-12 membered heteroaryl ring fused to A; and each hydrogen in R9 and R10 is optionally substituted by R3; each R11 is independently halogen, C1-12 alkyl, C1-12 alkoxy, C3.12 cycloalkyi, C6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -O-C1-12 alkyl, -O-(CH2)nC3-12 cycloalkyi, -O-(CH2)nC6-12 aryl, -O-(CH2)n(3-12 membered heteroalicyclic), -O-(CH2)n(5-12 membered heteroaryl) or -CN, and each hydrogen in R11 is optionally substituted by halogen, -OH, -CN, -C1-12 alkyl which may be partially or fully halogenated, -O-C1-12 alkyl which may be partially or fully halogenated, -CO, -SO or -SO2; R12 is hydrogen; each m is independently 0, 1 or 2; each n is independently 0,1,2, 3 or 4; each p is independently 1 or 2; wherein 5-12 membered heteroaryl is selected from furan, thiopene, pyrrole, oxazole, thiazole, imidazole, pyrazole, isoxazole, isothiazole, oxadiazole, triazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine, and triazine, 3-12 membered heteroalicyclic is selected from pyrroline, pyrrolidine, dioxolane, imidazoline, imidazolidine, pyrazoline, pyrazolidine, pyran, piperidine, dioxane, morpholine, dithiane, thiomorpholine, piperazine, trithiane, azitidine, and C6-12 aryl is phenyl; or a pharmaceutically acceptable salt thereof. 2. A compound as claimed in claim 1 of formula la (Formula Removed) wherein: Y is CH; R1 is a furan, thiophene, pyrrole, pyrroline, pyrrolidine, dioxolane, oxazole, thiazole, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, isoxazole, isothiazole, oxadiazole, triazole, thiadiazole, pyran, pyridine, piperidine, dioxane, morpholine, dithiane, thiomorpholine, pyridazine, pyrimidine, pyrazine, piperazine, triazine, trithiane, azitidine or phenyl group; and each hydrogen in R1 is optionally substituted by R3; each R3 is independently halogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -S(O)mR4, -SO2NR4R5, -S(O)20R4, -NO2, -NR4R5, -(CR6R7)nOR4, '-CN, -C(O)R4, -OC(O)R4, -O(CR6R7)nR4, -NR4C(O)R5, -(CR6R7)nC(O)OR4, -(CR6R7)nOR4, -(CR6R7)nC(O)NR4R5, -(CR6R7)nNCR4R5, -C(=NR6)NR4R5, -NR4C(O)NR5R6, -NR4S(O)pR5 or C(O)NR4R5, each hydrogen in R3 is optionally substituted by R8, and R3 groups on adjacent atoms may combine to form a C6-12 aryl, 5-12 membered heteroaryl, C3-12 cycloalkyl or 3-12 membered heteroalicyclic group; each R4, R5, R6 and R7 is independently hydrogen, halogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl; or any two of R4, R5, R6 and R7 bound to the same nitrogen atom may, together with the nitrogen to which they are bound, be combined to form a 3 to 12 membered heteroalicyclic or 5-12 membered heteroaryl group optionally containing 1 to 3 additional heteroatoms selected from N, O, and S; or any two of R4, R5, R6 and R7 bound to the same carbon atom may be combined to form a C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic or 5-12 membered heteroaryl group; and each hydrogen in R4, R5, R6 and R7 is optionally substituted by R8; each R is independently halogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -NH2, -CN, -OH, -O-C1-12 alkyl, -O-(CH2)nC3-12 cycloalkyl, -O-(CH2)nC6-12 aryl, -O-(CH2)n(3-12 membered heteroalicyclic) or -O-(CH2)n(5-12 membered heteroaryl); and each hydrogen in R8 is optionally substituted by R11; each R9 and R10 is independently hydrogen, halogen, C1-12 alkyl, C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic, 5-12 memebered heteroaryl, -S(O)mR4, -SO2NR4R5, -S(O)2OR4, -NO2, -NR4R5, -(CR4R7)nOR4, -CN, -C(O)R4, -CO(O)R4, -NR4C(O)R5, -(CR6R7)nC(O)OR4, -(CR6R7)nNCR4R5, -NR4C(O)NR5R6, -NR4S(O)pR5 or-C(O)NR4R5; R9 and R10 may combine with a ring atom of A or a substituted of A to form a C3-12 cycloalkyl, 3-12 memberbed heteroalicyclic, C6-12 aryl or 5-12 membered heteroaryl ring fused to A; and each hydrogen in R9 and R10 is optionally substituted by R3; each R11 is independently halogen, C1-12 alkyl, C1-12 alkoxy, C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -O-C1.12 alkyl, -O-(CH2)nC3-12 cycloalkyl, -O-(CH2)nC6-12 aryl, -O-(CH2)n(3-12 membered heteroalicyclic), -O-(CH2)n(5-12 membered heteroaryl) or -CN, and each hydrogen in R11 is optionally substituted by halogen, -OH, -CN, -C1-12 alkyl which may be partially or fully halogenated, -O-C1-12 alkyl which may be partially or fully halogenated, -CO, -SO or -SO2; each m is independently 0,1 or 2; each n is independently 0,1,2,3 or 4; each p is independently 1 or 2; or a pharmaceutically acceptable salt thereof. 3. An enantiomerically pure compound selected from the group consisting of 5-Bromo-3- [(R)-1 -(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-ylamine; 5-iodo-3-[(R) 1 -(2,6- dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine; 5-bromo-3-[ 1 (R)-(2,6-dichloro-3- fluoro-phenyl)-ethoxy]-pyridin-2-ylamine; 4-{5-Amino-6-[(R)-l-(2,6-dichloro-3-fluoro- phenyl)-ethoxy]-pyrazin-2-yl}-benzoic acid; (4-{5-Amino-6-[(R)-l-(2,6-dichloro-3- fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-piperazin-l-yl-methanone; 4-(4-{5- Amino-6-[(R)-l-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-benzoyl)- piperazine-1-carboxylic acid tert-butyl ester; 3-[(lR)-l-(2,6-dichloro-3- fluorophenyl)ethoxy]-5-[4-(piperazin-l-ylcarbonyl)phenyl] pyridin-2-amine; 4-{6- amino-5-[( 1R)-1 -(2,6-dichloro-3-fluorophenyl)ethoxy]pyridin-3-yl} -N-[2- (dimethylamino)ethyl]-N-methylbenzamide; (4-{6-amino-5-[(lR)-l-(2,6-dichloro-3- fluorophenyl)ethoxy]pyridin-3-yl}phenyl)methanol; 4-{6-amino-5-[(lR)-l-(2,6-dichloro- 3-fluorophenyl)ethoxy]pyridin-3-yl}-N-[3-(dimethylamino)propyl]-N-methylbenzamide; tert-butyl 4-(4-{6-amino-5-[(lR)-l-(2,6-dichloro-3-fluorophenyl)ethoxy]pyridin-3- yl }benzoyl)piperazine-1 -carboxylate; 3-[(R)-1 -(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-[ 1 -(1 -methyl-piperidin-4-yl)-1 H-pyrazol-4-yl]-pyridin-2-ylamine; 1 -[4-(4-{6-Amino-5- [(R)-1 -(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl} -pyrazol-1 -yl)-piperidin-1 - yl]-2-hydroxy-ethanone; 3-[(R)-1 -(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-( 1 -piperidin- 4-yl-lH-pyrazol-4-yl)-pyridin-2-ylamine; 3-[(R)-l-(2,6-Dichloro-3-fluoro-phenyl)- ethoxy]-5-( 1 -pifieridin-4-yl-1 H-pyrazol-4-yl)-pyridin-2-ylamine; 3-[(R)-1 -(2,6-Dichloro- 3-fluoro-phenyl)-ethoxy]-5-( 1 -piperidin-4-yl-1 H-pyrazol-4-yl)-pyrazin-2-ylamine; 3- [(R)-1 -(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-( 1 H-pyrazol-4-yl)-pyrazin-2-ylamine; l-[4-(4-{5-Amino-6-[(R)-l-(2,6-dichloro-3-fluorophenyl)-ethoxy]-pyrazin-2-yl}-pyrazol- 1 -yl)-piperidin-1 -yl]-2-hydroxy-ethanone; 3-[(R)-1 -(2,6-Dichloro-3-fluoro-phenyl)- ethoxy]-5-[ 1 -(1 -methyl-piperidin-4-yl)-1 H-pyrazol-4-yl] -pyrazin-2-ylamine; 1 -[4-(4- { 5-Amino-6-[(R)-1 -(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl} -pyrazol-1 -yl)-piperidin-1 -yl]-2-dimethylamino-ethanone; 3-[(R)-1 -(2-Chloro-3,6-difluoro-phenyl)-ethoxy]-5-(l-piperidin-4-yl-lH-pyrazol-4-yl)-pyridin-2-ylamine; or a pharmaceutically acceptable salt thereof. 4. A compound as claimed in claim 3 comprising 3-[(R)-l-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-(l-piperidin-4-yl-lH-pyrazol-4-yl)-pyridin-2-ylamine, or a pharmaceutically acceptable salt thereof. 5. A compound as claimed in any of claims 1 to 4 for use in treating abnormal cell growth in a mammal. 6. A compound as claimed in claim 5, wherein the abnormal cell growth is cancer. 7. A pharmaceutical composition comprising 1 wt% to 80 wt% of a compound or salt of any of claims 1 to 4 and a pharmaceutically acceptable carrier. |
|---|
144-DELNP-2007-Abstract-(19-11-2010).pdf
144-DELNP-2007-Claims-(19-11-2010).pdf
144-DELNP-2007-Correspondence-Others-(19-11-2010).pdf
144-delnp-2007-correspondence-others-1.pdf
144-DELNP-2007-Correspondence-Others.pdf
144-DELNP-2007-Description (Complete)-(19-11-2010).pdf
144-delnp-2007-description (complete).pdf
144-DELNP-2007-Form-1-(19-11-2010).pdf
144-DELNP-2007-Form-2-(19-11-2010).pdf
144-DELNP-2007-Form-3-(19-11-2010).pdf
144-DELNP-2007-GPA-(19-11-2010).pdf
144-delnp-2007-pct-notificatian.pdf
144-DELNP-2007-Petition 137-(19-11-2010).pdf
| Patent Number | 250050 | ||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Indian Patent Application Number | 144/DELNP/2007 | ||||||||||||||||||||||||||||||
| PG Journal Number | 48/2011 | ||||||||||||||||||||||||||||||
| Publication Date | 02-Dec-2011 | ||||||||||||||||||||||||||||||
| Grant Date | 30-Nov-2011 | ||||||||||||||||||||||||||||||
| Date of Filing | 05-Jan-2007 | ||||||||||||||||||||||||||||||
| Name of Patentee | PFIZER INC | ||||||||||||||||||||||||||||||
| Applicant Address | 235 EAST 42ND STREET, NEW YORK, NEW YORK 10017, USA | ||||||||||||||||||||||||||||||
Inventors:
|
|||||||||||||||||||||||||||||||
| PCT International Classification Number | C07D 241/20 | ||||||||||||||||||||||||||||||
| PCT International Application Number | PCT/IB2005/002837 | ||||||||||||||||||||||||||||||
| PCT International Filing date | 2005-08-15 | ||||||||||||||||||||||||||||||
PCT Conventions:
|
|||||||||||||||||||||||||||||||