NOVEL HETEROCYCLIC COMPOUNDS USEFUL AS AURORA A SELECTIVE INHIBITORS

Abstract

Provided are compounds of formula (I), or pharmaceutically acceptable salts thereof, which can be used for inhibiting the activity of Aurora A and treating cancer mediated by Aurora A.

##STR00001##

Claims

1-166. (canceled)

167. A compound of Formula VI or Formula VII, or a pharmaceutically acceptable salt thereof: ##STR00750## Y.sub.1 is selected from CH or CR.sub.Y1; Y.sub.2 is selected from CH or CR.sub.Y2; wherein R.sub.Y1 and R.sub.Y2 is independently selected from deuterium, —F, —Cl, —Br, —I, —CN, —OH, —NH.sub.2, —NO.sub.2, —NH(C.sub.1-3alkyl), —N(C.sub.1-3alkyl).sub.2, —COOH, —CONH.sub.2, —CO—C.sub.1-3alkyl, —S—C.sub.1-3alkyl, —SO—C.sub.1-3alkyl, —SO.sub.2, —SO.sub.2C.sub.1-3alkyl, C.sub.1-3lkyl, C.sub.1-3alkoxy, —CO—C.sub.3-6heterocyclic ring, 3-membered carbocyclic ring, 4-membered carbocyclic ring, 5-membered carbocyclic ring, 6-membered carbocyclic ring, 7-membered carbocyclic ring, 8-membered carbocyclic ring, 5-membered aryl, 6-membered aryl, 3-membered heterocyclic ring, 4-membered heterocyclic ring, 5-membered heterocyclic ring, 6-membered heterocyclic ring, 7-membered heterocyclic ring, 8-membered heterocyclic ring, 5-membered heteroaryl or 6-membered heteroaryl, and each of the heterocyclic ring and heteroaryl independently optionally contains 1, 2 or 3 heteroatoms selected from N, O or S; and each of which is independently optionally substituted with deuterium, —F, —Cl, —Br, —I, —NH.sub.2, —CN, —OH, —NO.sub.2, carbonyl, ═O, oxo, carboxyl, C.sub.1-3alkoxy, C.sub.1-3alkyl, —NH(C.sub.1-3alkyl), —N(C.sub.1-3alkyl).sub.2, —S—C.sub.1-3alkyl, or —SO.sub.2C.sub.1-3alkyl; each X.sub.1 and X.sub.2 is independently selected from —H, deuterium, —CN, —OH, —NH.sub.2, C.sub.1-3 alkyl, or C.sub.1-3 alkoxy; Y is selected from —(CH.sub.2).sub.m—CR.sub.4R.sub.5—(CH.sub.2).sub.m—; m is independently 0; R.sub.4 and R.sub.5 is independently selected from —H or deuterium; Ar.sub.2 is a 6-membered aryl, 5-membered heteroaryl or 9-membered heteroaryl, and each of the heteroaryl contains 1 or 2 heteroatoms selected from N, O or S; and each of which is independently optionally substituted with one or more of deuterium, —F, —Cl, —Br, —CN, —OH, —NH.sub.2, carbonyl, ═O, oxo, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, —CH.sub.2F, —CHF.sub.2, —CF.sub.3, —CH.sub.2D, CHD.sub.2, —CD.sub.3; and Ar.sub.1 is 5-membered heteroaryl which contains 1, 2 or 3 heteroatoms selected from N or S, and which is independently optionally substituted with one or more of deuterium; —F; —Cl; —Br; —I; —CN; —OH; —NH.sub.2; carbonyl; ═O; oxo; methyl; ethyl; propyl; isopropyl; methoxy; ethoxy; propoxy; isopropoxy; —CH.sub.2F, —CHF.sub.2, —CF.sub.3, —CH.sub.2D, CHD.sub.2, —CD.sub.3, —CH.sub.2NHmethyl, —CH.sub.2NHethyl, —CH.sub.2NHpropyl, —CH.sub.2NHisopropyl, —CH.sub.2N(CH.sub.3).sub.2.

168. The compound or pharmaceutically acceptable salt thereof of claim 167, wherein R.sub.Y1 and R.sub.Y2 is independently selected from deuterium, —F, —Cl, —Br, —I, —CN, —OH, —NH.sub.2, —NO.sub.2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, —NHmethyl, —NHethyl, —NHpropyl, —NHisopropyl, —N(CH.sub.3).sub.2, —COOH, —CONH.sub.2, —COCH.sub.3, —COCH.sub.2CH.sub.3, —CO—CH(CH.sub.3).sub.2, —SCH.sub.3, —SOCH.sub.3, —SO.sub.2, —SO.sub.2CH.sub.3, —CO-4-membered heterocyclic ring, —CO-5-membered heterocyclic ring, —CO-6-membered heterocyclic ring, 3-membered carbocyclic ring, 4-membered carbocyclic ring, 5-membered carbocyclic ring, 6-membered aryl, 3-membered heterocyclic ring, 4-membered heterocyclic ring, 5-membered heterocyclic ring, 6-membered heterocyclic ring, 5-membered heteroaryl or 6-membered heteroaryl, and each of the heterocyclic ring and heteroaryl independently optionally contains 1 or 2 heteroatoms selected from N, O or S; and each of which is independently optionally substituted with deuterium, —F, —Cl, —Br, —I, —NH.sub.2, —CN, —OH, —NO.sub.2, carbonyl, ═O, oxo, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy; each X.sub.1 and X.sub.2 is independently selected from —H, deuterium, —CN, —OH, —NH.sub.2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy; Y is selected from —CH.sub.2—; Ar.sub.2 is a phenyl, and each of which is independently optionally substituted with one or more of deuterium, —F, —Cl, —Br, —CN, —OH, —NH.sub.2, carbonyl, ═O, oxo, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, —CH.sub.2F, —CHF.sub.2, —CF.sub.3, —CH.sub.2D, CHD.sub.2, —CD.sub.3; or Ar.sub.1 is ##STR00751## and which is independently optionally substituted with one or more of deuterium, —F, —Cl, —Br, —I, —CN, —OH, —NH.sub.2, carbonyl, ═O, oxo, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy.

169. The compound or pharmaceutically acceptable salt thereof of claim 167, wherein R.sub.Y1 and R.sub.Y2 is independently selected from deuterium, —F, —Cl, —Br, —I, —CN, —OH, —NH.sub.2, —NO.sub.2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, —NHmethyl, —NHethyl, —NHpropyl, —NHisopropyl, —N(CH.sub.3).sub.2, —COOH, —CONH.sub.2, —COCH.sub.3, —COCH.sub.2CH.sub.3, —CO—CH(CH.sub.3).sub.2, —SCH.sub.3, —SOCH.sub.3, —SO.sub.2, —SO.sub.2CH.sub.3, ##STR00752## ##STR00753## and each of which is independently optionally substituted with deuterium, —F, —Cl, —NH.sub.2, —CN, —OH, carbonyl, ═O, oxo, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy; each X.sub.1 and X.sub.2 is independently —H, methyl, or ethyl; Ar.sub.2 is ##STR00754## ##STR00755## Ar.sub.1 is ##STR00756##

170. The compound or pharmaceutically acceptable salt thereof of claim 167, wherein R.sub.Y1 and R.sub.Y2 is independently selected from deuterium, —F, —Cl, —CN, —OH, methyl, ethyl, isopropyl, —NHmethyl, —COOH, —COCH.sub.3, —COCH.sub.2CH.sub.3, —CO—CH(CH.sub.3).sub.2, —CO—C(CH.sub.3).sub.3, —COCF.sub.3, —SOCH.sub.3, —SO.sub.2, —SO.sub.2CH.sub.3, —CHF.sub.2, —CF.sub.3, —CH(F)CH.sub.3, —C(F).sub.2CH.sub.3, —OCH.sub.3, —OCF.sub.3, —CH.sub.2OH, —CH.sub.2CH.sub.2OH, —CHOHCH.sub.3, —CH.sub.2F, —CH.sub.2D, CHD.sub.2, —CD.sub.3, —CH.sub.2CH.sub.2F, —CH.sub.2CHF.sub.2, —CH.sub.2CD.sub.3, —CH.sub.2CF.sub.3, —CH.sub.2CH.sub.2NH.sub.2, —CH.sub.2CH.sub.2NHCH.sub.3, —CH.sub.2CH.sub.2N(CH.sub.3).sub.2, —CH.sub.2CH.sub.2CH.sub.2F, —CH.sub.2CH.sub.2CD.sub.3, —CH.sub.2CH.sub.2CF.sub.3, —CH.sub.2N(CH.sub.3).sub.2, —CH(CH.sub.3)(CD.sub.3), —CH(CF.sub.3).sub.2, —CH(CD.sub.3).sub.2, —CH.sub.2NHmethyl, —CH.sub.2NHethyl, —CH.sub.2NHpropyl, ##STR00757## ##STR00758## ##STR00759##

171. The compound or pharmaceutically acceptable salt thereof of claim 167, wherein the compound is of Formula VII: ##STR00760## wherein, Y.sub.1 is independently CH or CR.sub.Y1; Y.sub.2 is independently CH or CR.sub.Y2; R.sub.Y1 and R.sub.Y2 is independently selected from deuterium, —F, —Cl, —Br, —I, —CN, —OH, —NH.sub.2, —CO—C.sub.1-3 alkyl, C.sub.1-3lkyl, or C.sub.1-3 alkoxy; and each of which is independently optionally substituted with deuterium or —F; Y is selected from —CH.sub.2—; each X.sub.1 and X.sub.2 is independently selected from —H, deuterium, —F, —Cl, —CN, —OH, —NH.sub.2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy; Ar.sub.2 is a 6-membered aryl, and which is optionally substituted with one or more of deuterium, —F, —Cl, methyl, ethyl, propyl, isopropyl, —CH.sub.2D, CHD.sub.2 or —CD.sub.3; Ar.sub.1 is 5-membered heteroaryl which contains 1 or 2 heteroatoms selected from N or S, and which is independently optionally substituted with one or more of deuterium; —F; —Cl; —CN; methyl; ethyl; propyl; isopropyl; —CH.sub.2D, CHD.sub.2, —CD.sub.3.

172. The compound or pharmaceutically acceptable salt thereof of claim 171, R.sub.Y1 and R.sub.Y2 is independently selected from deuterium, —F, —Cl, —Br, —I, —CN, —OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, —COCH.sub.3, —COCH.sub.2CH.sub.3, —CO—C(CH.sub.3).sub.2; and each of which is independently optionally substituted with deuterium, or —F; each X.sub.1 and X.sub.2 is independently selected from —H or methyl; Ar.sub.2 is a phenyl, and which is optionally substituted with one or more of deuterium, —F, —Cl, methyl, ethyl, propyl, —CH.sub.2D, CHD.sub.2 or —CD.sub.3; Ar.sub.1 is ##STR00761## and which is independently optionally substituted with one or more of deuterium, —F, —CN, methyl, or ethyl.

173. The compound or pharmaceutically acceptable salt thereof of claim 171, R.sub.Y1 and R.sub.Y2 is independently selected from deuterium, —F, —Cl, —CN, methyl, ethyl, isopropyl, —COCH.sub.3, —CHF.sub.2, —CF.sub.3, —COCH.sub.3, —COCH.sub.2CH.sub.3, —CO—C(CH.sub.3).sub.2, —CH(F) CH.sub.3, —C(F).sub.2CH.sub.3, —CH.sub.2F, —CH.sub.2D, CHD.sub.2, —CD.sub.3, —CH.sub.2CH.sub.2F, —CH.sub.2CHF.sub.2, —CH.sub.2CD.sub.3, —CH.sub.2CH.sub.2CD.sub.3, —CH(CD.sub.3).sub.2, ##STR00762## Ar.sub.2 is ##STR00763## ##STR00764## ##STR00765## Ar.sub.1 is ##STR00766##

174. The compound or pharmaceutically acceptable salt thereof of claim 167, wherein the compound is TABLE-US-00023 1. 1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2- yl)methyl)piperidine-4-carboxylic acid 2. 1-(3-chloro-2-fluorobenzyl)-2-ethyl-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin- 2-yl)methyl)piperidine-4-carboxylic acid 3. 1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2- yl)methyl)-2,6-dimethylpiperidine-4-carboxylic acid 4. 1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-6-(thiazol-2-ylamino)pyridin-2-yl)methyl)-2- methylpiperidine-4-carboxylic acid 5. (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((5-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin- 2-yl)methyl)-2-methylpiperidine-4-carboxylic acid 6. (2R,4R)-1-(3-chloro-2,6-difluorobenzyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3- yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid 8. (2R,4R)-1-(3-chloro-2-fluorobenzyl)-2-ethyl-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3- yl)amino)pyridin-2-yl)methyl)piperidine-4-carboxylic acid 9. (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((4-cyclopropyl-3-fluoro-6-((5-methyl-1H-pyrazol- 3-yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid 12. (2R,4R)-1-(2,6-difluorobenzyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin- 2-yl)methyl)-2-methylpiperidine-4-carboxylic acid 13. (2R,4R)-1-(2,6-dimethylbenzyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin- 2-yl)methyl)-2-methylpiperidine-4-carboxylic acid 14. (2R,4R)-1-(2,3-dichlorobenzyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin- 2-yl)methyl)-2-methylpiperidine-4-carboxylic acid 15. (2R,4R)-1-(2,3-difluorobenzyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin- 2-yl)methyl)-2-methylpiperidine-4-carboxylic acid 16. (2R,4R)-1-(2-fluoro-3-methylbenzyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin- 2-yl)methyl)-2-methylpiperidine-4-carboxylic acid 17. (2R,4R)-1-(2,6-dichlorobenzyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin- 2-yl)methyl)-2-methylpiperidine-4-carboxylic acid 18. (2R,4R)-1-(3-chloro-4-fluorobenzyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin- 2-yl)methyl)-2-methylpiperidine-4-carboxylic acid 19. (2R,4R)-1-(4-chloro-3-fluorobenzyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin- 2-yl)methyl)-2-methylpiperidine-4-carboxylic acid 20. (2R,4R)-1-(3,5-dichlorobenzyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin- 2-yl)methyl)-2-methylpiperidine-4-carboxylic acid 21. (2R,4R)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)methyl)-2-methyl- 1-(3-(trifluoromethyl)benzyl)piperidine-4-carboxylic acid 22. (2R,4R)-1-(3,4-dichloro-5-fluorobenzyl)-4-((3 -fluoro-6-((5-methyl-1H-pyrazol-3- yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid 23. (2R,4R)-1-(3,5-dichloro-4-fluorobenzyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3- yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid 24. (2R,4R)-1-(3,5-difluorobenzyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin- 2-yl)methyl)-2-methylpiperidine-4-carboxylic acid 27. (2R,4R)-1-(3-chloro-2,4-difluorobenzyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3- yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid 34. (2R,4R)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)methyl)-2-methyl- 1-(2-(trifluoromethyl)benzyl)piperidine-4-carboxylic acid 35. (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-5-methyl-6-((3-methyl-1H-pyrazol-5- yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid 44. (2R,4R)-1-(2-(3-chloro-2-fluorophenyl)-2-oxoethyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol- 3-yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid 46. 1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)-4-(oxetan- 3-yl)pyridin-2-yl)methyl)piperidine-4-carboxylic acid 47. (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-4-(3-hydroxyoxetan-3-yl)-6-((5-methyl- 1H-pyrazol-3-yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid 48. (2R,4R)-1-(3 -chloro-2-fluorobenzyl)-4-((3-fluoro-4-(3fluorooxetan-3-yl)-6-((5-methyl-1H- pyrazol-3-yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid 49. (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-4-methyl-6-((5-methyl-1H-pyrazol-3- yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid 50. (2R,4R)-1-(3-chloro-2,6-difluorobenzyl)-4-((3-fluoro-4-methyl-6-((5-methyl-1H-pyrazol-3- yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid 51. 1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin- 2-yl)methyl)piperidine-4-carboxylic acid 52. 1-(2,3-difluorobenzyl)-4-((3-fluoro-4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin- 2-yl)methyl)piperidine-4-carboxylic acid 53. (2R,4R)-1-(2,3-dichlorobenzyl)-4-((3-fluoro-4-methyl-6-((5-methyl-1H-pyrazol-3- yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid 54. 1-(2,3-dichlorobenzyl)-4-((3-fluoro-4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin- 2-yl)methyl)piperidine-4-carboxylic acid 55. 1-(3-chloro-2,6-difluorobenzyl)-4-((3-fluoro-4-methyl-6-((5-methyl-1H-pyrazol-3- yl)amino)pyridin-2-yl)methyl)piperidine-4-carboxylic acid 61. (2R,4R)-1-(2,3-difluorobenzyl)-4-((3-fluoro-4-methyl-6-((5-methyl-1H-pyrazol-3- yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid 62. (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-4-(2-hydroxypropan-2-yl)-6-((5-methyl- 1H-pyrazol-3-yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid 63. (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-4-isopropyl-6-((5-methyl-1H-pyrazol-3- yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid 64. (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((4-(difluoromethyl)-3-fluoro-6-((5-methyl-1H- pyrazol-3-yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid 65. (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((4-ethyl-3-fluoro-6-((5-methyl-1H-pyrazol-3- yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid 66. 1-(3-chloro-2-fluorobenzyl)-4-((4-ethyl-3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin- 2-yl)methyl)piperidine-4-carboxylic acid 67. (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((4-cyano-3-fluoro-6-((5-methyl-1H-pyrazol-3- yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid 68. (2R,4R)-4-((4-acetyl-3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)methyl)-1- (3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylic acid 69. 4-((4-acetyl-3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)methyl)-1-(3-chloro- 2-fluorobenzyl)piperidine-4-carboxylic acid 70. (2R,4R)-4-((4-acetyl-5-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)methyl)- 1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylic acid 71. (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((4-(1,1-difluoroethyl)-3-fluoro-6-((5-methyl-IH- pyrazol-3-yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid 72. (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((4-chloro-3-fluoro-6-((5-methyl-1H-pyrazol-3- yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid 73. (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((4-chloro-5-fluoro-6-((5-methyl-1H-pyrazol-3- yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid 74. (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((4-chloro-3,5-difluoro-6-((5-methyl-1H-pyrazol-3- yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid 75. (2R,4R)-4-((4-(azetidin-1-yl)-3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2- yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylic acid 76. (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-4-(1-hydroxyethyl)-6-((5-methyl-1H- pyrazol-3-yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid 77. (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-4-(1-fluoroethyl)-6-((5-methyl-1H-pyrazol- 3-yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid 78. (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((5-fluoro-4-methyl-6-((5-methyl-1H-pyrazol-3- yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid 79. 1-(3-chloro-2-fluorobenzyl)-4-((5-fluoro-4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin- 2-yl)methyl)piperidine-4-carboxylic acid 80. (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)-4- propionylpyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid 81. (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)-4- (methylsulfonyl)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid 82. (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((5-fluoro-3,4-dimethyl-6-((5-methyl-1H-pyrazol-3- yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid 83. (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((3′-fluoro-6′-((5-methyl-1H-pyrazol-3-yl)amino)-[2,4′- bipyridin]-2′-yl)methyl)-2-methylpiperidine-4-carboxylic acid 85. (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-4-isobutyryl-6-((5-methyl-1H-pyrazol-3- yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid 90. (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((4-cyano-5-fluoro-6-((5-methyl-1H-pyrazol-3- yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid 91. (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((3,5-difluoro-6-((5-methyl-1H-pyrazol-3- yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid 92. 1-(3-chloro-2-fluorobenzyl)-4-((3,5-difluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin- 2-yl)methyl)piperidine-4-carboxylic acid 93. (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((3,5-difluoro-4-methyl-6-((5-methyl-1H-pyrazol-3- yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid 94. (2R,4R)-4-((6-((1H-pyrazol-3-yl)amino)-3-fluoro-4-(2-fluoropropan-2-yl)pyridin-2- yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylic acid 96. (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-6-((4-fluoro-5-methyl-1H-pyrazol-3- yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid 97. 1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2- yl)methyl)-2-(trifluoromethyl)piperidine-4-carboxylic acid 100. (2R,4R)-1-(2-chloro-6-fluorobenzyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3- yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid 101. (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((3-cyano-6-((5-methyl-1H-pyrazol-3- yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid 102. 1-(3-chloro-2-fluorobenzyl)-4-((6-((4,5-dimethyl-1H-pyrazol-3-yl)amino)-3-fluoropyridin- 2-yl)methyl)-2-methylpiperidine-4-carboxylic acid 103. 1-(3-chloro-2-fluorobenzyl)-4-((6-((4-cyano-5-methyl-1H-pyrazol-3-yl)amino)-3-fluoropyridin- 2-yl)methyl)-2-methylpiperidine-4-carboxylic acid 104. (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((4-cyano-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin- 2-yl)methyl)-2-methylpiperidine-4-carboxylic acid 106. 1 -(3 -chloro-2-fluorobenzyl)-4-((3-fluoro-4-(3-hydroxy oxetan-3-yl)-6-((5-methyl-1H-pyrazol- 3-yl)amino)pyridin-2-yl)methyl)piperidine-4-carboxylic acid 107. 1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-4-(3-hydroxyazetidin-1-yl)-6-((5-methylthiazol-2- yl)amino)pyridin-2-yl)methyl)piperidine-4-carboxylic acid 108. 1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)-4-(4- methylpiperazin-1-yl)pyridin-2-yl)methyl)piperidine-4-carboxylic acid 122. (2R,4R)-2-ethyl-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)methyl)-1- (2-(trifluoromethyl)benzyl)piperidine-4-carboxylic acid 130. (2R,6R)-1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin- 2-yl)methyl)-2,6-dimethylpiperidine-4-carboxylic acid 131. (3R)-1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin- 2-yl)methyl)-3-methylpiperidine-4-carboxylic acid 132. (2R)-1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin- 2-yl)methyl)-2-methylpiperidine-4-carboxylic acid 133. (2R)-1-(3-chloro-2-fluorobenzyl)-2-ethyl-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3- yl)amino)pyridin-2-yl)methyl)piperidine-4-carboxylic acid 134. 1-(3-chloro-2,6-difluorobenzyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin- 2-yl)methyl)piperidine-4-carboxylic acid 135. (2R)-1-(3-chloro-2,6-difluorobenzyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin- 2-yl)methyl)-2-methylpiperidine-4-carboxylic acid 136. (2R)-1-(3-chloro-2,6-difluorobenzyl)-2-ethyl-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3- yl)amino)pyridin-2-yl)methyl)piperidine-4-carboxylic acid 137. 1-(3-chloro-2,4-difluorobenzyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin- 2-yl)methyl)piperidine-4-carboxylic acid 138. (2R)-1-(3-chloro-2,4-difluorobenzyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin- 2-yl)methyl)-2-methylpiperidine-4-carboxylic acid 139. (2R)-1-(3-chloro-2,4-difluorobenzyl)-2-ethyl-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3- yl)amino)pyridin-2-yl)methyl)piperidine-4-carboxylic acid 140. 1-(2,3-dichlorobenzyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2- yl)methyl)piperidine-4-carboxylic acid 141. (2R)-1-(2,3-dichlorobenzyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2- yl)methyl)-2-methylpiperidine-4-carboxylic acid 142. (2R)-1-(2,3-dichlorobenzyl)-2-ethyl-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin- 2-yl)methyl)piperidine-4-carboxylic acid 143. 1-(2,3-difluorobenzyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2- yl)methyl)piperidine-4-carboxylic acid 144. (2R)-1-(2,3-difluorobenzyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2- yl)methyl)-2-methylpiperidine-4-carboxylic acid 145. (2R)-1-(2,3-difluorobenzyl)-2-ethyl-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin- 2-yl)methyl)piperidine-4-carboxylic acid 146. 1-(3-chloro-2-fluoro-6-methylbenzyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin- 2-yl)methyl)piperidine-4-carboxylic acid 147. (2R)-1-(3-chloro-2-fluoro-6-methylbenzyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3- yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid 148. (2R)-1-(3-chloro-2-fluoro-6-methylbenzyl)-2-ethyl-4-((3-fluoro-6-((5-methyl-1H-pyrazol- 3-yl)amino)pyridin-2-yl)methyl)piperidine-4-carboxylic acid 149. 1-(3-chloro-2-methylbenzyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2- yl)methyl)piperidine-4-carboxylic acid 150. (2R)-1-(3-chloro-2-methylbenzyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin- 2-yl)methyl)-2-methylpiperidine-4-carboxylic acid 151. (2R)-1-(3-chloro-2-methylbenzyl)-2-ethyl-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3- yl)amino)pyridin-2-yl)methyl)piperidine-4-carboxylic acid 152. 4-((6-((1H-pyrazol-3-yl)amino)-3-fluoropyridin-2-yl)methyl)-1-(2-fluoro-3- methylbenzyl)piperidine-4-carboxylic acid 153. (2R)-4-((6-((1H-pyrazol-3-yl)amino)-3-fluoropyridin-2-yl)methyl)-1-(2-fluoro-3- methylbenzyl)-2-methylpiperidine-4-carboxylic acid 154. (2R)-4-((6-((1H-pyrazol-3-yl)amino)-3-fluoropyridin-2-yl)methyl)-2-ethyl-1-(2-fluoro-3- methylbenzyl)piperidine-4-carboxylic acid 155. 4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)methyl)-1-(2- fluorobenzyl)piperidine-4-carboxylic acid 156. (2R)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)methyl)-1-(2- fluorobenzyl)-2-methylpiperidine-4-carboxylic acid 157. (2R)-2-ethyl-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)methyl)-1-(2- fluorobenzyl)piperidine-4-carboxylic acid 158. 1-(2,6-dichlorobenzyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2- yl)methyl)piperidine-4-carboxylic acid 159. (2R)-1-(2,6-dichlorobenzyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2- yl)methyl)-2-methylpiperidine-4-carboxylic acid 160. (2R)-1-(2,6-dichlorobenzyl)-2-ethyl-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin- 2-yl)methyl)piperidine-4-carboxylic acid 161. 1-(2,6-difluorobenzyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2- yl)methyl)piperidine-4-carboxylic acid 162. (2R)-1-(2,6-difluorobenzyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2- yl)methyl)-2-methylpiperidine-4-carboxylic acid 163. (2R)-1-(2,6-difluorobenzyl)-2-ethyl-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin- 2-yl)methyl)piperidine-4-carboxylic acid 164. 1-(3-chloro-2-fluoro-4-methylbenzyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin- 2-yl)methyl)piperidine-4-carboxylic acid 165. (2R)-1-(3-chloro-2-fluoro-4-methylbenzyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3- yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid 166. (2R)-1-(3-chloro-2-fluoro-4-methylbenzyl)-2-ethyl-4-((3-fluoro-6-((5-methyl-1H-pyrazol- 3-yl)amino)pyridin-2-yl)methyl)piperidine-4-carboxylic acid 178. (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin- 2-yl)methyl)-2-methylpiperidine-4-carboxylic acid 179. (2R,4R)-1-(3-chloro-2-fluorobenzyl)-2-ethyl-4-((3-fluoro-4-(3-hydroxyoxetan-3-yl)-6-((5- methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)methyl)piperidine-4-carboxylic acid 180. (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)-4- (oxetan-3-yl)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid 181. (2R,4R)-1-(3-chloro-2-fluorobenzyl)-2-ethyl-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3- yl)amino)-4-(oxetan-3-yl)pyridin-2-yl)methyl)piperidine-4-carboxylic acid 182. 1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-4-(3-hydroxyazetidin-1-yl)-6-((5-methyl-1H-pyrazol- 3-yl)amino)pyridin-2-yl)methyl)piperidine-4-carboxylic acid 183. (2R,4R)-1-(3-chloro-2-fluorobenzyl)-2-ethyl-4-((3-fluoro-4-(3-hydroxyazetidin-1-yl)-6-((5- methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)methyl)piperidine-4-carboxylic acid 184. (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-4-(3-hydroxyazetidin-1-yl)-6-((5-methyl- 1H-pyrazol-3-yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid 185. (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)-4- (4-methylpiperazin-1-yl)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid 186. (2R,4R)-1-(3-chloro-2-fluorobenzyl)-2-ethyl-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3- yl)amino)-4-(4-methylpiperazin-1-yl)pyridin-2-yl)methyl)piperidine-4-carboxylic acid 187. (2R,4R)-4-((4-(azetidin-3-yl)-3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2- yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylic acid 188. 4-((4-(azetidin-3-yl)-3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)methyl)-1- (3-chloro-2-fluorobenzyl)piperidine-4-carboxylic acid 189. (2R,4R)-4-((4-(azetidin-3-yl)-3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl) methyl)-1-(3-chloro-2-fluorobenzyl)-2-ethylpiperidine-4-carboxylic acid 190. (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)-4- (l-methylazetidin-3-yl)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid 191. 1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)-4-(1- methylazetidin-3-yl)pyridin-2-yl)methyl)piperidine-4-carboxylic acid 192. (2R,4R)-1-(3-chloro-2-fluorobenzyl)-2-ethyl-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3- yl)amino)-4-(l-methylazetidin-3-yl)pyridin-2-yl)methyl)piperidine-4-carboxylic acid 193. (2R,4R)-1-(3-chloro-2-fluorobenzyl)-2-ethyl-4-((3-fluoro-4-methyl-6-((5-methyl-1H- pyrazol-3-yl)amino)pyridin-2-yl)methyl)piperidine-4-carboxylic acid 194. (2R,4R)-1-(3-chloro-2-fluorobenzyl)-2-ethyl-4-((4-ethyl-3-fluoro-6-((5-methyl-1H-pyrazol- 3-yl)amino)pyridin-2-yl)methyl)piperidine-4-carboxylic acid 195. 1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-4-isopropyl-6-((5-methyl-1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)piperidine-4-carboxylic acid 196. (2R,4R)-1-(3-chloro-2-fluorobenzyl)-2-ethyl-4-((3-fluoro-4-isopropyl-6-((5-methyl-1H- pyrazol-3-yl)amino)pyridin-2-yl)methyl)piperidine-4-carboxylic acid 197. 1-(3-chloro-2-fluorobenzyl)-4-((4-cyclopropyl-3-fluoro-6-((5-methyl-1H-pyrazol-3- yl)amino)pyridin-2-yl)methyl)piperidine-4-carboxylic acid 198. (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((4-cyclopropyl-3-fluoro-6-((5-methyl-1H-pyrazol- 3-yl)amino)pyridin-2-yl)methyl)-2-ethylpiperidine-4-carboxylic acid 199. 1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-4-(2-hydroxypropan-2-yl)-6-((5-methyl-1H-pyrazol- 3-yl)amino)pyridin-2-yl)methyl)piperidine-4-carboxylic acid 200. (2R,4R)-1-(3-chloro-2-fluorobenzyl)-2-ethyl-4-((3-fluoro-4-(2-hydroxypropan-2-yl)-6-((5- methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)methyl)piperidine-4-carboxylic acid 201. 1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)-4- phenylpyridin-2-yl)methyl)piperidine-4-carboxylic acid 202. (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)-4- phenylpyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid 203. (2R,4R)-1-(3-chloro-2-fluorobenzyl)-2-ethyl-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3- yl)amino)-4-phenylpyridin-2-yl)methyl)piperidine-4-carboxylic acid 204. 1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-4-(l-hydroxycyclopropyl)-6-((5-methyl-1H-pyrazol- 3-yl)amino)pyridin-2-yl)methyl)piperidine-4-carboxylic acid 205. (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-4-(l-hydroxycyclopropyl)-6-((5-methyl- 1H-pyrazol-3-yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid 206. (2R,4R)-1-(3-chloro-2-fluorobenzyl)-2-ethyl-4-((3-fluoro-4-(l-hydroxycyclopropyl)-6-((5- methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)methyl)piperidine-4-carboxylic acid 207. (2R,4R)-4-((4-(azetidin-1-yl)-3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl) methyl)-1-(3-chloro-2-fluorobenzyl)-2-ethylpiperidine-4-carboxylic acid 208. 4-((4-(azetidin-1-yl)-3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)methyl)-1- (3-chloro-2-fluorobenzyl)piperidine-4-carboxylic acid 209. (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((4-(difluoromethyl)-3-fluoro-6-((5-methyl-1H- pyrazol-3-yl)amino)pyridin-2-yl)methyl)-2-ethylpiperidine-4-carboxylic acid 210. 1-(3-chloro-2-fluorobenzyl)-4-((4-(difluoromethyl)-3-fluoro-6-((5-methyl-1H-pyrazol-3- yl)amino)pyridin-2-yl)methyl)piperidine-4-carboxylic acid 211. (2R,4R)-1-(3-chloro-2-fluorobenzyl)-2-ethyl-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3- yl)amino)-4-(trifluoromethyl)pyridin-2-yl)methyl)piperidine-4-carboxylic acid 212. 1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)-4- (trifluoromethyl)pyridin-2-yl)methyl)piperidine-4-carboxylic acid 213. (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)-4- (trifluoromethyl)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid 214. (2R,4R)-1-(3-chloro-2-fluorobenzyl)-2-ethyl-4-((3-fluoro-4-(l-hydroxycyclobutyl)-6-((5- methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)methyl)piperidine-4-carboxylic acid 215. 1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-4-(l-hydroxycyclobutyl)-6-((5-methyl-1H- pyrazol-3-yl)amino)pyridin-2-yl)methyl)piperidine-4-carboxylic acid 216. (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-4-(l-hydroxycyclobutyl)-6-((5-methyl-1H- pyrazol-3-yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid 217. (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((4-cyclobutyl-3-fluoro-6-((5-methyl-1H-pyrazol-3- yl)amino)pyridin-2-yl)methyl)-2-ethylpiperidine-4-carboxylic acid 218. 1-(3-chloro-2-fluorobenzyl)-4-((4-cyclobutyl-3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)piperidine-4-carboxylic acid 219. (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((4-cyclobutyl-3-fluoro-6-((5-methyl-1H-pyrazol-3- yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid 220. (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((4-cyano-3-fluoro-6-((5-methyl-1H-pyrazol-3- yl)amino)pyridin-2-yl)methyl)-2-ethylpiperidine-4-carboxylic acid 221. 1-(3-chloro-2-fluorobenzyl)-4-((4-cyano-3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin- 2-yl)methyl)piperidine-4-carboxylic acid 324. (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)-4- (methylamino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid 325. (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-4-isopropoxy-6-((5-methyl-1H-pyrazol- 3-yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid 326. (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-4-(l-fluorocyclopropyl)-6-((5-methyl-1H- pyrazol-3-yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid 327. (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-4-(2-hydroxyethyl)-6-((5-methyl-1H- pyrazol-3-yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid 336. (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-4-(2-fluoro-1,3-dihydroxypropan-2-yl)-6- ((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid 338. (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)-4- morpholinopyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid 342. (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)-4- (3-methyloxetan-3-yl)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid 346. (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)-4- (trifluoromethoxy)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid 348. 1-(3-chloro-2,6-difluorobenzyl)-4-((4-ethyl-3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)piperidine-4-carboxylic acid 349. 4-((4-acetyl-3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)methyl)-1-(3-chloro- 2,6-difluorobenzyl)piperidine-4-carboxylic acid 465. (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((3,5-difluoro-4-((R)-1-fluoroethyl)-6-((5-methyl- 1H-pyrazol-3-yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid 480. (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((3,5-difluoro-4-isobutyryl-6-((5-methyl-1H-pyrazol- 3-yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid 482. (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-4-((R)-1-fluoroethyl)-6-((5-methyl-1H- pyrazol-3-yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid 483. (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-4-((S)-1-fluoroethyl)-6-((5-methyl-1H- pyrazol-3-yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid 491. 1-(3-chloro-2-fluorobenzyl)-4-((4-(1,1-difluoroethyl)-3-fluoro-6-((5-methyl-1H-pyrazol-3- yl)amino)pyridin-2-yl)methyl)piperidine-4-carboxylic acid 492. (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((3,4-difluoro-6-((5-methyl-1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid.

175. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound or pharmaceutically acceptable salt thereof of claim 167 and at least one pharmaceutically acceptable excipient.

176. The pharmaceutical composition of claim 175, wherein, the said compound or pharmaceutically acceptable salt thereof in a weight ratio to the said excipient within the range from about 0.0001 to about 10.

177. The pharmaceutical composition of claim 175, further comprising at least one of additional active ingredient.

178. A method of treating a patient, comprising administering to the patient a therapeutically effective amount of at least one compound or pharmaceutically acceptable salt thereof as defined in claim 167.

179. A method for the treatment or prevention of cancer or cancer metastasis, comprising administering to the patient a therapeutically effective amount of at least one compound or pharmaceutically acceptable salt thereof as defined in claim 167.

180. The method of claim 179, wherein the cancer is selected from the group consisting of small cell lung cancer, colorectal cancer, gastric cancer, prostate cancer, breast cancer, triple-negative breast cancer, cervical cancer, head and neck cancer, esophageal cancer, ovarian cancer, non-small cell lung cancer, non-Hodgkin lymphoma, or any of combination thereof.

181. The method of claim 179, wherein the cancer is selected from small cell lung cancer, prostate cancer, triple-negative breast cancer, cervical cancer, or head and neck cancer.

182. A method of treating a patient having a condition which is mediated by the activity of Aurora A, said method comprising administering to the patient a therapeutically effective amount of at least one compound or pharmaceutically acceptable salt thereof as defined in claim 167.

183. The method of claim 182, wherein the condition mediated by the activity of Aurora A is cancer.

184. The method of claim 182, wherein the condition mediated by the activity of Aurora A is small cell lung cancer, colorectal cancer, gastric cancer, prostate cancer, breast cancer, triple-negative breast cancer, cervical cancer, head and neck cancer, esophageal cancer, ovarian cancer, non-small cell lung cancer, non-Hodgkin lymphoma, or any of combination thereof.

185. The method of claim 183, wherein the cancer is selected from small cell lung cancer, prostate cancer, triple-negative breast cancer, cervical cancer, or head and neck cancer.

186. A method of treating cancer selected from the group consisting of small cell lung cancer, colorectal cancer, gastric cancer, prostate cancer, breast cancer, triple-negative breast cancer, cervical cancer, head and neck cancer, esophageal cancer, ovarian cancer, non-small cell lung cancer, or non-Hodgkin lymphoma in a mammal comprising administering to a mammal in need of such treatment an effective amount of at least one compound or pharmaceutically acceptable salt thereof as defined in claim 167.

Description

EXAMPLES

[0276] The following Examples are provided to better illustrate the present invention. All parts and percentages are by weight and all temperatures are degrees Celsius, unless explicitly stated otherwise.

[0277] The compounds described herein can be prepared in a number of ways based on the teachings contained herein and synthetic procedures known in the art. In the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be chosen to be the conditions standard for that reaction, unless otherwise indicated. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule should be compatible with the reagents and reactions proposed. Substituents not compatible with the reaction conditions will be apparent to one skilled in the art, and alternate methods are therefore indicated. The starting materials for the examples are either commercially available or are readily prepared by standard methods from known materials.

[0278] Examples are provided herein to facilitate a more complete understanding of the disclosure. The following examples serve to illustrate the exemplary modes of making and practicing the subject matter of the disclosure. However, the scope of the disclosure is not to be construed as limited to specific embodiments disclosed in these examples, which are illustrative only.

Meanings of Abbreviations are as Follows.

[0279]

TABLE-US-00002 CCl.sub.4 Carbontetrachloride EtOAc Ethyl acetate ACN Acetonitrile MeOH Methanol DCM Dichloromethane DIBAH Diisobutylalumium hydride EtOH Ethanol NaBH.sub.4 Sodium borohydride NH.sub.4Cl Ammonium chloride THF Tetrahydrofuran K.sub.3PO.sub.4 Potassium phosphate H.sub.2 Hydrogen DIEA N,N-Diisopropylethylamine Pd/C Palladium-carbon LDA Lithium diisopropylamide CsF Cesium fluoride K.sub.2CO.sub.3 Potassium carbonate XPhos 2-(2,4,6- Triisopropylphenethyl)phenyl)dicyclohexylphosphine XPhos.Pd.G2 (SP-4-4)-[2′-Amino[1,1′-biphenyl]- 2-yl]chloro[dicyclohexyl[2′,4′,6′-tris(1- methylethyl)[1,1′-biphenyl]-2-yl]phosphine]palladium Cs.sub.2CO.sub.3 Cesium carbonate HCl Hydrochloric acid HATU Azabenzotriazolyl tetramethyluronium hexafluorophosphate DAST (N,N-diethylamino)sulfurtrifluoride SOCl.sub.2 Dichlorosulfoxide HOBT 1-Hydroxybenzotrizole Pd.sub.2(dba).sub.3 Tris(dibenzylideneacetone)dipalladium(0) Pd(dppf)Cl.sub.2 [1,1′- Bis(diphenylphosphino)ferrocene]dichloropalladium(II) ETCI 1-Ethyl[3-(dimethylamino)propyl]carbodiimide NCS N-Chlorosuccinimide AIBN Azodiisobutyronitrile NBS N-Bromosuccinimide TFA 2,2,2-Trifluoroacetic acid RT Room temperature min minute(s) h hour(s) INT Intermediate TLC Thin layer chromatography Prep—TLC Preparative thin layer chromatography Prep—HPLC Preparation high performance liquid chromatography

Syntheses of Intermediates:

TNT A1: 6-bromo-2-(bromomethyl)-3 fluoropyridine

[0280] ##STR00049##

[0281] A solution of 6-bromo-3-fluoro-2-methylpyridine (20.17 g, 106.15 mmol) in CCl.sub.4 (300 mL), NBS (28.49 g, 160.07 mmol) and benzoyl peroxide (5.17 g, 21.34 mmol) was stirred at reflux for overnight under nitrogen. The reaction was cooled to room temperature. The resulting mixture was added saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by C18 reversed phase column chromatography eluting with H.sub.2O/ACN to afford 6-bromo-2-(bromomethyl)-3-fluoropyridine (13.78 g, Y=48%) as a white solid. LCMS (ESI, m/z): 270 [M+H].sup.+.

INT A2: 2-(bromomethyl)-6-chloro-3-fluoropyridine

[0282] ##STR00050##

[0283] A solution of 2-chloro-3-fluoro-6-methylpyridine (23.55 g, 161.787 mmol) in ACN (400 mL), NBS (43.06 g, 241.932 mmol) and AIBN (14.10 g, 85.867 mmol) was stirred at 80° C. for overnight under nitrogen. The reaction was cooled to room temperature. The mixture was added saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by C18 reversed phase column chromatography eluting with H.sub.2O/ACN to afford 2-(bromomethyl)-6-chloro-3-fluoropyridine (18.72 g, Y=52%) as a yellow oil. LCMS (ESI, m/z): 224, 226 [M+H].sup.+.

INT A3: 2-(bromomethyl)-6-chloro-3,5-dimethylpyrazine

Step 1: (6-chloro-3,5-dimethylpyrazin-2-yl)methanol

[0284] ##STR00051##

[0285] Ethyl 6-chloro-3,5-dimethylpyrazine-2-carboxylate (0.846 g, 3.941 mmol) was dissolved in anhydrous THF under nitrogen. A solution of DIBAH (3.9 mL, 3.900 mmol) 1 M in THF was added slowly at −30° C.˜−50° C. under nitrogen. The resulting mixture was allowed to warm to room temperature. After completion, the reaction was quenched with saturated ammonium chloride aqueous solution (20 mL) at 0˜10° C. The resulting solution was diluted with brine and extracted with 50 mL of EtOAc washed with. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography eluting with EtOAc/hexane (0˜30%) to afford 702 mg of the title compound as a white solid. LCMS (ESI, m/z): 173 [M+H].sup.+.

Step 2: 2-(bromomethyl)-6-chloro-3,5-dimethylpyrazine

[0286] ##STR00052##

[0287] A solution of (6-chloro-3,5-dimethylpyrazin-2-yl)methanol (0.642 g, 3.719 mmol), triphenylphosphine (2.986 g, 11.385 mmol) in THF (40 mL) was cooled to 0° C.˜10° C. under nitrogen. NBS (2.085 g, 11.715 mmol) in THF (20 mL) was added to the above solution. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The resulting solution was diluted with brine and extracted with 50 mL of EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography eluting with EtOAc/hexane (0˜10%) to afford 559 mg of the title compound as a white solid. LCMS (ESI, m/z): 235,237 [M+H].sup.+.

INT A4: 2-(bromomethyl)-6-chloro-3-methylpyridine

Step 1: (6-chloro-3-methylpyridin-2-yl)methanol

[0288] ##STR00053##

[0289] To a solution of methyl-6-chloro-3-methylpicolinate (2.046 g, 11.023 mmol) in methanol (30 mL) was added NaBH.sub.4 (570 mg, 15.066 mmol) at 0° C. The reaction mixture was stirred for 3 h at room temperature. The resulting solution was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by C18 reversed phase column chromatography eluting with H.sub.2O/ACN to afford (6-chloro-3-methylpyridin-2-yl)methanol (1.23 g Y=71%) as a yellow oil. LCMS (ESI, m/z): 158 [M+H].sup.+.

Step 2: 2-(bromomethyl)-6-chloro-3-methylpyridine

[0290] ##STR00054##

[0291] To a solution of (2-chloro-5-fluoropyrimidin-4-yl)methanol (804 mg, 4.946 mmol) in DCM (10 mL) was added tribromophosphine (2.880 g, 10.640 mmol) at 0° C. The resulting mixture was stirred for 3 h at room temperature. The reaction solution was quenched with saturated NH.sub.4Cl aqueous solution. The resulting mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by C18 reversed phase column chromatography eluting with H.sub.2O/ACN to afford 2-(bromomethyl)-6-chloro-3-methylpyridine (326 mg, Y=29%) as a yellow oil. LCMS (ESI, m/z): 220 [M+H].sup.+.

INT A5: 2-bromo-4-(bromomethyl)-5-methylthiazole

Step 1: (2-bromo-5-methylthiazol-4-yl)methanol

[0292] ##STR00055##

[0293] To a solution of methyl 2-bromo-5-methylthiazole-4-carboxylate (5.179 g, 21.937 mmol) in methanol (100 mL) and water (10 mL) was added NaBH.sub.4 (4.474 g, 118.258 mmol) at 0° C. The reaction mixture was stirred for 3 h at room temperature. The resulting solution was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by C18 reversed phase column chromatography eluting with H.sub.2O/ACN to afford (2-bromo-5-methylthiazol-4-yl)methanol (1996 mg, Y=44%) as a yellow oil. LCMS (ESI, m/z): 208 [M+H].sup.+.

Step 2: 2-bromo-4-(bromomethyl)-5-methylthiazole

[0294] ##STR00056##

[0295] To a solution of (2-bromo-5-methylthiazol-4-yl) methanol (1.70 g, 8.170 mmol) in THF (20 mL) was added triphenylphosphine (2.37 g, 9.036 mmol) and carbon tetrabromide (3.00 g, 9.046 mmol) at 0° C. The reaction mixture was stirred for 3 h at room temperature. The resulting solution was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by C18 reversed phase column chromatography eluting with H.sub.2O/ACN to afford 2-bromo-4-(bromomethyl)-5-methylthiazole (890 mg, Y=40%) as a yellow oil. LCMS (ESI, m/z): 270 [M+H].sup.+.

[0296] The following compounds were synthesized using the above procedure or modifications to the above procedure with the corresponding starting materials.

TABLE-US-00003 INT A6 [00057] embedded image INT A7 [00058] INT A8 [00059] INT A9 [00060] INT A10 [00061] INT A11 [00062] INT A12: [00063] INT A13 [00064]

INT A14: 4-chloro-2-(chloromethyl)-6-methylpyrimidine

[0297] ##STR00065##

[0298] A mixture of 2-(chloromethyl)-6-methylpyrimidin-4-ol (1.87 g, 11.792 mmol) and phosphorus oxychloride (15 mL) was stirred at 80° C. for 1 h. The mixture was added saturated sodium bicarbonate aqueous solution to adjust pH to 7˜8. The resulting mixture was extracted with DCM (50 mL). The organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by C18 reversed phase column chromatography eluting with H.sub.2O/ACN to afford 4-chloro-2-(chloromethyl)-6-methylpyrimidine (1.74 g, Y=83%) as a yellow oil. LCMS (ESI, m/z): 177 [M+H].sup.+.

INT A15: 2-bromo-6-(bromomethyl)-4-fluoropyridine

Step 1: 2-bromo-4-fluoro-6-methylpyridine

[0299] ##STR00066##

[0300] To a solution of 2-bromo-6-methylpyridin-4-amine (2.08 g, 11.121 mmol) in pyridinium fluoride (30 mL) was added sodium nitrite (1.42 g, 20.581 mmol). The reaction mixture was heated to 55° C. and stirred for 3 h. The reaction solution was cooled to room temperature. The resulting solution was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by C18 reversed phase column chromatography eluting with H.sub.2O/ACN to afford 2-bromo-4-fluoro-6-methylpyridine (669 mg, Y=32%) as a yellow oil. LCMS (ESI, m/z): 190, 192 [M+H].sup.+.

Step 2: 2-bromo-6-(bromomethyl)-4-fluoropyridine

[0301] ##STR00067##

[0302] Following the procedure analogous to that described in the synthesis of INT A1, 2-bromo-4-fluoro-6-methylpyridine (341 mg, 1.795 mmol) was converted to the title compound (483 g, Y=100%) as a red oil. LCMS (ESI, m/z): 270 [M+H].sup.+.

INT A16: 2-(bromomethyl)-6-chloro-4-cyclopropyl-3-fluoropyridine

Step 1: 6-chloro-3-fluoro-4-iodo-2-methylpyridine

[0303] ##STR00068##

[0304] A solution of diisopropylamine (13.54 g, 133.809 mmol) in THF (30 mL) was added n-butyl lithium (2.5 M) in hexane (47 mL, 117.500 mmol) dropwise at −78° C. under nitrogen. The reaction was stirred at 0° C. for 1 h. A solution of 6-chloro-3-fluoro-2-methylpyridine (10.37 g, 71.241 mmol) in THF (20 ml) was added above solution at −78° C. The resulting solution was stirred at −40° C. for 1 h.

[0305] A solution of iodine (24.71 g, 97.357 mmol) in THF (20 ml) was added at −78° C. The solution was stirred at −60° C. for 1 h. The reaction solution was quenched with saturated NH.sub.4Cl aqueous solution. The resulting mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by C18 reversed phase column chromatography eluting with H.sub.2O/ACN to afford 6-chloro-3-fluoro-4-iodo-2-methylpyridine (13.46 g, Y=70%) as white solid. LCMS (ESI, m/z): 272 [M+H].sup.+.

Step 2: 6-chloro-4-cyclopropyl-3-fluoro-2-methylpyridine

[0306] ##STR00069##

[0307] To a solution of 6-chloro-3-fluoro-4-iodo-2-methylpyridine (2083 mg, 7.673 mmol) in toluene (30 mL) and water (5 mL) was added cyclopropylboronic acid (1207 mg, 14.052 mmol), palladium(II) acetate (353 mg, 1.572 mmol), tricyclohexylphosphonium tetrafluoroborate (1135 mg, 3.082 mmol) and K.sub.3PO.sub.4 (6319 mg, 29.769 mmol) under nitrogen. The reaction mixture was heated to 110° C. and stirred for 12 h. The reaction was cooled to room temperature. The resulting solution was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by C18 reversed phase column chromatography eluting with H.sub.2O/ACN to afford 6-chloro-4-cyclopropyl-3-fluoro-2-methylpyridine (1.30 g, Y=91%) as white solid. LCMS (ESI, m/z): 186 [M+H].sup.+.

Step 3: 2-(bromomethyl)-6-chloro-4-cyclopropyl-3-fluoropyridine

[0308] ##STR00070##

[0309] Following the procedure analogous to that described in the synthesis of INT A2, 6-chloro-4-cyclopropyl-3-fluoro-2-methylpyridine (1.30 g, 7.003 mmol) was converted to the title compound (302 mg, Y=16%) as a yellow oil. LCMS (ESI, m/z): 264 [M+H].sup.+.

INT A17: 2-(bromomethyl)-6-chloro-3-fluoro-5-methylpyridine

Step 1: methyl 3-amino-5-methylpicolinate

[0310] ##STR00071##

[0311] A solution of 3-amino-5-methylpicolinonitrile (4.75 g, 35.674 mmol) in 12 M hydrochloric acid aqueous solution (50 mL) was stirred at refluxed for 24 h. After the reaction completion, the solvent was evaporated. The resulting residue was added methanol (100 mL) and 98% sulphuric acid (10 mL). The reaction mixture was refluxed for 24 h. The resulting solution was adjusted pH to 7˜8 with saturated sodium bicarbonate aqueous solution. The resulting mixture was extracted with DCM. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford methyl 3-amino-5-methylpicolinate (4.70 g, Y=72%) as a yellow solid. LCMS (ESI, m/z): 167 [M+H].sup.+.

Step 2: methyl 3-amino-6-chloro-5-methylpicolinate

[0312] ##STR00072##

[0313] To a solution of methyl 3-amino-5-methylpicolinate (8.5 g, 51.150 mmol) in ACN (100 mL) was added NCS (9.20 g, 68.897 mmol) under nitrogen. The reaction mixture was heated to 70° C. and stirred for 12 h. The reaction was cooled to room temperature. The resulting solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate aqueous solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by C18 reversed phase column chromatography eluting with H.sub.2O/ACN to afford methyl 3-amino-6-chloro-5-methylpicolinate (6.17 g Y=60%) as a yellow solid. LCMS (ESI, m/z): 201 [M+H].sup.+.

Step 3: methyl 6-chloro-3-fluoro-5-methylpicolinate

[0314] ##STR00073##

[0315] Following the procedure analogous to that described in Step 1 for the synthesis of INT A15, methyl 3-amino-6-chloro-5-methylpicolinate (5.96 g, 29.708 mmol) was converted to the title compound (3.67 g, Y=65%) as a yellow oil. LCMS (ESI, m/z): 204 [M+H].sup.+.

Step 4: (6-chloro-3-fluoro-5-methylpyridin-2-yl)methanol

[0316] ##STR00074##

[0317] Following the procedure analogous to that described in Step 4 for the synthesis of INT A5, methyl 6-chloro-3-fluoro-5-methylpicolinate (3.57 g, 18.832 mmol) was converted to the title compound (1.60 g, Y=48%) as a white solid. LCMS (ESI, m/z): 176 [M+H].sup.+.

Step 5: 2-(bromomethyl)-6-chloro-3-fluoro-5-methylpyridine

[0318] ##STR00075##

[0319] Following the procedure analogous to that described in Step 1 for the synthesis of INT A5, (6-chloro-3-fluoro-5-methylpyridin-2-yl)methanol (1.50 g, 8.543 mmol) was converted to the title compound (1.93 g, Y=95%) as a yellow oil. LCMS (ESI, m/z): 238 [M+H].sup.+.

INT A18: 2-(bromomethyl)-3,5-difluoropyridine

Step 1: 3-amino-5-fluoropicolinonitrile

[0320] ##STR00076##

[0321] A solution of 5-fluoro-3-nitropicolinonitrile (20.01 g, 119.751 mmol) in methanol (250 mL) was purged with nitrogen and pressurized with H.sub.2. The solution was added Pd/C (9.23 g, 86.732 mmol) and stirred for 16 h. After completion, the mixture was filtrated and washed the filter cake with methanol (200 mL×3). The filtrate was removed under reduced pressure to afford 3-amino-5-fluoropicolinonitrile (15.42 g, 94%) as a yellow solid. LCMS (ESI, m/z): 138 [M+H].sup.+.

Step 2: methyl 3-amino-5-fluoropicolinate

[0322] ##STR00077##

[0323] A solution of 3-amino-5-fluoropicolinonitrile (17.49 g, 127.558 mmol) in 12 M hydrochloric acid aqueous solution (250 mL) was refluxed for 24 h. After completion, the solvent was evaporated. The resulting residue was added methanol (300 mL) and 98% sulphuric acid (60 mL). The reaction mixture was refluxed for 24 h before it was cooled to room temperature. The resulting solution was added saturated sodium bicarbonate aqueous solution to adjust pH to 7˜8. The resulting mixture was extracted with DCM. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford methyl 3-amino-5-fluoropicolinate (16.60 g, Y=76%) as a yellow solid. LCMS (ESI, m/z): 171 [M+H].sup.+.

Step 3: methyl-3,5-difluoropicolinate

[0324] ##STR00078##

[0325] To a solution of methyl 3-amino-5-fluoropicolinate (16.60 g, 97.566 mmol) in pyridinium fluoride (220 mL) was added sodium nitrite (13.87 g, 201.028 mmol). The mixture was heated to 55° C. and stirred for 3 h. The reaction mixture was cooled to room temperature. The resulting solution was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by C18 reversed phase column chromatography eluting with H.sub.2O/ACN to afford methyl-3,5-difluoropicolinate (10.86 g, Y=64%) as a yellow oil. LCMS (ESI, m/z): 174 [M+H].sup.+.

Step 4: (3,5-difluoropyridin-2-yl)methanol

[0326] ##STR00079##

[0327] To a solution of methyl-3,5-difluoropicolinate (10.86 g, 62.732 mmol) in methanol (100 mL) and water (20 mL) was added NaBH.sub.4 (7.39 g, 195.335 mmol) at 0° C. The mixture was stirred for 3 h at room temperature. The resulting solution was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by C18 reversed phase column chromatography eluting with H.sub.2O/ACN to afford (3,5-difluoropyridin-2-yl)methanol (8.19 g Y=90%) as a yellow oil. LCMS (ESI, m/z): 146 [M+H].sup.+.

Step 5: 2-(bromomethyl)-3,5-difluoropyridine

[0328] ##STR00080##

[0329] Following the procedure analogous to that described in Step 2 for the synthesis of INT A5, (3,5-difluoropyridin-2-yl)methanol (8.19 g, 56.441 mmol) was converted to the title compound (9.16 g, Y=78%) as a yellow oil. LCMS (ESI, m/z): 208, 210 [M+H].sup.+.

INT B1: di-tert-butyl-piperidine-1,4-dicarboxylate

Step 1: 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid

[0330] ##STR00081##

[0331] To a solution of 1-(tert-butyl) 4-methyl piperidine-1,4-dicarboxylate (4.95 g, 20.35 mmol), THF (90 mL), methanol (90 mL) and water (30 mL) was added lithium hydroxide (2.39 g, 99.715 mmol). The solution was stirred at room temperature for overnight. The resulting mixture was adjusted pH to 5 with 1N HCl aqueous solution, extracted with ethyl acetate (500 mL) and washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 1-(tert-butoxycarbonyl) piperidine-4-carboxylic acid (4.55 g, crude) as a white solid. The crude product is directly used in the next step without purification. LCMS (ESI, m/z): 230 [M+H].sup.+.

Step 2: di-tert-butyl piperidine-1,4-dicarboxylate

[0332] ##STR00082##

[0333] A solution of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (4.55 g, crude), 4-dimethylaminopyridine (0.64 g, 5.24 mmol) and di-tert-butyl dicarbonate (9.02 g, 41.33 mol) in tert-butanol (50 mL) was stirred at room temperature for overnight. The reaction solution was heated to 30° C. and stirred for overnight. The solvent was evaporated to remove. The resulting residue was purified by silica gel column chromatography eluting with EtOAc/hexane (0˜10%) to afford di-tert-butyl piperidine-1,4-dicarboxylate (5.23 g, Y=92%) as a white solid. LCMS (ESI, m/z): 286 [M+H].sup.+.

INT B2: di-tert-butyl (2R,4R)-2-methylpiperidine-1,4-dicarboxylate

Step 1: methyl 2-methylpiperidine-4-carboxylate hydrochloride

[0334] ##STR00083##

[0335] A solution of methyl 2-chloro-6-methylpyridine-4-carboxylate (99.10 g, 533.924 mmol), platinum dioxide (10.46 g, 46.064 mmol) and acetic acid (1.0 L) was purged with nitrogen and pressurized with H.sub.2. The reaction mixture was heated at 65° C. for 24 h. After completion, the reaction solution was filtered and the filtrate was removed under reduced pressure. The resulting residue was added methyl tert-butyl ether (1 L) and stirred at room temperature. The resulting solids was rinsed with methyl tert-butyl ether (2×500 mL), collected and dried under vacuum to provide the title compound as a white solid (101.70 g). LCMS (ESI, m/z): 158 [M+H].sup.+.

Step 2: methyl-1-(4-methoxybenzyl)-2-methylpiperidine-4-carboxylate

[0336] ##STR00084##

[0337] A solution of methyl 2-methylpiperidine-4-carboxylate (99.62 g, 514.379 mmol), potassium carbonate (284.360 g, 2.058 mol) in ACN (1.2 L) was refluxed for 2 h. The reaction was cooled to room temperature. The resulting solution was added 4-methoxybenzyl chloride (80.556 g, 514.379 mmol) dropwise and stirred for overnight. After completion, the mixture was filtered and the filtrate was removed under reduced pressure. The residue was dissolved in EtOAc and added 4N HCl aqueous solution to adjust pH to 1. The organic layer was separated, washed with saturated sodium bicarbonate aqueous solution and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by C18 reversed phase column chromatography eluting with H.sub.2O/ACN to afford methyl 1-[(4-methoxyphenyl)methyl]-2-methyl-piperidine-4-carboxylate (113.09 g) as a yellow oil. LCMS (ESI, m/z): 278 [M+H].sup.+.

Step 3: methyl (2R,4R)-1-(4-methoxybenzyl)-2-methylpiperidine-4-carboxylate

[0338] ##STR00085##

[0339] Two enantiomers of methyl 1-(4-methoxybenzyl)-2-methylpiperidine-4-carboxylate (36.67 g) was separated using chiral chromatography. Stationary phase: CHIRALPAK IA, Column size: 0.46 cm I.D.×15 cm L, mobile phase: n-hexane/EtOH 0.1% DIEA=75/25 (V/V), flow rate: 1.0 mL/min, wave length: UV 210 nm, temperature: 25° C. The first eluted enantiomer was collected as the title compound (20.01 g, 54.67% yield; Rr=2.615 min; LCMS (ESI, m/z): 278 [M+H].sup.+), the second eluted enantiomer was collected to give 15.88 g, Rr=4.449 min; LCMS (ESI, m/z): 278 [M+H].sup.+.

Step 4: methyl-(2R,4R)-2-methylpiperidine-4-carboxylate-hydrochloride

[0340] ##STR00086##

[0341] A solution of methyl (2R,4R)-1-(4-methoxy benzyl)-2-methylpiperidine-4-carboxylate (50.75 g, 182.977 mmol) in methanol (500 mL) was added Pd/C (10.44 g, 98.102 mmol), purged with nitrogen and pressurized with H.sub.2. The mixture was heated to 45° C. and stirred for 16 h. After completion, the resulting mixture was filtered and the filter cake was washed with methanol (200 mL×3). The filtrate was collected and removed under reduced pressure. The resulting residue was added 4 M HCl/ethyl acetate and stirred 2 h at room temperature. The solid was collected. The filter cake was rinsed with ethyl acetate and dried under vacuum to afford methyl (2R,4R)-2-methyl piperidine-4-carboxylate hydrochloride (32.97 g, Y=93%) as a white solid. LCMS (ESI, m/z): 158 [M+H].sup.+.

Step 5: 1-(tert-butyl)-4-methyl (2R,4R)-2-methylpiperidine-1,4-dicarboxylate

[0342] ##STR00087##

[0343] A solution of (2R,4R)-2-methylpiperidine-4-carboxylate hydrochloride (32.87 g, 169.721 mmol), N,N-diisopropylethylamine (102.58 g, 793.702 mmol), N-(4-pyridyl) dimethylamine (3.14 g, 25.703 mmol) and di-tert-butyl dicarbonate (56.31 g, 258.011 mmol) in DCM (500 mL) was stirred at room temperature for 2 h. The resulting solution was diluted with water and extracted with DCM. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by a silica gel column chromatography (eluent: 0˜100% hexane/DCM) to afford 1-(tert-butyl) 4-methyl (2R,4R)-2-methylpiperidine-1,4-dicarboxylate (37.11 g, Y=84.97%) as a yellow oil. LCMS (ESI, m/z): 258 [M+H].sup.+.

Step 6: (2R,4R)-1-(tert-butoxycarbonyl)-2-methylpiperidine-4-carboxylic acid

[0344] ##STR00088##

[0345] A mixture of 1-(tert-butyl) 4-methyl (2R,4R)-2-methylpiperidine-1,4-dicarboxylate (37.11 g, 144.214 mmol) in THF (260 mL) and water (130 mL) was added lithium hydroxide (16.95 g, 707.775 mmol). The reaction mixture was stirred at room temperature for overnight. The resulting solution was added 1N HCl aqueous solution to adjust pH to 3˜4 and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give (2R,4R)-1-(tert-butoxycarbonyl)-2-methyl piperidine-4-carboxylic acid (39.5 g, crude) as a yellow oil. LCMS (ESI, m/z): 244 [M+H].sup.+.

Step 7: di-tert-butyl-(2R,4R)-2-methylpiperidine-1,4-dicarboxylate

[0346] ##STR00089##

[0347] A solution of (2R, 4R)-1-(tert-butoxycarbonyl)-2-methylpiperidine-4-carboxylic acid (39.5 g, crude), N-(4-pyridyl)-dimethylamine (4.84 g, 39.618 mmol) and di-tert-butyl-di-carbonate (63.94 g, 292.972 mmol) in tert-Butanol (400 mL) was stirred at room temperature for overnight under nitrogen. After completion, the resulting solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue by a silica gel column chromatography (eluent: 0˜10% ethyl acetate/hexane) to afford di-tert-butyl (2R,4R)-2-methylpiperidine-1,4-di-carboxylate (35.7 g, Y=73%) as a white solid. LCMS (ESI, m/z): 300 [M+H].sup.+.

[0348] The following compounds were synthesized using the above procedure with the corresponding starting materials.

TABLE-US-00004 INT B3 [00090] embedded image INT B4 [00091]

INT B5: methyl 1-(3-chloro-2-fluorobenzyl)-2-ethylpiperidine-4-carboxylate

Step 1: methyl 2-vinylisonicotinate

[0349] ##STR00092##

[0350] To a solution of methyl 2-bromoisonicotinate (3.05 g, 14.12 mmol) in 1,4-dioxane (60 mL) was added tributyl(vinyl)stannane (7.44 g, 23.46 mmol), tetrakis(triphenylphosphine)palladium (1.72 g, 1.49 mmol) and cesium fluoride (4.37 g, 28.77 mmol) under nitrogen. The reaction mixture was stirred at 80° C. for 4 h. After cooling to room temperature, the resulting mixture was diluted with ethyl acetate (50 mL) and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified with column chromatography on silica gel eluting with ethyl acetate/hexane (10%˜30% to afford methyl 2-vinylisonicotinate (1.65 g) as light yellow oil. LCMS (ESI, m/z): 164 [M+H].sup.+.

Step 2: methyl 2-ethylpiperidine-4-carboxylate

[0351] ##STR00093##

[0352] To a solution of methyl 2-vinylisonicotinate (1.65 g, 10.11 mmol) in HOAc (30 mL) was added PtO.sub.2 (0.48 g, 2.11 mmol). The mixture was purged with nitrogen and pressurized with H.sub.2. The reaction mixture was stirred at 65° C. for 16 h. The resulting mixture was cooled to room temperature and filtered. The filter cake was washed with HOAc (3×50 mL) and the filtrate was concentrated under vacuum afford crude methyl 2-ethylpiperidine-4-carboxylate (1.83 g) as light yellow oil. LCMS (ESI, m/z): 172 [M+H].sup.+.

Step 3: methyl 1-(3-chloro-2-fluorobenzyl)-2-ethylpiperidine-4-carboxylate

[0353] ##STR00094##

[0354] To a solution of methyl 2-ethylpiperidine-4-carboxylate (1.83 g, 10.50 mmol) in ACN (30 mL) was added K.sub.2CO.sub.3 (4.65 g, 33.65 mmol) and 1-(bromomethyl)-3-chloro-2-fluorobenzene (3.05 g, 13.06 mmol). The reaction mixture was stirred at room temperature for 16 h. The resulting mixture was diluted with ethyl acetate (50 mL) and filtered. The filter cake was washed with ethyl acetate (3×50 mL) and the filtrate was concentrated under vacuum. The resulting residue was purified by column chromatography on silica gel eluting with ethyl acetate/hexane (0%˜30%) to afford methyl 1-(3-chloro-2-fluorobenzyl)-2-ethylpiperidine-4-carboxylate (2.36 g) as colorless oil. LCMS (ESI, m/z): 314 [M+H].sup.+.

INT B6: methyl 1-(3-chloro-2-fluorobenzyl)-2,6-dimethylpiperidine-4-carboxylate

Step 1: methyl 2,6-dimethylpiperidine-4-carboxylate

[0355] ##STR00095##

[0356] A solution of methyl 2,6-dimethylisonicotinate (1.92 g, 11.623 mmol), platinum dioxide (236 mg, 1.039 mmol) in acetic acid (20 mL) was purged with nitrogen and pressurized with H.sub.2. The reaction mixture was heated at 65° C. for 24 h. After completion, the resulting mixture was filtered and the filtrate was removed under reduced pressure. The resulting residue was added methyl tert-butyl ether (20 mL) and stirred at room temperature for 1 h. The solids was collected and dried in vacuum to provide methyl-2,6-dimethyl-piperidine-4-carboxylate (1.72 g Y=94%) as a white solid. LCMS (ESI, m/z): 172 [M+H].sup.+.

Step 2: methyl 1-(3-chloro-2-fluorobenzyl)-2,6-dimethylpiperidine-4-carboxylate

[0357] ##STR00096##

[0358] To a solution of methyl 2-methylpiperidine-4-carboxylate (520 mg, 3.037 mmol) in acetonitrile (30 ml) was added 1-(bromomethyl)-3-chloro-2-fluorobenzene (830 mg, 3.714 mmol) and K.sub.2CO.sub.3 (1.26 g, 9.117 mmol) at room temperature. The resulting mixture was stirred for 3 h at room temperature before it was filtrated. The filtrate was removed under reduced pressure. The resulting residue was purified by C18 reversed phase column chromatography eluting with H.sub.2O/ACN to afford methyl-1-(3-chloro-2-fluorobenzyl)-2,6-dimethyl-piperidine-4-carboxylate (500 mg Y=52%) as a yellow oil. LCMS (ESI, m/z): 314 [M+H].sup.+.

[0359] The following compounds were synthesized using the above procedure with the corresponding starting materials.

TABLE-US-00005 INT B7 [00097] embedded image

INT C1: di-tert-butyl (2R,4R)-4-((6-chloro-5-fluoropyridin-2-yl)methyl)-2 methylpiperidine-1,4-dicarboxylate

[0360] ##STR00098##

[0361] A solution of diisopropylamine (928 mg, 9.171 mmol) in THF (2 ml) was cooled to −70˜80° C. under nitrogen. n-Butyl lithium 2.5 M in THF (4.0 ml, 10 mmol) was added and the resulting solution was stirred at 0° C. for 30 min. Then a solution of INT B2 (1.28 g, 4.275 mmol) in THF (4 ml) was added slowly and the reaction was stirred at −50° C.˜−70° C. for 1 h.

[0362] A solution of INT A2 (1094 mg, 4.874 mmol) was added to above solution and the reaction solution was stirred at −70° C. to ˜80° C. for 2 h. After completion, the resulting solution was quenched with saturated ammonium chloride aqueous solution (50 mL) and extracted with EtOAc (100 ml×3). The organic layer was concentrated under reduced pressure. The resulting residue was purified by C18 reverse phase chromatography eluting with H.sub.2O/ACN to afford 879 mg of the title compound. LCMS (ESI, m/z): 443 [M+H].sup.+.

[0363] The following compounds were synthesized using the above procedure with the corresponding starting materials.

TABLE-US-00006 INT C2 [00099] embedded image INT C3 [00100] INT C4 [00101] INT C5 [00102]

INT C6: di-tert-butyl (2R,4R)-4-((6-chloro-3,5-difluoropyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate

Step 1: di-tert-butyl-(2R,4R)-4-((3,5-difluoropyridin-2-yl)methyl)-2-methyl-piperidine-1,4-dicarboxylate

[0364] ##STR00103##

[0365] Following the procedure analogous to that described in the synthesis of INT C1, INT A18 (5.62 g, 27.019 mmol) and INT B2 (5.98 g, 19.973 mmol) was converted to the title compound (7.47 g, Y=88%) as a yellow oil. MS: 427 [M+H].sup.+.

Step 2: 2-(((2R,4R)-1,4-bis(tert-butoxycarbonyl)-2-methylpiperidin-4-yl)methyl)-3,5-difluoropyridine-1-oxide

[0366] ##STR00104##

[0367] To a solution of di-tert-butyl (2R,4R)-4-((3,5-difluoropyridin-2-yl)methyl)-2-methyl-piperidine-1,4-dicarboxylate (7.47 g, 17.515 mmol) in DCM (60 mL) was added m-chloroperoxybenzoic (6.12 g, 35.465 mmol) at 0° C. The reaction mixture was stirred for 4 h at room temperature. The resulting solution was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by C18 reversed phase column chromatography eluting with H.sub.2O/ACN to afford 2-(((2R,4R)-1,4-bis(tert-butoxycarbonyl)-2-methylpiperidin-4-yl)methyl)-3,5-difluoropyridine-1-oxide (2.06 g Y=27%) as a yellow oil. MS: 443 [M+1].sup.+.

Step 3: di-tert-butyl-(2R,4R)-4-((6-chloro-3,5-difluoropyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate

[0368] ##STR00105##

[0369] To a solution of 2-(((2R,4R)-1,4-bis(tert-butoxycarbonyl)-2-methylpiperidin-4-yl)methyl)-3,5-difluoropyridine 1-oxide (2.06 g, 4.656 mmol) in DMF (10 mL) was added phosphorus oxychloride (6.41 g, 41.805 mmol) at 0° C. The reaction mixture was stirred for 4 h at room temperature. The resulting solution was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by C18 reversed phase column chromatography eluting with H.sub.2O/ACN to afford di-tert-butyl-(2R,4R)-4-((6-chloro-3,5-difluoropyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate (1.23 g Y=57%) as a yellow oil. MS: 461 [M+1].sup.+.

Example 1

1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)methyl) piperidine-4-carboxylic acid

Step 1: methyl 1-(3-chloro-2-fluorobenzyl)piperidine-4-carboxylate

[0370] ##STR00106##

[0371] To a solution of methyl piperidine-4-carboxylate (1.04 g, 7.26 mmol) in ACN (10 mL) was added K.sub.2CO.sub.3 (3.15 g, 22.79 mmol) and 1-(bromomethyl)-3-chloro-2-fluorobenzene (1.91 g, 8.55 mmol). The reaction mixture was stirred at room temperature for 16 h. The mixture was diluted with ethyl acetate (50 mL) and filtered. The filter cake was washed with ethyl acetate (3×50 mL) and the filtrate was combined and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel with (ethyl acetate/hexane, 0%-30%) to afford methyl 1-(3-chloro-2-fluorobenzyl) piperidine-4-carboxylate (1.69 g) as colorless oil. LCMS (ESI, m/z): 286 [M+H].sup.+.

Step 2: methyl 4-((6-bromo-3-fluoropyridin-2-yl)methyl)-1-(3-chloro-2-fluoro-benzyl) piperidine-4-carboxylate

[0372] ##STR00107##

[0373] A solution of methyl 1-(3-chloro-2-fluorobenzyl)piperidine-4-carboxylate (1.18 g, 4.13 mmol) in THF (15 mL) was cooled to −70° C. under nitrogen before LDA in hexane (2 M, 5 mL) was added dropwise. The reaction mixture was stirred at −70° C. for 30 min. A solution of INT A1 (1.43 g, 5.32 mmol) in THF (5 mL) was added. The mixture was stirred at −70° C. for 90 min before it is quenched with saturated ammonium chloride aqueous solution (20 mL) and extracted with ethyl acetate (3×50 mL).

[0374] The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel with ethyl acetate/hexane (0%˜30) to afford methyl 4-((6-bromo-3-fluoropyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)-piperidine-4-carboxylate (480 mg) as a light yellow oil. LCMS (ESI, m/z): 473 [M+H].sup.+.

Step 3: methyl 4-((6-((1-(tert-butoxycarbonyl)-5-methyl-1H-pyrazol-3-yl)amino)-3-fluoropyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)piperidine-4-carboxylate

[0375] ##STR00108##

[0376] To a solution of methyl 4-((6-bromo-3-fluoropyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)piperidine-4-carboxylate (201 mg, 0.42 mmol) in 1,4-dioxane (10 mL), was added tert-butyl 3-amino-5-methyl-1H-pyrazole-1-carboxylate (95 mg, 0.48 mmol), Xphos.Pd.G2 (39 mg, 0.05 mmol), Xphos (25 mg, 0.057 mmol) and Cs.sub.2CO.sub.3 (282 mg, 0.87 mmol) under nitrogen. The reaction mixture was stirred at 110° C. for 2 h. The mixture was cooled to room temperature and poured into water (50 mL). The resulting mixture was extracted with ethyl acetate (3×50 mL). The combined organic layer was concentrated under reduced pressure and the resulting residue was purified with column chromatography on silica gel with (ethyl acetate/hexane=10%˜50%) to afford methyl 4-((6-((1-(tert-butoxycarbonyl)-5-methyl-1H-pyrazol-3-yl)amino)-3-fluoropyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)piperidine-4-carboxylate (79 mg) as an off-white solid. LCMS (ESI, m/z): 590 [M+H].sup.+.

Step 4: methyl 1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)methyl)piperidine-4-carboxylate

[0377] ##STR00109##

[0378] To a solution of methyl 4-((6-((1-(tert-butoxycarbonyl)-5-methyl-1H-pyrazol-3-yl)amino)-3-fluoropyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)piperidine-4-carboxylate (79 mg, 0.13 mmol) in DCM (5 mL) was added TFA (5 mL). The reaction mixture was stirred at room temperature for 2 h before it is quenched with sat.NaHCO.sub.3 aqueous solution (20 mL). The mixture was extracted with DCM (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under the vacuum to afford methyl 1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl) methyl)piperidine-4-carboxylate (68 mg) as a light yellow solid. LCMS (ESI, m/z): 490 [M+H].sup.+.

Step 5: 1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl) amino)pyridin-2-yl)methyl)piperidine-4-carboxylic acid

[0379] ##STR00110##

[0380] To a solution of methyl 1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)methyl)piperidine-4-carboxylate (68 mg, 0.13 mmol) in MeOH (3 mL) and water (1 mL) was added sodium hydroxide (46 mg, 1.15 mmol). The reaction mixture was stirred at 70° C. overnight. The mixture was concentrated under reduced pressure. The resulting residue was added hydrochloric acid aqueous solution to adjust pH=6-7. The mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were concentrated under reduced pressure. The resulting residue was purified by prep-HPLC to afford 1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl) methyl)piperidine-4-carboxylic acid (38 mg) as an off-white solid. LCMS (ESI, m/z): 476 [M+H].sup.+. .sup.1H NMR (400 MHz, MeOD) δ 7.72 (t, J=7.2 Hz, 1H), 7.53 (t, J=6.4 Hz, 1H), 7.46 (t, J=9.2 Hz, 1H), 7.32 (t, J=7.6 Hz, 1H), 7.11 (d, J=6.4, 1H), 6.08 (s, 1H), 4.40 (s, 2H), 3.41 (d, J=11.6 Hz, 2H), 2.97-2.89 (m, 2H), 2.89 (s, 2H), 2.30-2.11 (m, 5H), 1.79 (t, J=12.5, 2H).

Example 2

1-(3-chloro-2-fluorobenzyl)-2-ethyl-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)methyl)piperidine-4-carboxylic acid

Step 1: methyl 4-((6-bromo-3-fluoropyridin-2-yl)methyl)-1-(3-chloro-2-fluoro-benzyl)-2-ethyl piperidine-4-carboxylate

[0381] ##STR00111##

[0382] Following the procedure analogous to that described in Step 2 for the synthesis of Example 1, INT B5 (1.10 g, 3.51 mmol) and INT A1 (1.19 g, 4.43 mmol) were converted to the title compound (1.07 g) as a light yellow oil. LCMS (ESI, m/z): 501 [M+H].sup.+.

Step 2: methyl 4-((6-((1-(tert-butoxycarbonyl)-5-methyl-1H-pyrazol-3-yl)amino)-3-fluoropyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2-ethylpiperidine-4-carboxylate

[0383] ##STR00112##

[0384] Following the procedure analogous to that described in Step 3 for the synthesis of Example 1, methyl 4-((6-bromo-3-fluoropyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2-ethylpiperidine-4-carboxylate (208 mg, 0.41 mmol) was converted to the title compound (201 mg) as colorless oil. LCMS (ESI, m/z): 618 [M+H].sup.+.

Step 3: methyl 1-(3-chloro-2-fluorobenzyl)-2-ethyl-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl) amino)pyridin-2-yl)methyl)piperidine-4-carboxylate

[0385] ##STR00113##

[0386] Following the procedure analogous to that described in Step 4 for the synthesis of Example 1, methyl 4-((6-((1-(tert-butoxycarbonyl)-5-methyl-1H-pyrazol-3-yl)amino)-3-fluoropyridin-2-yl) methyl)-1-(3-chloro-2-fluorobenzyl)-2-ethylpiperidine-4-carboxylate (201 mg, 0.33 mmol) was converted to the title compound (170 mg) as a light yellow solid. LCMS (ESI, m/z): 518 [M+H].sup.+.

Step 4: 1-(3-chloro-2-fluorobenzyl)-2-ethyl-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)piperidine-4-carboxylic acid

[0387] ##STR00114##

[0388] Following the procedure analogous to that described in Step 5 for the synthesis of Example 1, methyl 1-(3-chloro-2-fluorobenzyl)-2-ethyl-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)piperidine-4-carboxylate (170 mg, 0.33 mmol) was converted to the title compound (23 mg) as an off-white solid. LCMS (ESI, m/z): 504 [M+H].sup.+. .sup.1H NMR (400 MHz, MeOD) δ 7.73-7.67 (m, 1H), 7.64-7.47 (m, 2H), 7.38-7.31 (m, 1H), 6.92-6.88 (m, 1H), 6.02 (s, 1H), 4.40 (s, 2H), 3.75-3.67 (m, 1H), 3.53-3.36 (m, 3H), 3.27-3.04 (m, 2H), 2.39 (s, 3H), 2.31-2.05 (m, 3H), 1.91-1.77 (m, 2H), 1.09 (t, J=7.2 Hz, 3H).

Example 3

1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl) methyl)-2,6-dimethylpiperidine-4-carboxylic acid

Step 1: methyl-4-((6-bromo-3-fluoropyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2,6-dimethylpiperidine-4-carboxylate

[0389] ##STR00115##

[0390] Following the procedure analogous to that described in Step 2 for the synthesis of Example 1, INT B6 (604 mg, 1.929 mmol) was converted to the title compound (443 mg, Y=46%) as a yellow oil. LCMS (ESI, m/z): 503 [M+H].sup.+.

Step 2: Methyl 1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-6-((5-methyl-1-((2-(trimethylsilyl)-ethoxy)methyl)-1H-pyrazol-3-yl)amino)pyridin-2-yl)methyl)-2,6-dimethylpiperidine-4-carboxylate

[0391] ##STR00116##

[0392] To a solution of methyl-4-((6-bromo-3-fluoropyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2,6-dimethylpiperidine-4-carboxylate (391 mg, 0.779 mmol) in 1,4-dioxane (20 ml) was added 5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-amine (328 mg, 1.443 mmol), XPhos.Pd.G2 (98 mg, 0.125 mmol), Xphos (121 mg, 0.254 mmol) and Cs.sub.2CO.sub.3 (570 mg, 1.749 mmol) under nitrogen. The mixture was heated to 110° C. and stirred for 5 h. The reaction was cooled to room temperature. The resulting solution was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by C18 reversed phase column chromatography eluting with H.sub.2O/ACN to afford methyl 1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-6-((5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)amino)pyridin-2-yl)methyl)-2,6-dimethylpiperidine-4-carboxylate (295 mg, Y=58%) as a yellow oil. LCMS (ESI, m/z): 648 [M+H].sup.+.

Step 3: methyl-1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)-2,6-dimethylpiperidine-4-carboxylate

[0393] ##STR00117##

[0394] To a solution of methyl 1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-6-((5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)amino)pyridin-2-yl)methyl)-2,6-dimethylpiperidine-4-carboxylate (295 mg, 0.455 mmol) in DCM (1 mL) was added TFA (10 mL). The reaction mixture was stirred at room temperature for 2 h before it is quenched with saturated sodium bicarbonate solution (50 mL). Then the resulting mixture was extracted with DCM (50 mL). The organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by C18 reversed phase column chromatography eluting with H.sub.2O/ACN to afford methyl-1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)methyl)-2,6-dimethylpiperidine-4-carboxylate (171 mg, Y=73%) as a yellow oil. LCMS (ESI, m/z): 518 [M+H].sup.+.

Step 4: 1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)methyl)-2,6-dimethylpiperidine-4-carboxylic acid

[0395] ##STR00118##

[0396] Following the procedure analogous to that described in Step 5 for the synthesis of Example 1, Methyl-1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)-2,6-dimethylpiperidine-4-carboxylate (97 mg, 0.187 mmol) was converted to the tile compound (15 mg) as a white solid. LCMS (ESI, m/z): 504[M+H].sup.+. .sup.1H NMR (400 MHz, DMSO) δ 9.07 (s, 1H), 7.59 (s, 1H), 7.39 (m, 2H), 7.16 (s, 1H), 7.03 (m, 1H), 6.17 (s, 1H), 4.03 (s, 2H), 3.66 (s, 2H), 2.78 (s, 1H), 2.67 (s, 1H), 2.43 (s, 1H), 2.33 (s, 1H), 2.16 (s, 3H), 2.05 (d, J=12.7 Hz, 2H), 1.24 (s, 3H), 0.86 (d, J=5.7 Hz, 3H).

Example 4

1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-6-(thiazol-2-ylamino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid

Step 1: methyl 4-((6-bromo-3-fluoropyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylate

[0397] ##STR00119##

[0398] Following the procedure analogous to that described in Step 2 for the synthesis of Example 1, INT B7 (2.12 g, 4.963 mmol) and INT A1 (1.52 g, 6.802 mmol) were converted to the title compound (904 mg) as a yellow oil. LCMS (ESI, m/z): 467, 469 [M+H].sup.+.

Step 2: methyl 1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-6-(thiazol-2-ylamino) pyridin-2-yl) methyl)-2-methylpiperidine-4-carboxylate

[0399] ##STR00120##

[0400] To a solution of methyl 4-((6-bromo-3-fluoropyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylate (151 mg, 0.31 mmol) in 1,4-dioxane (5 mL) was added thiazol-2-amine (53 mg, 0.53 mmol), tris(dibenzylideneacetone)dipalladium (157 mg, 0.17 mmol), brettphos (99 mg, 0.18 mmol) and Cs.sub.2CO.sub.3 (346 mg, 1.06 mmol) under nitrogen. The reaction mixture was stirred at 110° C. for 4 h. The mixture was cooled to room temperature and poured into water (50 mL). The mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were concentrated under reduced pressure. The resulting residue was purified with column chromatography on silica gel with (ethyl acetate/hexane=20%˜100%) to afford methyl 1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-6-(thiazol-2-ylamino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylate (130 mg) as a light yellow solid. LCMS (ESI, m/z): 507 [M+H].sup.+.

Step 3: 1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-6-(thiazol-2-ylamino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid

[0401] ##STR00121##

[0402] Following the procedure analogous to that described in Step 5 for the synthesis of Example 1, methyl 1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-6-(thiazol-2-ylamino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylate (130 mg, 0.26 mmol) was converted to the title compound (14 mg) as a light yellow solid. LCMS (ESI, m/z): 493 [M+H].sup.+. .sup.1H NMR (400 MHz, MeOD) δ 7.75-7.67 (m, 1H), 7.63-7.53 (m, 2H), 7.46 (d, J=4.0 Hz, 1H), 7.41-7.30 (m, 1H), 7.11-7.01 (m, 2H), 4.40 (d, J=12.4 Hz, 2H), 4.04-3.90 (m, 1H), 3.66-3.36 (m, 4H), 2.43-2.19 (m, 2H), 2.11-19.2 (m, 2H), 1.63 (s, 3H).

Example 5

(2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((5-fluoro-6-((3-methyl-1H-pyrazol-5-yl)amino) pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid

Step 1: di-tert-butyl-(2R, 4R)-4-((6-chloro-5-fluoropyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate

[0403] ##STR00122##

[0404] A solution of diisopropylamine (928 mg, 9.171 mmol) in THF (2 ml) was cooled to −70˜−80° C. under nitrogen. n-Butyl lithium 2.5 M in THF (4.0 ml, 10 mmol) was added dropwise. The resulting solution was stirred for 30 min at 0° C. Then a solution of INT B2 (1.28 g, 4.275 mmol) in THF (4 ml) was added slowly and the reaction was stirred at −50° C.˜−70° C. for 1 h.

[0405] A solution of INT A2 (1094 mg, 4.874 mmol) in THF (4 mL) was added and the reaction solution was stirred at −70° C. to −80° C. for 2 h. After completion, the reaction was quenched with saturated ammonium chloride solution (50 mL). The resulting solution was diluted with EtOAc (100 ml×3). The organic layers were concentrated under reduced pressure and the resulting residue was purified by C18 reversed phase column chromatography eluting with H.sub.2O/ACN to afford 879 mg of the title compound. LCMS (ESI, m/z): 443 [M+H].sup.+.

Step 2: di-tert-butyl-(2R,4R)-4-((6-((1-(tert-butyl)-3-methyl-1H-pyrazol-5-yl)amino)-5-fluoropyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate

[0406] ##STR00123##

[0407] A mixture of di-tert-butyl-(2R,4R)-4-((6-chloro-5-fluoropyridin-2-yl)methyl)-2-methyl piperidine-1,4-dicarboxylate (1071 mg, 2.418 mmol), tris(dibenzylideneacetone)dipalladium (553 mg, 603.899 μmol), dimethylbisdiphenylphosphinoxant-hene (413 mg, 713.771 μmol), 1-tert-butyl-3-methyl-1H-pyrazol-5-amine (398 mg, 2.598 mmol) and K.sub.3PO.sub.4 (1442 mg, 6.793 mmol) in 1,4-dioxane (30 ml) was stirred at 110° C. for 5 h under nitrogen. The resulting solution was cooled to room temperature, diluted with brine and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.

[0408] The resulting residue was purified by C18 reverse phase chromatography eluting with H.sub.2O/ACN to afford 0.83 g of the title compound as a yellow solid. LCMS (ESI, m/z): 560 [M+H].sup.+.

Step 3: tert-butyl-(2R,4R)-4-((6-((1-(tert-butyl)-3-methyl-1H-pyrazol-5-yl)amino)-5-fluoro pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylate

[0409] ##STR00124##

[0410] A solution of di-tert-butyl-(2R,4R)-4-((6-((1-(tert-butyl)-3-methyl-1H-pyrazol-5-yl)amino)-5-fluoropyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate (1.98 g, 3.538 mmol) in dichloromethane (24 ml) was added trifluoroacetic acid (4 ml) and stirred at room temperature for 4 h. After completion, the reaction was quenched with saturated sodium bicarbonate aqueous solution (100 ml) and extracted with DCM. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by C18 reverse phase chromatography eluting with H.sub.2O/ACN/0.03 formic acid to afford 1.24 g of the title compound as a yellow solid. LCMS (ESI, m/z): 460 [M+H].sup.+.

Step 4: tert-butyl-(2R,4R)-4-((6-((1-(tert-butyl)-3-methyl-1H-pyrazol-5-yl)amino)-5-fluoropyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylate

[0411] ##STR00125##

[0412] A mixture of tert-butyl (2R,4R)-4-((6-((1-(tert-butyl)-3-methyl-1H-pyrazol-5-yl) amino)-5-fluoropyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylate (1.19 g, 2.589 mmol), potassium carbonate (1.65 g, 11.939 mmol) and 6-chloropyridine-3-carbonitrile (1.38 g, 9.96 mmol) in ACN (30 mL) was stirred for 6 h at room temperature. After completion, the resulting mixture was filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with EtOAc/hexane (0˜30%) to afford 1.309 g of the title compound as a yellow solid. LCMS (ESI, m/z): 602 [M+H].sup.+.

Step 5: (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((5-fluoro-6-((3-methyl-1H-pyrazol-5-yl)amino) pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid

[0413] ##STR00126##

[0414] A solution of tert-butyl (2R,4R)-4-((6-((1-(tert-butyl)-3-methyl-1H-pyrazol-5-yl)amino)-5-fluoropyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylate (1.28 g, 2.126 mmol) in formic acid (20 mL) was stirred at reflux for 4 h. After completion, the resulting solution was concentrated. The resulting residue was dissolved in water (40 mL) at 0° C. and adjusted PH=6˜7 with sodium hydroxide aqueous solution (5 M). The resulting mixture was extracted with DCM (3×100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by C18 reverse phase chromatography eluting with MeOH/water to afford 658 mg of the title compound as a white solid. LCMS (ESI, m/z): 490 [M+H].sup.+. .sup.1H NMR (400 MHz, MeOD) δ 7.56-7.42 (m, 2H), 7.29 (dd, J=11.1, 8.0 Hz, 1H), 7.23 (t, 1H), 6.68 (dd, J=8.0, 3.1 Hz, 1H), 6.08 (s, 1H), 4.41 (d, J=13.4 Hz, 1H), 3.78 (d, J=13.6 Hz, 1H), 3.28-3.16 (i, 2H), 3.12 (d, J=13.4 Hz, 1H), 2.97 (d, J=12.2 Hz, 1H), 2.86 (t, 1H), 2.27 (s, 3H), 1.92 (t, 2H), 1.84 (dd, J=14.2, 10.6 Hz, 2H), 1.32 (d, J=6.2 Hz, 3H).

[0415] The following example in Table 1 was synthesized using the above procedure with the corresponding starting materials and intermediates.

TABLE-US-00007 TABLE 1 Example No. Structure Chemical Name .sup.1HNMR & MS: (M + H).sup.+ 6. [00127] embedded image (2R,4R)-1-(3-chloro-2,6- difluorobenzyl)-4-((3- fluoro-6-((5-methyl-1H- pyrazol-3-yl)amino)- pyridin-2-yl)methyl)-2- methylpiperidine-4- carboxylic acid .sup.1H NMR (400 MHz, MeOD) δ 7.57 (d, J = 5.6 Hz, 1H), 7.36 (s, 1H), 7.10 (t, J = 8.7 Hz, 1H), 6.75 (d, J = 8.6 Hz, 1H), 5.78 (s, 1H), 4.39 (d, J = 13.1 Hz, 1H), 3.84 (d, J = 12.8 Hz, 1H), 3.16 (d, J = 66.6 Hz, 3H), 3.00 (s, 1H), 2.87 (d, J = 11.9 Hz, 1H), 2.22 (s, 3H), 2.07- 1.66 (m, 4H), 1.34 (t, J = 18.2 Hz, 3H). MS: 508(M + H).sup.+ 7. [00128] embedded image 4-((3-fluoro-6-((5-methyl- 1H-pyrazol-3-yl)amino)- pyridin-2-yl)methyl)-2- methyl-1-((1-methyl-1H- indazol-7-yl)methyl)- piperidine-4-carboxylic acid .sup.1H NMR (400 MHz, DMSO) δ 8.16 (s, 1H), 7.92 (d, J = 8.1 Hz, 1H), 7.58 (d, J = 6.9 Hz, 1H), 7.47 (t, J = 9.0 Hz, 1H), 7.25 (dd, J = 10.2, 4.9 Hz, 2H), 6.95 (dd, J = 8.8, 2.8 Hz, 1H), 4.36 (s, 3H), 4.29 (s, 2H), 3.52 (d, J = 9.5 Hz, 2H), 3.28 (d, J = 13.5 Hz, 3H), 3.13 (d, J = 12.0 Hz, 1H), 2.19 (s, 3H), 2.07-1.85 (m, 2H), 1.57 (dd, J = 14.3, 6.1 Hz, 4H). MS: 492(M + H).sup.+ 8. [00129] embedded image (2R,4R)-1-(3-chloro-2- fluorobenzyl)-2-ethyl-4- ((3-fluoro-6-((5-methyl- 1H-pyrazol-3-yl)amino)- pyridin-2-yl)methyl)- piperidine-4-carboxylic acid 1H NMR (400 MHz, MeOD) δ 7.43 (t, J = 7.4 Hz, 1H), 7.37 (t, J = 6.8 Hz, 1H), 7.26 (s, 1H), 7.13 (t, J = 7.8 Hz, 1H), 6.66 (d, J = 7.5 Hz, 1H), 5.68 (s, 1H), 4.34 (d, J = 13.5 Hz, 1H), 3.82 (d, J = 13.1 Hz, 1H), 3.18-3.08 (m, 2H), 3.03 (s, 2H), 2.87 (d, J = 10.7 Hz, 1H), 2.12 (s, 3H), 1.89 (dd, J = 37.2, 15.9 Hz, 6H), 0.85 (dd, J = 18.8, 11.9 Hz, 3H). MS: 504 (M + H).sup.+ 9. [00130] embedded image (2R,4R)-1-(3-chloro-2- fluorobenzyl)-4-((4-cyclo- propyl-3-fluoro-6-((5- methyl-1H-pyrazol-3-yl)- amino)pyridin-2-yl)meth- yl)-2-methylpiperidine-4- carboxylic acid .sup.1H NMR (400 MHz, MeOD) δ 7.68 (s, 1H), 7.54 (s, 1H), 7.33 (s, 1H), 6.33 (d, J = 4.2 Hz, 2H), 3.88 (s, 2H), 3.39 (s, 2H), 2.30 (s, 3H), 2.24 (s, 1H), 2.21 (s, 1H), 2.10 (s, 4H), 1.57 (d, J = 5.8 Hz, 3H), 1.14 (d, J = 7.5 Hz, 2H), 0.83 (s, 2H). MS: 530 (M + H).sup.+ 10. [00131] embedded image (2R,4R)-1-(3-chloro-2- fluorobenzyl)-2-methyl- 4-((3-methyl-6-((5-meth- yl-1H-pyrazol-3-yl)- amino)pyridin-2-yl)- methyl)piperidine-4- carboxylic acid .sup.1H NMR (400 MHz, MeOD) δ 7.85 (d, J = 8.8 Hz, 1H), 7.67 (t, J = 7.2 Hz, 1H), 7.58 (dd, J = 10.4, 4.0 Hz, 1H), 7.32 (t, J = 8.0 Hz, 1H), 7.03 (d, J = 8.8 Hz, 1H), 5.91 (s, 1H), 4.41 (d, J = 13.4 Hz, 1H), 3.96 (d, J = 5.2 Hz, 1H), 3.54-3.35 (m, 3H), 3.31-3.30 (m, 2H), 2.44- 2.07 (m, 10H), 1.57 (s, 3H). MS: 486 (M + H).sup.+ 11. [00132] embedded image (2R,4R)-1-(3-chloro-2- fluorobenzyl)-4-((3- chloro-6-((5-methyl-1H- pyrazol-3-yl)amino)- pyridin-2-yl)methyl)-2- methylpiperidine-4- carboxylic acid .sup.1H NMR (400 MHz, MeOD) δ = 7.76 (d, J = 8.8 Hz, 1H), 7.70 (t, J = 7.2 Hz, 1H), 7.57 (t, J = 7.2 Hz, 1H), 7.35 (t, J = 8.0 Hz, 1H), 6.88 (d, J = 8.8 Hz, 1H), 6.02 (s, 1H), 4.39 (d, J = 13.2 Hz, 1H), 3.90 (s, 1H), 3.59-3.37 (m, 4H), 2.40 (s, 3H), 2.35-2.04 (m, 4H), 1.60 (d, J = 6.0, 3H), 1.43-1.35 (m, 1H). MS: 506 (M + H).sup.+ 12. [00133] embedded image (2R,4R)-1-(2,6-difluoro benzyl)-4-((3-fluoro-6- ((5-methyl-1H-pyrazol-3- yl)amino)pyridin-2-yl)- methyl)-2-methylpiperi- dine-4-carboxylic acid .sup.1H NMR (400 MHz, MeOD) δ 7.57-7.35 (m, 1H), 7.25 (t, J = 8.4 Hz, 1H), 7.01 (t, J = 8.1 Hz, 2H), 6.66 (d, J = 8.5 Hz, 1H), 5.69 (s, 1H), 4.40 (d, J = 13.5 Hz, 1H), 3.91 (d, J = 13.3 Hz, 1H), 3.28 (d, J = 30.3 Hz, 1H), 3.20-2.86 (m, 4H), 2.12 (s, 3H), 1.86 (dd, J = 31.0, 19.9 Hz, 4H), 1.30 (t, J = 19.4 Hz, 3H). MS: 474 (M + H).sup.+ 13. [00134] embedded image (2R,4R)-1-(2,6-dimethyl- benzyl)-4-((3-fluoro-6- ((5-methyl-1H-pyrazol-3- yl)amino)pyridin-2-yl)- methyl)-2-methylpiperi- dine-4-carboxylic acid 1H NMR (400 MHz, MeOD) δ 7.49 (t, J = 8.9 Hz, 1H), 7.41- 7.28 (m, 1H), 7.22 (d, J = 7.5 Hz, 2H), 6.85 (d, J = 8.9 Hz, 1H), 5.91 (s, 1H), 4.42 (d, J = 13.7 Hz, 1H), 4.02 (s, 1H), 3.45 (s, 2H), 3.30 (s, 3H), 2.52 (s, 6H), 2.32 (s, 3H), 2.29-1.99 (m, 4H), 1.65 (d, J = 5.8 Hz, 3H). MS: 466 (M + H).sup.+ 14. [00135] embedded image (2R,4R)-1-(2,3-dichloro- benzyl)-4-((3-fluoro-6- ((5-methyl-1H-pyrazol-3- yl)amino)pyridin-2-yl)- methyl)-2-methylpiperi- dine-4-carboxylic acid .sup.1H NMR (400 MHz, MeOD) δ 7.61 (s, 2H), 7.40 (d, J = 6.9 Hz, 2H), 6.80 (s, 1H), 5.80 (s, 1H), 4.59 (d, J = 12.5 Hz, 1H), 4.05 (s, 1H), 3.66-3.38 (m, 2H), 3.08 (d, J = 45.2 Hz, 3H), 2.18 (d, J = 32.8 Hz, 3H), 1.99 (d, J = 58.4 Hz, 4H), 1.37 (d, J = 35.4 Hz, 3H).MS: 506 (M + H).sup.+ 15. [00136] embedded image (2R,4R)-1-(2,3-difluoro- benzyl)-4-((3-fluoro-6- ((5-methyl-1H-pyrazol-3- yl)amino)pyridin-2-yl)- methyl)-2-methylpiperi- dine-4-carboxylic acid .sup.1H NMR (400 MHz, MeOD) δ 7.35-7.17 (m, 3H), 7.14 (s, 1H), 6.65 (d, J = 9.0 Hz, 1H), 5.69 (s, 1H), 4.36 (d, J = 13.5 Hz, 1H), 3.82 (d, J = 13.2 Hz, 1H), 3.22 (s, 1H), 3.18-3.06 (m, 2H), 2.97 (s, 1H), 2.83 (t, J = 11.2 Hz, 1H), 2.12 (s, 3H), 1.89 (dd, J = 35.3, 16.3 Hz, 4H), 1.29 (d, J = 5.5 Hz, 3H). MS: 474 (M + H).sup.+ 16. [00137] embedded image (2R,4R)-1-(2-fluoro-3- methylbenzyl)-4-((3- fluoro-6-((5-methyl-1H- pyrazol-3-yl)amino)- pyridin-2-yl)methyl)-2- methylpiperidine-4- carboxylic acid .sup.1H NMR (400 MHz, MeOD) δ 7.37 (d, J = 6.8 Hz, 3H), 7.17 (t, J = 7.2 Hz, 1H), 6.79 (d, J = 7.7 Hz, 1H), 5.82 (s, 1H), 4.58 (d, J = 12.8 Hz, 1H), 4.09 (d, J = 13.5 Hz, 1H), 3.60 (s, 1H), 3.30-3.10 (m, 4H), 2.34 (s, 3H), 2.24 (s, 3H), 2.09 (dd, J = 39.6, 20.0 Hz, 4H), 1.49 (d, J = 5.7 Hz, 3H). MS: 470 (M + H).sup.+ 17. [00138] embedded image (2R,4R)-1-(2,6-dichloro- benzyl)-4-((3-fluoro-6- ((5-methyl-1H-pyrazol-3- yl)amino)pyridin-2-yl)- methyl)-2-methylpiperi- dine-4-carboxylic acid 1H NMR (400 MHz, MeOD) δ 7.51 (d, J = 8.0 Hz, 2H), 7.42 (dd, J = 17.7, 9.9 Hz, 2H), 6.78 (d, J = 7.3 Hz, 1H), 5.85 (d, J = 34.4 Hz, 1H), 4.63 (d, J = 13.1 Hz, 1H), 4.19 (d, J = 13.0 Hz, 1H), 3.47 (s, 1H), 3.29 (s, 2H), 3.07 (s, 2H), 2.23 (s, 3H), 2.05 (s, 3H), 1.87 (d, J = 13.8 Hz, 1H), 1.49 (t, J = 12.1 Hz, 3H). MS: 506 (M + H).sup.+ 18. [00139] embedded image (2R,4R)-1-(3-chloro-4- fluorobenzyl)-4-((3-fluoro- 6-((5-methyl-1H-pyrazol- 3-yl)amino)pyridin-2- yl)methyl)-2-methyl- piperidine-4-carboxylic acid .sup.1H NMR (400 MHz, MeOD) δ 7.64 (d, J = 6.3 Hz, 1H), 7.44 (s, 1H), 7.32 (dd, J = 17.4, 8.6 Hz, 2H), 6.78 (d, J = 8.1 Hz, 1H), 5.80 (s, 1H), 4.48 (d, J = 13.3 Hz, 1H), 3.85 (d, J = 12.2 Hz, 1H), 3.46-3.35 (m, 1H), 3.24 (t, J = 13.1 Hz, 2H), 3.07 (s, 1H), 2.96 (s, 1H), 2.23 (s, 3H), 2.01 (d, J = 46.3 Hz, 4H), 1.41 (d, J = 5.1 Hz, 3H). MS: 490 (M + H).sup.+ 19. [00140] embedded image (2R,4R)-1-(4-chloro-3- fluorobenzyl)-4-((3-fluoro- 6-((5-methyl-1H-pyrazol- 3-yl)amino)pyridin-2- yl)methyl)-2-methyl- piperidine-4-carboxylic acid .sup.1H NMR (400 MHz, MeOD) δ 7.83 (s, 1H), 7.75 (t, J = 7.1 Hz, 2H), 7.65 (t, J = 7.4 Hz, 1H), 7.36 (s, 1H), 6.77 (d, J = 8.1 Hz, 1H), 5.80 (s, 1H), 4.59 (d, J = 13.1 Hz, 1H), 3.95 (d, J = 12.7 Hz, 1H), 3.39 (d, J = 22.0 Hz, 1H), 3.25 (t, J = 14.0 Hz, 2H), 3.01 (d, J = 27.8 Hz, 2H), 2.22 (s, 3H), 2.00 (d, J = 53.4 Hz, 4H), 1.51-1.35 (m, 3H). MS: 490 (M + H).sup.+ 20. [00141] embedded image (2R,4R)-1-(3,5-dichloro- benzyl)-4-((3-fluoro-6- ((5-methyl-1H-pyrazol-3- yl)amino)pyridin-2-yl)- methyl)-2-methylpiperi- dine-4-carboxylic acid .sup.1H NMR (400 MHz, MeOD) δ 7.47 (d, J = 5.6 Hz, 3H), 7.42- 7.22 (m, 1H), 6.83-6.70 (m, 1H), 5.80 (s, 1H), 4.40 (d, J = 13.5 Hz, 1H), 3.69 (d, J = 13.3 Hz, 1H), 3.30-3.14 (m, 3H), 2.96 (s, 1H), 2.85 (t, J = 11.0 Hz, 1H), 2.24 (s, 3H), 1.95 (dd, J = 39.8, 15.4 Hz, 4H), 1.33 (t, J = 8.2 Hz, 3H). MS: 506 (M + H).sup.+ 21. [00142] embedded image (2R,4R)-4-((3-fluoro-6- ((5-methyl-1H-pyrazol-3- yl)amino)pyridin-2-yl)- methyl)-2-methyl-1-(3- (trifluoromethyl)benzyl)- piperidine-4-carboxylic acid .sup.1H NMR (400 MHz, MeOD) δ 7.83 (s, 1H), 7.75 (t, J = 7.1 Hz, 2H), 7.65 (t, J = 7.4 Hz, 1H), 7.36 (s, 1H), 6.77 (d, J = 8.1 Hz, 1H), 5.80 (s, 1H), 4.59 (d, J = 13.1 Hz, 1H), 3.95 (d, J = 12.7 Hz, 1H), 3.39 (d, J = 22.0 Hz, 1H), 3.25 (t, J = 14.0 Hz, 2H), 3.01 (d, J = 27.8 Hz, 2H), 2.22 (s, 3H), 2.00 (d, J = 53.4 Hz, 4H), 1.51-1.35 (m, 3H). MS: 506 (M + H).sup.+ 22. [00143] embedded image (2R,4R)-1-(3,4-dichloro- 5-fluorobenzyl)-4-((3- fluoro-6-((5-methyl-1H- pyrazol-3-yl)amino)- pyridin-2-yl)methyl)-2- methylpiperidine-4- carboxylic acid .sup.1H NMR (400 MHz, MeOD) δ 7.53 (s, 1H), 7.39 (s, 2H), 6.78 (s, 1H), 5.79 (s, 1H), 4.37 (s, 1H), 3.69 (s, 1H), 3.21 (d, J = 51.7 Hz, 3H), 2.84 (s, 2H), 2.23 (s, 3H), 2.02 (s, 4H), 1.33 (s, 3H). MS: 524 (M + H).sup.+ 23. [00144] embedded image (2R,4R)-1-(3,5-dichloro- 4-fluorobenzyl)-4-((3- fluoro-6-((5-methyl-1H- pyrazol-3-yl)amino)- pyridin-2-yl)methyl)-2- methylpiperidine-4- carboxylic acid .sup.1H NMR (400 MHz, MeOD) δ 7.58 (s, 2H), 7.40 (s, 1H), 6.77 (s, 1H), 5.79 (s, 1H), 4.39 (s, 1H), 3.81-3.62 (m, 1H), 3.15 (s, 3H), 2.86 (s, 2H), 2.23 (s, 3H), 2.04 (s, 4H), 1.31 (s, 3H). MS: 524 (M + H).sup.+ 24. [00145] embedded image (2R,4R)-1-(3,5-difluoro benzyl)-4-((3-fluoro-6- ((5-methyl-1H-pyrazol-3- yl)amino)pyridin-2-yl)- methyl)-2-methylpiperi- dine-4-carboxylic acid .sup.1H NMR (400 MHz, MeOD) δ 7.36 (s, 1H), 7.12 (d, J = 5.7 Hz, 2H), 7.00 (s, 1H), 6.77 (d, J = 7.7 Hz, 1H), 5.79 (s, 1H), 4.44 (d, J = 13.3 Hz, 1H), 3.78 (d, J = 13.3 Hz, 1H), 3.35 (d, J = 11.6 Hz, 1H), 3.23 (d, J = 11.2 Hz, 2H), 3.01 (s, 1H), 2.89 (s, 1H), 2.23 (s, 3H), 1.98 (d, J = 43.1 Hz, 4H), 1.36 (d, J = 4.4 Hz, 3H). MS: 474 (M + H).sup.+ 25. [00146] embedded image (2R,4R)-1-(3-chloro-2- fluorobenzyl)-2-methyl-4- ((3-methyl-6-((5-methyl- 1H-pyrazol-3-yl)amino)- pyrazin-2-yl)methyl)- piperidine-4-carboxylic acid .sup.1H NMR (400 MHz, MeOD) δ 8.05 (s, 1H), 7.48 (dt, J = 14.3, 6.7 Hz, 2H), 7.22 (t, J = 7.8 Hz, 1H), 5.92 (s, 1H), 3.15 (m, 4H), 2.82 (s, 2H), 2.42 (s, 3H), 2.24 (s, 3H), 2.14 (d, J = 15.1 Hz, 1H), 2.03 (d, J = 14.8 Hz, 2H), 1.91 (m, 2H), 1.34 (d, J = 6.2 Hz, 3H). MS: 487 (M + H).sup.+ 26. [00147] embedded image (2R,4R)-1-(3-chloro-2- fluorobenzyl)-4-((5-fluoro- 2-((5-methyl-1H-pyrazol- 3-yl)amino)pyrimidin- 4-yl)methyl)-2-methyl- piperidine-4-carboxylic acid MS: 491 (M + H).sup.+ 27. [00148] (2R,4R)-1-(3-chloro-2,4- difluorobenzyl)-4-((3- fluoro-6-((5-methyl-1H- pyrazol-3-yl)amino)- pyridin-2-yl)methyl)-2- methylpiperidine-4- carboxylic acid .sup.1H NMR (400 MHz, MeOD) δ 7.50 (dd, J = 14.5, 7.9 Hz, 1H), 7.35 (s, 1H), 7.18 (t, J = 8.5 Hz, 1H), 6.75 (d, J = 7.6 Hz, 1H), 5.77 (s, 1H), 4.38 (d, J = 13.8 Hz, 1H), 3.81 (d, J = 13.6 Hz, 1H), 3.23 (s, 3H), 3.01 (s, 1H), 2.84 (t, J = 11.3 Hz, 1H), 2.21 (s, 3H), 2.10-1.77 (m, 4H), 1.35 (d, J = 5.8 Hz, 3H). MS: 508 (M + H).sup.+ 28. [00149] embedded image (2S,4S)-1-(3-chloro-2- fluorobenzyl)-2-ethyl-4- ((3-fluoro-6-((5-methyl- 1H-pyrazol-3-yl)amino)- pyridin-2-yl)methyl)- piperidine-4-carboxylic acid .sup.1H NMR (400 MHz, MeOD) δ 7.38 (ddt, J = 60.4, 51.4, 7.7 Hz, 4H), 6.75 (d, J = 6.5 Hz, 1H), 5.77 (s, 1H), 4.37 (d, J = 13.8 Hz, 1H), 3.84 (d, J = 13.7 Hz, 1H), 3.26-3.14 (m, 2H), 3.04 (s, 2H), 2.88 (t, J = 11.5 Hz, 1H), 2.21 (s, 3H), 2.11- 1.78 (m, 5H), 1.72-1.48 (m, 1H), 1.04-0.81 (m, 3H). MS: 504 (M + H).sup.+ 29. [00150] embedded image (2R,4R)-1-(3-chloro-2- fluorobenzyl)-2-methyl- 4-((6-((5-methyl-1H- pyrazol-3-yl)amino)- pyridin-2-yl)methyl)- piperidine-4-carboxylic acid .sup.1H NMR (400 MHz, MeOD) δ 7.86 (t, J = 7.6 Hz, 1H), 7.68- 7.53 (m, 2H), 7.24 (t, J = 7.2 Hz, 1H), 7.02 (d, J = 8.8 Hz, 1H), 6.96 (d, J = 5.6 Hz, 1H), 5.85 (s, 1H), 4.90-4.78 (m, 2H), 4.38 (d, J = 12.8 Hz, 1H), 3.99-3.87 (m, 1H), 3.51-3.40 (m, 2H), 3.29 (d, J = 11.6 Hz, 1H), 2.27 (s, 3H), 2.18-1.99 (m, 3H), 1.56 (s, 3H), 1.25- 1.16 (m, 1H). MS: 472 (M + H).sup.+ 30. [00151] embedded image (2R,4R)-1-(3-chloro-2- fluorobenzyl)-4-((4- fluoro-6-((5-methyl-1H- pyrazol-3-yl)amino)- pyridin-2-yl)methyl)-2- methylpiperidine-4- carboxylic acid .sup.1H NMR (400 MHz, MeOD) δ 7.74-7.65 (m, 2H), 7.35 (t, J = 7.6 Hz, 1H), 6.90 (d, J = 9.6 Hz, 1H), 6.72 (d, J = 9.2 Hz, 1H), 6.03 (s, 1H), 4.46 (d, J = 12.4 Hz, 1H), 4.08-3.96 (m, 1H), 3.61-3.46 (m, 3H), 3.42- 3.36 (m, 1H), 2.41 (s, 3H), 2.28-1.99 (m, 4H), 1.61 (s, 3H), 1.35-1.26 (m, 1H). MS: 409 (M + H).sup.+ 31. [00152] embedded image (2R,4R)-1-(3-chloro-2- fluorobenzyl)-2-methyl-4- ((4-methyl-6-((5-methyl- 1H-pyrazol-3-yl)amino)- pyrimidin-2-yl)methyl)- piperidine-4-carboxylic acid MS: 409 (M + H).sup.+ 32. [00153] (2R,4R)-1-(3-chloro-2- fluorobenzyl)-4-((3,5- dimethyl-6-((5-methyl- 1H-pyrazol-3-yl)amino)- pyrazin-2-yl)methyl)-2- methylpiperidine-4- carboxylic acid .sup.1H NMR (400 MHz, MeOD) δ 7.75-7.64 (m, 2H), 7.35 (t, 1H), 6.48 (s, 1H), 4.52 (d, J = 13.3 Hz, 1H), 4.13 (s, 1H), 3.79 (d, J = 16.2 Hz, 1H), 3.72-3.48 (m, 2H), 3.41 (m, 2H), 2.79 (s, 3H), 2.73 (s, 3H), 2.50 (s, 3H), 2.40-2.17 (m, 4H), 1.57 (d, J = 5.6 Hz, 3H). MS: 501(M + H).sup.+ 33. [00154] embedded image (2R,4R)-1-(3-chloro-2- fluorobenzyl)-2-methyl-4- ((5-methyl-6-((5-methyl- 1H-pyrazol-3-yl)amino)- pyrazin-2-yl)methyl)- piperidine-4-carboxylic acid 1H NMR (400 MHz, DMSO) δ 7.76 (t, J = 7.4 Hz, 1H), 7.64- 7.57 (m, 2H), 7.37 (t, J = 7.8 Hz, 1H),, 6.33 (s, 1H), 4.85 (d, J = 12.6 Hz, 1H), 4.33 (d, J = 13.5 Hz, 2H), 3.89 (s, 1H), 3.44-3.40 (s, 1H), 3.08-3.10 (dd, J = 31.8, 13.6 Hz, 2H), 2.42 (s, 3H), 2.23 (s, 3H), 2.09-2.08 (d, J = 14.8 Hz, 1H), 1.99 (t, J = 7.3 Hz, 1H), 1.87- 1.85 (t, J = 13.2 Hz, 2H), 1.42 (d, J = 6.0 Hz, 3H), 1.27 (d, J = 22.2 Hz, 1H). MS: 487(M + H).sup.+ 34. [00155] embedded image (2R,4R)-4-((3-fluoro-6- ((5-methyl-1H-pyrazol-3- yl)amino)pyridin-2-yl)- methyl)-2-methyl-1-(2- (trifluoromethyl)benzyl)- piperidine-4-carboxylic acid .sup.1H NMR (400 MHz, DMSO) δ 9.15 (s, 1H), 8.97 (s, 1H), 7.79 (d, J = 64.3 Hz, 4H), 7.43 (t, J = 9.0 Hz, 1H), 6.96 (s, 1H), 6.11 (s, 1H), 4.06 (s, 2H), 3.38-3.33 (m, 1H), 3.22 (s, 2H), 3.04-3.15 (m, 2H), 2.34- 2.20 (m, 2H), 2.14 (s, 3H), 1.96 (d, J = 14.0 Hz, 2H), 1.44 (s, 3H). MS: 506(M + H).sup.+ 35. [00156] embedded image (2R,4R)-1-(3-chloro-2- fluorobenzyl)-4-((3- fluoro-5-methyl-6-((3- methyl-1H-pyrazol-5-yl)- amino)pyridin-2-yl)meth- yl)-2-methylpiperidine-4- carboxylic acid .sup.1H NMR (400 MHz, MeOD) δ 7.71-7.65 (m, 2H), 7.58 (d, J = 9.6 Hz, 1H), 7.36 (t, J = 7.8 Hz, 1H), 6.20 (s, 1H), 4.45 (d, J = 13.2 Hz, 1H), 4.02-3.93 (m, 1H), 3.58-3.35 (m, 4H), 3.32-3.25 (m, 2H), 2.44 (s, 3H), 2.38 (s, 3H), 2.26-2.11 (m, 2H), 2.11-2.01 (m, 1H), 1.63 (s, 3H). MS: 504(M + H).sup.+ 36. [00157] embedded image (2R,4R)-1-(3-chloro-2- fluorobenzyl)-4-(2,6- difluoro-3-((5-methyl- 1H-pyrazol-3-yl)amino)- benzyl)-2-methylpiperi- dine-4-carboxylic acid 1H NMR (400 MHz, DMSO) δ 7.94 (d, J = 8.6 Hz, 2H), 7.76 (dd, J = 15.3, 7.6 Hz, 1H), 7.59 (t, J = 7.0 Hz, 1H), 7.44-7.25 (m, 1H), 6.90 (t, J = 9.3 Hz, 1H), 4.82 (d, J = 13.2 Hz, 1H), 4.38 (dd, J = 23.0, 12.8 Hz, 2H), 3.85 (s, 1H), 3.41 (s, 1H), 3.21 (d, J = 12.3 Hz, 1H), 3.15 (s, 1H), 2.92 (d, J = 20.5 Hz, 1H), 2.17 (s, 3H), 2.10-2.07(m, 1H) 1.92-1.82 (m, 2H), 1.51 (d, J = 6.0 Hz, 3H), 1.33 (d, J = 6.4 Hz, 1H). MS: 507(M + H).sup.+

Example 37

(2R,4R)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)methyl)-2-methyl-1-(2-(trifluoromethyl)benzoyl)piperidine-4-carboxylic acid

Step 1: methyl (2R,4R)-4-((6-bromo-3 fluoropyridin-2 yl)methyl)-2-methylpiperidine-4-carboxylate trifluoroacetate

[0416] ##STR00158##

[0417] To a solution of INT C5 (310 mg, 0.898 mmol) in DCM (4 ml) was added trifluoroacetic acid (2 mL). The resulting solution was stirred for 1 h at room temperature. The resulting solution was removed under reduced pressure to afford methyl-(2R,4R)-4-((6-bromo-3-fluoropyridin-2-yl) methyl)-2-methyl-1-(2-(trifluoromethyl)benzoyl)piperidine-4-carboxylate hydrochloride (310 mg) as a yellow oil. LCMS (ESI, m/z): 517 [M+H].sup.+.

Step 2: methyl-(2R,4R)-4-((6-bromo-3 fluoropyridin-2-yl)methyl)-2-methyl-1-(2-(trifluoromethyl)benzoyl)piperidine-4-carboxylate

[0418] ##STR00159##

[0419] To a solution of methyl (2R,4R)-4-((6-bromo-3-fluoropyridin-2-yl)methyl)-2-methyl piperidine-4-carboxylate trifluoroacetat (310 mg, 0.898 mmol) in DMF (10 ml) was added 2-(trifluoromethyl)benzoic acid (255 mg, 1.341 mmol), DIEA (698 mg, 6.911 mmol) and HATU (689 mg, 1.812 mmol). The resulting solution was stirred for 3 h at room temperature. The resulting mixture was filtrated. The filtrate was removed under reduced pressure. The resulting residue was purified by C18 reversed phase column chromatography eluting with H.sub.2O/ACN to afford methyl-(2R,4R)-4-((6-bromo-3-fluoropyridin-2-yl)methyl)-2-methyl-1-(2-(trifluoromethyl) benzoyl)piperidine-4-carboxylate (451 mg, Y=97%) as a yellow oil. LCMS (ESI, m/z): 517 [M+H].sup.+.

Step 3: methyl-(2R,4R)-4-((6-((1-(tert-butoxycarbonyl)-5-methyl-1H-pyrazol-3-yl)amino)-3-fluoropyridin-2-yl)methyl)-2-methyl-1-(2-(trifluoromethyl)benzoyl)piperidine-4-carboxylate

[0420] ##STR00160##

[0421] Following the procedure analogous to that described in Step 3 for the synthesis of Example 1, methyl 1-(2R,4R)-4-((6-bromo-3-fluoropyridin-2-yl)methyl)-2-methyl-1-(2-(trifluoromethyl) benzoyl)piperidine-4-carboxylate (451 mg, 0.872 mmol) was converted to the title compound (450 mg) as a yellow oil. LCMS (ESI, m/z): 634 [M+H].sup.+.

Step 4: methyl-(2R,4R)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl) methyl)-2-methyl-1-(2-(trifluoromethyl)benzoyl)piperidine-4-carboxylate

[0422] ##STR00161##

[0423] Following the procedure analogous to that described in Step 4 for the synthesis of Example 1, methyl-(2R,4R)-4-((6-((1-(tert-butoxycarbonyl)-5-methyl-1H-pyrazol-3-yl)amino)-3-fluoropyridin-2-yl)methyl)-2-methyl-1-(2-(trifluoromethyl)-benzoyl)piperidine-4-carboxylate (450 mg, 0.699 mmol) was converted to the title compound (391 mg) as a yellow oil. LCMS (ESI, m/z): 534 [M+H].sup.+.

Step 5: (2R,4R)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)methyl)-2-methyl-1-(2-(trifluoromethyl)benzoyl)piperidine-4-carboxylic acid

[0424] ##STR00162##

[0425] Following the procedure analogous to that described in Step 5 for the synthesis of Example 1, methyl-(2R,4R)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)-pyridin-2-yl)methyl)-2-methyl-1-(2-(trifluoromethyl)benzoyl)piperidine-4-carboxylate (191 mg, 0.367 mmol) was converted to the title compound 11 mg as a white solid. LCMS (ESI, m/z): 520 [M+H].sup.+. .sup.1H NMR (400 MHz, MeOD) δ 7.89-7.26 (m, 5H), 6.89 (dd, J=15.6, 6.3 Hz, 1H), 6.07-5.91 (m, 1H), 3.75-3.34 (m, 2H), 3.25-2.94 (m, 3H), 2.57-2.26 (m, 4H), 2.16-1.77 (m, 2H), 1.52 (dd, J=27.1, 13.7 Hz, 1H), 1.24 (ddd, J=31.3, 22.2, 7.1 Hz, 3H).

[0426] The following examples in Table 2 were synthesized using the above procedure with the corresponding starting materials and intermediates.

TABLE-US-00008 TABLE 2 Example No. Structure Chemical Name .sup.1HNMR & MS: (M + H).sup.+ 38 [00163] embedded image (2R,4R)-1-(2-(3-chloro-2- fluorophenyl)acetyl)-4-((3- fluoro-6-((5-methyl-1H- pyrazol-3-yl)amino)pyridin- 2-yl)methyl)-2-methylpiperidine- 4-carboxylic acid .sup.1H NMR (400 MHz, MeOD) δ 7.25 (t, J = 7.6 Hz, 2H), 7.07 (s, 1H), 6.99 (t, J = 7.7 Hz, 1H), 6.67 (s, 1H), 5.65 (s, 1H), 4.25 (s, 1H), 3.66 (dd, J = 34.5, 19.0 Hz, 4H), 2.86 (dd, J = 25.6, 8.9 Hz, 2H), 2.71 (s, 3H), 2.06 (dd, J = 34.9, 27.2 Hz, 4H), 1.19 (s, 3H). MS: 518 (M + H).sup.+

Example 39

(2R,4R)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)methyl)-2-methyl-1-(2-(trifluoromethyl)benzoyl)piperidine-4-carboxylic acid

Step 1: methyl (2R,4R)-4-((6-bromo-3-fluoropyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylate trifluoroacetate

[0427] ##STR00164##

[0428] Following the procedure analogous to that described in Step 1 for the synthesis of Example 37, INT C5 (1.54 g, 3.458 mmol) was converted to the title compound (1.33 g) as a yellow oil. LCMS (ESI, m/z): 345, 347 [M+H].sup.+.

Step 2: methyl (2R,4R)-4-((6-bromo-3-fluoropyridin-2-yl)methyl)-2-methyl-1-((2-(trifluoromethyl)phenyl)sulfonyl)piperidine-4-carboxylate

[0429] ##STR00165##

[0430] To a solution of methyl (2R,4R)-4-((6-bromo-3-fluoropyridin-2-yl)methyl)-2-methyl piperidine-4-carboxylate trifluoroacetate (1.33 g, 3.853 mmol) and K.sub.2CO.sub.3 (1.62 g, 11.721 mmol) in THF (15 ml) was added 2-(trifluoromethyl)benzenesulfonyl chloride (1.42 g, 5.805 mmol). The resulting solution was stirred for 3 h at 60° C. The resulting mixture was filtrated and the filtrate was removed under reduced pressure. The resulting residue was purified by C18 reversed phase column chromatography eluting with H.sub.2O/ACN to afford methyl (2R,4R)-4-((6-bromo-3-fluoropyridin-2-yl)methyl)-2-methyl-1-((2-(trifluoro-methyl)phenyl) sulfonyl)piperidine-4-carboxylate (1.07 g) as a yellow oil. LCMS (ESI, m/z): 553,555 [M+H].sup.+.

Step 3: methyl (2R,4R)-4-((6-((1-(tert-butoxycarbonyl)-5-methyl-1H-pyrazol-3-yl)amino)-3-fluoropyridin-2-yl)methyl)-2-methyl-1-((2-(trifluoromethyl)phenyl)sulfonyl)piperidine-4-carboxylate

[0431] ##STR00166##

[0432] Following the procedure analogous to that described in Step 3 for the synthesis of Example 1, methyl (2R,4R)-4-((6-bromo-3-fluoropyridin-2-yl)methyl)-2-methyl-1-((2-(trifluoromethyl) phenyl)sulfonyl)piperidine-4-carboxylate (1.07 g, 1.927 mmol) was converted to the title compound (2.56 g) as a yellow oil. LCMS (ESI, m/z): 670 [M+H].sup.+.

Step 4: methyl (2R,4R)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)methyl)-2-methyl-1-((2-(trifluoromethyl)phenyl)sulfonyl)piperidine-4-carboxylate

[0433] ##STR00167##

[0434] Following the procedure analogous to that described in Step 4 for the synthesis of Example 1, methyl(2R,4R)-4-((6-((1-(tert-butoxycarbonyl)-5-methyl-1H-pyrazol-3-yl)amino)-3-fluoro pyridin-2-yl)methyl)-2-methyl-1-((2-(trifluoromethyl)phenyl)sulfonyl)piperidine-4-carboxylate (2.51 g, 3.746 mmol) was converted to the title compound (812 mg) as a yellow oil. LCMS (ESI, m/z): 570 [M+H].sup.+.

Step 5: (2R,4R)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl) methyl)-2-methyl-1-((2-(trifluoromethyl)phenyl)sulfonyl)piperidine-4-carboxylic acid

[0435] ##STR00168##

[0436] Following the procedure analogous to that described in Step 5 for the synthesis of Example 1, methyl (2R,4R)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)-pyridin-2-yl)methyl)-2-methyl-1-((2-(trifluoromethyl)phenyl)sulfonyl)piperidine-4-carboxylate (812 mg, 1.425 mmol) was converted to the title compound 215 mg as a white solid. LCMS (ESI, m/z): 556 [M+H].sup.+. .sup.1H NMR (400 MHz, MeOD) δ 8.22 (dd, J=5.6, 3.6 Hz, 1H), 7.95 (dd, J=5.6, 3.6 Hz, 1H), 7.85-7.77 (m, 2H), 7.59 (t, J=8.9 Hz, 1H), 6.88 (dd, J=9.0, 3.1 Hz, 1H), 6.01 (d, J=0.4 Hz, 1H), 4.35-4.20 (m, 1H), 3.69-3.58 (m, 1H), 3.47-3.35 (m, 1H), 3.15 (dd, J=13.7, 2.8 Hz, 1H), 2.99 (dd, J=13.7, 2.4 Hz, 1H), 2.41 (s, 3H), 2.37 (s, 1H), 2.21-2.10 (m, 1H), 1.90 (dd, J=13.9, 5.7 Hz, 1H), 1.54-1.41 (m, 1H), 1.14 (d, J=7.2 Hz, 3H).

Example 40 & Example 41

(2R,4R)-1-((S)-1-(3-chloro-2-fluorophenyl)ethyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid

[0437] ##STR00169##

Step 1: 1-(3-chloro-2-fluorophenyl)ethan-1-ol

[0438] ##STR00170##

[0439] To a solution of 1-(3-chloro-2-fluorophenyl)ethan-1-one (2.69 g, 15.587 mmol) in methanol (20 mL) was added sodium borohydride (1.24 g, 32.778 mmol) at 0° C. The resulting solution was stirred at 0° C. for 1 h before it is quenched with 1 N HCl aqueous solution (50 mL). The resulting solution was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was applied onto a silica gel column eluting with EtOAc/hexane (0˜20%) to afford 2.57 g of the title compound as a yellow oil.

Step 2: 1-(1-bromoethyl)-3-chloro-2-fluorobenzene

[0440] ##STR00171##

[0441] A solution of 1-(3-chloro-2-fluorophenyl)ethan-1-ol (2.57 g, 14.719 mmol), phosphorus tribromide (4.03 g, 14.888 mmol) and 4-dimethylaminopyridine (120 mg, 0.982 mmol) in DCM (20 mL) was stirred for 1 h at room temperature. The resulting solution was concentrated under reduced pressure. The resulting residue was applied onto a silica gel column eluting with EtOAc/hexane (0˜10%) to afford 2.12 g of the title compound as colorless oil.

Step 3: methyl (2R,4R)-4-((6-bromo-3-fluoropyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylate hydrochloride

[0442] ##STR00172##

[0443] Following the procedure analogous to that described in Step 1 for the synthesis of Example 37, INT C5 (2.10 g, 4.719 mmol) was converted to the title compound (1.75 g) as a yellow oil. LCMS (ESI, m/z): 345, 347 [M+H].sup.+.

Step 4: methyl-(2R,4R)-4-((6-bromo-3-fluoropyridin-2-yl)methyl)-1-(-1-(3-chloro-2-fluo-rophenyl)ethyl)-2-methylpiperidine-4-carboxylate

[0444] ##STR00173##

[0445] Following the procedure analogous to that described in Step 1 for the synthesis of Example 1, methyl (2R,4R)-4-((6-bromo-3-fluoropyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylate (1.03 g, 2.984 mmol) was converted to the title compound (756 mg, Y=51%) as a yellow oil. LCMS (ESI, m/z): 501, 503 [M+1].sup.+.

Step 5: methyl-(2R,4R)-4-((6-((1-(tert-butoxycarbonyl)-5-methyl-1H-pyrazol-3-yl)amino)-3-fluoropyridin-2-yl)methyl)-1-(-1-(3-chloro-2-fluorophenyl)ethyl)-2-methylpiperidine-4-carboxylate

[0446] ##STR00174##

[0447] Following the procedure analogous to that described in Step 3 for the synthesis of Example 1, methyl-(2R,4R)-4-((6-bromo-3-fluoropyridin-2-yl)methyl)-1-(-1-(3-chloro-2-fluorophenyl)ethyl)-2-methylpiperidine-4-carboxylate (756 mg, 1.509 mmol) was converted to the title compound (953 mg) as a yellow oil. LCMS (ESI, m/z): 618 [M+H].sup.+.

Step 6: methyl-(2R,4R)-1-(1-(3-chloro-2-fluorophenyl)ethyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylate

[0448] ##STR00175##

[0449] Following the procedure analogous to that described in Step 4 for the synthesis of Example 1, methyl-(2R,4R)-4-((6-((1-(tert-butoxycarbonyl)-5-methyl-1H-pyrazol-3-yl)amino)-3-fluoropyridin-2-yl)methyl)-1-(1-(3-chloro-2-fluorophenyl)ethyl)-2-methylpiperidine-4-carboxylate (953 mg, 1.542 mmol) was converted to the title compound (421 mg) as a yellow solid. LCMS (ESI, m/z): 518 [M+H].sup.+.

Step 7: (2R,4R)-1-(1-(3-chloro-2-fluorophenyl)ethyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid

[0450] ##STR00176##

[0451] Following the procedure analogous to that described in Step 5 for the synthesis of Example 1, methyl-(2R,4R)-1-(-1-(3-chloro-2-fluorophenyl)ethyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylate (421 mg, 0.813 mmol) was converted to the title compound 224 mg as a white solid. LCMS (ESI, m/z): 504 [M+H].sup.+.

[0452] (2R,4R)-1-(1-(3-chloro-2-fluorophenyl)ethyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl) amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid was further purified by Prep-HPLC, yielding Example 40 (121 mg) and Example 41 (87 mg) as white solids.

Example 40

[0453] LCMS (ESI, m/z): 504 [M+H].sup.+.

.SUP.1.H NMR (400 MHz, MeOD) δ 7.85-7.53 (m, 3H), 7.37 (t, J=8.0 Hz, 1H), 6.91 (dd, J=8.9, 2.8 H z, 1H), 6.03 (s, 1H), 3.92 (s, 1H), 3.64-3.42 (m, 2H), 3.40-3.33 (m, 3H), 2.40 (s, 3H), 2.19 (d, J=37.9 Hz, 4H), 1.80 (d, J=5.3 Hz, 3H), 1.59 (s, 3H).

Example 41

[0454] LCMS (ESI, m/z): 504 [M+H].sup.+.
.sup.1H NMR (400 MHz, MeOD) δ 7.70 (t, J=7.0 Hz, 2H), 7.57 (t, J=8.8 Hz, 1H), 7.39 (t, J=7.9 Hz, 1H), 6.88 (dd, J=8.9, 2.6 Hz, 1H), 6.01 (s, 1H), 5.46 (s, 1H), 3.67 (d, J=35.9 Hz, 1H), 3.50 (s, 1H), 3.14 (dd, J=20.5, 12.4 Hz, 2H), 2.90 (s, 1H), 2.40 (s, 3H), 2.26 (d, J=14.5 Hz, 2H), 2.11 (d, J=25.2 Hz, 1H), 1.81 (s, 3H), 1.61 (s, 1H), 1.45-1.11 (m, 3H).

Example 42

(2R,4R)-1-(3-chloro-2-fluorophenethyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid

Step 1: 2-(3-chloro-2-fluorophenyl)ethan-1-ol

[0455] ##STR00177##

[0456] To a solution of 2-(3-chloro-2-fluorophenyl)acetic acid (510 mg, 2.704 mmol) in THF (5 mL) was added borane-tetrahydrofuran complex (5.4 ml). The resulting solution was stirred at reflux for 3 h. Then the mixture was evaporated to remove solvent. The resulting residue was purified by silica gel chromatography eluting with EtOAc/hexane (0˜30%) to afford 2-(3-chloro-2-fluorophenyl)ethan-1-ol (466 mg) as an oil.

Step 2: 3-chloro-2-fluorophenethyl methanesulfonate

[0457] ##STR00178##

[0458] To a solution of 2-(3-chloro-2-fluorophenyl)ethan-1-ol (107 mg, 0.613 mmol) and triethylamine (183 mg, 1.808 mmol) in dichloromethane (4 ml) was added dropwise methanesulfonyl chloride (129 mg, 1.126 mmol) at 0˜5° C. The mixture was stirred for 2 h before it is quenched with water (10 mL). The resulting solution was extracted with DCM (3×30 mL). The organic layer was combined, dried over anhydrous sodium sulfate and concentrated under vacuum to give 3-chloro-2-fluorophenethyl methanesulfonate (164 mg, 0.649 mmol) as a yellow oil. The crude product was used in the next step without purification.

Step 3: tert-butyl (2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-3-fluoropyridin-2-yl)methyl)-1-(3-chloro-2-fluorophenethyl)-2-methylpiperidine-4-carboxylate

[0459] ##STR00179##

[0460] To a mixture of tert-butyl (2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-3-fluoropyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylate (97 mg, 0.211 mmol), potassium carbonate (138 mg, 0.999 mmol) in ACN (4 ml) was added 3-chloro-2-fluorophenethyl methanesulfonate (164 mg, 0.649 mmol). The reaction mixture was stirred at 80° C. for 15 h, then the solids were filtered out and the resulting solution was concentrated under vacuum. The resulting residue was applied onto a silica gel column eluting with EtOAc/hexane (0˜70%) to afford the title compound (17 mg, 0.130 mmol) as a yellow oil. LCMS (ESI, m/z): 616 [M+1].sup.+.

Step 4: (2R,4R)-1-(3-chloro-2-fluorophenethyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl) amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid

[0461] ##STR00180##

[0462] Following the procedure analogous to that described in step 5 of Example 5, tert-butyl (2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-3-fluoropyridin-2-yl)methyl)-1-(3-chloro-2-fluorophenethyl)-2-methylpiperidine-4-carboxylate (17 mg, 0.130 mmol) was converted to the title compound (12 mg) as a white solid. LCMS (ESI, m/z): 504 [M+H].sup.+. .sup.1H NMR (400 MHz, MeOD) δ 7.57 (t, J=9.0 Hz, 1H), 7.45 (t, J=7.5 Hz, 1H), 7.35 (s, 1H), 7.19 (t, J=7.8 Hz, 1H), 6.88 (dd, J=9.0, 3.1 Hz, 1H), 6.00 (d, J=9.7 Hz, 1H), 3.77 (s, 2H), 3.68-3.33 (m, 5H), 3.20-3.08 (m, 2H), 2.36 (s, 3H), 2.21 (d, J=11.9 Hz, 2H), 2.05 (s, 2H), 1.44 (s, 3H).

[0463] The following example in Table 3 was synthesized using the above procedure with the corresponding starting materials and intermediates.

TABLE-US-00009 TABLE 3 Example No. Structure Chemical Name .sup.1HNMR & MS: (M + H).sup.+ 43 [00181] embedded image (2R,4R)-1-(2,6-dichlorophenethyl)- 4-((3-fluoro-6-((5-methyl- 1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)-2-methyl piperidine-4-carboxylic acid .sup.1H NMR (400 MHz, MeOD) δ 7.61 (t, J = 9.0 Hz, 1H), 7.53- 7.43 (m, 2H), 7.32 (t, J = 8.0 Hz, 1H), 6.90 (dd, J = 9.0, 3.0 Hz, 1H), 6.02 (s, 1H), 3.84 (s, 1H), 3.68-3.35 (m, 6H), 2.38 (d, J = 3.8 Hz, 3H), 2.19 (t, J = 30.8 Hz, 4H), 1.50 (d, J = 13.7 Hz, 3H), −0.00 (s, 2H). MS: 520 (M + H).sup.+

Example 44

(2R,4R)-1-(2-(3-chloro-2-fluorophenyl)-2-oxoethyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl) amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid

Step 1: 2-bromo-1-(3-chloro-2-fluorophenyl)ethan-1-one

[0464] ##STR00182##

[0465] The mixture of 1-(3-chloro-2-fluorophenyl)ethan-1-one (1.004 g, 5.817 mmol), NBS (1.393 g, 7.827 mmol), potassium dihydrogen phosphate (0.282 g, 2.072 mmol) and ethanol (12 mL) was refluxed for 3 h. The reaction mixture was evaporated to remove solvent. The resulting residue was purified by C18 reversed phase column chromatography eluting with H.sub.2O/ACN to afford 2-bromo-1-(3-chloro-2-fluoro phenyl)ethan-1-one (297 mg, 1.181 mmol) as an brown oil. LCMS (ESI, m/z): 251,253 [M+1].sup.+.

Step 2: tert-butyl (2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-3-fluoropyridin-2-yl)methyl)-1-(2-(3-chloro-2-fluorophenyl)-2-oxoethyl)-2-methylpiperidine-4-carboxylate

[0466] ##STR00183##

[0467] To a solution of tert-butyl (2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-3-fluoropyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylate (156 mg, 0.339 mmol), 2-bromo-1-(3-chloro-2-fluorophenyl)ethan-1-one (109 mg, 0.433 mmol) in THF (8 ml) was added trimethylamine (362 mg, 3.577 mmol) at 0° C. The resulting solution was stirred at room temperature for overnight. The mixture was evaporated to remove solvent. The resulting residue was purified by silica gel column chromatography eluting with EtOAc/hexane (0˜30%) to give tert-butyl (2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-3-fluoropyridin-2-yl)methyl)-1-(2-(3-chloro-2-fluorophenyl)-2-oxoethyl)-2-methylpiperidine-4-carboxylate (68 mg, 0.107 mmol) as a yellow oil. LCMS (ESI, m/z): 630 [M+1].sup.+.

Step 3: (2R,4R)-1-(2-(3-chloro-2-fluorophenyl)-2-oxoethyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid

[0468] ##STR00184##

[0469] Following the procedure analogous to that described in step 5 of Example 5, tert-butyl (2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-3-fluoropyridin-2-yl)methyl)-1-(2-(3-chloro-2-fluorophenyl)-2-oxoethyl)-2-methylpiperidine-4-carboxylate (68 mg, 0.107 mmol) was converted to the title compound (34 mg) as a white solid. LCMS (ESI, m/z): 518 [M+1].sup.+. .sup.1H NMR (400 MHz, MeOD) δ 8.00 (ddd, J=8.0, 6.4, 1.6 Hz, 1H), 7.92-7.83 (m, 1H), 7.62 (t, J=9.0 Hz, 1H), 7.40 (t, J=8.0 Hz, 1H), 6.90 (dd, J=9.0, 3.1 Hz, 1H), 4.86 (d, J=18.0 Hz, 1H), 4.05-3.87 (m, 1H), 3.71 (s, 2H), 3.56 (t, J=11.1 Hz, 2H), 3.46 (s, 2H), 2.40 (s, 3H), 2.24 (s, 2H), 2.10 (d, J=14.1 Hz, 2H), 1.42 (d, J=6.3 Hz, 3H).

Example 45

(2R,4R)-1-(3-chloro-2-fluorobenzyl)-2-methyl-4-((6-((5-methyl-1H-pyrazol-3-yl)amino)pyrazin-2-yl)methyl)piperidine-4-carboxylic acid

Step 1: methyl (2R,4R)-4-((6-chloropyrazin-2-yl)methyl)-2-methylpiperidine-4-carboxylate

[0470] ##STR00185##

[0471] Following the procedure analogous to that described in Step 1 for the synthesis of Example 37, INT C4 (298 mg, 0.776 mmol) was converted to the title compound (210 mg) as a yellow oil. LCMS (ESI, m/z): 284 [M+H].sup.+.

Step 2: methyl-(2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((6-chloropyrazin-2-yl)methyl)-2-methylpiperidine-4-carboxylate

[0472] ##STR00186##

[0473] Following the procedure analogous to that described in Step 1 for the synthesis of Example 1, methyl (2R,4R)-4-((6-chloropyrazin-2-yl)methyl)-2-methylpiperidine-4-carboxylate (210 mg, 0.0.64 mmol) was converted to the title compound (216 mg, crude) as a yellow oil. LCMS (ESI, m/z): 426 [M+H].sup.+.

Step 3: methyl-(2R,4R)-4-((6-((1-(tert-butoxycarbonyl)-5-methyl-1H-pyrazol-3-yl)amino)pyrazin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylate

[0474] ##STR00187##

[0475] Following the procedure analogous to that described in Step 3 for the synthesis of Example 1, methyl-(2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((6-chloropyrazin-2-yl)methyl)-2-methyl piperidine-4-carboxylate (216 mg, crude) was converted to the title compound (923 mg) as a yellow oil. LCMS (ESI, m/z): 587 [M+H].sup.+.

Step 4: methyl-(2R,4R)-1-(3-chloro-2-fluorobenzyl)-2-methyl-4-((6-((5-methyl-1H-pyrazol-3-yl)amino)pyrazin-2-yl)methyl)piperidine-4-carboxylate

[0476] ##STR00188##

[0477] Following the procedure analogous to that described in Step 4 for the synthesis of Example 1, methyl-(2R,4R)-4-((6-((1-(tert-butoxycarbonyl)-5-methyl-1H-pyrazol-3-yl)amino) pyrazin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylate (923 mg) was converted to the title compound (325 mg, crude) as a yellow oil. LCMS (ESI, m/z): 487 [M+H].sup.+.

Step 5: (2R,4R)-1-(3-chloro-2-fluorobenzyl)-2-methyl-4-((6-((5-methyl-1H-pyrazol-3-yl)amino) pyrazin-2-yl)methyl)piperidine-4-carboxylic acid

[0478] ##STR00189##

[0479] Following the procedure analogous to that described in Step 5 for the synthesis of Example 1, methyl-(2R,4R)-1-(3-chloro-2-fluorobenzyl)-2-methyl-4-((6-((5-methyl-1H-pyrazol-3-yl)amino)pyrazin-2-yl)methyl)piperidine-4-carboxylate (325 mg) was converted to the title compound 9 mg as a yellow solid. LCMS (ESI, m/z): 487 [M+H].sup.+. .sup.1H NMR (400 MHz, DLCMS (ESI, m/z)O) δ 9.61 (s, 1H), 8.19 (s, 1H), 7.77 (t, J=7.9 Hz, 1H), 7.68 (s, 1H), 7.68 (s, 2H), 7.59 (d, J=6.4 Hz, 2H), 7.38 (t, J=7.9 Hz, 2H), 6.28 (s, 1H), 3.54 (s, 50H), 3.14 (d, J=9.9 Hz, 4H), 2.50 (m, 109H), 2.33 (s, 1H), 2.23 (s, 4H), 2.23 (s, 6H), 2.02 (d, J=13.4 Hz, 3H), 1.88 (m, 4H), 1.48 (d, J=6.1 Hz, 5H).

Example 46

1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-4-(3-hydroxyoxetan-3-yl)-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)methyl)piperidine-4-carboxylic acid

Step 1: 1-(tert-butyl)-4-methyl-4-((6-bromo-3-fluoropyridin-2-yl)methyl)piperidine-1,4-dicarboxylate

[0480] ##STR00190##

[0481] Following the procedure analogous to that described in Step 1 for the synthesis of Example 5, 1-(tert-butyl) 4-methyl piperidine-1,4-dicarboxylate (2.47 g, 10.152 mmol), INT A6 (2.95 g, 13.142 mmol) was converted to the title compound (1808 mg, Y=46%) as a yellow oil. LCMS (ESI, m/z): 387 [M+H].sup.+.

Step 2: 1-(tert-butyl)-4-methyl-4-((6-chloro-3-fluoro-4-(3-hydroxyoxetan-3-yl)pyridin-2-yl)methyl)piperidine-1,4-dicarboxylate

[0482] ##STR00191##

[0483] To a solution of diisopropylamine (374 mg, 3.696 mmol) in THF (5 mL) was cooled to −78° C. under nitrogen. n-Butyl lithium (2.5 M) in hexane (1.3 mL, 3.250 mmol) was added dropwise over 10 min maintaining the internal temperature below −40° C. The resulting solution was stirred at 0° C. for 30 min before a solution of 1-(tert-butyl)-4-methyl-4-((6-bromo-3-fluoropyridin-2-yl)methyl) piperidine-1,4-dicarboxylate (777 mg, 2.013 mmol) in THF (5 ml) was added dropwise at −78° C. The mixture was stirred at −40° C. for 1 h.

[0484] A solution of oxetan-3-one (295 mg, 4.094 mmol) in THF (5 ml) was added. The resulting solution was stirred at −60° C. for 1 h before it was quenched with saturated aqueous NH.sub.4Cl aqueous solution. The resulting mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by C18 reversed phase column chromatography eluting with H.sub.2O/ACN to afford 1-(tert-butyl)-4-methyl-4-((6-chloro-3-fluoro-4-(3-hydroxyoxetan-3-yl)pyridin-2-yl)methyl) piperidine-1,4-dicarboxylate (476 mg, Y=52%) as yellow oil. LCMS (ESI, m/z): 459 [M+H].sup.+.

Step 3: methyl-1-(3-chloro-2-fluorobenzyl)-4-((6-chloro-3-fluoro-4-(3-hydroxyoxetan-3-yl) p-yridin-2-yl)methyl)piperidine-4-carboxylate

[0485] ##STR00192##

[0486] Following the procedure analogous to that described in Step 3&4 for the synthesis of Example 5, 1-(tert-butyl)-4-methyl-4-((6-chloro-3-fluoro-4-(3-hydroxyoxetan-3-yl)pyridin-2-yl) methyl)piperidine-1,4-dicarboxylate (476 mg, 1.037 mmol) was converted to the title compound (168 mg, Y=32%) as a yellow oil. LCMS (ESI, m/z): 501 [M+H].sup.+.

Step 4: methyl-4-((6-((1-(tert-butoxycarbonyl)-5-methyl-1H-pyrazol-3-yl)amino)-3-fluoro-4-(3-hydroxyoxetan-3-yl)pyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)piperidine-4-carboxylate

[0487] ##STR00193##

[0488] Following the procedure analogous to that described in step 3 for the synthesis of Example 1, methyl-1-(3-chloro-2-fluorobenzyl)-4-((6-chloro-3-fluoro-4-(3-hydroxyoxetan-3-yl) p-yridin-2-yl)methyl)piperidine-4-carboxylate (168 mg, 0.335 mmol) was converted to the title compound (255 mg, crude) as a yellow oil. LCMS (ESI, m/z): 662 [M+H].sup.+.

Step 5: methyl-1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-4-(3-hydroxyoxetan-3-yl)-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)methyl)piperidine-4-carboxylate

[0489] ##STR00194##

[0490] Following the procedure analogous to that described in step 4 for the synthesis of Example 1, methyl-4-((6-((1-(tert-butoxycarbonyl)-5-methyl-1H-pyrazol-3-yl)amino)-3-fluoro-4-(3-hydroxyoxetan-3-yl)pyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)piperidine-4-carboxylate (255 mg, crude) was converted to the title compound (65 mg, crude) as a yellow oil. LCMS (ESI, m/z): 562 [M+H].sup.+.

Step 6: 1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-4-(3-hydroxyoxetan-3-yl)-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)methyl)piperidine-4-carboxylic acid

[0491] ##STR00195##

[0492] Following the procedure analogous to that described in step 5 for the synthesis of Example 1, methyl-1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-4-(3-hydroxyoxetan-3-yl)-6-((5-met-hyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)methyl) piperidine-4-carboxylate (65 mg) was converted to the title compound 10 mg as a yellow solid. LCMS (ESI, m/z): 548 [M+H].sup.+. .sup.1H NMR (400 MHz, MeOD) δ 7.69 (t, J=7.4 Hz, 1H), 7.52 (s, 1H), 7.33 (t, J=8.0 Hz, 1H), 6.96 (d, J=4.7 Hz, 1H), 5.99 (s, 1H), 5.08 (d, J=7.1 Hz, 2H), 4.80 (d, J=7.1 Hz, 1H), 4.46 (s, 2H), 3.53 (m, 3H), 3.17 (d, J=13.1 Hz, 3H), 2.46 (s, 2H), 2.35 (s, 3H), 1.93 (s, 2H), 1.31 (s, 2H).

[0493] The following example in Table 4 was synthesized using the above procedure with the corresponding starting materials and intermediates.

TABLE-US-00010 TABLE 4 Example No. Structure Chemical Name .sup.1HNMR & MS: (M + H).sup.+ 47 [00196] embedded image (2R,4R)-1-(3-chloro-2-fluoro benzyl)-4-((3-fluoro-4-(3- hydroxyoxetan-3-yl)-6-((5- methyl-1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)-2-methyl piperidine-4-carboxylic acid .sup.1H NMR (400 MHz, MeOD) δ 7.68 (t, J = 7.6 Hz, 1H), 7.55 (t, J = 6.4 Hz, 1H), 7.34 (t, J = 7.9 Hz, 1H), 6.93 (d, J = 4.7 Hz, 1H), 5.95 (s, 1H), 5.07 (d, J = 7.0 Hz, 2H), 4.79 (d, J = 7.0 Hz, 2H), 4.33 (d, J = 12.6 Hz, 1H), 3.91 (s, 2H), 3.44 (d, J = 29.1 Hz, 4H), 2.33 (s, 3H), 2.15 (dd, J = 73.5, 26.6 Hz, 5H), 1.57 (d, J = 6.0 Hz, 3H). MS: 562 (M + H).sup.+

Example 48

(2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-4-(3-fluorooxetan-3-yl)-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid

Step 1: di-tert-butyl-(2R,4R)-4-((6-bromo-3-fluoro-4-(3-hydroxyoxetan-3-yl)pyridin-2-yl) methyl)-2-methylpiperidine-1,4-dicarboxylate

[0494] ##STR00197##

[0495] Following the procedure analogous to that described in Step 2 for the synthesis of Example 43, INT C2 (881 mg, 1.808 mmol) was converted to the title compound (826 mg, Y=83%) as a yellow oil. LCMS (ESI, m/z): 559 [M+H].sup.+.

Step 2: tert-butyl-(2R,4R)-4-((6-bromo-3-fluoro-4-(3-hydroxyoxetan-3-yl)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylate

[0496] ##STR00198##

[0497] Following the procedure analogous to that described in step 3 for the synthesis of Example 5, di-tert-butyl-(2R,4R)-4-((6-bromo-3-fluoro-4-(3-hydroxyoxetan-3-yl)pyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate (826 mg, 1.476 mmol) was converted to the title compound (669 mg, Y=98%) as a yellow oil. LCMS (ESI, m/z): 459 [M+H].sup.+.

Step 3: tert-butyl-(2R,4R)-4-((6-bromo-3-fluoro-4-(3-hydroxyoxetan-3-yl)pyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylate

[0498] ##STR00199##

[0499] Following the procedure analogous to that described in Step 4 for the synthesis of Example 5, tert-butyl-(2R,4R)-4-((6-bromo-3-fluoro-4-(3-hydroxyoxetan-3-yl)pyridin-2-yl) methyl)-2-methylpiperidine-4-carboxylate (669 mg, 1.456 mmol) was converted to the title compound (577 mg, Y=66%) as a yellow oil. LCMS (ESI, m/z): 601 [M+H].sup.+.

Step 4: tert-butyl-(2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-3-fluoro-4-(3-hydroxyoxetan-3-yl)pyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylate

[0500] ##STR00200##

[0501] Following the procedure analogous to that described in step 2 for the synthesis of Example 5, tert-butyl-(2R,4R)-4-((6-bromo-3-fluoro-4-(3-hydroxyoxetan-3-yl)pyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylate (577 mg, 958.62 umol) was converted to the title compound (445 mg, Y=69%) as a yellow oil. LCMS (ESI, m/z): 674 [M+H].sup.+.

Step 5: tert-butyl-(2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-3-fluoro-4-(3-fluorooxetan-3-yl)pyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylate

[0502] ##STR00201##

[0503] To a solution of tert-butyl-(2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-3-fluoro-4-(3-hydroxyoxetan-3-yl)pyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylate (194 mg, 0.288 mmol) in DCM (10 ml) was added DAST (0.5 mL). The solution was stirred at room temperature for 2 h. The resulting solution was quenched with saturated sodium bicarbonate aqueous solution. The resulting solution was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was applied onto a silica gel column eluting with EtOAc/hexane (0˜30%) to afford the title compound (146 mg, Y=75%) as a yellow oil. LCMS (ESI, m/z): 676 [M+H].sup.+.

Step 6: (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-4-(3-fluorooxetan-3-yl)-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid

[0504] ##STR00202##

[0505] Following the procedure analogous to that described in step 5 for the synthesis of Example 5, tert-butyl-(2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-3-fluoro-4-(3-fluorooxetan-3-yl)pyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylate (146 mg, 215.909 umol) was converted to the title compound 21 mg as a white solid. LCMS (ESI, m/z): 564 [M+H].sup.+. .sup.1H NMR (400 MHz, MeOD) δ 7.71 (t, J=7.6 Hz, 1H), 7.56 (t, J=6.4 Hz, 1H), 7.36 (t, J=7.9 Hz, 1H), 6.95 (d, J=4.4 Hz, 1H), 6.03 (s, 1H), 5.07 (m, 4H), 3.97 (d, J=23.5 Hz, 2H), 3.47 (dd, J=24.6, 3.3 Hz, 4H), 2.37 (s, 3H), 2.10 (m, 5H), 1.60 (m, 3H).

Example 49

(2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-4-methyl-6-((5-methyl-1H-pyraz-ol-3-yl)amino) pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid

Step 1: di-tert-butyl-(2R,4R)-4-((6-chloro-3-fluoro-4-methylpyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate

[0506] ##STR00203##

[0507] A solution of diisopropylamine (2.13 g, 21.050 mmol) in THF (10 mL) was cooled to −78° C. under nitrogen. n-Butyl lithium (2.5 M) in n-hexane (7.2 mL, 18.286 mmol) was added. The solution was stirred at 0° C. for 30 min before it was added a solution of INT C2 (4.05 g, 9.143 mmol) in THF (5 ml) dropwise over 10 min maintaining the internal temperature below −40° C. The resulting solution was stirred at −40° C. for 1 h.

[0508] A solution of iodomethane (2.22 mg, 15.641 mmol) in THF (5 ml) was added dropwise below −70° C. and stirred 1 h. The reaction was quenched with saturated NH.sub.4Cl aqueous solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by C18 reversed phase column chromatography eluting with H.sub.2O/ACN to afford di-tert-butyl (2R,4R)-4-((6-chloro-3-fluoro-4-methylpyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate (3.55 g, Y=85%) as yellow oil. LCMS (ESI, m/z): 457 [M+H].sup.+.

Step 2: di-tert-butyl(2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-3-fluoro-4-methylpyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate

[0509] ##STR00204##

[0510] A mixture of di-tert-butyl-(2R,4R)-4-((6-chloro-3-fluoro-4-methylpyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate (3.54 g, 7.747 mmol), tris(dibenzylideneacetone)dipalladium (2.01 g, 2.195 mmol), dimethylbisdiphenylphosphinoxanthene (1.43 g, 2.471 mmol), 1-tert-butyl-3-methyl-1H-pyrazol-5-amine (1.56 mg, 10.181 mmol) and K.sub.3PO.sub.4 (5.30 g, 24.969 mmol) in 1,4-dioxane (50 ml) was stirred at 110° C. for 5 h under nitrogen. The resulting solution was cooled to room temperature and diluted with brine and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by C18 reverse phase chromatography eluting with H.sub.2O/ACN to afford (4.03 g, 7.024 mmol, Y=91%) of the title compound as a yellow solid. LCMS (ESI, m/z): 574 [M+H].sup.+.

Step 3: tert-butyl-(2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-3-fluoro-4-methylpyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylate

[0511] ##STR00205##

[0512] A solution of di-tert-butyl(2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-3-fluoro-4-methylpyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate (3.95 g, 6.885 mmol) in dichloromethane (60 ml) was added trifluoroacetic acid (6 ml) and stirred at room temperature for 4 h. After completion, the reaction was quenched with saturated sodium bicarbonate aqueous solution (100 ml) and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by C18 reverse phase chromatography eluting with H.sub.2O/ACN to afford (3.47 g, 7.326 mmol, Y=106%) of the title compound as a yellow solid. LCMS (ESI, m/z): 474 [M+H].sup.+.

Step 4: tert-butyl(2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-3-fluoro-4-methylpyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylate

[0513] ##STR00206##

[0514] A mixture of tert-butyl-(2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-3-fluoro-4-methylpyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylate (3.39 g, 7.158 mmol), potassium carbonate (3.49 g, 25.252 mmol) and 1-(bromomethyl)-3-chloro-2-fluorobenzene (1.48 g, 6.623 mmol) in ACN (10 mL) was stirred for 6 h at room temperature. After completion, the resulting mixture was filtered and concentrated under vacuum. The crude product was purified by silica gel column chromatography eluting with EtOAc/hexane (0˜30%) to afford (3.02 g, 4.410 mmol, Y=68%) of the title compound as a yellow solid. LCMS (ESI, m/z): 616 [M+H].sup.+.

Step 5: (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid

[0515] ##STR00207##

[0516] A solution of tert-butyl(2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-3-fluoro-4-methylpyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylate (1.81 g, 2.937 mmol) in formic acid (10 mL) was stirred at reflux for 4 h. After completion, the resulting solution was concentrated under reduced pressure. The residue was dissolved in water (60 mL) at 0° C. and adjusted PH=6-7 with sodium hydroxide aqueous solution (5 M). The resulting mixture was extracted with DCM (3×100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by C18 reverse phase chromatography eluting with MeOH/water to afford (1.25 g, 2.480 mmol, Y=84%) of the title compound as a white solid. LCMS (ESI, m/z): 504 [M+H].sup.+. .sup.1H NMR (400 MHz, MeOD) δ 7.71 (t, J=7.7 Hz, 1H), 7.56 (t, J=6.7 Hz, 1H), 7.36 (t, J=8.0 Hz, 1H), 6.75 (d, J=4.6 Hz, 1H), 5.94 (s, 1H), 4.36 (d, J=14.0 Hz, 1H), 3.89 (s, 1H), 3.44 (t, J=19.8 Hz, 8H), 2.40-2.04 (m, 7H), 1.60 (d, J=6.0 Hz, 2H), 1.31 (s, 1H).

[0517] The following examples in Table 5 were synthesized using the above procedure with the corresponding starting materials and intermediates.

TABLE-US-00011 TABLE 5 Example No. Structure Chemical Name .sup.1HNMR & MS: (M + H).sup.+ 50 [00208] embedded image (2R,4R)-1-(3-chloro-2,6- difluorobenzyl)-4-((3-fluoro-4- methyl-6-((5-methyl-1H-pyrazol- 3-yl)amino)pyridin-2-yl) methyl)-2-methylpiperidine-4- carboxylic acid .sup.1H NMR (400 MHz, MeOD) δ 7.60 (dd, J = 14.3, 8.6 Hz, 1H), 7.13 (t, J = 8.8 Hz, 1H), 6.64 (s, 1H), 5.77 (d, J = 17.9 Hz, 1H), 4.41 (d, J = 13.4 Hz, 1H), 3.87 (d, J = 11.7 Hz, 1H), 3.20 (d, J = 38.9 Hz, 3H), 3.03 (s, 1H), 2.88 (d, J = 2.1 Hz, 1H), 2.24 (d, J = 16.1 Hz, 6H), 1.95 (dd, J = 38.0, 18.5 Hz, 4H), 1.43- 1.37 (m, 3H). MS: 522 (M + H).sup.+ 51 [00209] embedded image 1-(3-chloro-2-fluorobenzyl)- 4-((3-fluoro-4-methyl-6-((5- methyl-1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)piperidine- 4-carboxylic acid .sup.1H NMR (400 MHz, MeOD) δ 8.22 (s, 2H), 7.62 (s, 1H), 7.50 (s, 1H), 7.28 (t, J = 7.7 Hz, 1H), 6.68 (s, 1H), 5.81 (s, 1H), 4.27 (s, 2H), 3.37 (s, 5H), 3.12 (d, J = 22.1Hz, 3H), 2.37 (s, 2H), 2.27 (s, 4H), 1.86 (s, 2H). MS: 490 (M + H).sup.+ 52 [00210] embedded image 1-(2,3-difluorobenzyl)-4-((3- fluoro-4-methyl-6-((5-methyl- 1H-pyrazol-3-yl)amino)pyridin- 2-yl)methyl)piperidine-4- carboxylic acid .sup.1H NMR (400 MHz, MeOD) δ 8.27 (s, 1H), 7.47-7.16 (m, 2H), 6.67 (s, 1H), 5.81 (s, 1H), 4.20 (s, 2H), 3.40-3.34 (m, 3H), 3.08 (dd, J = 73.2, 39.5 Hz, 5H), 2.30 (d, J = 35.5 Hz, 6H), 1.82 (s, 2H). MS: 474 (M + H).sup.+ 53 [00211] embedded image (2R,4R)-1-(2,3-dichlorobenzyl)- 4-((3-fluoro-4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino)pyridin-2-yl)methyl)-2- methylpiperidine-4-carboxylic acid .sup.1H NMR (400 MHz, MeOD) δ 7.47 (d, J = 7.7 Hz, 2H), 7.25 (t, J = 7.8 Hz, 1H), 6.52 (s, 1H), 5.66 (d, J = 17.9 Hz, 1H), 4.39 (d, J = 13.6 Hz, 1H), 3.82 (s, 1H), 3.31 (dd, J = 58.4, 5.0 Hz, 1H), 3.15 (s, 2H), 2.90 (s, 1H), 2.79 (s, 1H), 2.13 (d, J = 14.0 Hz, 6H), 1.83 (d, J = 55.0 Hz, 4H), 1.25 (d, J = 7.2 Hz, 3H). MS: 520 (M + H).sup.+ 54 [00212] embedded image 1-(2,3-dichlorobenzyl)-4-((3- fluoro-4-methyl-6-((5-methyl- 1H-pyrazol-3-yl)amino)pyridin- 2-yl)methyl)piperidine-4- carboxylic acid .sup.1H NMR (400 MHz, MeOD) δ 8.27 (s, 1H), 7.60 (d, J = 5.8 Hz, 1H), 7.11 (t, J = 8.6 Hz, 1H), 6.66 (s, 1H), 5.78 (s, 1H), 4.10 (dd, J = 16.5, 9.4 Hz, 2H), 3.23-2.66 (m, 6H), 2.27 (s, 4H), 2.19 (s, 2H), 1.78 (t, J = 11.1 Hz, 2H), 1.44-1.16 (m, 2H). MS: 506 (M + H).sup.+ 55 [00213] embedded image 1-(3-chloro-2,6-difluorobenzyl)- 4-((3-fluoro-4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino)pyridin-2-yl)methyl) piperidine-4-carboxylic acid .sup.1H NMR (400 MHz, MeOD) δ 8.27 (s, 1H), 7.60 (d, J = 5.8 Hz, 1H), 7.11 (t, J = 8.6 Hz, 1H), 6.66 (s, 1H), 5.78 (s, 1H), 4.10 (dd, J = 16.5, 9.4 Hz, 2H), 3.23-2.66 (m, 6H), 2.27 (s, 4H), 2.19 (s, 2H), 1.78 (t, J = 11.1 Hz, 2H), 1.49-0.73 (m, 4H). MS: 508 (M + H).sup.+ 56 [00214] embedded image 1-(2,3-difluorophenethyl)-4- ((3-fluoro-4-methyl-6-((5-methyl- 1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)piperidine- 4-carboxylic acid .sup.1H NMR (400 MHz, MeOD) δ 7.18 (dd, J = 20.6, 10.0 Hz, 3H), 6.75 (d, J = 4.6 Hz, 1H), 5.94 (s, 1H), 3.67 (d, J = 11.9 Hz, 2H), 3.34 (s, 2H), 3.23- 2.99 (m, 6H), 2.48 (d, J = 14.7 Hz, 2H), 2.33 (d, J = 15.3 Hz, 6H), 1.95 (s, 2H). MS: 488 (M + H).sup.+ 57 [00215] embedded image 1-(2,3-dichlorophenethyl)-4- ((3-fluoro-4-methyl-6-((5-methyl- 1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)piperidine- 4-carboxylic acid .sup.1H NMR (400 MHz, MeOD) δ 7.49 (d, J = 7.5 Hz, 1H), 7.40- 7.20 (m, 2H), 6.78 (d, J = 4.6 Hz, 1H), 5.99 (s, 1H), 3.70 (d, J = 12.8 Hz, 2H), 3.45 (d, J = 19.0 Hz, 2H), 3.21 (s, 2H), 3.09 (t, J = 12.9 Hz, 2H), 2.50 (t, J = 16.2 Hz, 2H), 2.36 (d, J = 20.6 Hz, 6H), 2.00 (t, J = 13.8 Hz, 2H), 0.00 (d, J = 3.1 Hz, 2H). MS: 520 (M + H).sup.+ 58 [00216] embedded image 1-(3-chloro-2,6-difluorophenethyl)- 4-((3-fluoro-4-methyl- 6-((5-methyl-1H-pyrazol-3- yl)amino)pyridin-2-yl)methyl) piperidine-4-carboxylic acid .sup.1H NMR (400 MHz, MeOD) δ 7.48 (dd, J = 14.4, 8.6 Hz, 1H), 7.06 (t, J = 8.8 Hz, 1H), 6.76 (d, J = 4.7 Hz, 1H), 5.96 (s, 1H), 3.69 (d, J = 10.1 Hz, 2H), 3.15 (d, J = 21.2 Hz, 4H), 2.49 (d, J = 13.7 Hz, 2H), 2.34 (d, J = 17.2 Hz, 6H), 1.95 (s, 2H), 0.01- −0.01 (m, 4H). MS: 522 (M + H).sup.+ 59 [00217] embedded image 1-(2,6-dichlorophenethyl)-4- ((3-fluoro-4-methyl-6-((5-methyl- 1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)piperidine- 4-carboxylic acid .sup.1H NMR (400 MHz, MeOD) δ 7.43 (d, J = 8.0 Hz, 2H), 7.29 (t, J = 8.0 Hz, 1H), 6.77 (d, J = 4.7 Hz, 1H), 5.97 (s, 1H), 3.75 (d, J = 12.0 Hz, 2H), 3.39 (t, J = 19.5 Hz, 3H), 3.28-3.04 (m, 5H), 2.50 (d, J = 13.3 Hz, 2H), 2.35 (d, J = 18.0 Hz, 6H), 2.01 (d, J = 13.7 Hz, 2H). MS: 520 (M + H).sup.+ 60 [00218] embedded image 1-(2,4-dichlorophenethyl)-4- ((3-fluoro-4-methyl-6-((5-methyl- 1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)piperidine- 4-carboxylic acid .sup.1H NMR (400 MHz, MeOD) δ 7.51 (s, 1H), 7.35 (dd, J = 15.7, 8.1 Hz, 2H), 6.77 (d, J = 4.7 Hz, 1H), 5.97 (s, 1H), 3.69 (d, J = 12.3 Hz, 2H), 3.19 (s, 4H), 3.09 (t, J = 13.3 Hz, 2H), 2.48 (d, J = 14.3 Hz, 2H), 2.35 (d, J = 18.3 Hz, 6H), 1.97 (t, J = 12.9 Hz, 2H), −0.00 (s, 2H). MS: 520 (M + H).sup.+ 61 [00219] embedded image (2R,4R)-1-(2,3-difluorobenzyl)- 4-((3-fluoro-4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino)pyridin-2-yl)methyl)-2- methylpiperidine-4-carboxylic acid .sup.1H NMR (400 MHz, MeOD) δ 7.60 (dd, J = 14.3, 8.6 Hz, 1H), 7.13 (t, J = 8.8 Hz, 1H), 6.64 (s, 1H), 5.77 (d, J = 17.9 Hz, 1H), 4.41 (d, J = 13.4 Hz, 1H), 3.87 (d, J = 11.7 Hz, 1H), 3.20 (d, J = 38.9 Hz, 3H), 3.03 (s, 1H), 2.88 (d, J = 12.7 Hz, 1H), 2.24 (d, J = 16.1 Hz, 6H), 1.95 (dd, J = 38.0, 18.5 Hz, 4H), 1.43- 1.37 (m, 3H). MS: 488 (M + H).sup.+

Example 62

(2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-4-(2-hydroxypropan-2-yl)-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid

Step 1: di-tert-butyl-(2R,4R)-4-((6-chloro-3-fluoro-4-(2-hydroxypropan-2-yl)pyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate

[0518] ##STR00220##

[0519] A solution of diisopropylamine (365 mg, 3.607 mmol) in THF (5 mL) was added n-butyl lithium (2.5 M) in hexane (1.2 mL, 3.000 mmol) at −78° C. under nitrogen. The solution was stirred at 0° C. for 30 min before it was added a solution of INT C3 (616 mg, 1.391 mmol) in THF (5 ml) dropwise at −70° C. The resulting solution was stirred at −40° C. for 1 h. The resulting solution was added a solution of acetone (1.17 g, 0.202 mol) in THF (5 ml) dropwise over 10 min maintaining the internal temperature below −70° C. and stirred for 1 h. The reaction was quenched with saturated aqueous NH.sub.4Cl solution. The resulting mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by C18 reversed phase column chromatography eluting with H.sub.2O/ACN to afford di-tert-butyl-(2R,4R)-4-((6-chloro-3-fluoro-4-(2-hydroxypropan-2-yl)pyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate (519 mg, Y=74%) as yellow oil. LCMS (ESI, m/z): 501[M+H].sup.+.

Step 2: tert-butyl-(2R,4R)-4-((6-chloro-3-fluoro-4-(2-hydroxypropan-2-yl)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylate

[0520] ##STR00221##

[0521] Following the procedure analogous to that described in Step 3 for the synthesis of Example 5, di-tert-butyl-(2R,4R)-4-((6-chloro-3-fluoro-4-(2-hydroxypropan-2-yl)pyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate (519 mg, 1.036 mmol) was converted to the title compound (326 mg, Y=79%) as a yellow oil. LCMS (ESI, m/z): 401 [M+H].sup.+.

Step 3: tert-butyl-(2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((6-chloro-3-fluoro-4-(2-hydroxypropan-2-yl)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylate

[0522] ##STR00222##

[0523] Following the procedure analogous to that described in Step 4 for the synthesis of Example 5, tert-butyl-(2R,4R)-4-((6-chloro-3-fluoro-4-(2-hydroxypropan-2-yl)-pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylate (326 mg, 0.813 mmol) was converted to the title compound (377 mg, Y=85%) as a yellow oil. LCMS (ESI, m/z): 543 [M+H].sup.+.

Step 4: tert-butyl-(2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-3-fluoro-4-(2-hydroxypropan-2-yl)pyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylate

[0524] ##STR00223##

[0525] Following the procedure analogous to that described in Step 2 for the synthesis of Example 5, tert-butyl-(2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((6-chloro-3-fluoro-4-(2-hydroxypropan-2-yl) pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylate (243 mg, 0.447 mmol) was converted to the title compound (168 mg, Y=57%) as a yellow oil. LCMS (ESI, m/z): 660 [M+H].sup.+.

Step 5: (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-4-(2-hydroxypropan-2-yl)-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid

[0526] ##STR00224##

[0527] Following the procedure analogous to that described in Step 5 for the synthesis of Example 5, tert-butyl-(2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)-amino)-3-fluoro-4-(2-hydroxypropan-2-yl)pyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylate (168 mg, 0.254 mmol) was converted to the title compound (34 mg) as a white solid. LCMS (ESI, m/z): 548 [M+H].sup.+. .sup.1H NMR (400 MHz, MeOD) δ 7.34 (m, 2H), 7.08 (t, J=7.7 Hz, 1H), 6.84 (s, 1H), 5.56 (s, 1H), 4.13 (s, 1H), 3.52 (d, J=17.6 Hz, 2H), 3.12 (d, J=6.6 Hz, 2H), 2.74 (s, 2H), 2.11 (s, 3H), 1.76 (s, 2H), 1.69 (s, 2H), 1.45 (s, 6H), 1.19 (s, 3H).

Example 63

(2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-4-isopropyl-6-((5-methyl-1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid

Step 1: tert-butyl-(2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((6-chloro-3-fluoro-4-(prop-1-en-2-yl)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylate

[0528] ##STR00225##

[0529] To a solution of tert-butyl-(2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((6-chloro-3-fluoro-4-(2-hydroxypropan-2-yl)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylate (185 mg, 0.340 μmol) in THF (5 mL) was added thionyl chloride (2.5 ml) and pyridine (1 mL). The reaction mixture was stirred at room temperature for 2 h. The resulting mixture was quenched with saturated sodium bicarbonate aqueous solution and extracted with DCM (50 mL). The organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by C18 reversed phase column chromatography eluting with H.sub.2O/ACN to afford tert-butyl (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((6-chloro-3-fluoro-4-(prop-1-en-2-yl)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylate (118 mg Y=66%) as a yellow oil. LCMS (ESI, m/z): 525 [M+H].sup.+.

Step 2: tert-butyl-(2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-3-fluoro-4-(prop-1-en-2-yl)pyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylate

[0530] ##STR00226##

[0531] Following the procedure analogous to that described in Step 2 for the synthesis of Example 5, tert-butyl-(2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((6-chloro-3-fluoro-4-(prop-1-en-2-yl) pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylate (118 mg, 0.225 mmol) was converted to the title compound (111 mg, Y=77%) as a yellow oil. LCMS (ESI, m/z): 642 [M+H].sup.+.

Step 3: tert-butyl-(2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-3-fluoro-4-isopropylpyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylate

[0532] ##STR00227##

[0533] A solution of tert-butyl-(2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-3-fluoro-4-(prop-1-en-2-yl)pyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylate (111 mg, 0.173 mmol) and Pd/C (32 mg) in ethyl acetate (20 mL) was purged it with H.sub.2 and pressurized with H.sub.2. The reaction mixture was stirred at room temperature for 4 h. After completion, the resulting mixture was filtrated. The filtrate was removed under reduced pressure. The resulting residue was purified by C18 reversed phase column chromatography eluting with H.sub.2O/ACN to afford tert-butyl (2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-3-fluoro-4-isopropylpyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylate (95 mg, Y=85%) as yellow oil. LCMS (ESI, m/z): 644 [M+H].sup.−.

Step 4: (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-4-isopropyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid

[0534] ##STR00228##

[0535] Following the procedure analogous to that described in Step 5 for the synthesis of Example 5, tert-butyl-(2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)-amino)-3-fluoro-4-isopropylpyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylate (95 mg, 0.147 mmol) was converted to the title compound (35 mg) as a white solid. LCMS (ESI, m/z): 532 [M+H].sup.+. .sup.1H NMR (400 MHz, MeOD) δ 7.68 (t, J=7.6 Hz, 1H), 7.56 (dd, J=16.2, 8.7 Hz, 1H), 7.33 (t, J=7.9 Hz, 1H), 6.78 (d, J=4.6 Hz, 1H), 5.97 (s, 1H), 3.41 (d, J=5.5 Hz, 4H), 3.20 (m, 2H), 2.38 (s, 3H), 2.13 (m, 6H), 1.59 (d, J=6.0 Hz, 3H), 1.29 (d, J=6.9 Hz, 6H).

Example 64

(2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((4-(difluoromethyl)-3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid

Step 1: di-tert-butyl-(2R,4R)-4-((6-chloro-3-fluoro-4-formylpyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate

[0536] ##STR00229##

[0537] A solution of diisopropylamine (1.68 g, 16.603 mmol) in THF (10 mL) was added n-butyl lithium (2.5 M) in hexane (4 mL, 10.00 mmol) at −78° C. under nitrogen. The solution was stirred at 0° C. for 30 min. The resulting solution was added a solution of INT C3 (2.16 g, 4.876 mmol) in THF (15 ml) dropwise over 10 min maintaining the internal temperature below −78° C. and stirred at −40° C. for 1 h.

[0538] A solution of DMF (2.19 g, 29.962 mmol) in THF (5 ml) was added to the above solution at −78° C. The resulting solution was stirred at −78° C. for 1 h. The reaction was quenched with saturated NH.sub.4Cl aqueous solution. The resulting mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by C18 reversed phase column chromatography eluting with H.sub.2O/ACN to afford di-tert-butyl-(2R,4R)-4-((6-chloro-3-fluoro-4-formylpyridin-2-yl) methyl)-2-methylpiperidine-1,4-dicarboxylate (1316 mg, Y=57%) as yellow oil. LCMS (ESI, m/z): 471 [M+H].sup.+.

Step 2: di-tert-butyl-(2R,4R)-4-((6-chloro-4-(difluoromethyl)-3-fluoropyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate

[0539] ##STR00230##

[0540] To a solution of di-tert-butyl-(2R,4R)-4-((6-chloro-3-fluoro-4-formylpyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate (0.189 g, 401.307 μmol) in DCM (50 ml) was added DAST (0.5 ml). The reaction was stirred at room temperature for 2 h. The reaction was quenched with saturated sodium bicarbonate aqueous solution. The resulting mixture was extracted with DCM. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by C18 reversed phase column chromatography eluting with H.sub.2O/ACN to afford di-tert-butyl-(2R,4R)-4-((6-chloro-4-(difluoromethyl)-3-fluoropyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate (151 mg Y=76%) as a yellow oil. LCMS (ESI, m/z): 493 [M+H].sup.+.

Step 3: di-tert-butyl-(2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-4-(difluoromethyl)-3-fluoropyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate

[0541] ##STR00231##

[0542] Following the procedure analogous to that described in Step 2 for the synthesis of Example 5, di-tert-butyl-(2R,4R)-4-((6-chloro-4-(difluoromethyl)-3-fluoropyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate (0.151 g, 306.314 μmol) was converted to the title compound (107 mg, Y=57%) as a yellow oil. LCMS (ESI, m/z): 610 [M+H].sup.+.

Step 4: tert-butyl-(2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-4-(difluoromethyl)-3-fluoropyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylate

[0543] ##STR00232##

[0544] Following the procedure analogous to that described in Step 3 for the synthesis of Example 5, di-tert-butyl-(2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-4-(difluoromethyl)-3-fluoropyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate (0.107 g, 175.490 μmol) was converted to the title compound (72 mg, Y=80%) as a yellow oil. LCMS (ESI, m/z): 510 [M+H].sup.+.

Step 5: tert-butyl-(2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-4-(difluoromethyl)-3-fluoropyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylate

[0545] ##STR00233##

[0546] Following the procedure analogous to that described in Step 4 for the synthesis of Example 5, tert-butyl-(2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-4-(difluoromethyl)-3-fluoropyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylate (72 mg, 141.176 μmol) was converted to the title compound (68 mg, Y=74%) as a yellow oil. LCMS (ESI, m/z): 652 [M+H].sup.+.

Step 6: (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((4-(difluoromethyl)-3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid

[0547] ##STR00234##

[0548] Following the procedure analogous to that described in Step 5 for the synthesis of Example 5, tert-butyl-(2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)-amino)-4-(difluoromethyl)-3-fluoropyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylate (68 mg, 104.294 μmol) was converted to the title compound (11 mg) as a white solid. LCMS (ESI, m/z): 540 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO) δ 7.77 (t, J=7.1 Hz, 1H), 7.60 (t, J=6.5 Hz, 1H), 7.39 (t, J=7.9 Hz, 1H), 7.30-7.01 (m, 2H), 6.12 (s, 1H), 4.85 (d, J=13.4 Hz, 1H), 4.36-4.23 (m, 1H), 3.89 (s, 2H), 3.28-3.12 (m, 3H), 2.71-2.64 (m, 1H), 2.32 (dd, J=11.0, 9.2 Hz, 1H), 2.28-2.13 (m, 3H), 1.97-1.81 (m, 2H), 1.42 (t, J=27.9 Hz, 3H).

Example 65

(2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((4-ethyl-3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid

[0549] ##STR00235##

Step 1: di-tert-butyl-(2R,4R)-4-((6-chloro-3-fluoro-4-iodopyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate

[0550] ##STR00236##

[0551] To a solution of diisopropylamine (1.380 g, 13.636 mmol) in THF (15 mL) was added n-butyl lithium (2.5 M) in hexane (2.4 mL, 6.00 mmol) dropwise at −78° C. under nitrogen. The resulting solution was stirred at 0° C. for 30 min. A solution of INT C3 (3.02 g, 6.818 mmol) in THF (10 ml) was added below −78° C. The mixture was stirred at −78° C. for 1 h.

[0552] The resulting mixture was added a solution of iodine (2.06 g, 8.116 mmol) in THF (5 ml) dropwise at −70° C. The reaction solution was stirred at −60° C. for 1 h before it was quenched with saturated NH.sub.4Cl aqueous solution. The resulting mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by C18 reversed phase column chromatography eluting with H.sub.2O/ACN to afford di-tert-butyl-(2R,4R)-4-((6-chloro-3-fluoro-4-iodopyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate (2.8 g, Y=72%) as a yellow solid. LCMS (ESI, m/z): 569 [M+H].sup.+

Step 2: di-tert-butyl (2R,4R)-4-((6-chloro-3-fluoro-4-vinylpyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate

[0553] ##STR00237##

[0554] A solution of di-tert-butyl (2R,4R)-4-((6-chloro-3-fluoro-4-iodopyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate (504 mg, 886.003 μmol), tributyl(vinyl)tin (310 mg, 977.619 μmol), C.sub.SF (180 mg, 1.185 mmol) and tetrakis(triphenylphosphine)palladium (112 mg, 737.311 μmol) in 1,4-Dioxane (15 mL) was stirred at 95° C. for 4 h under nitrogen. The mixture was cooled to room temperature. The resulting solution was diluting with EtOAc (130 mL) and washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography eluting with EtOAc/hexane (0˜10%) to afford the title compound (394 mg, Y=95%) as a white oil. LCMS (ESI, m/z): 469[M+H].sup.+.

Step 3: di-tert-butyl-(2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-3-fluoro-4-vinylpyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate

[0555] ##STR00238##

[0556] Following the procedure analogous to that described in Step 2 for the synthesis of Example 5, di-tert-butyl(2R,4R)-4-((6-chloro-3-fluoro-4-vinylpyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate (394 mg, 840.107 μmol) was converted to the title compound (110 mg, Y=22%) as a white oil. LCMS (ESI, m/z): 586[M+H].sup.+.

Step 4: di-tert-butyl (2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)-amino)-4-ethyl-3-fluoropyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate

[0557] ##STR00239##

[0558] A solution of di-tert-butyl (2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-3-fluoro-4-vinylpyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate (110 mg, 187.793 μmol) and Pd/C (175 mg) in MeOH (10 mL) was purged with H.sub.2 and pressurized with H.sub.2. The resulting mixture was stirred at room temperature for 4 h. After completion, the mixture was filtered and the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure to afford the title compound (110 mg) as a yellow oil. LCMS (ESI, m/z): 588[M+H].sup.+.

Step 5: tert-butyl (2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-4-ethyl-3-fluoropyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylate

[0559] ##STR00240##

[0560] Following the procedure analogous to that described in Step 3 for the synthesis of Example 5, di-tert-butyl (2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-4-ethyl-3-fluoropyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate (110 mg, 187.15 μmol) was converted to the title compound (107 mg) as a crude yellow oil. LCMS (ESI, m/z): 488[M+H].sup.+.

Step 6: tert-butyl (2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-4-ethyl-3-fluoropyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylate

[0561] ##STR00241##

[0562] Following the procedure analogous to that described in Step 4 for the synthesis of Example 5, tert-butyl (2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-4-ethyl-3-fluoropyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylate (107 mg) was converted to the title compound (70 mg, Y=50%) as a yellow oil. LCMS (ESI, m/z): 616[M+H].sup.+.

Step 7: (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((4-ethyl-3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid

[0563] ##STR00242##

[0564] Following the procedure analogous to that described in Step 5 for the synthesis of Example 5, tert-butyl (2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-4-ethyl-3-fluoropyridin-2-yl)methyl)-1-(3-chloro-2-fluorophenyl)-2-methylpiperidine-4-carboxylate (70 mg, 110.074 μmol) was converted to the title compound (38 mg, Y=71%) as a white solid. LCMS (ESI, m/z): 518 [M+H].sup.+. .sup.1H NMR (400 MHz, MeOD) δ 7.69-7.66 (t, J=7.4 Hz, 1H), 7.56-7.54 (t, J=6.7 Hz, 1H), 7.34-7.32 (t, J=7.8 Hz, 1H), 6.77 (d, J=4.3 Hz, 1H), 5.98 (s, 1H), 4.36 (s, 1H), 3.90 (s, 1H), 3.41 (s, 4H), 2.73 (q, J=7.5 Hz, 3H), 2.38 (s, 3H), 2.20 (s, 2H), 2.08-2.06 (m, 2H), 1.60-1.57 (s, 3H), 1.29-1.24 (t, J=7.4 Hz, 3H).

[0565] The following example in Table 6 was synthesized using the above procedure with the corresponding starting materials and intermediates.

TABLE-US-00012 TABLE 6 Example No. Structure Chemical Name .sup.1HNMR & MS: (M + H).sup.+ 66 [00243] embedded image 1-(3-chloro-2-fluorobenzyl)- 4-((4-ethyl-3-fluoro-6-((5- methyl-1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)piperidine- 4-carboxylic acid .sup.1H NMR (400 MHz, MeOD) δ 7.66 (t, J = 7.3 Hz, 2H), 7.32 (t, J = 7.6 Hz, 1H), 6.85 (d, J = 4.4 Hz, 1H), 6.03 (s, 1H), 4.46 (s, 2H), 3.61-3.50 (m, 2H), 3.25 (s, 2H), 3.13 (t, J = 12.3 Hz, 2H), 2.73 (q, J = 7.5 Hz, 2H), 2.44 (d, J = 14.4 Hz, 5H), 2.12 (t, J = 13.0 Hz, 2H), 1.25 (dt, J = 26.2, 12.3 Hz, 3H). MS: 504 (M + H).sup.+

Example 67

(2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((4-cyano-3-fluoro-6-((3-methyl-1H-pyrazol-5-yl)amino) pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid

Step 1: tert-butyl (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((6-chloro-3-fluoro-4-formylpyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylate

[0566] ##STR00244##

[0567] A solution of tert-butyl-(2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((6-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylate (0.258 g, 531.528 μmol) in THF (10 mL) was added lithium diisopropylamide (2.0 M) in hexane (2.0 mL, 4.000 mmol) at −78° C. under nitrogen. The resulting solution was stirred at −40° C. for 1 h.

[0568] A solution of DMF (0.5 mL) in THF (10 ml) was added dropwise to the above solution at −78° C. The resulting solution was stirred at −78° C. for 1 h. The reaction was quenched with saturated aqueous NH.sub.4Cl aqueous solution. The resulting mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by C18 reversed phase column chromatography eluting with H.sub.2O/ACN to afford tert-butyl-(2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((6-chloro-3-fluoro-4-formylpyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylate (78 mg, Y=29%) as a yellow oil. LCMS (ESI, m/z): 513 [M+H].sup.+.

Step 2: tert-butyl (2R,4R)-4-((6-((1-(tert-butyl)-3-methyl-1H-pyrazol-5-yl)amino)-3-fluoro-4-formylpyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylate

[0569] ##STR00245##

[0570] Following the procedure analogous to that described in Step 2 for the synthesis of Example 5, tert-butyl (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((6-chloro-3-fluoro-4-formylpyridin-2-yl) methyl)-2-methylpiperidine-4-carboxylate (78 mg, 151.927 μmol) was converted to the title compound (95 mg, Y=100%) as a yellow oil. LCMS (ESI, m/z): 630 [M+H].sup.+.

Step 3: tert-butyl (2R,4R)-4-((6-((1-(tert-butyl)-3-methyl-1H-pyrazol-5-yl)amino)-3-fluoro-4-((E)-(hydroxyimino)methyl)pyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylate

[0571] ##STR00246##

[0572] A solution of tert-butyl (2R,4R)-4-((6-((1-(tert-butyl)-3-methyl-1H-pyrazol-5-yl)amino)-3-fluoro-4-formylpyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxy late (96 mg, 152.341 μmol), hydroxylammoniumchlorid (27 mg, 388.541 μmol) and potassium carbonate (75 mg, 542.670 μmol) in methanol (3 mL) was stirred for 3 h at room temperature. The resulting solution added water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by C18 reversed phase column chromatography eluting with H.sub.2O/ACN to afford (6-chloro-3-methylpyridin-2-yl)methanol (98 mg Y=100%) as a yellow oil. LCMS (ESI, m/z): 645 [M+H].sup.+.

Step 4: (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((4-cyano-3-fluoro-6-((3-methyl-1H-pyrazol-5-yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid

[0573] ##STR00247##

[0574] Following the procedure analogous to that described in Step 5 for the synthesis of Example 5, tert-butyl-(2R,4R)-4-((6-((1-(tert-butyl)-3-methyl-1H-pyrazol-5-yl)amino)-3-fluoro-4-((E)-(hydroxyimino)methyl)pyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylate (98 mg, 151.895 μmol) was converted to the title compound (7 mg) as a white solid. LCMS (ESI, m/z): 515 [M+H].sup.+.

Example 68

(2R,4R)-4-((4-acetyl-3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylic acid

Step 1: di-tert-butyl-(2R,4R)-4-((6-chloro-3-fluoro-4-iodopyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate

[0575] ##STR00248##

[0576] Following the procedure analogous to that described in step 1 of Example 65, INT C3 (3.02 g, 6.818 mmol) was converted to the title compound (2.8 g, Y=72%) as a yellow solid. LCMS (ESI, m/z): 569 [M+H].sup.+.

Step 2: di-tert-butyl (2R,4R)-4-((6-chloro-4-(1-ethoxyvinyl)-3-fluoropyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate

[0577] ##STR00249##

[0578] To a solution of di-tert-butyl (2R,4R)-4-((6-chloro-3-fluoro-4-iodopyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate (1.54 g, 2.707 mmol) in 1,4-dioxane (20 mL) was added tributyl(1-ethoxyvinyl)-stannane (1.11 g, 3.074 mmol) bis(triphenylphosphine)palladium(II) chloride (0.39 g, 552.465 μmol) and cesium fluoride (0.84 g, 5.530 mmol) under nitrogen. The mixture was refluxed at 90° C. for 3 h. The resulting mixture was cooled to room temperature and filtrated. The filtrate was diluted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by C18 reversed phase column chromatography eluting with H.sub.2O/ACN to afford di-tert-butyl (2R,4R)-4-((6-amino-4-(1-ethoxyvinyl)-3-fluoropyridin-2-yl) methyl)-2-methylpiperidine-1,4-dicarboxylate (960 mg, Y=72%) as a yellow oil. LCMS (ESI, m/z): 494 [M+H].sup.+.

Step 3: di-tert-butyl(2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-4-(1-ethoxyvinyl)-3-fluoropyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate

[0579] ##STR00250##

[0580] Following the procedure analogous to that described in step 2 of Example 5, di-tert-butyl-(2R,4R)-4-((6-amino-4-(1-ethoxyvinyl)-3-fluoropyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate (960 mg, 1.871 mmol) was converted to the title compound (1.06 g, Y=90%) as a yellow oil. LCMS (ESI, m/z): 630 [M+H].sup.+.

Step 4: tert-butyl(2R,4R)-4-((4-acetyl-6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)ami-no)-3-fluoropyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylate

[0581] ##STR00251##

[0582] Following the procedure analogous to that described in step 3 of Example 5, di-tert-butyl(2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-4-(1-ethoxyvinyl)-3-fluoropyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate (806 mg, 1.280 mmol) was converted to the title compound (766 mg) as a yellow oil. LCMS (ESI, m/z): 502 [M+H].sup.+.

Step 5: tert-butyl(2R,4R)-4-((4-acetyl-6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)a-mino)-3-fluoropyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylate

[0583] ##STR00252##

[0584] Following the procedure analogous to that described in step 4 of Example 5, tert-butyl(2R,4R)-4-((4-acetyl-6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-3-fluoropyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylate (766 mg, 1.527 mmol) was converted to the title compound (420 mg) as a white solid. LCMS (ESI, m/z): 644 [M+H].sup.+.

Step 6: (2R,4R)-4-((4-acetyl-3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)-pyridin-2-yl)met-hyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylic acid

[0585] ##STR00253##

[0586] Following the procedure analogous to that described in step 5 of Example 5, tert-butyl(2R,4R)-4-((4-acetyl-6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-3-fluoropyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylate (74 mg, 114.872 μmol) was converted to the title compound (21 mg) as a white solid. LCMS (ESI, m/z): 532 [M+H].sup.+. .sup.1H NMR (400 MHz, MeOD) δ 8.42 (s, 1H), 7.49 (dt, J=23.1, 7.1 Hz, 2H), 7.23 (t, J=7.9 Hz, 1H), 7.07 (d, J=3.8 Hz, 1H), 5.88 (s, 1H), 4.44 (d, J=13.4 Hz, 1H), 3.86 (d, J=13.5 Hz, 1H), 3.30-3.29 (m, 2H), 3.25 (s, 1H), 3.05 (d, J=13.1 Hz, 1H), 2.90 (t, J=10.6 Hz, 1H), 2.58 (d, J=3.5 Hz, 3H), 2.24 (s, 3H), 2.10-1.81 (m, 4H), 1.37 (d, J=6.1 Hz, 3H).

[0587] The following examples in Table 7 were synthesized using the above procedure with the corresponding starting materials and intermediates.

TABLE-US-00013 TABLE 7 Example No. Structure Chemical Name .sup.1HNMR & MS: (M + H).sup.+ 69 [00254] embedded image 4-((4-acetyl-3-fluoro-6-((5- methyl-1H-pyrazol-3-yl) amino)pyridin-2-yl)methyl)-1- (3-chloro-2-fluorobenzyl) piperidine-4-carboxylic acid .sup.1H NMR (400 MHz, MeOD) δ 7.66 (t, J = 7.7 Hz, 2H), 7.32 (t, J = 7.9 Hz, 1H), 7.16 (d, J = 4.0 Hz, 1H), 6.13 (s, 1H), 4.46 (s, 2H), 3.64-3.49 (m, 4H), 3.12 (t, J = 12.6 Hz, 2H), 2.64 (d, J = 3.6 Hz, 3H), 2.48- 2.43 (m, 2H), 2.45 (s, 3H), 2.15 (t, J = 12.4 Hz, 2H). MS: 518 (M + H).sup.+ 70 [00255] embedded image (2R,4R)-4-((4-acetyl-5-fluoro- 6-((5-methyl-1H-pyrazol- 3-yl)amino)pyridin-2-yl) methyl)-1-(3-chloro-2-fluoro benzyl)-2-methylpiperidine- 4-carboxylic acid .sup.1H NMR (400 MHz, MeOD) δ 7.70 (t, J = 7.3 Hz, 1H), 7.62 (t, J = 7.0 Hz, 1H), 7.36 (t, J = 7.8 Hz, 1H), 7.21 (s, 1H), 6.25 (s, 1H), 4.42 (s, 1H), 3.99 (s, 1H), 3.42 (d, J = 59.9 Hz, 5H), 2.68 (d, J = 3.5 Hz, 3H), 2.44 (s, 3H), 2.24- 1.94 (m, 4H), 1.59 (s, 3H). MS: 532 (M + H).sup.+

Example 71

(2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((4-(1,1-difluoroethyl)-3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid

Step 1: tert-butyl(2R,4R)-4-((4-acetyl-6-chloro-3 fluoropyridin-2 yl)methyl)-2-methylpiperidine-4-carboxylate

[0588] ##STR00256##

[0589] To a solution of di-tert-butyl (2R,4R)-4-((6-chloro-4-(1-ethoxyvinyl)-3-fluoropyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate (346 mg, 674.411 μmol) in DCM (15 mL) was added trifluoroacetic acid (1.5 mL) at room temperature. The reaction mixture was stirred for 4 h before it was quenched with sodium bicarbonate solution at 0° C. The resulting mixture was extracted with DCM (100 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound (340 mg) as a crude yellow oil. LCMS (ESI, m/z): 385 [M+H].sup.+.

Step 2: tert-butyl (2R,4R)-4-((4-acetyl-6-chloro-3-fluoropyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylate

[0590] ##STR00257##

[0591] Following the procedure analogous to that described in Step 4 for the synthesis of Example 5, tert-butyl(2R,4R)-4-((4-acetyl-6-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylate (340 mg) was converted to the title compound (148 mg, Y=32%) as a yellow oil. LCMS (ESI, m/z): 527 [M+H].sup.+.

Step 3: tert-butyl (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((6-chloro-4-(1,1-difluoroethyl)-3-fluoropyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylate

[0592] ##STR00258##

[0593] To a solution of tert-butyl(2R,4R)-4-((4-acetyl-6-chloro-3-fluoropyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylate (133 mg, 345.570 μmol) in toluene (5 mL) was added bis(2-methoxyethyl)aminosulfur trifluoride (377 mg, 1.704 mmol) under nitrogen. The reaction mixture was stirred at 75° C. for 10 h before it was quenched with sodium bicarbonate solution at 0° C. The resulting mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by TLC to afford the title compound (82 mg, Y=43%) as a white solid. LCMS (ESI, m/z): 549[M+H].sup.+.

Step 4: tert-butyl (2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-4-(1,1-difluoroethyl)-3-fluoropyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylate

[0594] ##STR00259##

[0595] Following the procedure analogous to that described in Step 2 for the synthesis of Example 5, tert-butyl (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((6-chloro-4-(1,1-difluoroethyl)-3-fluoropyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylate (82 mg, 149.246 μmol) was converted to the title compound (72 mg, 73% yield) as a white solid. LCMS (ESI, m/z): 666 [M+H].sup.+.

Step 5: (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((4-(1,1-difluoroethyl)-3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid

[0596] ##STR00260##

[0597] Following the procedure analogous to that described in Step 5 for the synthesis of Example 5, tert-butyl(2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)-amino)-4-(1,1-difluoroethyl)-3-fluoropyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylate (72 mg, 108.077 μmol) was converted to the title compound (21 mg, Y=70%) as a white solid. LCMS (ESI, m/z): 554[M+H].sup.+. .sup.1H NMR (400 MHz, DLCMS (ESI, m/z)O) δ 7.77 (d, J=28.1 Hz, 2H), 7.35 (d, J=7.2 Hz, 1H), 7.15 (s, 1H), 6.18 (s, 1H), 4.80 (d, J=12.7 Hz, 1H), 4.38 (s, 2H), 3.99-4.014.38 (s, 1H), 3.39 (d, J=14.4 Hz, 3H), 3.28-3.27 (d, J=13.2 Hz, 1H), 3.13-3.11 (s, 1H), 2.25 (s, 3H), 2.03-2.02 (d, J=11.1 Hz, 2H), 2.01-1.95 (d, J=19.5 Hz, 2H), 1.44 (d, J=5.3 Hz, 3H), 1.36-1.15 (m, 1H).

Example 72

(2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((4-chloro-3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid

Step 1: di-tert-butyl-(2R,4R)-4-((4,6-dichloro-3-fluoropyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate

[0598] ##STR00261##

[0599] A solution of diisopropylamine (3.37 g, 33.304 mmol) in THF (15 mL) was added n-butyl lithium (2.5 M) in hexane (11 mL, 27.5 mmol) dropwise at −78° C. under nitrogen. The resulting solution was stirred at 0° C. for 30 min before it was added a solution of INT C3 (6.30 g, 14.223 mmol) in THF (15 ml) at −78° C. The resulting solution was stirred at −40° C. for 1 h.

[0600] A solution of hexachloroethane (2.38 g, 10.053 mmol) in THF (15 ml) was added dropwise to above solution at −78° C. The resulting solution was stirred at −40° C. for 1 h. The reaction was quenched with saturated aqueous NH4Cl aqueous solution. The resulting mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by C18 reversed phase column chromatography eluting with H2O/ACN to afford di-tert-butyl-(2R,4R)-4-((4,6-dichloro-3-fluoropyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate (2.30 g, Y=34%) as yellow oil. LCMS (ESI, m/z): 477 [M+H].sup.+.

Step 2: di-tert-butyl-(2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-4-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate

[0601] ##STR00262##

[0602] A mixture of di-tert-butyl-(2R,4R)-4-((4,6-dichloro-3-fluoropyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate (2.3 g, 4.818 mmol), tris(dibenzylideneacetone)dipalladium (437 mg, 477.233 μmol), dimethylbisdiphenylphosphinoxanthene (198 mg, 953.955 μmol), 1-tert-butyl-3-methyl-1H-pyrazol-5-amine (797 mg, 5.202 mmol) and Cs.sub.2CO.sub.3 (3137 mg, 9.628 mmol) in N,N-dimethylacetamide (180 ml) was stirred at 110° C. for 5 h under nitrogen. The resulting solution was cooled to room temperature, diluted with brine and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by C18 reverse phase chromatography eluting with H.sub.2O/ACN to afford the title compound (1.38 g, Y=48%) as a yellow solid. LCMS (ESI, m/z): 594 [M+H].sup.+.

Step 3: tert-butyl-(2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-4-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylate

[0603] ##STR00263##

[0604] A solution of di-tert-butyl-(2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-4-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate (1.38 g, 2.323 mmol) in dichloromethane (20 ml) was added trifluoroacetic acid (2 ml) and stirred at room temperature for 4 h. After completion, the reaction was quenched with saturated sodium bicarbonate aqueous solution (100 ml) and extracted with DCM. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by C18 reverse phase chromatography eluting with H.sub.2O/CH.sub.3CN/0.03 formic acid to afford (1.24 g, Y=69%) of the title compound as a yellow solid. LCMS (ESI, m/z): 494 [M+H].sup.+.

Step 4: tert-butyl-(2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-4-chloro-3-fluoropyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylate

[0605] ##STR00264##

[0606] A mixture of tert-butyl-(2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-4-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylate (792 mg, 1.603 mmol), potassium carbonate (0.69 g, 4.993 mmol) and 1-(bromomethyl)-3-chloro-2-fluorobenzene (0.4 g, 1.790 mmol) in ACN (20 mL) was stirred for 6 h at room temperature. After completion, the resulting mixture was filtered and concentrated under vacuum. The crude product was purified by silica gel column chromatography eluting with EtOAc/hexane (0˜30%) to afford (910 g, Y=89%) of the title compound as a yellow solid. LCMS (ESI, m/z): 636 [M+H].sup.+.

Step 5: (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((4-chloro-3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid

[0607] ##STR00265##

[0608] A solution of tert-butyl-(2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-4-chloro-3-fluoropyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylat e (910 mg, 1.429 mmol) in formic acid (10 mL) was stirred at reflux for 4 h. After completion, the resulting solution was concentrated. The residue was dissolved in water (40 mL) at 0° C. and adjusted PH=6-7 with sodium hydroxide aqueous solution (5 M). The resulting mixture was extracted with DCM (3×100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by C18 reverse phase chromatography eluting with MeOH/water to afford (612 mg, 1.167 mmol, Y=82%) of the title compound as a white solid. LCMS (ESI, m/z): 524 [M+H].sup.+. .sup.1H NMR (400 MHz, MeOD) δ 7.50 (dt, J=18.9, 7.1 Hz, 2H), 7.23 (t, J=7.9 Hz, 1H), 7.00 (s, 1H), 5.86 (s, 1H), 4.40 (d, J=13.6 Hz, 1H), 3.79 (t, J=18.0 Hz, 1H), 3.23 (s, 2H), 3.23-3.02 (m, 1H), 3.02 (s, 1H), 2.83 (s, 1H), 2.24 (s, 3H), 2.08-1.86 (m, 4H), 1.37 (d, J=6.0 Hz, 3H).

[0609] The following examples in Table 8 were synthesized using the above procedure with the corresponding starting materials and intermediates.

TABLE-US-00014 TABLE 8 Example No. Structure Chemical Name .sup.1HNMR & MS: (M + H).sup.+ 73 [00266] embedded image (2R,4R)-1-(3-chloro-2-fluoro benzyl)-4-((4-chloro-5-fluoro- 6-((5-methyl-1H-pyrazol-3- yl)amino)pyridin-2-yl)methyl)- 2-methylpiperidine-4- carboxylic acid .sup.1H NMR (400 MHz, MeOD) δ 7.67 (t, J = 7.6 Hz, 2H), 7.33 (t, J = 7.8 Hz, 1H), 7.14 (t, J = 18.3 Hz, 1H), 6.23 (s, 1H), 4.94 (d, J = 11.1 Hz, 2H), 4.46 (t, J = 21.8 Hz, 1H), 4.08 (d, J = 6.3 Hz, 1H), 3.69-3.38 (m, 3H), 2.46 (s, 3H), 2.21-1.92 (m, 4H), 1.58 (d, J = 6.0 Hz, 3H). MS: 524 (M + H).sup.+ 74 [00267] embedded image (2R,4R)-1-(3-chloro-2-fluoro benzyl)-4-((4-chloro-3,5- difluoro-6-((5-methyl-1H-pyrazol- 3-yl)amino)pyridin-2-yl) methyl)-2-methylpiperidine-4- carboxylic acid .sup.1H NMR (400 MHz, MeOD) δ 7.67 (dt, J = 19.3, 7.0 Hz, 2H), 7.36 (t, J = 7.9 Hz, 1H), 6.25 (s, 1H), 4.45 (d, J = 13.0 Hz, 1H), 4.00 (s, 1H), 3.51 (dd, J = 53.6, 35.6 Hz, 4H), 2.44 (s, 3H), 2.26 (d, J = 12.9 Hz, 2H), 2.08 (d, J = 25.5 Hz, 3H), 1.59 (s, 3H). MS: 542 (M + H).sup.+

Example 75

(2R,4R)-4-((4-(azetidin-1-yl)-3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylic acid

[0610] ##STR00268##

Step 1: di-tert-butyl(2R,4R)-4-((4-(azetidin-1-yl)-6-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate

[0611] ##STR00269##

[0612] To a solution of di-tert-butyl (2R,4R)-4-((4,6-dichloro-3-fluoropyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate (102 mg, 213.659 μmol) in 1-Methylpyrrolidin-3-one (5 mL) was added azetidine (64 mg, 1.121 mmol) and N,N-diisopropylethylamine (123 mg, 951.700 μmol). The resulting mixture was stirred at 110° C. for 2 h before was cooled to room temperature. The mixture was added brine (15 mL) and extracted with EtOAc (60 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography eluting with EtOAc/hexane (10˜20%) to afford the title compound (136 mg, crude) as a white oil. LCMS (ESI, m/z): 498 [M+H].sup.+.

Step 2: Di-tert-butyl (2R,4R)-4-((4-(azetidin-1-yl)-6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-3-fluoropyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate

[0613] ##STR00270##

[0614] Following the procedure analogous to that described in Step 2 for the synthesis of Example 5, di-tert-butyl (2R,4R)-4-((4-(azetidin-1-yl)-6-chloro-3-fluoro pyridin-2-yl)methyl)-2-methyl piperidine-1,4-dicarboxylate (136 mg, 273.076 μmol) was converted to the title compound (132 mg, Y=78%) as a white oil. LCMS (ESI, m/z): 615[M+H].sup.+.

Step 3: Tert-butyl (2R,4R)-4-((4-(azetidin-1-yl)-6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)-amino)-3-fluoropyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylate

[0615] ##STR00271##

[0616] Following the procedure analogous to that described in Step 3 for the synthesis of Example 5, di-tert-butyl (2R,4R)-4-((4-(azetidin-1-yl)-6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-3-fluoropyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate (132 mg, 214.707 μmol) was converted to the title compound (115 mg) as a crude yellow oil. LCMS (ESI, m/z): 515 [M+H].sup.+.

Step 4: tert-butyl (2R,4R)-4-((4-(azetidin-1-yl)-6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-3-fluoropyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylate

[0617] ##STR00272##

[0618] Following the procedure analogous to that described in Step 4 for the synthesis of Example 5, tert-butyl (2R,4R)-4-((4-(azetidin-1-yl)-6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-3-fluoropyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylate (115 mg, 223.441 μmol) was converted to the title compound (102 mg, Y=69%) as a yellow oil. LCMS (ESI, m/z): 657[M+H].sup.+.

Step 5: (2R,4R)-4-((4-(azetidin-1-yl)-3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl) methyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylic acid

[0619] ##STR00273##

[0620] Following the procedure analogous to that described in Step 5 for the synthesis of Example 5, tert-butyl (2R,4R)-4-((4-(azetidin-1-yl)-6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-3-fluoropyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylate (102 mg, 155.196 μmol) was converted to the title compound (21 mg, Y=25%) as a white solid. LCMS (ESI, m/z): 545[M+H].sup.+. .sup.1H NMR (400 MHz, MeOD) δ 7.71-7.67 (t, J=7.4 Hz, 1H), 7.56-7.54 (t, J=6.8 Hz, 1H), 7.35-7.33 (t, J=8.0 Hz, 1H), 5.73 (s, 1H), 5.65-5.63 (d, J=7.3 Hz, 1H), 4.35 (s, 5H), 3.84 (s, 2H), 3.43 (dd, J=29.3, 16.3 Hz, 4H), 2.54 (dd, J=15.3, 7.8 Hz, 3H), 2.29 (s, 3H), 2.21-2.19 (m, 2H), 2.06-2.05 ((m, 1H) 1.60 (s, 3H).

Example 76

(2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-4-(1-hydroxyethyl)-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid

Step 1: tert-butyl (2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-3-fluoro-4-(1-hydroxyethyl)pyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylate

[0621] ##STR00274##

[0622] NaBH4 (25 mg, 660.809 μmol) was added to a mixture of tert-butyl (2R,4R)-4-((4-acetyl-6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-3-fluoropyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylate (180 mg, 279.419 μmol) in methanol (5 mL). The resulting mixture was stirred at room temperature for 1.5 h. After completion, the resulting solution was diluted with brine (10 ml) and extracted with EtOAc (10 ml). The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give tert-butyl (2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-3-fluoro-4-(1-hydroxyethyl) pyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylate (222 mg) as a white solid. LCMS (ESI, m/z): 647 [M+H].sup.+.

Step 2: (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-4-(1-hydroxyethyl)-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid

[0623] ##STR00275##

[0624] Following the procedure analogous to that described in step 5 of Example 5, tert-butyl (2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-3-fluoro-4-(1-hydroxyethyl) pyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylate (64 mg, 99.039 μmol) was converted to the title compound (46 mg) as a white solid. LCMS (ESI, m/z): 571 [M+H].sup.+. .sup.1H NMR (400 MHz, MeOD) δ 7.68 (t, J=7.6 Hz, 1H), 7.55 (t, J=7.1 Hz, 1H), 7.33 (t, J=7.8 Hz, 1H), 7.04 (d, J=4.3 Hz, 1H), 5.06 (q, J=6.4 Hz, 1H), 4.93 (s, 1H), 4.34 (d, J=13.1 Hz, 1H), 3.89 (s, 1H), 3.40 (s, 3H), 3.31 (s, 2H), 2.38 (s, 3H), 2.16 (t, J=32.8 Hz, 4H), 1.58 (d, J=5.6 Hz, 3H), 1.44 (d, J=6.5 Hz, 3H).

Example 77

(2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-4-(1-fluoroethyl)-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid

Step 1: tert-butyl (2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-3-fluoro-4-(1-fluoroethyl)pyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylate

[0625] ##STR00276##

[0626] DAST (64 mg, 397.050 μmol) was added to a solution of tert-butyl (2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-3-fluoro-4-(1-hydroxyethyl)pyridin-2-yl)meth yl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylate (120 mg, 185.699 μmol) in DCM (3 mL). The resulting solution was stirred at 0° C. for 1 h. The solution was quenched with saturated NaHCO.sub.3 aqueous and extract with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl (2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-3-fluoro-4-(1-hydroxyethyl)pyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylate (81 mg) as a yellow oil. LCMS (ESI, m/z): 649 [M+H].sup.+.

Step 2: (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-4-(1-fluoroethyl)-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid

[0627] ##STR00277##

[0628] Following the procedure analogous to that described in step 5 of Example 5, tert-butyl (2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-3-fluoro-4-(1-fluoroethyl) pyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylate (81 mg, 124.961 μmol) was converted to the title compound (56 mg) as a white solid. LCMS (ESI, m/z): 573 [M+H].sup.+. .sup.1H NMR (400 MHz, MeOD) δ 7.68 (t, J=7.5 Hz, 1H), 7.54 (t, J=6.9 Hz, 1H), 7.33 (t, J=7.9 Hz, 1H), 6.92 (d, J=3.9 Hz, 1H), 6.01 (s, 1H), 5.88 (dd, J=46.9, 6.5 Hz, 1H), 4.34 (d, J=12.7 Hz, 1H), 3.90 (s, 1H), 3.36 (d, J=36.1 Hz, 5H), 2.38 (s, 3H), 2.33-1.91 (m, 4H), 1.73-1.47 (m, 6H).

Example 78

(2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((5-fluoro-4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid

Step 1: di-tert-butyl (2R,4R)-4-((6-chloro-5-fluoro-4-methylpyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate

[0629] ##STR00278##

[0630] A solution of diisopropylamine (2.46 g, 24.311 mmol) in THF (10 ml) was added n-butyl lithium 2.5 M in THF (8.4 ml, 21086 mmol) at −70˜-60° C. under nitrogen. The solution was stirred for 1 h at −10° C.˜0° C. The resulting solution was slowly added INT C1 (4.67 g, 10.543 mmol) in THF (10 ml). The solution was stirred at −70° C.˜-60° C. for 1 h.

[0631] A solution of iodomethane (1.82 g, 12.822 mmol) in THF (2 ml) was added to the above solution. The resulting solution was stirred at −70° C.˜-60° C. for 2 h. After completion, the reaction was quenched with saturated ammonium chloride aqueous solution and extracted with EtOAc. The organic layer was combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by C18 reverse phase chromatography eluting with H.sub.2O/ACN to afford 2.84 g of the title compound as a yellow oil. LCMS (ESI, m/z): 457 [M+H].sup.+.

Step 2: di-tert-butyl-(2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-5-fluoro-4-methylpyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate

[0632] ##STR00279##

[0633] A mixture of di-tert-butyl-(2R,4R)-4-((6-chloro-5-fluoro-4-methylpyridin-2-yl) methyl)-2-methylpiperidine-1,4-dicarboxylate (2.77 g, 6.062 mmol), tris(dibenzylideneacetone)dipalladium (1.63 g, 1.780 mmol), dimethylbisdiphenylphosphinoxanthene (1.06 g, 1.832 mmol), 1-tert-butyl-3-methyl-1H-pyrazol-5-amine (1.22 g, 7.962 mmol) and K.sub.3PO.sub.4 (5.56 g, 26.194 mmol) in 1,4-dioxane (30 ml) was stirred at 110° C. for 5 h under nitrogen. The resulting solution was cooled to room temperature, diluted with brine and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by C18 reverse phase chromatography eluting with H.sub.2O/ACN to afford (2.92 g, 5.089 mmol, Y=83%) of the title compound as a yellow solid. LCMS (ESI, m/z): 574 [M+H].sup.+.

Step 3: tert-butyl-(2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-5-fluoro-4-methylpyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylate

[0634] ##STR00280##

[0635] A solution of di-tert-butyl-(2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-5-fluoro-4-methylpyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate (2.92 g, 5.089 mmol) in dichloromethane (30 ml) was added trifluoroacetic acid (3 ml) and stirred at room temperature for 4 h. After completion, the reaction was quenched with saturated sodium bicarbonate aqueous solution (100 ml) and extracted with DCM. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by C18 reverse phase column chromatography eluting with H.sub.2O/CAN/0.03 formic acid to afford (1.71 g, 3.610 mmol, Y=71%) of the title compound as a yellow solid. LCMS (ESI, m/z): 474 [M+H].sup.+.

Step 4: tert-butyl-(2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-5-fluoro-4-methylpyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylate

[0636] ##STR00281##

[0637] A mixture of tert-butyl (2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-5-fluoro-4-methylpyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylate (1.70 g, 3.589 mmol) and potassium carbonate (2.54 g, 18.387 mmol), 1-(bromomethyl)-3-chloro-2-fluorobenzene (0.91 g, 4.072 mmol) in ACN (20 mL) was stirred for 6 h at room temperature. After completion, the resulting mixture was filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with EtOAc/n-hexane (0˜30%) to afford (1.96 g, 3.818 mmol, Y=89%) of the title compound as a yellow solid. LCMS (ESI, m/z): 616 [M+H].sup.+.

Step 5: (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((5-fluoro-4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid

[0638] ##STR00282##

[0639] A solution of tert-butyl (2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-5-fluoro-4-methylpyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylate (1.95 g, 3.165 mmol) in formic acid (15 mL) was stirred at reflux for 1.5 h. After completion, the resulting solution was concentrated. The residue was dissolved in water (40 mL) at 0° C., and adjusted PH=6˜7 with sodium hydroxide aqueous solution (5 M). The resulting mixture was extracted with DCM. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by C18 reverse phase column chromatography eluting with MeOH/water to afford (1.595 g, 2.937 mmol, Y=93%) of the title compound as a white solid. LCMS (ESI, m/z): 504 [M+H].sup.+. .sup.1H NMR (400 MHz, MeOD) δ 7.47-7.33 (m, 2H), 7.12 (t, 1H), 6.47 (d, J=4.5 Hz, 1H), 5.93 (s, 1H), 4.29 (d, J=13.6 Hz, 1H), 3.68 (d, J=13.5 Hz, 1H), 3.13 (s, 1H), 3.04 (d, J=13.4 Hz, 1H), 2.96 (d, J=13.5 Hz, 1H), 2.87 (d, J=12.3 Hz, 1H), 2.75 (t, 1H), 2.16 (s, 3H), 2.13 (s, 3H), 1.83 (d, J=11.2 Hz, 2H), 1.75 (t, 2H), 1.22 (d, J=6.0 Hz, 3H).

[0640] The following examples in Table 9 were synthesized using the above procedure with the corresponding starting materials and intermediates.

TABLE-US-00015 TABLE 9 Example No. Structure Chemical Name .sup.1HNMR & MS: (M + H).sup.+ 79 [00283] embedded image 1-(3-chloro-2-fluorobenzyl)- 4-((5-fluoro-4-methyl-6-((5- methyl-1H-pyrazol-3-yl) amino)pyridin-2-yl)methyl) piperidine-4-carboxylic acid .sup.1H NMR (400 MHz, MeOD) δ 7.73-7.59 (m, 2H), 7.33 (t, J = 7.9 Hz, 1H), 6.87 (d, J = 4.9 Hz, 1H), 6.13 (s, 1H), 4.45 (s, 2H), 3.56 (d, J = 12.7 Hz, 2H), 3.40-3.50 (m, 1H), 3.14 (s, 2H), 3.18-3.09 (m, 1H), 2.42 (s, 3H), 2.40 (d, J = 19.8 Hz, 2H), 2.37 (s, 3H), 2.07 (t, J = 12.8 Hz, 2H). MS: 490 (M + H).sup.+

Example 80

(2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)-4-propionylpyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid

Step 1: di-tert-butyl-(2R,4R)-4-((6-chloro-3-fluoro-4-(1-hydroxypropyl)pyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate

[0641] ##STR00284##

[0642] A solution of diisopropylamine (228 mg, 2.253 mmol) in THF (2 ml) was cooled to −78° C. under nitrogen. n-butyl lithium 2.5 M in THF (1.0 ml, 2.500 mmol) was added. The resulting solution was stirred for 1 h at 0° C. and a solution of INT C3 (4.67 g, 10.543 mmol) in THF (2 ml) was slowly added. The resulting solution was stirred at −30° C.˜-40° C. for 1 h.

[0643] A solution of propionaldehyde (102 mg, 1.756 mmol) in THF (1 ml) was added to above solution at −70° C.˜−60° C. The resulting solution was stirred for 2 h. After completion, the reaction was quenched with saturated ammonium chloride aqueous solution and extracted with EtOAc. The organic layer was combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by C18 reverse phase chromatography eluting with H.sub.2O/ACN to afford the title compound (426 mg, Y=74%) as a white solid. LCMS (ESI, m/z): 501 [M+H].sup.+.

Step 2: di-tert-butyl-(2R,4R)-4-((6-chloro-3-fluoro-4-propionylpyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate

[0644] ##STR00285##

[0645] To a solution of di-tert-butyl-(2R,4R)-4-((6-chloro-3-fluoro-4-(1-hydroxy-propyl)pyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate (483 mg, 964.015 μmol) in DCM (10 ml) was added Dess-Martin periodinane (818 mg, 1.929 mmol). The reaction was stirred at room temperature for 2 h. The resulting mixture was added water and extracted with DCM. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by C18 reversed phase column chromatography eluting with H.sub.2O/ACN to afford di-tert-butyl (2R,4R)-4-((6-chloro-3-fluoro-4-propionyl pyridin-2-yl) methyl)-2-methylpiperidine-1,4-dicarboxylate (389 mg, Y=81%) as a yellow oil. LCMS (ESI, m/z): 499 [M+H].sup.+.

Step 3: di-tert-butyl-(2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)-amino)-3-fluoro-4-propionylpyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate

[0646] ##STR00286##

[0647] Following the procedure analogous to that described in Step 2 for the synthesis of Example 5, di-tert-butyl-(2R,4R)-4-((6-chloro-3-fluoro-4-propionylpyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate (389 mg, 779.538 μmol) was converted to the title compound (122 mg, Y=25%) as a yellow oil. LCMS (ESI, m/z): 616 [M+H].sup.+.

Step 4: tert-butyl-(2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-3-fluoro-4-propionylpyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylate

[0648] ##STR00287##

[0649] Following the procedure analogous to that described in Step 3 for the synthesis of Example 5, di-tert-butyl-(2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-3-fluoro-4-propionylpyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate (177 mg, 287.442 μmol) was converted to the title compound (148 mg) as a yellow oil. LCMS (ESI, m/z): 516 [M+H].sup.+.

Step 5: tert-butyl-(2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-3-fluoro-4-propionylpyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylate

[0650] ##STR00288##

[0651] Following the procedure analogous to that described in Step 4 for the synthesis of Example 5, tert-butyl-(2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-3-fluoro-4-propionylpyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylate (148 mg, 287.010 μmol) was converted to the title compound (112 mg, Y=59%) as a yellow oil. LCMS (ESI, m/z): 658 [M+H].sup.+.

Step 6: (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)-4-propionylpyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid

[0652] ##STR00289##

[0653] Following the procedure analogous to that described in Step 5 for the synthesis of Example 5, tert-butyl-(2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-3-fluoro-4-propionylpyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylate (112 mg, 170.156 μmol) was converted to the title compound 66 mg as a white solid. LCMS (ESI, m/z): 546 [M+H].sup.+. .sup.1H NMR (400 MHz, MeOD) δ 7.62-7.51 (m, 2H), 7.24 (t, J=7.9 Hz, 1H), 7.04 (t, J=6.7 Hz, 1H), 6.00 (s, 1H), 4.40-4.28 (m, 1H), 3.92 (s, 1H), 3.61-3.23 (m, 5H), 2.93 (d, J=7.0 Hz, 2H), 2.33 (s, 3H), 2.24-1.94 (m, 4H), 1.49 (t, J=21.0 Hz, 3H), 1.09 (t, J=7.1 Hz, 3H).

Example 81

(2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)-4-(methylsulfonyl) pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid

[0654] ##STR00290##

Step 1: di-tert-butyl (2R,4R)-4-((6-chloro-3-fluoro-4-(methylthio)pyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate

[0655] ##STR00291##

[0656] To a solution of di-tert-butyl (2R,4R)-4-((6-chloro-3-fluoro-4-iodopyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate (457 mg, 803.397 mol) in 1,4-Dioxane (15 mL) was added tris(dibenzylideneacetonyl)bis-palladium (153 mg, 167.082 μmol), sodium thiomethoxide (168 mg, 2.413 mmol), diisopropylethylamine (450 mg, 3.482 mmol), dimethylbisdiphenylphosphinoxanthene (217 mg, 375.032 mol) under nitrogen. The mixture was stirred for 3 h at 100° C. The resulting mixture was cooled to room temperature and diluted with water. The resulting solution was extracted with ethyl acetate (150 mL). The organic layer was washed with sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography eluting with EtOAc/hexane (10˜20%) to afford the title compound (380 mg, Y=90%) as a white solid. LCMS (ESI, m/z): 489[M+H].sup.+.

Step 2: di-tert-butyl (2R,4R)-4-((6-chloro-3-fluoro-4-(methylsulfonyl)pyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate

[0657] ##STR00292##

[0658] To a solution of di-tert-butyl (2R,4R)-4-((6-chloro-3-fluoro-4-(methylthio)pyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate (330 mg, 674.789 μmol) in DCM (20 mL) was added m-chloroperoxybenzoic acid (733 mg, 4.248 mmol) at room temperature. The mixture was stirred for 10 h. The resulting mixture was quenched with sodium bicarbonate solution and extracted with DCM (100 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by prep-TLC to afford the title compound (207 mg, Y=59%) as a white solid. LCMS (ESI, m/z): 521[M+H].sup.+.

Step 3: di-tert-butyl (2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-3-fluoro-4-(methylsulfonyl)pyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate

[0659] ##STR00293##

[0660] Following the procedure analogous to that described in step 2 for the synthesis of Example 5, di-tert-butyl (2R,4R)-4-((6-chloro-3-fluoro-4-(methylsulfonyl) pyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate (207 mg, 397.282 μmol) was converted to the title compound (212 mg, 83% yield) as a white solid. LCMS (ESI, m/z): 638[M+H].sup.+.

Step 4: tert-butyl (2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-3-fluoro-4-(methylsulfonyl)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylate

[0661] ##STR00294##

[0662] Following the procedure analogous to that described in step 3 for the synthesis of Example 5, di-tert-butyl (2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-3-fluoro-4-(methylsulfonyl)pyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate (212 mg, 332.391 μmol) was converted to the title compound (225 mg) as a crude white solid. LCMS (ESI, m/z): 538[M+H].sup.+.

Step 5: tert-butyl (2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-3-fluoro-4-(methylsulfonyl)pyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylate

[0663] ##STR00295##

[0664] Following the procedure analogous to that described in step 4 for the synthesis of Example 5, tert-butyl (2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-3-fluoro-4-(methylsulfonyl)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylate (225 mg, 418.458 μmol) was converted to the title compound (122 mg) as a white oil. LCMS (ESI, m/z): 680[M+H].sup.+.

Step 6: (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)-4-(methylsulfonyl)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid

[0665] ##STR00296##

[0666] Following the procedure analogous to that described in step 5 for the synthesis of Example 5, tert-butyl (2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-3-fluoro-4-(methylsulfonyl)pyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylate (122 mg, 418.458 μmol) was converted to the title compound (92 mg, Y=90%) as a white solid. LCMS (ESI, m/z): 568[M+H].sup.+. .sup.1H NMR (400 MHz, DLCMS (ESI, m/z)O-d6) δ9.56 (s, 1H), 9.32 (s, 1H), 7.76 (t, J=7.5 Hz, 1H), 7.58 (dd, J=18.3, 11.0 Hz, 2H), 7.38 (t, J=7.8 Hz, 1H), 6.14 (s, 1H), 4.85 (d, J=14.1 Hz, 2H), 4.32 (d, J=14.1 Hz, 2H), 3.46 (s, 2H), 3.34 (s, 3H), 3.28 (d, J=7.5 Hz, 2H), 3.18 (d, J=12.2 Hz, 1H), 2.21 (s, 3H), 1.94-1.84 (m, 2H), 1.45-1.47 (d, J=5.8 Hz, 3H).

Example 82

(2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((4-ethyl-5-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid

Step 1: di-tert-butyl-(2R,4R)-4-((6-chloro-4-ethyl-5-fluoropyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate

[0667] ##STR00297##

[0668] A solution of diisopropylamine (625 mg, 6.177 mmol) in THF (2 mL) was added n-butyl lithium (2.5 M) in hexane (2.0 mL, 5.00 mmol) dropwise below −40° C. The solution was stirred at 0° C. for 30 min. A solution of INT C3 (831 mg, 1.876 mmol) in THF (5 mL) was added below −70° C. The resulting solution was stirred at −40° C. for 1 h.

[0669] A solution of methyl iodide (430 mg, 3.029 mmol) in THF (2 ml) dropwise was added to above solution below −70° C. The resulting solution was stirred at −30° C. for 1 h. The reaction was quenched with saturated aqueous NH.sub.4Cl aqueous solution. The resulting mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by C18 reversed phase column chromatography eluting with H.sub.2O/ACN to afford di-tert-butyl-(2R,4R)-4-((6-chloro-4-ethyl-5-fluoropyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate (249 mg, Y=28%) as yellow oil. LCMS (ESI, m/z): 471 [M+H].sup.+.

Step 2: di-tert-butyl-(2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-4-ethyl-5-fluoropyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate

[0670] ##STR00298##

[0671] Following the procedure analogous to that described in Step 2 for the synthesis of Example 5, di-tert-butyl-(2R,4R)-4-((6-chloro-4-ethyl-5-fluoropyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate (249 mg, 528.658 μmol) was converted to the title compound (153 mg, Y=61%) as a yellow oil. LCMS (ESI, m/z): 588 [M+H].sup.+.

Step 3: tert-butyl-(2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-4-ethyl-5-fluoropyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylate

[0672] ##STR00299##

[0673] Following the procedure analogous to that described in Step 3 for the synthesis of Example 5, di-tert-butyl-(2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-4-ethyl-5-fluoropyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate (153 mg, 253.502 μmol) was converted to the title compound (78 mg, Y=63%) as a yellow oil. LCMS (ESI, m/z): 488 [M+H].sup.+.

Step 4: tert-butyl-(2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-4-ethyl-5-fluoropyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylate

[0674] ##STR00300##

[0675] Following the procedure analogous to that described in Step 4 for the synthesis of Example 5, tert-butyl-(2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-4-ethyl-5-fluoropyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylate (78 mg, 159.836 μmol) was converted to the title compound (61 mg, Y=61%) as a yellow oil. LCMS (ESI, m/z): 630 [M+H].sup.+.

Step 5: (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((4-ethyl-5-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid

[0676] ##STR00301##

[0677] Following the procedure analogous to that described in Step 5 for the synthesis of Example 5, tert-butyl-(2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-4-ethyl-5-fluoropyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylate (61 mg, 96.793 μmol) was converted to the title compound 16 mg as a white solid. LCMS (ESI, m/z): 518 [M+H].sup.+. .sup.1H NMR (400 MHz, MeOD) δ 7.70 (s, 2H), 7.36 (t, J=7.9 Hz, 1H), 6.99 (d, J=4.7 Hz, 1H), 6.15 (s, 1H), 3.50 (s, 2H), 3.33 (s, 2H), 3.32 (s, 2H), 2.78 (d, J=7.6 Hz, 2H), 2.44 (s, 3H), 2.08 (d, J=77.6 Hz, 5H), 1.62 (d, J=6.0 Hz, 3H), 1.30 (t, J=7.5 Hz, 3H).

Example 83

(2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((3′-fluoro-6′-((5-methyl-1H-pyrazol-3-yl)amino)-[2,4′-bipyridin]-2′-yl)methyl)-2-methylpiperidine-4-carboxylic acid

[0678] ##STR00302##

Step 1: di-tert-butyl (2R,4R)-4-((6′-chloro-3′-fluoro-[2,4′-bipyridin]-2′-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate

[0679] ##STR00303##

[0680] To a solution of di-tert-butyl (2R,4R)-4-((6-chloro-3-fluoro-4-iodopyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate (450 mg, 791.074 μmol) in THF (12 mL) and water (4 mL) was added 2-pyridineboronic acid (149 mg, 1.212 mmol), 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride (102 mg, 139.401 μmol), K.sub.3PO.sub.4 (914 mg, 4.306 mmol) under nitrogen. The reaction mixture was stirred for 3 h at 90° C. The reaction was cooled to room temperature. The resulting mixture was diluting with water and extracted with ethyl acetate (100 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by TLC to afford the title compound (87 mg, 22% yield) as a white oil. LCMS (ESI, m/z): 520[M+H].sup.+.

Step 2: (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((3′-fluoro-6′-((5-methyl-1H-pyrazol-3-yl)amino)-[2,4′-bipyridin]-2′-yl)methyl)-2-methylpiperidine-4-carboxylic acid

[0681] ##STR00304##

[0682] Following the procedure analogous to that described in step2, step3, step4, step5 for the synthesis of example 5, di-tert-butyl(2R,4R)-4-((6′-chloro-3′-fluoro-[2,4′-bipyridin]-2′-yl) methyl)-2-methylpiperidine-1,4-dicarboxylate (87 mg, 167.296 μmol) was converted to the title compound (14 mg) as a white solid. LCMS (ESI, m/z): 567[M+H].sup.+. .sup.1H NMR (400 MHz, DLCMS (ESI, m/z)O) δ 7.99-7.96 (t, J=7.3 Hz, 1H), 7.78-7.74 (t, J=7.6 Hz, 2H), 7.63-7.60 (t, J=7.2 Hz, 1H), 7.51-7.48 (dd, J=7.2, 5.4 Hz, 2H), 7.40-7.35 (t, J=7.8 Hz, 1H), 7.29-6.98 (m, 1H), 6.17 (s, 1H), 4.86 (d, J=12.9 Hz, 1H), 4.35 (d, J=7.8 Hz, 2H), 3.94 (s, 1H), 3.45 (d, J=12.6 Hz, 2H), 3.31 (t, J=16.8 Hz, 2H), 3.19 (d, J=11.9 Hz, 1H), 2.30 (m, 3H), 1.99-1.80 (m, 1H), 1.48-1.50 (t, J=10.6 Hz, 3H), 1.39-1.10 (m, 3H).

Example 84

(2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((4,5-dichloro-3-fluoro-6-((5-methyl-1H-pyrazol-3-yl) amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid

Step 1: di-tert-butyl-(2R,4R)-2-methyl-4-((4,5,6-trichloro-3-fluoropyridin-2-yl)methyl) piperidine-1,4-dicarboxylate

[0683] ##STR00305##

[0684] Following the procedure analogous to that described in Step 1 for the synthesis of Example 72, di-tert-butyl-(2R,4R)-4-((6-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate (1.50 g, 3.386 mmol) was converted to the title compound (1.38 g, Y=80%) as a yellow oil. LCMS (ESI, m/z): 511 [M+H].sup.+.

Step 2: di-tert-butyl-(2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-4,5-dichloro-3-fluoropyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate

[0685] ##STR00306##

[0686] Following the procedure analogous to that described in Step 2 for the synthesis of Example 5, di-tert-butyl-(2R,4R)-2-methyl-4-((4,5,6-trichloro-3-fluoropyridin-2-yl)methyl)piperidine-1,4-dicarboxylate (2.10 g, 4.103 mmol) was converted to the title compound (1.21 g, Y=47%) as a yellow oil. LCMS (ESI, m/z): 628 [M+H].sup.+.

Step 3: tert-butyl-(2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-4,5-dichloro-3-fluoropyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylate

[0687] ##STR00307##

[0688] Following the procedure analogous to that described in Step 3 for the synthesis of Example 5, di-tert-butyl-(2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-4,5-dichloro-3-fluoropyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate (1.21 g, 1.925 mmol) was converted to the title compound (0.98 g, Y=96%) as a yellow oil. LCMS (ESI, m/z): 528 [M+H].sup.+.

Step 4: tert-butyl-(2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-4,5-dichloro-3-fluoropyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylate

[0689] ##STR00308##

[0690] Following the procedure analogous to that described in Step 4 for the synthesis of Example 5, tert-butyl-(2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-4,5-dichloro-3-fluoropyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylate (0.98 g, 1.856 mmol) was converted to the title compound (0.86 g, Y=69%) as a yellow oil. LCMS (ESI, m/z): 671 [M+H].sup.+.

Step 5: (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((4,5-dichloro-3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid

[0691] ##STR00309##

[0692] Following the procedure analogous to that described in Step 5 for the synthesis of Example 5, tert-butyl-(2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-4,5-dichloro-3-fluoropyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylate (0.86 g, 1.282 mmol) was converted to the title compound 589 mg as a white solid. LCMS (ESI, m/z): 558 [M+H].sup.+. .sup.1H NMR (400 MHz, MeOD) δ 7.70 (dd, J=14.9, 7.0 Hz, 2H), 7.35 (t, J=7.9 Hz, 1H), 6.40 (s, 1H), 4.93 (s, 2H), 4.53 (d, J=13.5 Hz, 1H), 4.18-3.99 (m, 1H), 3.74-3.50 (m, 3H), 2.49 (s, 3H), 2.28-2.06 (m, 4H), 1.61 (d, J=6.2 Hz, 3H).

Example 85

(2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-4-isobutyryl-6-((5-methyl-1H-pyrazol-3-yl) amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid

Step 1: di-tert-butyl (2R,4R)-4-((6-chloro-3-fluoro-4-formylpyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate

[0693] ##STR00310##

[0694] Following the procedure analogous to that described in Step 1 for the synthesis of Example 64, INT C3 (1.22 g, 2.754 mmol) was converted to the title compound (1.071 g, 2.274 mmol) as a white solid. LCMS (ESI, m/z): 471 [M+H].sup.+.

Step 2: di-tert-butyl (2R,4R)-4-((6-chloro-3-fluoro-4-(1-hydroxy-2-methylpropyl)-pyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate

[0695] ##STR00311##

[0696] To a solution of (2R,4R)-4-((6-chloro-3-fluoro-4-formylpyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate (839 mg, 1.781 mmol) in THF (10 mL) was added isopropylmagnesium bromide (2.8 ml, 1 mol/L) at 0˜5° C. under nitrogen. The resulting solution was stirred for 2 h. After completion, the reaction solution was quenched with saturated ammonium chloride aqueous solution and extracted with ethyl acetate. The organic layer was washed with brine, dried anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by prep-TLC using a gradient ethyl acetate/Hex=1/5 solvent to give (2R,4R)-4-((6-chloro-3-fluoro-4-(1-hydroxy-2-methylpropyl)pyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate (323 mg, 0.627 mmol) as a white solid. LCMS (ESI, m/z): 515 [M+H].sup.+.

Step 3: di-tert-butyl (2R,4R)-4-((6-chloro-3-fluoro-4-isobutyrylpyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate

[0697] ##STR00312##

[0698] A solution of (2R,4R)-4-((6-chloro-3-fluoro-4-(1-hydroxy-2-methylpropyl)pyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate (323 mg, 627.116 μmol), Dess-Martin periodinane (877.753 mg, 2.069 mmol) in dichloromethane (10 mL) was stirred at room temperature for 5 h. The reaction solution was quenched with saturated sodium thiosulfate solution and extracted with DCM. The organic layer was concentrated under reduced pressure. The crude product was purified by prep-TLC using a gradient ethyl acetate/Hex=1/5 to give di-tert-butyl (2R,4R)-4-((6-chloro-3-fluoro-4-isobutyrylpyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate (315 mg) as a yellow oil. LCMS (ESI, m/z): 513 [M+H].sup.+.

Step 4: di-tert-butyl (2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-3-fluoro-4-isobutyrylpyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate

[0699] ##STR00313##

[0700] Following the procedure analogous to that described in step 2 of Example 5, di-tert-butyl (2R,4R)-4-((6-chloro-3-fluoro-4-isobutyrylpyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate (315 mg, 0.613 mmol) was converted to the title compound (333 mg) as a yellow solid. LCMS (ESI, m/z): 630 [M+H].sup.+.

Step 5: tert-butyl (2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-3-fluoro-4-isobutyrylpyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylate

[0701] ##STR00314##

[0702] Following the procedure analogous to that described in step 3 of Example 5, di-tert-butyl (2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-3-fluoro-4-isobutyrylpyridin-2-yl) methyl)-2-methylpiperidine-1,4-dicarboxylate (333 mg, 0.529 mmol) was converted to the title compound (233 mg) as a yellow solid. LCMS (ESI, m/z): 530 [M+H].sup.+.

Step 6: tert-butyl (2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-3-fluoro-4-isobutyrylpyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylate

[0703] ##STR00315##

[0704] Following the procedure analogous to that described in step 4 of Example 5, tert-butyl (2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-3-fluoro-4-isobutyrylpyridin-2-yl) methyl)-2-methylpiperidine-4-carboxylate (233 mg, 0.440 mmol) was converted to the title compound (375 mg) as a yellow solid. LCMS (ESI, m/z): 672 [M+H].sup.+.

Step 7: (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-4-isobutyryl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid

[0705] ##STR00316##

[0706] Following the procedure analogous to that described in step 5 of Example 5, tert-butyl (2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-3-fluoro-4-isobutyrylpyridin-2-yl) methyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylate (375 mg, 0.558 mmol) was converted to the title compound (94 mg) as a white solid. LCMS (ESI, m/z): 560 [M+H].sup.+. .sup.1H NMR (400 MHz, MeOD) δ 8.47 (d, J=8.9 Hz, 1H), 8.40 (d, J=5.0 Hz, 1H), 7.24 (d, J=4.5 Hz, 1H), 6.82 (dd, J=16.7, 10.6 Hz, 1H), 6.30 (dd, J=16.7, 1.9 Hz, 1H), 5.81 (dd, J=10.6, 1.9 Hz, 1H), 4.70 (s, 2H), 4.60-4.37 (m, 2H), 3.83 (t, J=13.6 Hz, 2H), 2.89-2.69 (m, 2H), 2.03 (d, J=10.7 Hz, 3H), 1.51 (d, J=4.1 Hz, 2H), 1.46 (t, J=6.7 Hz, 3H), 1.29 (s, 1H), 1.18 (d, J=6.8 Hz, 3H), 1.00 (dd, J=12.2, 6.8 Hz, 3H).

Example 86

2-(((2R,4R)-4-carboxy-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidin-4-yl)methyl)-3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)isonicotinic acid

Step 1: tert-butyl-(2R,4R)-4-((6-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylate

[0707] ##STR00317##

[0708] Following the procedure analogous to that described in Step 3 for the synthesis of Example 5, INT C3 (3.79 g, 8.556 mmol) was converted to the title compound (2.63 g, Y=89%) as a yellow oil. LCMS (ESI, m/z): 343 [M+H].sup.+.

Step 2: tert-butyl-(2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((6-chloro-3-fluoropyridin-2-yl) methyl)-2-methylpiperidine-4-carboxylate

[0709] ##STR00318##

[0710] Following the procedure analogous to that described in Step 4 for the synthesis of Example 5, tert-butyl-(2R,4R)-4-((6-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylate (2.63 g, 7.671 mmol) was converted to the title compound (2.09 g, Y=56%) as a yellow oil. LCMS (ESI, m/z): 485 [M+H].sup.+.

Step 3: 2-(((2R,4R)-4-(tert-butoxycarbonyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidin-4-yl)methyl)-6-chloro-3-fluoroisonicotinic acid

[0711] ##STR00319##

[0712] A solution of diisopropylamine (1.18 g, 11.661 mmol) in THF (5 mL) was added n-Butyl lithium (2.5 M) in hexane (3.5 mL, 8.75 mmol) at −78° C. under nitrogen. The solution was stirred at 0° C. for 30 min. A solution of tert-butyl-(2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((6-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylate (2.09 g, 4.306 mmol) in THF (5 ml) was added dropwise to above solution. The resulting solution was stirred at −40° C. for 1 h. Carbon dioxide was bubbled into the reaction and the solution was stirred at −60° C. for 1 h. The resulting solution was quenched with saturated aqueous NH.sub.4Cl aqueous solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by C18 reversed phase column chromatography eluting with H.sub.2O/ACN to afford 2-(((2R,4R)-4-(tert-butoxycarbonyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidin-4-yl)methyl)-6-chloro-3-fluoroisonicotinic acid (906 mg, Y=40%) as white solid. LCMS (ESI, m/z): 529 [M+H].sup.+.

Step 4: Methyl-2-(((2R,4R)-4-(tert-butoxycarbonyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidin-4-yl)methyl)-6-chloro-3-fluoroisonicotinate

[0713] ##STR00320##

[0714] To a solution of 2-(((2R,4R)-4-(tert-butoxycarbonyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidin-4-yl)methyl)-6-chloro-3-fluoroisonicotinic-acid (906 mg, 1.711 mmol) in DMF (30 ml) was added methyl iodide (408 mg, 2.874 mmol), K.sub.2CO.sub.3 (489 mg, 3.538 mmol) at room temperature. The resulting solution was stirred for 3 h at room temperature. The resulting mixture was filtrated. The filtrate was removed under reduced pressure. The resulting residue was purified by C18 reversed phase column chromatography eluting with H.sub.2O/ACN to afford methyl-2-(((2R,4R)-4-(tert-butoxycarbonyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidin-4-yl) methyl)-6-chloro-3-fluoroisonicotinate (607 mg Y=65%) as a yellow oil. LCMS (ESI, m/z): 543 [M+H].sup.+.

Step 5: methyl-2-(((2R,4R)-4-(tert-butoxycarbonyl)-1-(3-chloro-2-fluoro-benzyl)-2-methylpiperidin-4-yl)methyl)-6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-3-fluoroisonicotinate

[0715] ##STR00321##

[0716] Following the procedure analogous to that described in Step 2 for the synthesis of Example 5, methyl-2-(((2R,4R)-4-(tert-butoxycarbonyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidin-4-yl)methyl)-6-chloro-3-fluoroisonicotinate (426 mg, 783.911 μmol) was converted to the title compound (433 mg, Y=84%) as a yellow oil. LCMS (ESI, m/z): 660 [M+H].sup.+.

Step 6: 2-(((2R,4R)-4-(tert-butoxycarbonyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidin-4-yl)methyl)-6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-3-fluoroisonicotinic acid

[0717] ##STR00322##

[0718] A solution of methyl-2-(((2R,4R)-4-(tert-butoxycarbonyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidin-4-yl)methyl)-6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-3-fluoroisonicotinate (433 mg, 655.870 μmol), lithium hydroxide (122 mg, 2.907 mmol) in methanol (10 mL) and water (10 mL) was stirred at room temperature for 3 h. The resulting solution was added 1N HCl aq. to adjust pH to 5 and extracted with ethyl acetate (100 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-(((2R,4R)-4-(tert-butoxycarbonyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidin-4-yl)methyl)-6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-3-fluoroisonicotinic acid (402 mg, crude) as a yellow solid. The crude product was not purified and used for the next step directly. LCMS (ESI, m/z): 646 [M+H].sup.+

Step 7: 2-(((2R,4R)-4-carboxy-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidin-4-yl)methyl)-3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)isonicotinic acid

[0719] ##STR00323##

[0720] Following the procedure analogous to that described in Step 5 for the synthesis of Example 5, 2-(((2R,4R)-4-(tert-butoxycarbonyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidin-4-yl) methyl)-6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-3-fluoroisonicotinic acid (47 mg, 72.737 μmol) was converted to the title compound (24 mg) as a white solid. LCMS (ESI, m/z): 534 [M+H].sup.+. .sup.1H NMR (400 MHz, MeOD) δ 7.68 (t, J=7.3 Hz, 1H), 7.60 (t, J=7.0 Hz, 1H), 7.32 (m, 2H), 6.09 (s, 1H), 3.56 (s, 2H), 3.41 (t, J=25.3 Hz, 4H), 2.42 (s, 3H), 2.21 (m, 5H), 1.61 (s, 3H).

Example 87

(2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((4-(dimethylcarbamoyl)-3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid

Step 1: tert-butyl-(2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-4-(dimethylcarbamoyl)-3-fluoropyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylate

[0721] ##STR00324##

[0722] To a solution of 2-(((2R,4R)-4-(tert-butoxycarbonyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidin-4-yl)methyl)-6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-3-fluoroisonicotinic acid (100 mg, 154.759 μmol) in ACN (30 ml) was added dimethylamine (20.931 mg, 464.277 μmol), triethylamine (46.980 mg, 464.277 μmol) and HATU (117.688 mg, 309.518 μmol). The resulting solution was stirred for 3 h at room temperature. The resulting mixture was filtrated. The filtrate was removed under reduced pressure. The resulting residue was purified by C18 reversed phase column chromatography eluting with H.sub.2O/ACN to afford tert-butyl-(2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-4-(dimethylcarbamoyl)-3-fluoropyridin-2-yl) methyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylate (72 mg Y=69%) as a yellow oil. LCMS (ESI, m/z): 673 [M+H].sup.+.

Step 2: (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((4-(dimethylcarbamoyl)-3-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid

[0723] ##STR00325##

[0724] Following the procedure analogous to that described in Step 5 for the synthesis of Example 5, tert-butyl-(2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-4-(dimethylcarbamoyl)-3-fluoropyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylate (72 mg, 106.984 μmol) was converted to the title compound (24 mg) as a white solid. LCMS (ESI, m/z): 561 [M+H].sup.+. 1H NMR (400 MHz, MeOD) δ 7.64 (dt, J=13.8, 7.1 Hz, 2H), 7.34 (t, J=7.9 Hz, 1H), 6.84 (d, J=3.6 Hz, 1H), 6.10 (s, 1H), 3.56 (s, 2H), 3.41 (t, J=24.0 Hz, 4H), 3.13 (s, 3H), 2.97 (s, 3H), 2.43 (s, 3H), 2.26 (d, J=14.0 Hz, 1H), 2.05 (dd, J=67.0, 21.9 Hz, 4H), 1.61 (d, J=5.7 Hz, 3H).

[0725] The following example in Table 10 was synthesized using the above procedure with the corresponding starting materials and intermediates.

TABLE-US-00016 TABLE 10 Example No. Structure Chemical Name .sup.1HNMR & MS: (M + H).sup.+ 88 [00326] embedded image (2R,4R)-1-(3-chloro-2-fluoro benzyl)-4-((3-fluoro-6-((5- methyl-1H-pyrazol-3-yl)amino)- 4-(morpholine-4-carbonyl) pyridin-2-yl)methyl)-2- methylpiperidine-4-carboxylic acid .sup.1H NMR (400 MHz, MeOD) δ 7.49 (dd, J = 15.1, 7.3 Hz, 2H), 7.22 (t, J = 7.8 Hz, 1H), 6.82 (s, 1H), 5.90 (s, 1H), 3.76 (s, 4H), 3.67 (s, 2H), 3.39 (s, 2H), 3.16 (m, 4H), 2.77 (s, 2H), 2.26 (s, 3H), 2.02 (m, 5H), 1.33 (d, J = 4.2 Hz, 3H). MS: 603 (M + H).sup.+ 89 [00327] embedded image (2R,4R)-1-(3-chloro-2-fluoro benzyl)-4-((3-fluoro-6-((5- methyl-1H-pyrazol-3-yl)amino)- 4-(4-methylpiperazine-1- carbonyl)pyridin-2-yl)methyl)- 2-methylpiperidine-4-carboxylic acid .sup.1H NMR (400 MHz, MeOD) δ 7.66 (d, J = 7.3 Hz, 3H), 7.33 (t, J = 7.6 Hz, 1H), 6.97 (s, 1H), 6.13 (s, 1H), 3.75 (d, J = 26.1 Hz, 2H), 3.56 (d, J = 67.8 Hz, 8H), 3.34 (s, 2H), 3.21 (d, J = 6.7 Hz, 2H), 2.98 (s, 3H), 2.44 (s, 3H), 2.14 (t, J = 47.8 Hz, 5H), 1.59 (s, 3H). MS: 616 (M + H).sup.+

Example 90

(2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((4-cyano-5-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid

Step 1: tert-butyl (2R,4R)-4-((4-carbamoyl-6-chloro-5-fluoropyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylate

[0726] ##STR00328##

[0727] A solution of 6-(((2R,4R)-4-(tert-butoxycarbonyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidin-4-yl)methyl)-2-chloro-3-fluoroisonicotinic acid (699 mg, 1.320 mmol) in DMF (8 mL), ammonium chloride (204 mg, 3.814 mmol), 1-hydroxy benzotriazole anhydrous (191 mg, 1.414 mmol), N-(3-(Dimethylamino)propyl) propionimidamidehydrochloride (423 mg, 2.207 mmol), triethylamine (315 mg, 3.113 mmol) was stirred at room temperature for 20 h. After completion, the reaction solution was diluted with brine and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by C18 reversed phase column chromatography eluting with H.sub.2O/ACN to afford tert-butyl (2R,4R)-4-((4-carbamoyl-6-chloro-5-fluoropyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2-methyl piperidine-4-carboxylate (573 mg) as a white solid. LCMS (ESI, m/z): 530 [M+H].sup.+.

Step 2: tert-butyl (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((6-chloro-4-cyano-5-fluoropyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylate

[0728] ##STR00329##

[0729] To a solution of tert-butyl (2R,4R)-4-((4-carbamoyl-6-chloro-5-fluoropyridin-2-yl) methyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylate (473 mg, 893.459 μmol) and pyridine (298 mg, 3.767 mmol) in THF (6 mL) was added trifluoroacetic anhydride (530 mg, 2.523) at 0˜5° C. The resulting solution was stirred at room temperature for 3 h. After completion, the reaction was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by C18 reversed phase column chromatography eluting with H.sub.2O/ACN to afford tert-butyl (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((6-chloro-4-cyano-5-fluoropyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylate (547 mg). LCMS (ESI, m/z): 510 [M+H].sup.+.

Step 3: tert-butyl (2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-4-cyano-5-fluoropyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylate

[0730] ##STR00330##

[0731] Following the procedure analogous to that described in step 2 of Example 5, tert-butyl (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((6-chloro-4-cyano-5-fluoropyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylate (547 mg, 1.072 mmol) was converted to the title compound (87 mg) as a white solid. LCMS (ESI, m/z): 627 [M+H].sup.+.

Step 4: (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((4-cyano-5-fluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid

[0732] ##STR00331##

[0733] Following the procedure analogous to that described in step 5 of Example 5, tert-butyl (2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-4-cyano-5-fluoropyridin-2-yl) methyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylate (87 mg, 0.139 mmol) was converted to the title compound (47 mg) as a yellow solid. LCMS (ESI, m/z): 515 [M+H].sup.+. .sup.1H NMR (400 MHz, MeOD) δ 7.67 (dt, J=14.1, 7.0 Hz, 2H), 7.35 (t, J=7.9 Hz, 1H), 7.17 (s, 1H), 6.30 (s, 1H), 4.44 (d, J=12.2 Hz, 2H), 4.02 (s, 2H), 3.50 (s, 1H), 3.50 (s, 2H), 2.44 (s, 3H), 2.18 (dd, J=51.9, 37.7 Hz, 4H), 1.56 (s, 3H).

Example 91

(2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((3,5-difluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid

Step 1: di-tert-butyl-(2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-3,5-difluoropyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate

[0734] ##STR00332##

[0735] Following the procedure analogous to that described in Step 2 for the synthesis of Example 5, INT C6 (275 mg, 596.606 μmol) was converted to the title compound (178 mg, Y=52%) as a yellow oil. LCMS (ESI, m/z): 578 [M+H].sup.+.

Step 2: (2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-3,5-difluoropyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylate

[0736] ##STR00333##

[0737] Following the procedure analogous to that described in Step 3 for the synthesis of Example 5, di-tert-butyl-(2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-3,5-difluoropyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate (178 mg, 308.116 μmol) was converted to the title compound (131 mg, Y=89%) as a yellow oil. LCMS (ESI, m/z): 478 [M+H].sup.+.

Step 3: tert-butyl-(2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-3,5-difluoropyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylate

[0738] ##STR00334##

[0739] Following the procedure analogous to that described in Step 4 for the synthesis of Example 5, (2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-3,5-difluoropyridin-2-yl)-methyl)-2-methylpiperidine-4-carboxylate (131 mg, 274.294 μmol) was converted to the title compound (77 mg, Y=45%) as a yellow oil. LCMS (ESI, m/z): 620 [M+H].sup.+.

Step 4: (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((3,5-difluoro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid

[0740] ##STR00335##

[0741] Following the procedure analogous to that described in Step 5 for the synthesis of Example 5, tert-butyl-(2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-3,5-difluoropyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylate (77 mg, 124.164 μmol) was converted to the title compound 48 mg as a white solid. LCMS (ESI, m/z): 508 [M+H].sup.+. .sup.1H NMR (400 MHz, MeOD) δ 7.59 (m, 3H), 7.24 (t, J=8.0 Hz, 1H), 6.10 (s, 1H), 3.44 (s, 2H), 3.22 (d, J=1.6 Hz, 2H), 3.20 (d, J=1.6 Hz, 2H), 2.34 (s, 3H), 2.06 (dd, J=30.2, 18.6 Hz, 5H), 1.52 (d, J=6.2 Hz, 3H).

[0742] The following example in Table 11 was synthesized using the above procedure with the corresponding starting materials and intermediates.

TABLE-US-00017 TABLE 11 Example No. Structure Chemical Name .sup.1HNMR & MS: (M + H).sup.+ 92 [00336] embedded image 1-(3-chloro-2-fluorobenzyl)- 4-((3,5-difluoro-6-((5-methyl- 1H-pyrazol-3-yl)amino)pyridin- 2-yl)methyl)piperidine-4- carboxylic acid 1H NMR (400 MHz, MeOD) δ 7.67 (ddd, J = 20.1, 14.1, 8.2 Hz, 3H), 7.32 (t, J = 7.8 Hz, 1H), 6.23 (s, 1H), 4.45 (s, 2H), 3.56 (d, J = 12.9 Hz, 2H), 3.25 (s, 2H), 3.11 (t, J = 12.8 Hz, 2H), 2.43 (d, J = 18.8 Hz, 5H), 2.08 (t, J = 12.3 Hz, 2H). MS: 494 (M + H).sup.+

Example 93

(2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((3,5-difluoro-4-methyl-6-((5-methyl-1H-pyrazol-3-yl) amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid

Step 1: tert-butyl-(2R,4R)-4-((6-chloro-3,5-difluoropyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylate

[0743] ##STR00337##

[0744] A solution of INT C6 (1.23 g, 2.668 mmol) in dichloromethane (18 ml) was added trifluoroacetic acid (2 ml) and stirred at room temperature for 1 h. After completion, the reaction was quenched with saturated sodium bicarbonate solution (100 ml) and extracted with DCM. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford (0.93 g, 2.577 mmol, Y=97%) of the title compound as a yellow solid. LCMS (ESI, m/z): 361 [M+H].sup.+.

Step 2: tert-butyl-(2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((6-chloro-3,5-difluoropyridin-2-yl) methyl)-2-methylpiperidine-4-carboxylate

[0745] ##STR00338##

[0746] A mixture of tert-butyl-(2R,4R)-4-((6-chloro-3,5-difluoropyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylate (0.93 g, 2.577 mmol), potassium carbonate (0.91 g, 6.584 mmol) and 1-(bromomethyl)-3-chloro-2-fluorobenzene (0.59 g, 2.640 mmol) in ACN (10 mL) was stirred for 2 h at room temperature. After completion, the resulting mixture was filtered and concentrated under vacuum. The crude product was purified by silica gel column chromatography eluting with EtOAc/hexane (0˜30%) to afford (0.91 g, Y=70%) of the title compound as a yellow solid. LCMS (ESI, m/z): 503 [M+H].sup.+.

Step 3: tert-butyl-(2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((6-chloro-3,5-difluoro-4-methylpyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylate

[0747] ##STR00339##

[0748] A solution of diisopropylamine (527 mg, 5.208 mmol) in THF (3 ml) was added n-butyllithium 2.5 M in THF (1.5 ml, 3.75 mmol) at −70˜-60° C. under nitrogen. The solution was stirred for 1 h at −10° C.˜0° C. The resulting solution was slowly added tert-butyl-(2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((6-chloro-3,5-difluoropyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylate (0.91 g, 1.808 mmol) in THF (5 ml). The solution was stirred at −70° C.˜-60° C. for 1 h.

[0749] A solution of iodomethane (450 mg, 3.170 mmol) in THF (3 ml) was added to the above solution. The resulting solution was stirred at −70° C.˜-60° C. for 2 h. After completion, the reaction was quenched with saturated ammonium chloride solution (100 mL) and extracted with EtOAc. The organic layer were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by C18 reverse phase chromatography eluting with H.sub.2O/ACN to afford (0.92 g, 1.778 mmol, Y=98%) of the title compound as a yellow oil. LCMS (ESI, m/z): 517 [M+H].sup.+.

Step 4: tert-butyl-(2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-3,5-difluoro-4-methylpyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylate

[0750] ##STR00340##

[0751] A mixture of tert-butyl-(2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((6-chloro-3,5-difluoro-4-methylpyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylate (0.92 g, 1.778 mmol), tris(dibenzylideneacetone)dipalladium (488.467 mg, 533.426 μmol), dimethylbwasdiphenylphosphinoxanthene (411.533 mg, 711.235 μmol), 1-tert-butyl-3-methyl-1H-pyrazol-5-amine (354.180 mg, 2.312 mmol) and K.sub.3PO.sub.4 (754.856 mg, 3.556 mmol) in 1,4-dioxane (15 ml) was stirred at 110° C. for 5 h under nitrogen. The resulting solution was cooled to room temperature and diluted with brine and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by C18 reverse phase chromatography eluting with H.sub.2O/CH.sub.3CN to afford (714 mg, 1.126 mmol, Y=63%) of the title compound as a yellow solid. LCMS (ESI, m/z): 634 [M+H].sup.+.

Step 5: (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((3,5-difluoro-4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid

[0752] ##STR00341##

[0753] A solution of tert-butyl-(2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-3,5-difluoro-4-methylpyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylat (714 mg, 1.126 mmol) in formic acid (15 mL) was stirred at reflux for 4 h. After completion, the resulting solution was concentrated under reduced pressure. The residue was dissolved in water (40 mL) at 0° C. and adjusted PH=6-7 with sodium hydroxide aqueous solution (5 M). The resulting mixture was extracted with DCM. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by C18 reverse phase column chromatography eluting with MeOH/Water to afford (349 mg, 668.632 umol, Y=59%) of the title compound as a white solid. LCMS (ESI, m/z): 522 [M+H].sup.+. .sup.1H NMR (400 MHz, MeOD) δ 7.35 (m, 2H), 7.09 (s, 1H), 5.89 (s, 1H), 4.18 (d, J=13.6 Hz, 1H), 3.53 (m, 1H), 3.06 (s, 2H), 2.95 (s, 1H), 2.80 (d, J=12.4 Hz, 1H), 2.59 (t, J=11.2 Hz, 1H), 2.13 (s, 6H), 1.83 (t, J=11.1 Hz, 2H), 1.73 (s, 2H), 1.19 (d, J=6.1 Hz, 3H).

Example 94

(2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-4-(2-fluoropropan-2-yl)-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid

Step 1: di-tert-butyl-(2R,4R)-4-((6-bromo-3-fluoro-4-(2-hydroxypropan-2-yl)pyridin-2-yl) methyl)-2-methylpiperidine-1,4-dicarboxylate

[0754] ##STR00342##

[0755] Following the procedure analogous to that described in Step 1 for the synthesis of Example 62, INT C2 (635 mg, 1.303 mmol) was converted to the title compound (431 mg, Y=61%) as a yellow oil. LCMS (ESI, m/z): 545 [M+H].sup.+.

Step 2: di-tert-butyl-(2R,4R)-4-((6-bromo-3-fluoro-4-(2-fluoropropan-2-yl)pyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate

[0756] ##STR00343##

[0757] To a solution of di-tert-butyl-(2R,4R)-4-((6-bromo-3-fluoro-4-(2-hydroxypropan-2-yl) pyridin-2-yl)methyl)-2-methylpiperidine-1,4-dicarboxylate (431 mg, 790.128 μmol) in DCM (20 ml) was added DAST (0.5 mL). The reaction mixture was stirred at room temperature for 2 h. The resulting solution was quenched with saturated sodium bicarbonate aqueous solution and extracted with DCM (50 mL). The organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by C18 reversed phase column chromatography eluting with H.sub.2O/ACN to afford di-tert-butyl-(2R,4R)-4-((6-bromo-3-fluoro-4-(2-fluoropropan-2-yl)pyridin-2-yl)methyl)-2-methyl piperidine-1,4-dicarboxylate (387 mg, Y=89%) as a yellow oil. LCMS (ESI, m/z): 547 [M+H].sup.+.

Step 3: tert-butyl-(2R,4R)-4-((6-bromo-3-fluoro-4-(2-fluoropropan-2-yl)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylate

[0758] ##STR00344##

[0759] Following the procedure analogous to that described in Step 3 for the synthesis of Example 5, di-tert-butyl (2R,4R)-4-((6-bromo-3-fluoro-4-(2-fluoropropan-2-yl)pyridin-2-yl) methyl)-2-methyl piperidine-1,4-dicarboxylate (387 mg, 706.885 μmol) was converted to the title compound (268 mg, Y=85%) as a yellow oil. LCMS (ESI, m/z): 447 [M+H].sup.+.

Step 4: tert-butyl-(2R,4R)-4-((6-bromo-3-fluoro-4-(2-fluoropropan-2-yl)pyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylate

[0760] ##STR00345##

[0761] Following the procedure analogous to that described in Step 4 for the synthesis of Example 5, tert-butyl-(2R,4R)-4-((6-bromo-3-fluoro-4-(2-fluoropropan-2-yl)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylate (268 mg, 599.075 μmol) was converted to the title compound (167 mg, Y=47%) as a yellow oil. LCMS (ESI, m/z): 589 [M+H].sup.+.

Step 5: tert-butyl-(2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-3-fluoro-4-(2-fluoropropan-2-yl)pyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylate

[0762] ##STR00346##

[0763] Following the procedure analogous to that described in Step 2 for the synthesis of Example 5, tert-butyl-(2R,4R)-4-((6-bromo-3-fluoro-4-(2-fluoropropan-2-yl)pyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylate (167 mg, 283.092 umol) was converted to the title compound (168 mg, Y=89%) as a yellow oil. LCMS (ESI, m/z): 662 [M+H].sup.+.

Step 6: (2R,4R)-1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-4-(2-fluoropropan-2-yl)-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)methyl)-2-methylpiperidine-4-carboxylic acid

[0764] ##STR00347##

[0765] Following the procedure analogous to that described in Step 5 for the synthesis of Example 5, tert-butyl-(2R,4R)-4-((6-((1-(tert-butyl)-5-methyl-1H-pyrazol-3-yl)amino)-3-fluoro-4-(2-fluoropropan-2-yl)pyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2-methylpiperidine-4-carboxylate (168 mg, 253.690 umol) was converted to the title compound (27 mg) as a white solid. LCMS (ESI, m/z): 550 [M+H].sup.+. .sup.1H NMR (400 MHz, MeOD) δ 7.70 (t, J=7.6 Hz, 1H), 7.56 (t, J=6.9 Hz, 1H), 7.36 (t, J=7.9 Hz, 1H), 6.96 (d, J=4.6 Hz, 1H), 5.99 (s, 1H), 3.42 (s, 4H), 2.37 (s, 3H), 2.19 (dd, J=43.0, 16.1 Hz, 5H), 1.74 (d, J=22.7 Hz, 6H), 1.58 (d, J=6.1 Hz, 3H).

[0766] The following examples in Table 12 were synthesized using the above procedure or modified procedure with the corresponding starting materials.

TABLE-US-00018 TABLE 12 Example No. Structure Chemical Name MS: (M + H).sup.+ 95. [00348] embedded image (1R,5S)-8-(3-chloro-2-fluorobenzyl)- 3-((3-fluoro-6-((5-methyl-1H- pyrazol-3-yl)amino)pyridin-2- yl)methyl)-8-azabicyclo[3.2.1] octane-3-carboxylic acid 502 96. [00349] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((3-fluoro-6-((4-fluoro-5- methyl-1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)-2-methyl piperidine-4-carboxylic acid 508 97. [00350] embedded image 1-(3-chloro-2-fluorobenzyl)-4-((3- fluoro-6-((5-methyl-1H-pyrazol- 3-yl)amino)pyridin-2-yl)methyl)- 2-(trifluoromethyl)piperidine- 4-carboxylic acid 544 98. [00351] 4-(3-chloro-2-fluorobenzyl)-7-((3- fluoro-6-((5-methyl-1H-pyrazol- 3-yl)amino)pyridin-2-yl)methyl)- 4-azaspiro[2.5]octane-7- carboxylic acid 502 99. [00352] embedded image (2R,4S)-1-(3-chloro-2-fluorobenzyl)- 4-((3-fluoro-6-((5-methyl-1H- pyrazol-3-yl)amino)pyridin-2- yl)oxy)-2-methylpiperidine-4- carboxylic acid 492 100. [00353] (2R,4R)-1-(2-chloro-6-fluorobenzyl)- 4-((3-fluoro-6-((5-methyl-1 H-pyrazol-3-yl)amino)pyridin-2- yl)methyl)-2-methylpiperidine-4- carboxylic acid 490 101. [00354] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((3-cyano-6-((5-methyl-1 H-pyrazol-3-yl)amino)pyridin-2- yl)methyl)-2-methylpiperidine-4- carboxylic acid 497 102. [00355] 1-(3-chloro-2-fluorobenzyl)-4-((6- ((4,5-dimethyl-1H-pyrazol-3-yl) amino)-3-fluoropyridin-2-yl) methyl)-2-methylpiperidine-4- carboxylic acid 504 103. [00356] embedded image 1-(3-chloro-2-fluorobenzyl)-4-((6- ((4-cyano-5-methyl-1H-pyrazol- 3-yl)amino)-3-fluoropyridin-2- yl)methyl)-2-methylpiperidine- 4-carboxylic acid 515 104. [00357] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((4-cyano-6-((5-methyl-1 H-pyrazol-3-yl)amino)pyridin-2- yl)methyl)-2-methylpiperidine-4- carboxylic acid 497 105. [00358] embedded image 1-(3-chloro-2-fluorobenzyl)-4-((3- fluoro-6-((5-methyl-1H-pyrazol- 3-yl)amino)-4-(3-methyloxetan- 3-yl)pyridin-2-yl)methyl)piperidine- 4-carboxylic acid 546 106. [00359] 1-(3-chloro-2-fluorobenzyl)-4-((3- fluoro-4-(3-hydroxyoxetan-3- yl)-6-((5-methyl-1H-pyrazol-3- yl)amino)pyridin-2-yl)methyl) piperidine-4-carboxylic acid 548 107. [00360] embedded image 1-(3-chloro-2-fluorobenzyl)-4-((3- fluoro-4-(3-hydroxyazetidin-1- yl)-6-((5-methylthiazol-2-yl) amino)pyridin-2-yl)methyl) piperidine-4-carboxylic acid 564 108. [00361] 1-(3-chloro-2-fluorobenzyl)-4-((3- fluoro-6-((5-methyl-1H-pyrazol- 3-yl)amino)-4-(4-methylpiperazin- 1-yl)pyridin-2-yl)methyl) piperidine-4-carboxylic acid 574 109. [00362] embedded image (2R,4R)-4-((3-fluoro-6-((5-methyl- 1H-pyrazol-3-yl)amino)pyridin- 2-yl)methyl)-2-methyl-1-((S)- 1-(2-(trifluoromethyl)phenyl)ethyl) piperidine-4-carboxylic acid 520 110. [00363] (2R,4R)-4-((3-fluoro-6-((5-methyl- 1H-pyrazol-3-yl)amino)pyridin- 2-yl)methyl)-2-methyl-1-((R)- 1-(2-(trifluoromethyl)phenyl)ethyl) piperidine-4-carboxylic acid 520 111. [00364] embedded image (S)-4-((3-fluoro-6-((5-methyl-1 H-pyrazol-3-yl)amino)pyridin-2-yl) methyl)-1-(1-(2-(trifluoromethyl) phenyl)ethyl)piperidine-4- carboxylic acid 505 112. [00365] (S)-1-(1-(3-chloro-2-fluorophenyl) ethyl)-4-((3-fluoro-6-((5-methyl- 1H-pyrazol-3-yl)amino)pyridin- 2-yl)methyl)piperidine-4- carboxylic acid 490 113. [00366] embedded image (R)-1-(1-(3-chloro-2-fluorophenyl) ethyl)-4-((3-fluoro-6-((5-methyl- 1H-pyrazol-3-yl)amino)pyridin- 2-yl)methyl)piperidine-4- carboxylic acid 490 114. [00367] (R)-4-((3-fluoro-6-((5-methyl-1 H-pyrazol-3-yl)amino)pyridin-2- yl)methyl)-1-(1-(2-(trifluoromethyl) phenyl)ethyl)piperidine-4- carboxylic acid 506 115. [00368] embedded image 4-((3-fluoro-6-((5-methyl-1H- pyrazol-3-yl)amino)pyridin-2-yl) methyl)-1-(2-(2-(trifluoromethyl) phenyl)propan-2-yl)piperidine-4- carboxylic acid 520 116. [00369] 4-((3-fluoro-6-((5-methyl-1H- pyrazol-3-yl)amino)pyridin-2-yl) methyl)-1-(1-(2-(trifluoromethyl) phenyl)cyclopropyl)piperidine-4- carboxylic acid 518 117. [00370] embedded image 4-((3-fluoro-6-((5-methyl-1H- pyrazol-3-yl)amino)pyridin-2-yl) methyl)-1-(3-(2-(trifluoromethyl) phenyl)oxetan-3-yl)piperidine-4- carboxylic acid 534 118. [00371] 1-((3-chloro-2-fluorophenyl) difluoromethyl)-4-((3-fluoro-6-((5- methyl-1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)piperidine-4- carboxylic acid 512 119. [00372] embedded image (R)-1-(1-(3-chloro-2-fluorophenyl)- 2,2,2-trifluoroethyl)-4-((3- fluoro-6-((5-methyl-1H-pyrazol-3- yl)amino)pyridin-2-yl)methyl) piperidine-4-carboxylic acid 544 120. [00373] (S)-1-(1-(3-chloro-2-fluorophenyl)- 2,2,2-trifluoroethyl)-4-((3-fluoro- 6-((5-methyl-1H-pyrazol-3- yl)amino)pyridin-2-yl)methyl) piperidine-4-carboxylic acid 544 121. [00374] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzoyl)- 2-ethyl-4-((3-fluoro-6-((5- methyl-1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)piperidine-4- carboxylic acid 518 122. [00375] (2R,4R)-2-ethyl-4-((3-fluoro-6- ((5-methyl-1H-pyrazol-3-yl) amino)pyridin-2-yl)methyl)-1-(2- (trifluoromethyl)benzyl)piperidine-4- carboxylic acid 520 123. [00376] embedded image (2R,4R)-2-ethyl-4-((3-fluoro-6- ((5-methyl-1H-pyrazol-3-yl) amino)pyridin-2-yl)methyl)-1-(2- (trifluoromethyl)benzoyl)piperidine- 4-carboxylic acid 534 124. [00377] (2R,4R)-2-ethyl-4-((3-fluoro-6- ((5-methyl-1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)-1-((2- (trifluoromethyl)phenyl)sulfonyl) piperidine-4-carboxylic acid 570 125. [00378] embedded image (2R,4R)-2-ethyl-4-((3-fluoro-6-((5- methyl-1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)-1-((S)-1- (2-(trifluoromethyl)phenyl)ethyl) piperidine-4-carboxylic acid 534 126. [00379] (2R,4R)-2-ethyl-4-((3-fluoro-6- ((5-methyl-1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)-1-((R)-1- (2-(trifluoromethyl)phenyl)ethyl) piperidine-4-carboxylic acid 534 127. [00380] embedded image (2R,4R)-1-((3-chloro-2-fluorophenyl) sulfonyl)-2-ethyl-4-((3-fluoro- 6-((5-methyl-1H-pyrazol-3-yl) amino)pyridin-2-yl)methyl) piperidine-4-carboxylic acid 554 128. [00381] (2R,4R)-1-(1-(3-chloro-2-fluoro phenyl)cyclopropyl)-2-ethyl-4-((3- fluoro-6-((5-methyl-1H-pyrazol- 3-yl)amino)pyridin-2-yl)methyl) piperidine-4-carboxylic acid 530 129. [00382] embedded image (2R,4R)-1-((3-chloro-2-fluorophenyl) difluoromethyl)-2-ethyl-4-((3- fluoro-6-((5-methyl-1H-pyrazol- 3-yl)amino)pyridin-2-yl)methyl) piperidine-4-carboxylic acid 540 130. [00383] (2R,6R)-1-(3-chloro-2-fluorobenzyl)- 4-((3-fluoro-6-((5-methyl-1 H-pyrazol-3-yl)amino)pyridin-2- yl)methyl)-2,6-dimethylpiperidine- 4-carboxylic acid 504 131. [00384] embedded image (3R)-1-(3-chloro-2-fluorobenzyl)- 4-((3-fluoro-6-((5-methyl-1H- pyrazol-3-yl)amino)pyridin-2-yl) methyl)-3-methylpiperidine-4- carboxylic acid 490 132. [00385] (2R)-1-(3-chloro-2-fluorobenzyl)- 4-((3-fluoro-6-((5-methyl-1H- pyrazol-3-yl)amino)pyridin-2-yl) methyl)-2-methylpiperidine-4- carboxylic acid 490 133. [00386] embedded image (2R)-1-(3-chloro-2-fluorobenzyl)- 2-ethyl-4-((3-fluoro-6-((5-methyl- 1H-pyrazol-3-yl)amino)pyridin- 2-yl)methyl)piperidine-4- carboxylic acid 504 134. [00387] 1-(3-chloro-2,6-difluorobenzyl)- 4-((3-fluoro-6-((5-methyl-1H- pyrazol-3-yl)amino)pyridin-2-yl) methyl)piperidine-4-carboxylic acid 494 135. [00388] embedded image (2R)-1-(3-chloro-2,6-difluorobenzyl)- 4-((3-fluoro-6-((5-methyl- 1H-pyrazol-3-yl)amino)pyridin- 2-yl)methyl)-2-methylpiperidine- 4-carboxylic acid 508 136. [00389] (2R)-1-(3-chloro-2,6-difluorobenzyl)- 2-ethyl-4-((3-fluoro-6-((5- methyl-1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)piperidine-4- carboxylic acid 522 137. [00390] embedded image 1-(3-chloro-2,4-difluorobenzyl)- 4-((3-fluoro-6-((5-methyl-1H- pyrazol-3-yl)amino)pyridin-2-yl) methyl)piperidine-4-carboxylic acid 494 138. [00391] (2R)-1-(3-chloro-2,4-difluorobenzyl)- 4-((3-fluoro-6-((5-methyl- 1H-pyrazol-3-yl)amino)pyridin- 2-yl)methyl)-2-methylpiperidine- 4-carboxylic acid 508 139. [00392] embedded image (2R)-1-(3-chloro-2,4-difluorobenzyl)- 2-ethyl-4-((3-fluoro-6-((5- methyl-1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)piperidine-4- carboxylic acid 522 140. [00393] 1-(2,3-dichlorobenzyl)-4-((3- fluoro-6-((5-methyl-1H-pyrazol-3- yl)amino)pyridin-2-yl)methyl) piperidine-4-carboxylic acid 492 141. [00394] embedded image (2R)-1-(2,3-dichlorobenzyl)-4-((3- fluoro-6-((5-methyl-1H-pyrazol- 3-yl)amino)pyridin-2-yl)methyl)- 2-methylpiperidine-4-carboxylic acid 506 142. [00395] (2R)-1-(2,3-dichlorobenzyl)-2- ethyl-4-((3-fluoro-6-((5-methyl-1 H-pyrazol-3-yl)amino)pyridin-2- yl)methyl)piperidine-4-carboxylic acid 520 143. [00396] embedded image 1-(2,3-difluorobenzyl)-4-((3- fluoro-6-((5-methyl-1H-pyrazol-3- yl)amino)pyridin-2-yl)methyl) piperidine-4-carboxylic acid 460 144. [00397] (2R)-1-(2,3-difluorobenzyl)-4-((3- fluoro-6-((5-methyl-1H-pyrazol- 3-yl)amino)pyridin-2-yl)methyl)- 2-methylpiperidine-4- carboxylic acid 474 145. [00398] embedded image (2R)-1-(2,3-difluorobenzyl)-2- ethyl-4-((3-fluoro-6-((5-methyl-1 H-pyrazol-3-yl)amino)pyridin-2- yl)methyl)piperidine-4-carboxylic acid 488 146. [00399] 1-(3-chloro-2-fluoro-6-methylbenzyl)- 4-((3-fluoro-6-((5-methyl- 1H-pyrazol-3-yl)amino)pyridin- 2-yl)methyl)piperidine-4- carboxylic acid 490 147. [00400] embedded image (2R)-1-(3-chloro-2-fluoro-6- methylbenzyl)-4-((3-fluoro-6-((5- methyl-1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)-2-methyl piperidine-4-carboxylic acid 504 148. [00401] (2R)-1-(3-chloro-2-fluoro-6- methylbenzyl)-2-ethyl-4-((3-fluoro- 6-((5-methyl-1H-pyrazol-3-yl) amino)pyridin-2-yl)methyl) piperidine-4-carboxylic acid 518 149. [00402] embedded image 1-(3-chloro-2-methylbenzyl)-4- ((3-fluoro-6-((5-methyl-1H-pyrazol- 3-yl)amino)pyridin-2-yl)methyl) piperidine-4-carboxylic acid 472 150. [00403] (2R)-1-(3-chloro-2-methylbenzyl)- 4-((3-fluoro-6-((5-methyl-1H- pyrazol-3-yl)amino)pyridin-2-yl) methyl)-2-methylpiperidine-4- carboxylic acid 486 151. [00404] embedded image (2R)-1-(3-chloro-2-methylbenzyl)- 2-ethyl-4-((3-fluoro-6-((5-methyl- 1H-pyrazol-3-yl)amino)pyridin- 2-yl)methyl)piperidine-4- carboxylic acid 500 152. [00405] 4-((6-((1H-pyrazol-3-yl)amino)- 3-fluoropyridin-2-yl)methyl)-1- (2-fluoro-3-methylbenzyl) piperidine-4-carboxylic acid 442 153. [00406] embedded image (2R)-4-((6-((1H-pyrazol-3-yl) amino)-3-fluoropyridin-2-yl)methyl)- 1-(2-fluoro-3-methylbenzyl)-2- methylpiperidine-4-carboxylic acid 456 154. [00407] (2R)-4-((6-((1H-pyrazol-3-yl) amino)-3-fluoropyridin-2-yl)methyl)- 2-ethyl-1-(2-fluoro-3-methylbenzyl) piperidine-4-carboxylic acid 470 155. [00408] embedded image 4-((3-fluoro-6-((5-methyl-1H- pyrazol-3-yl)amino)pyridin-2-yl) methyl)-1-(2-fluorobenzyl)piperidine- 4-carboxylic acid 442 156. [00409] (2R)-4-((3-fluoro-6-((5-methyl-1 H-pyrazol-3-yl)amino)pyridin-2- yl)methyl)-1-(2-fluorobenzyl)-2- methylpiperidine-4-carboxylic acid 456 157. [00410] embedded image (2R)-2-ethyl-4-((3-fluoro-6-((5- methyl-1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)-1-(2-fluoro benzyl)piperidine-4-carboxylic acid 470 158. [00411] 1-(2,6-dichlorobenzyl)-4-((3- fluoro-6-((5-methyl-1H-pyrazol-3- yl)amino)pyridin-2-yl)methyl) piperidine-4-carboxylic acid 492 159. [00412] embedded image (2R)-1-(2,6-dichlorobenzyl)-4-((3- fluoro-6-((5-methyl-1H-pyrazol- 3-yl)amino)pyridin-2-yl)methyl)- 2-methylpiperidine-4- carboxylic acid 506 160. [00413] (2R)-1-(2,6-dichlorobenzyl)-2- ethyl-4-((3-fluoro-6-((5-methyl-1 H-pyrazol-3-yl)amino)pyridin-2- yl)methyl)piperidine-4-carboxylic acid 520 161. [00414] embedded image 1-(2,6-difluorobenzyl)-4-((3- fluoro-6-((5-methyl-1H-pyrazol-3- yl)amino)pyridin-2-yl)methyl) piperidine-4-carboxylic acid 560 162. [00415] (2R)-1-(2,6-difluorobenzyl)-4-((3- fluoro-6-((5-methyl-1H-pyrazol- 3-yl)amino)pyridin-2-yl)methyl)- 2-methylpiperidine-4- carboxylic acid 474 163. [00416] embedded image (2R)-1-(2,6-difluorobenzyl)-2- ethyl-4-((3-fluoro-6-((5-methyl-1 H-pyrazol-3-yl)amino)pyridin-2- yl)methyl)piperidine-4-carboxylic acid 488 164. [00417] 1-(3-chloro-2-fluoro-4-methylbenzyl)- 4-((3-fluoro-6-((5-methyl- 1H-pyrazol-3-yl)amino)pyridin- 2-yl)methyl)piperidine-4- carboxylic acid 490 165. [00418] embedded image (2R)-1-(3-chloro-2-fluoro-4- methylbenzyl)-4-((3-fluoro-6-((5- methyl-1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)-2-methyl piperidine-4-carboxylic acid 504 166. [00419] (2R)-1-(3-chloro-2-fluoro-4- methylbenzyl)-2-ethyl-4-((3-fluoro- 6-((5-methyl-1H-pyrazol-3-yl) amino)pyridin-2-yl)methyl) piperidine-4-carboxylic acid 518 167. [00420] embedded image 1-(2-(3-chloro-2-fluorophenyl) propan-2-yl)-4-((3-fluoro-6-((5- methyl-1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)piperidine-4- carboxylic acid 504 168. [00421] (2R,4R)-1-(2-(3-chloro-2-fluoro phenyl)propan-2-yl)-4-((3-fluoro- 6-((5-methyl-1H-pyrazol-3-yl) amino)pyridin-2-yl)methyl)-2- methylpiperidine-4-carboxylic acid 518 169. [00422] embedded image (2R,4R)-1-(2-(3-chloro-2-fluoro phenyl)propan-2-yl)-2-ethyl-4-((3- fluoro-6-((5-methyl-1H-pyrazol- 3-yl)amino)pyridin-2-yl)methyl) piperidine-4-carboxylic acid 532 170. [00423] 1-(1-(3-chloro-2-fluorophenyl) cyclopropyl)-4-((3-fluoro-6-((5- methyl-1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)piperidine-4- carboxylic acid 502 171. [00424] embedded image (2R,4R)-1-(1-(3-chloro-2-fluoro phenyl)cyclopropyl)-4-((3-fluoro- 6-((5-methyl-1H-pyrazol-3-yl) amino)pyridin-2-yl)methyl)-2- methylpiperidine-4-carboxylic acid 516 172. [00425] 1-(3-(3-chloro-2-fluorophenyl) oxetan-3-yl)-4-((3-fluoro-6-((5- methyl-1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)piperidine-4- carboxylic acid 518 173. [00426] embedded image (2R,4R)-1-(3-(3-chloro-2-fluoro phenyl)oxetan-3-yl)-4-((3-fluoro- 6-((5-methyl-1H-pyrazol-3-yl) amino)pyridin-2-yl)methyl)-2- methylpiperidine-4-carboxylic acid 532 174. [00427] (2R,4R)-1-(3-(3-chloro-2-fluoro phenyl)oxetan-3-yl)-2-ethyl-4-((3- fluoro-6-((5-methyl-1H-pyrazol- 3-yl)amino)pyridin-2-yl)methyl) piperidine-4-carboxylic acid 545 175. [00428] embedded image 1-(1-(3-chloro-2-fluorophenyl) cyclobutyl)-4-((3-fluoro-6-((5- methyl-1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)piperidine-4- carboxylic acid 516 176. [00429] (2R,4R)-1-(1-(3-chloro-2-fluoro phenyl)cyclobutyl)-4-((3-fluoro- 6-((5-methyl-1H-pyrazol-3-yl) amino)pyridin-2-yl)methyl)-2- methylpiperidine-4-carboxylic acid 530 177. [00430] embedded image (2R,4R)-1-(1-(3-chloro-2-fluoro phenyl)cyclobutyl)-2-ethyl-4-((3- fluoro-6-((5-methyl-1H-pyrazol- 3-yl)amino)pyridin-2-yl)methyl) piperidine-4-carboxylic acid 544 178. [00431] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((3-fluoro-6-((5-methyl-1 H-pyrazol-3-yl)amino)pyridin-2- yl)methyl)-2-methylpiperidine- 4-carboxylic acid 490 179. [00432] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 2-ethyl-4-((3-fluoro-4-(3- hydroxyoxetan-3-yl)-6-((5-methyl- 1H-pyrazol-3-yl)amino)pyridin- 2-yl)methyl)piperidine-4- carboxylic acid 576 180. [00433] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((3-fluoro-6-((5-methyl-1 H-pyrazol-3-yl)amino)-4-(oxetan- 3-yl)pyridin-2-yl)methyl)-2- methylpiperidine-4-carboxylic acid 546 181. [00434] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 2-ethyl-4-((3-fluoro-6-((5- methyl-1H-pyrazol-3-yl)amino)- 4-(oxetan-3-yl)pyridin-2-yl) methyl)piperidine-4-carboxylic acid 560 182. [00435] 1-(3-chloro-2-fluorobenzyl)-4-((3- fluoro-4-(3-hydroxyazetidin-1- yl)-6-((5-methyl-1H-pyrazol-3- yl)amino)pyridin-2-yl)methyl) piperidine-4-carboxylic acid 547 183. [00436] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 2-ethyl-4-((3-fluoro-4-(3- hydroxyazetidin-1-yl)-6-((5-methyl- 1H-pyrazol-3-yl)amino)pyridin- 2-yl)methyl)piperidine-4- carboxylic acid 575 184. [00437] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((3-fluoro-4-(3-hydroxyazetidin- 1-yl)-6-((5-methyl-1H- pyrazol-3-yl)amino)pyridin-2-yl) methyl)-2-methylpiperidine-4- carboxylic acid 561 185. [00438] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((3-fluoro-6-((5-methyl-1 H-pyrazol-3-yl)amino)-4-(4- methylpiperazin-1-yl)pyridin-2-yl) methyl)-2-methylpiperidine-4- carboxylic acid 588 186. [00439] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 2-ethyl-4-((3-fluoro-6-((5- methyl-1H-pyrazol-3-yl)amino)- 4-(4-methylpiperazin-1-yl)pyridin- 2-yl)methyl)piperidine-4- carboxylic acid 602 187. [00440] embedded image (2R,4R)-4-((4-(azetidin-3-yl)-3- fluoro-6-((5-methyl-1H-pyrazol- 3-yl)amino)pyridin-2-yl)methyl)- 1-(3-chloro-2-fluorobenzyl)-2- methylpiperidine-4-carboxylic acid 545 188. [00441] 4-((4-(azetidin-3-yl)-3-fluoro-6- ((5-methyl-1H-pyrazol-3-yl) amino)pyridin-2-yl)methyl)-1-(3- chloro-2-fluorobenzyl)piperidine-4- carboxylic acid 531 189. [00442] embedded image (2R,4R)-4-((4-(azetidin-3-yl)-3- fluoro-6-((5-methyl-1H-pyrazol- 3-yl)amino)pyridin-2-yl)methyl)- 1-(3-chloro-2-fluorobenzyl)-2- ethylpiperidine-4-carboxylic acid 559 190. [00443] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((3-fluoro-6-((5-methyl-1 H-pyrazol-3-yl)amino)-4-(1- methylazetidin-3-yl)pyridin-2-yl) methyl)-2-methylpiperidine-4- carboxylic acid 559 191. [00444] embedded image 1-(3-chloro-2-fluorobenzyl)-4-((3- fluoro-6-((5-methyl-1H-pyrazol- 3-yl)amino)-4-(1-methylazetidin- 3-yl)pyridin-2-yl)methyl) piperidine-4-carboxylic acid 545 192. [00445] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 2-ethyl-4-((3-fluoro-6-((5- methyl-1H-pyrazol-3-yl)amino)- 4-(1-methylazetidin-3-yl)pyridin- 2-yl)methyl)piperidine-4- carboxylic acid 573 193. [00446] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 2-ethyl-4-((3-fluoro-4-methyl- 6-((5-methyl-1H-pyrazol-3-yl) amino)pyridin-2-yl)methyl) piperidine-4-carboxylic acid 518 194. [00447] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 2-ethyl-4-((4-ethyl-3-fluoro- 6-((5-methyl-1H-pyrazol-3-yl) amino)pyridin-2-yl)methyl) piperidine-4-carboxylic acid 532 195. [00448] embedded image 1-(3-chloro-2-fluorobenzyl)-4-((3- fluoro-4-isopropyl-6-((5-methyl- 1H-pyrazol-3-yl)amino)pyridin- 2-yl)methyl)piperidine-4- carboxylic acid 518 196. [00449] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 2-ethyl-4-((3-fluoro-4-isopropyl- 6-((5-methyl-1H-pyrazol-3- yl)amino)pyridin-2-yl)methyl) piperidine-4-carboxylic acid 546 197. [00450] embedded image 1-(3-chloro-2-fluorobenzyl)-4-((4- cyclopropyl-3-fluoro-6-((5- methyl-1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)piperidine-4- carboxylic acid 516 198. [00451] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((4-cyclopropyl-3-fluoro- 6-((5-methyl-1H-pyrazol-3-yl) amino)pyridin-2-yl)methyl)-2- ethylpiperidine-4-carboxylic acid 544 199. [00452] embedded image 1-(3-chloro-2-fluorobenzyl)-4-((3- fluoro-4-(2-hydroxypropan-2- yl)-6-((5-methyl-1H-pyrazol-3- yl)amino)pyridin-2-yl)methyl) piperidine-4-carboxylic acid 534 200. [00453] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 2-ethyl-4-((3-fluoro-4-(2- hydroxypropan-2-yl)-6-((5-methyl- 1H-pyrazol-3-yl)amino)pyridin- 2-yl)methyl)piperidine-4-carboxylic acid 562 201. [00454] embedded image 1-(3-chloro-2-fluorobenzyl)-4-((3- fluoro-6-((5-methyl-1H-pyrazol- 3-yl)amino)-4-phenylpyridin- 2-yl)methyl)piperidine-4- carboxylic acid 552 202. [00455] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((3-fluoro-6-((5-methyl-1 H-pyrazol-3-yl)amino)-4-phenyl pyridin-2-yl)methyl)-2-methyl piperidine-4-carboxylic acid 566 203. [00456] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 2-ethyl-4-((3-fluoro-6-((5- methyl-1H-pyrazol-3-yl)amino)- 4-phenylpyridin-2-yl)methyl) piperidine-4-carboxylic acid 580 204. [00457] 1-(3-chloro-2-fluorobenzyl)-4-((3- fluoro-4-(1-hydroxycyclopropyl)- 6-((5-methyl-1H-pyrazol-3-yl) amino)pyridin-2-yl)methyl) piperidine-4-carboxylic acid 532 205. [00458] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((3-fluoro-4-(1-hydroxycyclo propyl)-6-((5-methyl-1H- pyrazol-3-yl)amino)pyridin-2-yl) methyl)-2-methylpiperidine-4- carboxylic acid 546 206. [00459] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 2-ethyl-4-((3-fluoro-4-(1- hydroxycyclopropyl)-6-((5-methyl- 1H-pyrazol-3-yl)amino)pyridin- 2-yl)methyl)piperidine-4- carboxylic acid 560 207. [00460] embedded image (2R,4R)-4-((4-(azetidin-1-yl)-3- fluoro-6-((5-methyl-1H-pyrazol- 3-yl)amino)pyridin-2-yl)methyl)- 1-(3-chloro-2-fluorobenzyl)-2- ethylpiperidine-4-carboxylic acid 559 208. [00461] 4-((4-(azetidin-1-yl)-3-fluoro-6- ((5-methyl-1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)-1-(3-chloro- 2-fluorobenzyl)piperidine-4- carboxylic acid 531 209. [00462] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((4-(difluoromethyl)-3-fluoro- 6-((5-methyl-1H-pyrazol-3- yl)amino)pyridin-2-yl)methyl)-2- ethylpiperidine-4-carboxylic acid 554 210. [00463] 1-(3-chloro-2-fluorobenzyl)-4-((4- (difluoromethyl)-3-fluoro-6-((5- methyl-1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)piperidine- 4-carboxylic acid 526 211. [00464] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 2-ethyl-4-((3-fluoro-6-((5- methyl-1H-pyrazol-3-yl)amino)- 4-(trifluoromethyl)pyridin-2-yl) methyl)piperidine-4-carboxylic acid 572 212. [00465] 1-(3-chloro-2-fluorobenzyl)-4-((3- fluoro-6-((5-methyl-1H-pyrazol- 3-yl)amino)-4-(trifluoromethyl) pyridin-2-yl)methyl)piperidine- 4-carboxylic acid 544 213. [00466] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((3-fluoro-6-((5-methyl-1 H-pyrazol-3-yl)amino)-4-(trifluoro methyl)pyridin-2-yl)methyl)-2- methylpiperidine-4-carboxylic acid 558 214. [00467] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 2-ethyl-4-((3-fluoro-4-(1- hydroxycyclobutyl)-6-((5-methyl-1 H-pyrazol-3-yl)amino)pyridin-2- yl)methyl)piperidine-4-carboxylic acid 574 215. [00468] embedded image 1-(3-chloro-2-fluorobenzyl)-4-((3- fluoro-4-(1-hydroxycyclobutyl)- 6-((5-methyl-1H-pyrazol-3-yl) amino)pyridin-2-yl)methyl) piperidine-4-carboxylic acid 546 216. [00469] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((3-fluoro-4-(1-hydroxycyclobutyl)- 6-((5-methyl-1H-pyrazol- 3-yl)amino)pyridin-2-yl) methyl)-2-methylpiperidine-4- carboxylic acid 560 217. [00470] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((4-cyclobutyl-3-fluoro-6- ((5-methyl-1H-pyrazol-3-yl) amino)pyridin-2-yl)methyl)-2-ethyl piperidine-4-carboxylic acid 558 218. [00471] 1-(3-chloro-2-fluorobenzyl)-4-((4- cyclobutyl-3-fluoro-6-((5-methyl- 1H-pyrazol-3-yl)amino)pyridin- 2-yl)methyl)piperidine-4- carboxylic acid 530 219. [00472] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((4-cyclobutyl-3-fluoro-6- ((5-methyl-1H-pyrazol-3-yl) amino)pyridin-2-yl)methyl)-2- methylpiperidine-4-carboxylic acid 544 220. [00473] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((4-cyano-3-fluoro-6-((5- methyl-1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)-2- ethylpiperidine-4-carboxylic acid 529 221. [00474] embedded image 1-(3-chloro-2-fluorobenzyl)-4-((4- cyano-3-fluoro-6-((5-methyl-1 H-pyrazol-3-yl)amino)pyridin-2- yl)methyl)piperidine-4-carboxylic acid 501 222. [00475] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 2-ethyl-4-((3-methyl-6-((5- methyl-1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)piperidine-4- carboxylic acid 500 223. [00476] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((3-cyano-6-((5-methyl-1 H-pyrazol-3-yl)amino)pyridin-2- yl)methyl)-2-ethylpiperidine-4- carboxylic acid 511 224. [00477] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((3-chloro-6-((5-methyl-1 H-pyrazol-3-yl)amino)pyridin-2- yl)methyl)-2-ethylpiperidine-4- carboxylic acid 520 225. [00478] embedded image 1-(3-chloro-2-fluorobenzyl)-4-((3- methyl-6-((5-methyl-1H-pyrazol- 3-yl)amino)pyridin-2-yl)methyl) piperidine-4-carboxylic acid 472 226. [00479] 1-(3-chloro-2-fluorobenzyl)-4-((3- cyano-6-((5-methyl-1H-pyrazol- 3-yl)amino)pyridin-2-yl)methyl) piperidine-4-carboxylic acid 483 227. [00480] embedded image 1-(3-chloro-2-fluorobenzyl)-4-((3- chloro-6-((5-methyl-1H-pyrazol- 3-yl)amino)pyridin-2-yl)methyl) piperidine-4-carboxylic acid 492 228. [00481] (2S)-1-(3-chloro-2-fluorobenzyl)- 2-ethyl-4-((3-fluoro-6-((5-methyl- 1H-pyrazol-3-yl)amino)pyridin- 2-yl)methyl)piperidine-4- carboxylic acid 504 229. [00482] embedded image 1-(1-(3-chloro-2-fluorophenyl)ethyl)- 4-((3-fluoro-6-((5-methyl-1 H-pyrazol-3-yl)amino)pyridin-2- yl)methyl)piperidine-4-carboxylic acid 490 230. [00483] 1-(difluoro(2-(trifluoromethyl) phenyl)methyl)-4-((3-fluoro-6-((5- methyl-1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)piperidine-4- carboxylic acid 527 231. [00484] embedded image (2R,4R)-1-(3-chloro-2-fluoro-6- methylbenzyl)-4-((3-fluoro-6-((5- methyl-1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)-2-methyl piperidine-4-carboxylic acid 504 232. [00485] (2R,4R)-1-(3-chloro-2-fluoro-4- methylbenzyl)-4-((3-fluoro-6-((5- methyl-1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)-2-methyl piperidine-4-carboxylic acid 504 233. [00486] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((3-fluoro-4-(3-hydroxyazetidin- 1-yl)-6-((5-methylthiazol- 2-yl)amino)pyridin-2-yl)methyl)- 2-methylpiperidine-4-carboxylic acid 578 234. [00487] (2R,4R)-1-((4,5-dichlorothiophen- 2-yl)methyl)-4-((3-fluoro-6-((5- methyl-1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)-2-methyl piperidine-4-carboxylic acid 512 235. [00488] embedded image (2R,4R)-1-((4,5-dimethylthiophen- 2-yl)methyl)-4-((3-fluoro-6-((5- methyl-1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)-2-methyl piperidine-4-carboxylic acid 472 236. [00489] (3R,4S)-1-(3-chloro-2-fluorobenzyl)- 4-((3-fluoro-6-((5-methyl-1 H-pyrazol-3-yl)amino)pyridin-2- yl)methyl)-3-methylpiperidine-4- carboxylic acid 490 237. [00490] embedded image (2R,4R)-1-((3-chloro-2-fluorophenyl) difluoromethyl)-4-((3-fluoro-6- ((5-methyl-1H-pyrazol-3-yl) amino)pyridin-2-yl)methyl)-2- methylpiperidine-4-carboxylic acid 526 238. [00491] 1-(3-chloro-2-fluorobenzyl)-4-((3- fluoro-6-((5-methyl-1H-pyrazol- 3-yl)amino)pyridin-2-yl)methyl)- 3-methylpiperidine-4- carboxylic acid 490 239. [00492] embedded image (3S,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((3-fluoro-6-((5-methyl-1H- pyrazol-3-yl)amino)pyridin-2- yl)methyl)-3-methylpiperidine-4- carboxylic acid 490 240. [00493] 1-(3-chloro-2-fluorobenzyl)-4-((3- fluoro-4-(1-fluorocyclopropyl)- 6-((5-methyl-1H-pyrazol-3-yl) amino)pyridin-2-yl)methyl) piperidine-4-carboxylic acid 534 241. [00494] embedded image 1-(3-chloro-2-fluorobenzyl)-4-((3- fluoro-6-((5-methyl-1H-pyrazol- 3-yl)amino)-4-(methylamino) pyridin-2-yl)methyl)piperidine-4- carboxylic acid 505 242. [00495] 1-(3-chloro-2-fluorobenzyl)-4-((3- fluoro-4-isopropoxy-6-((5-methyl- 1H-pyrazol-3-yl)amino)pyridin- 2-yl)methyl)piperidine-4- carboxylic acid 534 243. [00496] embedded image (2R,4R)-1-(((3-chloro-2-fluorophenyl) sulfonyl)methyl)-4-((3-fluoro- 6-((5-methyl-1H-pyrazol-3- yl)amino)pyridin-2-yl)methyl)-2- methylpiperidine-4-carboxylic acid 554 244. [00497] 1-(1-(3,5-dichlorophenyl)cyclopropyl)- 4-((3-fluoro-6-((5-methyl- 1H-pyrazol-3-yl)amino)pyridin- 2-yl)methyl)piperidine-4-carboxylic acid 518 245. [00498] embedded image 1-(3-(3,5-dichlorophenyl)oxetan- 3-yl)-4-((3-fluoro-6-((5-methyl- 1H-pyrazol-3-yl)amino)pyridin- 2-yl)methyl)piperidine-4-carboxylic acid 534 246. [00499] (2R,4R)-1-(3-chloro-4,5-difluoro benzyl)-4-((3-fluoro-6-((5-methyl- 1H-pyrazol-3-yl)amino)pyridin- 2-yl)methyl)-2-methylpiperidine- 4-carboxylic acid 508 247. [00500] embedded image (2R,4R)-1-(2,3-difluorobenzyl)- 4-((3-fluoro-4-(1-hydroxycyclopropyl)- 6-((5-methyl-1H-pyrazol- 3-yl)amino)pyridin-2-yl)methyl)- 2-methylpiperidine-4-carboxylic acid 530 248. [00501] (2R,4R)-1-(2,3-difluorobenzyl)- 4-((3-fluoro-4-(2-hydroxypropan- 2-yl)-6-((5-methyl-1H-pyrazol- 3-yl)amino)pyridin-2-yl)methyl)- 2-methylpiperidine-4-carboxylic acid 532 249. [00502] embedded image 1-(2,3-difluorobenzyl)-4-((3- fluoro-4-(1-hydroxycyclopropyl)-6- ((5-methyl-1H-pyrazol-3-yl) amino)pyridin-2-yl)methyl) piperidine-4-carboxylic acid 516 250. [00503] 1-(2,3-difluorobenzyl)-4-((3-fluoro- 4-(2-hydroxypropan-2-yl)-6- ((5-methyl-1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)piperidine- 4-carboxylic acid 518 251. [00504] embedded image (2R,4R)-1-(2,3-difluorobenzyl)- 2-ethyl-4-((3-fluoro-4-(1-hydroxy cyclopropyl)-6-((5-methyl-1H- pyrazol-3-yl)amino)pyridin-2-yl) methyl)piperidine-4-carboxylic acid 544 252. [00505] (2R,4R)-1-(2,3-difluorobenzyl)- 2-ethyl-4-((3-fluoro-4-methyl-6- ((5-methyl-1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)piperidine- 4-carboxylic acid 502 253. [00506] embedded image (2R,4R)-1-(2,3-difluorobenzyl)- 2-ethyl-4-((3-fluoro-4-(2-hydroxy propan-2-yl)-6-((5-methyl-1H- pyrazol-3-yl)amino)pyridin-2-yl) methyl)piperidine-4-carboxylic acid 546 254. [00507] (2R,4R)-1-(2,3-dichlorobenzyl)- 2-ethyl-4-((3-fluoro-4-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino)pyridin-2-yl)methyl) piperidine-4-carboxylic acid 534 255. [00508] embedded image (2R,4R)-1-(3-chloro-2,6-difluoro benzyl)-2-ethyl-4-((3-fluoro-4- (1-hydroxycyclopropyl)-6-((5- methyl-1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)piperidine-4- carboxylic acid 578 256. [00509] (2R,4R)-1-(3-chloro-2,6-difluoro benzyl)-2-ethyl-4-((3-fluoro-4- methyl-6-((5-methyl-1H-pyrazol- 3-yl)amino)pyridin-2-yl)methyl) piperidine-4-carboxylic acid 536 257. [00510] embedded image (2R,4R)-1-(3-chloro-2,6-difluoro benzyl)-2-ethyl-4-((3-fluoro-4- (2-hydroxypropan-2-yl)-6-((5- methyl-1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)piperidine-4- carboxylic acid 580 258. [00511] 1-(3-chloro-2,6-difluorobenzyl)- 4-((3-fluoro-4-(1-hydroxycyclopropyl)- 6-((5-methyl-1H-pyrazol- 3-yl)amino)pyridin-2-yl)methyl) piperidine-4-carboxylic acid 550 259. [00512] embedded image 1-(3-chloro-2,6-difluorobenzyl)- 4-((3-fluoro-4-(2-hydroxypropan- 2-yl)-6-((5-methyl-1H-pyrazol- 3-yl)amino)pyridin-2-yl)methyl) piperidine-4-carboxylic acid 552 260. [00513] (2R,4R)-1-(3-chloro-2,6-difluoro benzyl)-4-((3-fluoro-4-(1-hydroxy cyclopropyl)-6-((5-methyl-1 H-pyrazol-3-yl)amino)pyridin-2- yl)methyl)-2-methylpiperidine-4- carboxylic acid 564 261. [00514] embedded image (2R,4R)-1-(3-chloro-2,6-difluoro benzyl)-4-((3-fluoro-4-(2-hydroxy propan-2-yl)-6-((5-methyl-1 H-pyrazol-3-yl)amino)pyridin-2- yl)methyl)-2-methylpiperidine-4- carboxylic acid 566 262. [00515] 1-(3-chloro-2-fluorobenzyl)-4-((6- ethyl-5-fluoro-2-((5-methyl-1H- pyrazol-3-yl)amino)pyrimidin- 4-yl)methyl)piperidine-4-carboxylic acid 505 263. [00516] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((6-ethyl-5-fluoro-2-((5- methyl-1H-pyrazol-3-yl)amino) pyrimidin-4-yl)methyl)-2-methyl piperidine-4-carboxylic acid 519 264. [00517] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 2-ethyl-4-((6-ethyl-5-fluoro-2- ((5-methyl-1H-pyrazol-3-yl) amino)pyrimidin-4-yl)methyl) piperidine-4-carboxylic acid 533 265. [00518] embedded image 1-(3-chloro-2-fluorobenzyl)-4-((5- fluoro-6-methyl-2-((5-methyl- 1H-pyrazol-3-yl)amino)pyrimidin- 4-yl)methyl)piperidine-4- carboxylic acid 491 266. [00519] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((5-fluoro-6-methyl-2-((5- methyl-1H-pyrazol-3-yl)amino) pyrimidin-4-yl)methyl)-2-methyl piperidine-4-carboxylic acid 505 267. [00520] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 2-ethyl-4-((5-fluoro-6-methyl- 2-((5-methyl-1H-pyrazol-3-yl) amino)pyrimidin-4-yl)methyl) piperidine-4-carboxylic acid 519 268. [00521] 1-(3-chloro-2-fluorobenzyl)-4-((5- fluoro-6-isopropyl-2-((5-methyl- 1H-pyrazol-3-yl)amino)pyrimidin- 4-yl)methyl)piperidine-4- carboxylic acid 519 269. [00522] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((5-fluoro-6-isopropyl-2-((5- methyl-1H-pyrazol-3-yl)amino) pyrimidin-4-yl)methyl)-2- methylpiperidine-4-carboxylic acid 533 270. [00523] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 2-ethyl-4-((5-fluoro-6-isopropyl- 2-((5-methyl-1H-pyrazol-3- yl)amino)pyrimidin-4-yl)methyl) piperidine-4-carboxylic acid 547 271. [00524] embedded image 1-(3-chloro-2-fluorobenzyl)-4-((6- cyclopropyl-5-fluoro-2-((5- methyl-1H-pyrazol-3-yl)amino) pyrimidin-4-yl)methyl)piperidine-4- carboxylic acid 517 272. [00525] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((6-cyclopropyl-5-fluoro- 2-((5-methyl-1H-pyrazol-3-yl) amino)pyrimidin-4-yl)methyl)-2- methylpiperidine-4-carboxylic acid 531 273. [00526] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((6-cyclopropyl-5-fluoro- 2-((5-methyl-1H-pyrazol-3-yl) amino)pyrimidin-4-yl)methyl)-2- ethylpiperidine-4-carboxylic acid 545 274. [00527] 1-(3-chloro-2-fluorobenzyl)-4-((5- fluoro-6-(2-hydroxypropan-2- yl)-2-((5-methyl-1H-pyrazol-3- yl)amino)pyrimidin-4-yl)methyl) piperidine-4-carboxylic acid 535 275. [00528] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((5-fluoro-6-(2-hydroxypropan- 2-yl)-2-((5-methyl-1H-pyrazol- 3-yl)amino)pyrimidin-4-yl) methyl)-2-methylpiperidine-4- carboxylic acid 549 276. [00529] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 2-ethyl-4-((5-fluoro-6-(2- hydroxypropan-2-yl)-2-((5-methyl- 1H-pyrazol-3-yl)amino)pyrimidin- 4-yl)methyl)piperidine-4- carboxylic acid 563 277. [00530] embedded image 1-(3-chloro-2-fluorobenzyl)-4-((5- fluoro-2-((5-methyl-1H-pyrazol- 3-yl)amino)-6-phenylpyrimidin- 4-yl)methyl)piperidine-4- carboxylic acid 553 278. [00531] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((5-fluoro-2-((5-methyl-1 H-pyrazol-3-yl)amino)-6-phenyl pyrimidin-4-yl)methyl)-2-methyl piperidine-4-carboxylic acid 567 279. [00532] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 2-ethyl-4-((5-fluoro-2-((5- methyl-1H-pyrazol-3-yl)amino)- 6-phenylpyrimidin-4-yl)methyl) piperidine-4-carboxylic acid 581 280. [00533] 1-(3-chloro-2-fluorobenzyl)-4-((5- fluoro-6-(1-hydroxycyclopropyl)- 2-((5-methyl-1H-pyrazol-3-yl) amino)pyrimidin-4-yl)methyl) piperidine-4-carboxylic acid 533 281. [00534] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((5-fluoro-6-(1-hydroxycyclo propyl)-2-((5-methyl-1H- pyrazol-3-yl)amino)pyrimidin-4-yl) methyl)-2-methylpiperidine-4- carboxylic acid 547 282. [00535] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 2-ethyl-4-((5-fluoro-6-(1- hydroxycyclopropyl)-2-((5-methyl- 1H-pyrazol-3-yl)amino)pyrimidin- 4-yl)methyl)piperidine-4- carboxylic acid 561 283. [00536] embedded image (2R,4R)-4-((6-(azetidin-1-yl)-5- fluoro-2-((5-methyl-1H-pyrazol- 3-yl)amino)pyrimidin-4-yl)methyl)- 1-(3-chloro-2-fluorobenzyl)- 2-ethylpiperidine-4-carboxylic acid 560 284. [00537] 4-((6-(azetidin-1-yl)-5-fluoro-2- ((5-methyl-1H-pyrazol-3-yl)amino) pyrimidin-4-yl)methyl)-1-(3- chloro-2-fluorobenzyl)piperidine- 4-carboxylic acid 532 285. [00538] embedded image (2R,4R)-4-((6-(azetidin-1-yl)-5- fluoro-2-((5-methyl-1H-pyrazol- 3-yl)amino)pyrimidin-4-yl)methyl)- 1-(3-chloro-2-fluorobenzyl)- 2-methylpiperidine-4-carboxylic acid 546 286. [00539] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((6-(difluoromethyl)-5-fluoro- 2-((5-methyl-1H-pyrazol-3- yl)amino)pyrimidin-4-yl)methyl)- 2-ethylpiperidine-4-carboxylic acid 555 287. [00540] embedded image 1-(3-chloro-2-fluorobenzyl)-4-((6- (difluoromethyl)-5-fluoro-2-((5- methyl-1H-pyrazol-3-yl)amino) pyrimidin-4-yl)methyl)piperidine- 4-carboxylic acid 527 288. [00541] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((6-(difluoromethyl)-5-fluoro- 2-((5-methyl-1H-pyrazol-3- yl)amino)pyrimidin-4-yl)methyl)- 2-methylpiperidine-4-carboxylic acid 541 289. [00542] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 2-ethyl-4-((5-fluoro-2-((5- methyl-1H-pyrazol-3-yl)amino)- 6-(trifluoromethyl)pyrimidin-4- yl)methyl)piperidine-4-carboxylic acid 573 290. [00543] 1-(3-chloro-2-fluorobenzyl)-4-((5- fluoro-2-((5-methyl-1H-pyrazol- 3-yl)amino)-6-(trifluoromethyl) pyrimidin-4-yl)methyl)piperidine- 4-carboxylic acid 545 291. [00544] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((5-fluoro-2-((5-methyl-1 H-pyrazol-3-yl)amino)-6-(trifluoro methyl)pyrimidin-4-yl)methyl)- 2-methylpiperidine-4-carboxylic acid 559 292. [00545] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 2-ethyl-4-((5-fluoro-6-(1- hydroxycyclobutyl)-2-((5-methyl-1 H-pyrazol-3-yl)amino)pyrimidin- 4-yl)methyl)piperidine-4- carboxylic acid 575 293. [00546] embedded image 1-(3-chloro-2-fluorobenzyl)-4-((5- fluoro-6-(1-hydroxycyclobutyl)- 2-((5-methyl-1H-pyrazol-3-yl) amino)pyrimidin-4-yl)methyl) piperidine-4-carboxylic acid 547 294. [00547] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((5-fluoro-6-(1-hydroxycyclo butyl)-2-((5-methyl-1H-pyrazol- 3-yl)amino)pyrimidin-4-yl) methyl)-2-methylpiperidine-4- carboxylic acid 561 295. [00548] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((6-cyclobutyl-5-fluoro-2- ((5-methyl-1H-pyrazol-3-yl)amino) pyrimidin-4-yl)methyl)-2- ethylpiperidine-4-carboxylic acid 559 296. [00549] 1-(3-chloro-2-fluorobenzyl)-4-((6- cyclobutyl-5-fluoro-2-((5-methyl- 1H-pyrazol-3-yl)amino)pyrimidin- 4-yl)methyl)piperidine-4- carboxylic acid 531 297. [00550] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((6-cyclobutyl-5-fluoro-2- ((5-methyl-1H-pyrazol-3-yl) amino)pyrimidin-4-yl)methyl)-2- methylpiperidine-4-carboxylic acid 545 298. [00551] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((6-cyano-5-fluoro-2-((5- methyl-1H-pyrazol-3-yl)amino) pyrimidin-4-yl)methyl)-2-ethyl piperidine-4-carboxylic acid 530 299. [00552] embedded image 1-(3-chloro-2-fluorobenzyl)-4-((6- cyano-5-fluoro-2-((5-methyl-1 H-pyrazol-3-yl)amino)pyrimidin- 4-yl)methyl)piperidine-4- carboxylic acid 502 300. [00553] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((6-cyano-5-fluoro-2-((5- methyl-1H-pyrazol-3-yl)amino) pyrimidin-4-yl)methyl)-2-methyl piperidine-4-carboxylic acid 516 301. [00554] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((5-fluoro-6-(3-hydroxyoxetan- 3-yl)-2-((5-methyl-1H-pyrazol- 3-yl)amino)pyrimidin-4-yl) methyl)-2-methylpiperidine-4- carboxylic acid 563 302. [00555] 1-(3-chloro-2-fluorobenzyl)-4-((5- fluoro-6-(3-hydroxyoxetan-3- yl)-2-((5-methyl-1H-pyrazol-3- yl)amino)pyrimidin-4-yl)methyl) piperidine-4-carboxylic acid 549 303. [00556] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 2-ethyl-4-((5-fluoro-6-(3- hydroxyoxetan-3-yl)-2-((5-methyl- 1H-pyrazol-3-yl)amino)pyrimidin- 4-yl)methyl)piperidine-4- carboxylic acid 577 304. [00557] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((5-fluoro-2-((5-methyl-1 H-pyrazol-3-yl)amino)-6-(oxetan- 3-yl)pyrimidin-4-yl)methyl)-2- methylpiperidine-4-carboxylic acid 547 305. [00558] embedded image 1-(3-chloro-2-fluorobenzyl)-4-((5- fluoro-2-((5-methyl-1H-pyrazol- 3-yl)amino)-6-(oxetan-3-yl) pyrimidin-4-yl)methyl)piperidine- 4-carboxylic acid 533 306. [00559] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 2-ethyl-4-((5-fluoro-2-((5- methyl-1H-pyrazol-3-yl)amino)- 6-(oxetan-3-yl)pyrimidin-4-yl) methyl)piperidine-4-carboxylic acid 561 307. [00560] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((3-fluoro-6-((5-methyl-1 H-pyrazol-3-yl)amino)pyrazin-2- yl)methyl)-2-methylpiperidine- 4-carboxylic acid 491 308. [00561] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 2-methyl-4-((5-methyl-2-((5- methyl-1H-pyrazol-3-yl)amino) pyrimidin-4-yl)methyl)piperidine- 4-carboxylic acid 487 309. [00562] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((6-fluoro-3-((5-methyl-1 H-pyrazol-3-yl)amino)-1,2,4-triazin- 5-yl)methyl)-2-methylpiperidine- 4-carboxylic acid 492 310. [00563] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 2-ethyl-4-((3-fluoro-6-((5- methyl-1H-pyrazol-3-yl)amino) pyrazin-2-yl)methyl)piperidine- 4-carboxylic acid 505 311. [00564] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 2-ethyl-4-((5-fluoro-2-((5- methyl-1H-pyrazol-3-yl)amino) pyrimidin-4-yl)methyl)piperidine- 4-carboxylic acid 505 312. [00565] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 2-ethyl-4-((6-fluoro-3-((5- methyl-1H-pyrazol-3-yl)amino)- 1,2,4-triazin-5-yl)methyl)piperidine- 4-carboxylic acid 506 313. [00566] embedded image 1-(3-chloro-2-fluorobenzyl)-4-((3- fluoro-6-((5-methyl-1H-pyrazol- 3-yl)amino)pyrazin-2-yl)methyl) piperidine-4-carboxylic acid 477 314. [00567] 1-(3-chloro-2-fluorobenzyl)-4-((5- fluoro-2-((5-methyl-1H-pyrazol- 3-yl)amino)pyrimidin-4-yl) methyl)piperidine-4-carboxylic acid 477 315. [00568] embedded image 1-(3-chloro-2-fluorobenzyl)-4-((6- fluoro-3-((5-methyl-1H-pyrazol- 3-yl)amino)-1,2,4-triazin-5-yl) methyl)piperidine-4-carboxylic acid 478 316. [00569] (2R)-1-(((3-chloro-2-fluorophenyl) sulfonyl)methyl)-4-((3-fluoro- 6-((5-methyl-1H-pyrazol-3-yl) amino)pyridin-2-yl)methyl)-2- methylpiperidine-4-carboxylic acid 554 317. [00570] embedded image (2R)-1-((1-(3-chloro-2-fluorophenyl) cyclopropyl)methyl)-4-((3- fluoro-6-((5-methyl-1H-pyrazol- 3-yl)amino)pyridin-2-yl)methyl)- 2-methylpiperidine-4-carboxylic acid 530 318. [00571] (2R)-1-((1-(3-chloro-2-fluorophenyl) cyclobutyl)methyl)-4-((3- fluoro-6-((5-methyl-1H-pyrazol-3- yl)amino)pyridin-2-yl)methyl)- 2-methylpiperidine-4-carboxylic acid 544 319. [00572] embedded image (2R)-1-((3-(3-chloro-2-fluorophenyl) oxetan-3-yl)methyl)-4-((3- fluoro-6-((5-methyl-1H-pyrazol- 3-yl)amino)pyridin-2-yl)methyl)- 2-methylpiperidine-4-carboxylic acid 546 320. [00573] (2R)-1-(1-(3-chloro-2-fluorobenzyl) cyclopropyl)-4-((3-fluoro-6- ((5-methyl-1H-pyrazol-3-yl) amino)pyridin-2-yl)methyl)-2- methylpiperidine-4-carboxylic acid 530 321. [00574] embedded image (2R)-1-(1-(3-chloro-2-fluorobenzyl) cyclobutyl)-4-((3-fluoro-6-((5- methyl-1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)-2-methyl piperidine-4-carboxylic acid 544 322. [00575] (2R)-1-(3-(3-chloro-2-fluorobenzyl) oxetan-3-yl)-4-((3-fluoro-6- ((5-methyl-1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)-2-methyl piperidine-4-carboxylic acid 546 323. [00576] embedded image (2R)-1-(2-(3-chloro-2-fluorophenyl)- 2,2-difluoroethyl)-4-((3-fluoro- 6-((5-methyl-1H-pyrazol-3- yl)amino)pyridin-2-yl)methyl)-2- methylpiperidine-4-carboxylic acid 540 324. [00577] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((3-fluoro-6-((5-methyl-1 H-pyrazol-3-yl)amino)-4-(methyl amino)pyridin-2-yl)methyl)-2- methylpiperidine-4-carboxylic acid 519 325. [00578] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((3-fluoro-4-isopropoxy-6- ((5-methyl-1H-pyrazol-3-yl) amino)pyridin-2-yl)methyl)-2- methylpiperidine-4-carboxylic acid 548 326. [00579] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((3-fluoro-4-(1-fluorocyclo propyl)-6-((5-methyl-1H-pyrazol- 3-yl)amino)pyridin-2-yl)methyl)- 2-methylpiperidine-4-carboxylic acid 548 327. [00580] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((3-fluoro-4-(2-hydroxyethyl)- 6-((5-methyl-1H-pyrazol-3- yl)amino)pyridin-2-yl)methyl)-2- methylpiperidine-4-carboxylic acid 534 328. [00581] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((3-fluoro-4,5-dimethyl-6- ((5-methyl-1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)-2-methyl piperidine-4-carboxylic acid 518 329. [00582] embedded image (2R,4R)-1-(2,3-difluorophenethyl)- 4-((3-fluoro-6-((5-methyl-1H- pyrazol-3-yl)amino)pyridin-2-yl) methyl)-2-methylpiperidine-4- carboxylic acid 487 330. [00583] (2R,4R)-1-(2,3-dichlorophenethyl)- 4-((3-fluoro-6-((5-methyl-1H- pyrazol-3-yl)amino)pyridin-2- yl)methyl)-2-methylpiperidine-4- carboxylic acid 520 331. [00584] embedded image (2R,4R)-1-(3-chloro-2,6-difluoro phenethyl)-4-((3-fluoro-6-((5- methyl-1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)-2-methyl piperidine-4-carboxylic acid 522 332. [00585] (2R,4R)-1-(2,4-dichlorophenethyl)- 4-((3-fluoro-6-((5-methyl-1H- pyrazol-3-yl)amino)pyridin-2-yl) methyl)-2-methylpiperidine-4- carboxylic acid 520 333. [00586] embedded image (2R,4R)-1-(2-(3-chloro-2-fluoro phenyl)-2,2-difluoroethyl)-4-((3- fluoro-6-((5-methyl-1H-pyrazol- 3-yl)amino)pyridin-2-yl)methyl)- 2-methylpiperidine-4-carboxylic acid 540 334. [00587] (2R,4R)-1-((1-(3-chloro-2-fluoro phenyl)cyclopropyl)methyl)-4- ((3-fluoro-6-((5-methyl-1H-pyrazol- 3-yl)amino)pyridin-2-yl)methyl)- 2-methylpiperidine-4-carboxylic acid 530 335. [00588] embedded image (2R,4R)-1-((1-(3-chloro-2-fluoro phenyl)cyclobutyl)methyl)-4-((3- fluoro-6-((5-methyl-1H-pyrazol- 3-yl)amino)pyridin-2-yl)methyl)- 2-methylpiperidine-4-carboxylic acid 544 336. [00589] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((3-fluoro-4-(2-fluoro-1,3- dihydroxypropan-2-yl)-6-((5- methyl-1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)-2- methylpiperidine-4-carboxylic acid 582 337. [00590] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 2-methyl-4-((6-((5-methyl- 1H-pyrazol-3-yl)amino)-3-(trifluoro methyl)pyridin-2-yl)methyl) piperidine-4-carboxylic acid 540 338. [00591] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((3-fluoro-6-((5-methyl-1 H-pyrazol-3-yl)amino)-4-morpholino pyridin-2-yl)methyl)-2- methylpiperidine-4-carboxylic acid 575 339. [00592] embedded image (2R,4R)-4-((3-fluoro-6-((5-methyl- 1H-pyrazol-3-yl)amino)-4-(4- methylpiperazin-1-yl)pyridin-2- yl)methyl)-2-methyl-1-((2-(trifluoro methyl)phenyl)sulfonyl)piperidine- 4-carboxylic acid 654 340. [00593] (2R,4R)-4-((3-fluoro-6-((5-methyl- 1H-pyrazol-3-yl)amino)-4-(1- methylazetidin-3-yl)pyridin-2-yl) methyl)-2-methyl-1-((2-(trifluoro methyl)phenyl)sulfonyl)piperidine- 4-carboxylic acid 625 341. [00594] embedded image (2R,4R)-4-((4-(azetidin-1-yl)-3- fluoro-6-((5-methyl-1H-pyrazol- 3-yl)amino)pyridin-2-yl)methyl)- 2-methyl-1-((2-(trifluoromethyl) phenyl)sulfonyl)piperidine-4- carboxylic acid 611 342. [00595] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((3-fluoro-6-((5-methyl-1H- pyrazol-3-yl)amino)-4-(3- methyloxetan-3-yl)pyridin-2-yl) methyl)-2-methylpiperidine-4- carboxylic acid 560 343. [00596] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((3-fluoro-5-methyl-6-((5- methyl-1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)-2-methyl piperidine-4-carboxylic acid 504 344. [00597] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 2-methyl-4-((4-((5-methyl- 1H-pyrazol-3-yl)amino)pyrimidin- 2-yl)methyl)piperidine-4- carboxylic acid 473 345. [00598] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 2-methyl-4-((6-((5-methyl- 1H-pyrazol-3-yl)amino)-4-(trifluoro methoxy)pyridin-2-yl)methyl) piperidine-4-carboxylic acid 556 346. [00599] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((3-fluoro-6-((5-methyl-1 H-pyrazol-3-yl)amino)-4-(trifluoro methoxy)pyridin-2-yl)methyl)- 2-methylpiperidine-4-carboxylic acid 574 347. [00600] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 2-methyl-4-((6-((5-methyl- 1H-pyrazol-3-yl)amino)-3- (trifluoromethyl)pyrazin-2-yl)methyl) piperidine-4-carboxylic acid 541 348. [00601] 1-(3-chloro-2,6-difluorobenzyl)- 4-((4-ethyl-3-fluoro-6-((5-methyl- 1H-pyrazol-3-yl)amino)pyridin- 2-yl)methyl)piperidine-4- carboxylic acid 522 349. [00602] embedded image 4-((4-acetyl-3-fluoro-6-((5-methyl- 1H-pyrazol-3-yl)amino)pyridin- 2-yl)methyl)-1-(3-chloro-2,6- difluorobenzyl)piperidine-4- carboxylic acid 536 350. [00603] (2R,4R)-4-((4-acetyl-3-methyl-6- ((5-methyl-1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)-1-(3- chloro-2-fluorobenzyl)-2-methyl piperidine-4-carboxylic acid 528 351. [00604] embedded image (2R,4R)-4-((4-acetyl-6-((5-methyl- 1H-pyrazol-3-yl)amino)pyridin- 2-yl)methyl)-1-(3-chloro-2- fluorobenzyl)-2-methylpiperidine-4- carboxylic acid 514 352. [00605] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((3′-fluoro-3-methyl-6′-((5- methyl-1H-pyrazol-3-yl)amino)- [2,4′-bipyridin]-2′-yl)methyl)- 2-methylpiperidine-4-carboxylic acid 581 353. [00606] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((3-fluoro-6-((5-methyl-1H- pyrazol-3-yl)amino)-4-(pyrimidin- 2-yl)pyridin-2-yl)methyl)-2- methylpiperidine-4-carboxylic acid 568 354. [00607] (2R,4R)-4-((4-acetyl-3-chloro-6- ((5-methyl-1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)-1-(3-chioro- 2-fluorobenzyl)-2-methylpiperidine- 4-carboxylic acid 548 355. [00608] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 2-methyl-4-((6′-((5-methyl- 1H-pyrazol-3-yl)amino)-[2,4′- bipyridin]-2′-yl)methyl)piperidine- 4-carboxylic acid 549 356. [00609] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 2-methyl-4-((3-methyl-6′-((5- methyl-1H-pyrazol-3-yl)amino)- [2,4′-bipyridin]-2′-yl)methyl) piperidine-4-carboxylic acid 563 357. [00610] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 2-methyl-4-((6-((5-methyl- 1H-pyrazol-3-yl)amino)-4- (pyrimidin-2-yl)pyridin-2-yl) methyl)piperidine-4-carboxylic acid 550 358. [00611] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 2-methyl-4-((3′-methyl-6′-((5- methyl-1H-pyrazol-3-yl)amino)- [2,4′-bipyridin]-2′-yl)methyl) piperidine-4-carboxylic acid 563 359. [00612] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((3,3′-dimethyl-6′-((5-methyl- 1H-pyrazol-3-yl)amino)-[2,4′- bipyridin]-2′-yl)methyl)-2-methyl piperidine-4-carboxylic acid 577 360. [00613] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 2-methyl-4-((3-methyl-6-((5- methyl-1H-pyrazol-3-yl)amino)- 4-(pyrimidin-2-yl)pyridin-2-yl) methyl)piperidine-4-carboxylic acid 564 361. [00614] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((3′-chloro-6′-((5-methyl- 1H-pyrazol-3-yl)amino)-[2,4′- bipyridin]-2′-yl)methyl)-2-methyl piperidine-4-carboxylic acid 583 362. [00615] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((3′-chloro-3-methyl-6′-((5- methyl-1H-pyrazol-3-yl)amino)- [2,4′-bipyridin]-2′-yl)methyl)- 2-methylpiperidine-4-carboxylic acid 598 363. [00616] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((3-chloro-6-((5-methyl-1 H-pyrazol-3-yl)amino)-4-(pyrimidin- 2-yl)pyridin-2-yl)methyl)-2- methylpiperidine-4-carboxylic acid 584 364. [00617] 1-(3-chloro-2-fluorobenzyl)-4-(2,6- difluoro-3-((5-methyl-1H-pyrazol- 3-yl)amino)benzyl)piperidine- 4-carboxylic acid 493 365. [00618] embedded image (2R,4R)-4-((4-acetyl-3,5-difluoro- 6-((5-methyl-1H-pyrazol-3-yl) amino)pyridin-2-yl)methyl)-1-(3- chloro-2-fluorobenzyl)-2-methyl piperidine-4-carboxylic acid 550 366. [00619] (2R,4R)-4-((4-acetyl-3-fluoro-5- methyl-6-((5-methyl-1H-pyrazol-3- yl)amino)pyridin-2-yl)methyl)- 1-(3-chloro-2-fluorobenzyl)-2- methylpiperidine-4-carboxylic acid 546 367. [00620] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((4-(1,1-difluoroethyl)-3, 5-difluoro-6-((5-methyl-1H-pyrazol- 3-yl)amino)pyridin-2-yl)methyl)- 2-methylpiperidine-4- carboxylic acid 572 368. [00621] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((3,5-difluoro-6-((5-methyl- 1H-pyrazol-3-yl)amino)-4-(3- methyloxetan-3-yl)pyridin-2-yl) methyl)-2-methylpiperidine-4- carboxylic acid 578 369. [00622] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((3,5-difluoro-4-(1-fluoroethyl)- 6-((5-methyl-1H-pyrazol- 3-yl)amino)pyridin-2-yl)methyl)-2- methylpiperidine-4-carboxylic acid 554 370. [00623] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((3,5-difluoro-6-((5-methyl- 1H-pyrazol-3-yl)amino)-4- (methylsulfonyl)pyridin-2-yl) methyl)-2-methylpiperidine-4- carboxylic acid 586 371. [00624] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((4-(1,1-difluoroethyl)-3-fluoro- 5-methyl-6-((5-methyl-1H- pyrazol-3-yl)amino)pyridin-2- yl)methyl)-2-methylpiperidine-4- carboxylic acid 568 372. [00625] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((3-fluoro-5-methyl-6-((5- methyl-1H-pyrazol-3-yl)amino)-4- (3-methyloxetan-3-yl)pyridin-2- yl)methyl)-2-methylpiperidine- 4-carboxylic acid 574 373. [00626] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((5-fluoro-3-methyl-6-((5- methyl-1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)-2-methyl piperidine-4-carboxylic acid 504 374. [00627] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((4-ethyl-5-fluoro-3-methyl- 6-((5-methyl-1H-pyrazol-3-yl) amino)pyridin-2-yl)methyl)-2- methylpiperidine-4-carboxylic acid 532 375. [00628] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((4-chloro-3-methyl-5- fluoro-6-((5-methyl-1H-pyrazol-3- yl)amino)pyridin-2-yl)methyl)-2- methylpiperidine-4-carboxylic acid 538 376. [00629] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((5-fluoro-3-methyl-6-((5- methyl-1H-pyrazol-3-yl)amino)- 4-propionylpyridin-2-yl)methyl)- 2-methylpiperidine-4-carboxylic acid 560 377. [00630] embedded image (2R,4R)-4-((4-acetyl-3-methyl-5- fluoro-6-((5-methyl-1H-pyrazol-3- yl)amino)pyridin-2-yl)methyl)- 1-(3-chloro-2-fluorobenzyl)-2- methylpiperidine-4-carboxylic acid 546 378. [00631] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((4-ethyl-5-fluoro-6-((5- methyl-1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)-2-methyl piperidine-4-carboxylic acid 518 379. [00632] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((5-fluoro-6-((5-methyl-1 H-pyrazol-3-yl)amino)-4-propionyl pyridin-2-yl)methyl)-2-methyl piperidine-4-carboxylic acid 546 380. [00633] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((4-ethyl-3,5-difluoro-6-((5- methyl-1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)-2-methyl piperidine-4-carboxylic acid 536 381. [00634] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((3,5-difluoro-6-((5-methyl- 1H-pyrazol-3-yl)amino)-4- propionylpyridin-2-yl)methyl)-2- methylpiperidine-4-carboxylic acid 564 382. [00635] 1-(3-chloro-2-fluorobenzyl)-4-((3- methyl-5-fluoro-6-((5-methyl- 1H-pyrazol-3-yl)amino)pyridin- 2-yl)methyl)piperidine-4-carboxylic acid 490 383. [00636] embedded image 1-(3-chloro-2-fluorobenzyl)-4-((3- methyl-5-fluoro-4-methyl-6-((5- methyl-1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)piperidine- 4-carboxylic acid 504 384. [00637] 1-(3-chloro-2-fluorobenzyl)-4-((4- ethyl-5-fluoro-3-methyl-6-((5- methyl-1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)piperidine-4- carboxylic acid 518 385. [00638] embedded image 1-(3-chloro-2-fluorobenzyl)-4-((4- chloro-3-methyl-5-fluoro-6-((5- methyl-1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)piperidine- 4-carboxylic acid 524 386. [00639] 1-(3-chloro-2-fluorobenzyl)-4-(( 3-methyl-5-fluoro-6-((5-methyl- 1H-pyrazol-3-yl)amino)-4-propionyl pyridin-2-yl)methyl)piperidine- 4-carboxylic acid 546 387. [00640] embedded image 4-((4-acetyl-3-methyl-5-fluoro-6- ((5-methyl-1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)-1-(3- chloro-2-fluorobenzyl)piperidine-4- carboxylic acid 532 388. [00641] 1-(3-chloro-2-fluorobenzyl)-4-((5- fluoro-6-((5-methyl-1H-pyrazol- 3-yl)amino)pyridin-2-yl)methyl) piperidine-4-carboxylic acid 476 389. [00642] embedded image 1-(3-chloro-2-fluorobenzyl)-4-((4- ethyl-5-fluoro-6-((5-methyl-1 H-pyrazol-3-yl)amino)pyridin-2- yl)methyl)piperidine-4-carboxylic acid 504 390. [00643] 1-(3-chloro-2-fluorobenzyl)-4-((4- chloro-5-fluoro-6-((5-methyl- 1H-pyrazol-3-yl)amino)pyridin- 2-yl)methyl)piperidine-4- carboxylic acid 510 391. [00644] embedded image 1-(3-chloro-2-fluorobenzyl)-4-((5- fluoro-6-((5-methyl-1H-pyrazol- 3-yl)amino)-4-propionylpyridin- 2-yl)methyl)piperidine-4- carboxylic acid 532 392. [00645] 4-((4-acetyl-5-fluoro-6-((5- methyl-1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)-1-(3-chloro-2- fluorobenzyl)piperidine-4-carboxylic acid 518 393. [00646] embedded image 1-(3-chloro-2-fluorobenzyl)-4-((3, 5-difluoro-4-methyl-6-((5-methyl- 1H-pyrazol-3-yl)amino)pyridin- 2-yl)methyl)piperidine-4- carboxylic acid 508 394. [00647] 1-(3-chloro-2-fluorobenzyl)-4-((4- ethyl-3,5-difluoro-6-((5-methyl- 1H-pyrazol-3-yl)amino)pyridin-2- yl)methyl)piperidine-4- carboxylic acid 522 395. [00648] embedded image 1-(3-chloro-2-fluorobenzyl)-4-((4- chloro-3,5-difluoro-6-((5-methyl- 1H-pyrazol-3-yl)amino)pyridin- 2-yl)methyl)piperidine-4- carboxylic acid 528 396. [00649] 1-(3-chloro-2-fluorobenzyl)-4-((3, 5-difluoro-6-((5-methyl-1H- pyrazol-3-yl)amino)-4-propionyl pyridin-2-yl)methyl)piperidine-4- carboxylic acid 550 397. [00650] embedded image 4-((4-acetyl-3,5-difluoro-6-((5- methyl-1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)-1-(3-chloro- 2-fluorobenzyl)piperidine-4- carboxylic acid 536 398. [00651] 1-(3-chloro-2-fluorobenzyl)-4-((3- fluoro-4,5-dimethyl-6-((5-methyl- 1H-pyrazol-3-yl)amino)pyridin- 2-yl)methyl)piperidine-4- carboxylic acid 504 399. [00652] embedded image 4-((4-acetyl-3-fluoro-5-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino)pyridin-2-yl)methyl)-1-(3- chloro-2-fluorobenzyl)piperidine-4- carboxylic acid 532 400. [00653] 1-(3-chloro-2-fluorobenzyl)-4-((4- (1,1-difluoroethyl)-3,5-difluoro- 6-((5-methyl-1H-pyrazol-3-yl) amino)pyridin-2-yl)methyl) piperidine-4-carboxylic acid 558 401. [00654] embedded image 1-(3-chloro-2-fluorobenzyl)-4-((3, 5-difluoro-6-((5-methyl-1H- pyrazol-3-yl)amino)-4-(3-methyl oxetan-3-yl)pyridin-2-yl)methyl) piperidine-4-carboxylic acid 564 402. [00655] 1-(3-chloro-2-fluorobenzyl)-4-((3, 5-difluoro-4-(1-fluoroethyl)-6- ((5-methyl-1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)piperidine- 4-carboxylic acid 540 403. [00656] embedded image 1-(3-chloro-2-fluorobenzyl)-4-((3, 5-difluoro-6-((5-methyl-1H-pyrazol- 3-yl)amino)-4-(methylsulfonyl) pyridin-2-yl)methyl)piperidine- 4-carboxylic acid 572 404. [00657] 1-(3-chloro-2-fluorobenzyl)-4-((4- (1,1-difluoroethyl)-3-fluoro-5- methyl-6-((5-methyl-1H-pyrazol- 3-yl)amino)pyridin-2-yl)methyl) piperidine-4-carboxylic acid 554 405. [00658] embedded image 1-(3-chloro-2-fluorobenzyl)-4-((3- fluoro-5-methyl-6-((5-methyl- 1H-pyrazol-3-yl)amino)-4-(3- methyloxetan-3-yl)pyridin-2-yl) methyl)piperidine-4-carboxylic acid 560 406. [00659] 1-(3-chloro-2-fluorobenzyl)-4-((3, 5-dimethyl-6-((5-methyl-1H- pyrazol-3-yl)amino)pyridin-2-yl) methyl)piperidine-4-carboxylic acid 486 407. [00660] embedded image 1-(3-chloro-2-fluorobenzyl)-4-((3, 4,5-trimethyl-6-((5-methyl-1H- pyrazol-3-yl)amino)pyridin-2-yl) methyl)piperidine-4-carboxylic acid 500 408. [00661] 1-(3-chloro-2-fluorobenzyl)-4-((4- ethyl-3,5-dimethyl-6-((5-methyl- 1H-pyrazol-3-yl)amino)pyridin- 2-yl)methyl)piperidine-4- carboxylic acid 514 409. [00662] embedded image 1-(3-chloro-2-fluorobenzyl)-4-((4- chloro-3,5-dimethyl-6-((5-methyl- 1H-pyrazol-3-yl)amino)pyridin- 2-yl)methyl)piperidine-4- carboxylic acid 520 410. [00663] 1-(3-chloro-2-fluorobenzyl)-4-((3, 5-dimethyl-6-((5-methyl-1H- pyrazol-3-yl)amino)-4-propionyl pyridin-2-yl)methyl)piperidine-4- carboxylic acid 542 411. [00664] embedded image 4-((4-acetyl-3,5-dimethyl-6-((5- methyl-1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)-1-(3-chloro- 2-fluorobenzyl)piperidine-4- carboxylic acid 528 412. [00665] 1-(3-chloro-2-fluorobenzyl)-4-((5- methyl-6-((5-methyl-1H-pyrazol- 3-yl)amino)pyridin-2-yl)methyl) piperidine-4-carboxylic acid 472 413. [00666] embedded image 1-(3-chloro-2-fluorobenzyl)-4-((4, 5-dimethyl-6-((5-methyl-1H- pyrazol-3-yl)amino)pyridin-2-yl) methyl)piperidine-4-carboxylic acid 486 414. [00667] 1-(3-chloro-2-fluorobenzyl)-4-((4- ethyl-5-methyl-6-((5-methyl-1 H-pyrazol-3-yl)amino)pyridin-2- yl)methyl)piperidine-4-carboxylic acid 500 415. [00668] embedded image 1-(3-chloro-2-fluorobenzyl)-4-((4- chloro-5-methyl-6-((5-methyl- 1H-pyrazol-3-yl)amino)pyridin- 2-yl)methyl)piperidine-4- carboxylic acid 506 416. [00669] 1-(3-chloro-2-fluorobenzyl)-4-((5- methyl-6-((5-methyl-1H-pyrazol- 3-yl)amino)-4-propionylpyridin- 2-yl)methyl)piperidine-4- carboxylic acid 528 417. [00670] embedded image 4-((4-acetyl-5-methyl-6-((5-methyl- 1H-pyrazol-3-yl)amino)pyridin- 2-yl)methyl)-1-(3-chloro-2- fluorobenzyl)piperidine-4- carboxylic acid 514 418. [00671] 1-(3-chloro-2-fluorobenzyl)-4-((3- fluoro-5-methyl-6-((5-methyl- 1H-pyrazol-3-yl)amino)pyridin- 2-yl)methyl)piperidine-4- carboxylic acid 490 419. [00672] embedded image 1-(3-chloro-2-fluorobenzyl)-4-((4- ethyl-3-fluoro-5-methyl-6-((5- methyl-1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)piperidine-4- carboxylic acid 518 420. [00673] 1-(3-chloro-2-fluorobenzyl)-4-((4- chloro-3-fluoro-5-methyl-6-((5- methyl-1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)piperidine- 4-carboxylic acid 524 421. [00674] embedded image 1-(3-chloro-2-fluorobenzyl)-4-((3- fluoro-5-methyl-6-((5-methyl- 1H-pyrazol-3-yl)amino)-4-propionyl pyridin-2-yl)methyl)piperidine- 4-carboxylic acid 546 422. [00675] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((3,5-dimethyl-6-((5-methyl- 1H-pyrazol-3-yl)amino)pyridin- 2-yl)methyl)-2-methylpiperidine- 4-carboxylic acid 500 423. [00676] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 2-methyl-4-((3,4,5-trimethyl- 6-((5-methyl-1H-pyrazol-3-yl) amino)pyridin-2-yl)methyl) piperidine-4-carboxylic acid 514 424. [00677] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((4-ethyl-3,5-dimethyl-6- ((5-methyl-1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)-2-methyl piperidine-4-carboxylic acid 528 425. [00678] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((4-chloro-3,5-dimethyl- 6-((5-methyl-1H-pyrazol-3-yl) amino)pyridin-2-yl)methyl)-2-methyl piperidine-4-carboxylic acid 534 426. [00679] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((3,5-dimethyl-6-((5-methyl- 1H-pyrazol-3-yl)amino)-4- propionylpyridin-2-yl)methyl)-2- methylpiperidine-4-carboxylic acid 556 427. [00680] embedded image (2R,4R)-4-((4-acetyl-3,5-dimethyl- 6-((5-methyl-1H-pyrazol-3-yl) amino)pyridin-2-yl)methyl)-1- (3-chloro-2-fluorobenzyl)-2-methyl piperidine-4-carboxylic acid 542 428. [00681] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 2-methyl-4-((5-methyl-6-((5- methyl-1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)piperidine- 4-carboxylic acid 486 429. [00682] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((4,5-dimethyl-6-((5-methyl- 1H-pyrazol-3-yl)amino)pyridin- 2-yl)methyl)-2-methylpiperidine- 4-carboxylic acid 500 430. [00683] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((4-ethyl-5-methyl-6-((5- methyl-1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)-2-methyl piperidine-4-carboxylic acid 514 431. [00684] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((4-chloro-5-methyl-6-((5- methyl-1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)-2-methyl piperidine-4-carboxylic acid 520 432. [00685] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 2-methyl-4-((5-methyl-6-((5- methyl-1H-pyrazol-3-yl)amino)- 4-propionylpyridin-2-yl)methyl) piperidine-4-carboxylic acid 542 433. [00686] embedded image (2R,4R)-4-((4-acetyl-5-methyl-6- ((5-methyl-1H-pyrazol-3-yl) amino)pyridin-2-yl)methyl)-1-(3- chloro-2-fluorobenzyl)-2-methyl piperidine-4-carboxylic acid 528 434. [00687] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((4-ethyl-3-fluoro-5-methyl- 6-((5-methyl-1H-pyrazol-3-yl) amino)pyridin-2-yl)methyl)-2- methylpiperidine-4-carboxylic acid 532 435. [00688] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((4-chloro-3-fluoro-5-methyl- 6-((5-methyl-1H-pyrazol-3- yl)amino)pyridin-2-yl)methyl)-2- methylpiperidine-4-carboxylic acid 538 436. [00689] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((3-fluoro-5-methyl-6-((5- methyl-1H-pyrazol-3-yl)amino)- 4-propionylpyridin-2-yl)methyl)- 2-methylpiperidine-4-carboxylic acid 560 437. [00690] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((5-fluoro-4-((R)-1-fluoro ethyl)-6-((5-methyl-1H-pyrazol- 3-yl)amino)pyridin-2-yl)methyl)- 2-methylpiperidine-4-carboxylic acid 536 438. [00691] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((5-fluoro-4-((S)-1-fluoro ethyl)-6-((5-methyl-1H-pyrazol- 3-yl)amino)pyridin-2-yl)methyl)- 2-methylpiperidine-4-carboxylic acid 536 439. [00692] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((4-(1,1-difluoroethyl)-5- fluoro-6-((5-methyl-1H-pyrazol- 3-yl)amino)pyridin-2-yl)methyl)- 2-methylpiperidine-4-carboxylic acid 554 440. [00693] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((5-fluoro-6-((5-methyl-1 H-pyrazol-3-yl)amino)-4-(3- methyloxetan-3-yl)pyridin-2-yl) methyl)-2-methylpiperidine-4- carboxylic acid 560 441. [00694] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((5′-fluoro-6′-((5-methyl- 1H-pyrazol-3-yl)amino)-[2,4′- bipyridin]-2′-yl)methyl)-2-methyl piperidine-4-carboxylic acid 567 442. [00695] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((5-fluoro-6-((5-methyl-1 H-pyrazol-3-yl)amino)-4-(pyrimidin- 2-yl)pyridin-2-yl)methyl)-2- methylpiperidine-4-carboxylic acid 568 443. [00696] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((5′-fluoro-3-methyl-6′-((5- methyl-1H-pyrazol-3-yl)amino)- [2,4′-bipyridin]-2′-yl)methyl)- 2-methylpiperidine-4-carboxylic acid 581 444. [00697] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((5′-fluoro-6′-((5-methyl- 1H-pyrazol-3-yl)amino)-[3,4′- bipyridin]-2′-yl)methyl)-2-methyl piperidine-4-carboxylic acid 567 445. [00698] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((5-fluoro-6-((5-methyl-1 H-pyrazol-3-yl)amino)-4-(pyridazin- 3-yl)pyridin-2-yl)methyl)-2- methylpiperidine-4-carboxylic acid 568 446. [00699] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((5-fluoro-6-((5-methyl-1 H-pyrazol-3-yl)amino)-4-(oxazol- 2-yl)pyridin-2-yl)methyl)-2- methylpiperidine-4-carboxylic acid 557 447. [00700] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((5-fluoro-6-((5-methyl-1 H-pyrazol-3-yl)amino)-4-(thiazol- 2-yl)pyridin-2-yl)methyl)-2- methylpiperidine-4-carboxylic acid 573 448. [00701] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((5-fluoro-4-( 1-methyl-1 H-imidazol-2-yl)-6-((5-methyl-1 H-pyrazol-3-yl)amino)pyridin-2- yl)methyl)-2-methylpiperidine-4- carboxylic acid 570 449. [00702] embedded image 6-(((2R,4R)-4-carboxy-1-(3-chloro- 2-fluorobenzyl)-2-methylpiperidin- 4-yl)methyl)-3-fluoro-2-((5- methyl-1H-pyrazol-3-yl)amino) isonicotinic acid 534 450. [00703] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((4-(dimethylcarbamoyl)- 5-fluoro-6-((5-methyl-1H-pyrazol- 3-yl)amino)pyridin-2-yl)methyl)- 2-methylpiperidine-4-carboxylic acid 561 451. [00704] embedded image (2R,4R)-4-((4-(azetidine-1-carbonyl)- 5-fluoro-6-((5-methyl-1H- pyrazol-3-yl)amino)pyridin-2-yl) methyl)-1-(3-chloro-2-fluorobenzyl)- 2-methylpiperidine-4- carboxylic acid 573 452. [00705] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((5-fluoro-6-((5-methyl-1 H-pyrazol-3-yl)amino)-4- (morpholine-4-carbonyl)pyridin-2-yl) methyl)-2-methylpiperidine-4- carboxylic acid 603 453. [00706] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((5-fluoro-6-((5-methyl-1 H-pyrazol-3-yl)amino)-4-(4- methylpiperazine-1-carbonyl)pyridin- 2-yl)methyl)-2-methylpiperidine- 4-carboxylic acid 616 454. [00707] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((4-chloro-5-fluoro-3-methyl- 6-((5-methyl-1H-pyrazol-3- yl)amino)pyridin-2-yl)methyl)-2- methylpiperidine-4-carboxylic acid 538 455. [00708] embedded image (2R,4R)-4-((4-acetyl-5-fluoro-3- methyl-6-((5-methyl-1H-pyrazol- 3-yl)amino)pyridin-2-yl)methyl)- 1-(3-chloro-2-fluorobenzyl)-2- methylpiperidine-4-carboxylic acid 546 456. [00709] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((5-fluoro-4-isobutyryl-6- ((5-methyl-1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)-2-methyl piperidine-4-carboxylic acid 560 457. [00710] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((5-fluoro-6-((5-methyl-1 H-pyrazol-3-yl)amino)-4- pivaloylpyridin-2-yl)methyl)-2- methylpiperidine-4-carboxylic acid 574 458. [00711] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((3′-fluoro-5′-methyl-6′-((5- methyl-1H-pyrazol-3-yl)amino)- [2,4′-bipyridin]-2′-yl)methyl)- 2-methylpiperidine-4-carboxylic acid 581 459. [00712] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((3-fluoro-5-methyl-6-((5- methyl-1H-pyrazol-3-yl)amino)- 4-(pyrimidin-2-yl)pyridin-2-yl) methyl)-2-methylpiperidine-4- carboxylic acid 582 460. [00713] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((3-fluoro-5-methyl-6-((5- methyl-1H-pyrazol-3-yl)amino)- 4-(oxazol-2-yl)pyridin-2-yl)methyl)- 2-methylpiperidine-4- carboxylic acid 571 461. [00714] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((5-fluoro-4-isobutyryl-3- methyl-6-((5-methyl-1H-pyrazol- 3-yl)amino)pyridin-2-yl)methyl)- 2-methylpiperidine-4-carboxylic acid 574 462. [00715] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((5-fluoro-3-methyl-6-((5- methyl-1H-pyrazol-3-yl)amino)- 4-pivaloylpyridin-2-yl)methyl)- 2-methylpiperidine-4-carboxylic acid 588 463. [00716] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((3-fluoro-4-isobutyryl-5- methyl-6-((5-methyl-1H-pyrazol- 3-yl)amino)pyridin-2-yl)methyl)- 2-methylpiperidine-4-carboxylic acid 574 464. [00717] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((3-fluoro-5-methyl-6-((5- methyl-1H-pyrazol-3-yl)amino)- 4-pivaloylpyridin-2-yl)methyl)- 2-methylpiperidine-4-carboxylic acid 588 465. [00718] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((3,5-difluoro-4-((R)-1- fluoroethyl)-6-((5-methyl-1H- pyrazol-3-yl)amino)pyridin-2-yl) methyl)-2-methylpiperidine-4- carboxylic acid 554 466. [00719] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((3,5-difluoro-4-((S)-1- fluoroethyl)-6-((5-methyl-1H- pyrazol-3-yl)amino)pyridin-2-yl) methyl)-2-methylpiperidine-4- carboxylic acid 554 467. [00720] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((3′,5′-difluoro-6′-((5-methyl- 1H-pyrazol-3-yl)amino)-[2,4′- bipyridin]-2′-yl)methyl)-2- methylpiperidine-4-carboxylic acid 585 468. [00721] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((3,5-difluoro-6-((5-methyl- 1H-pyrazol-3-yl)amino)-4- (pyrimidin-2-yl)pyridin-2-yl)methyl)- 2-methylpiperidine-4-carboxylic acid 586 469. [00722] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((3′,5′-difluoro-3-methyl- 6′-((5-methyl-1H-pyrazol-3-yl) amino)-[2,4′-bipyridin]-2′-yl) methyl)-2-methylpiperidine-4- carboxylic acid 599 470. [00723] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((3′,5′-difluoro-6′-((5-methyl- 1H-pyrazol-3-yl)amino)-[3,4′- bipyridin]-2′-yl)methyl)-2- methylpiperidine-4-carboxylic acid 585 471. [00724] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((3,5-difluoro-6-((5-methyl- 1H-pyrazol-3-yl)amino)-4- (pyridazin-3-yl)pyridin-2-yl)methyl)- 2-methylpiperidine-4-carboxylic acid 586 472. [00725] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((3,5-difluoro-6-((5-methyl- 1H-pyrazol-3-yl)amino)-4- (oxazol-2-yl)pyridin-2-yl)methyl)- 2-methylpiperidine-4-carboxylic acid 575 473. [00726] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((3,5-difluoro-6-((5-methyl- 1H-pyrazol-3-yl)amino)-4- (thiazol-2-yl)pyridin-2-yl)methyl)- 2-methylpiperidine-4-carboxylic acid 591 474. [00727] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((3,5-difluoro-4-(1-methyl- 1H-imidazol-2-yl)-6-((5-methyl- 1H-pyrazol-3-yl)amino)pyridin- 2-yl)methyl)-2-methylpiperidine- 4-carboxylic acid 588 475. [00728] embedded image 2-(((2R,4R)-4-carboxy-1-(3-chloro- 2-fluorobenzyl)-2-methylpiperidin- 4-yl)methyl)-3,5-difluoro- 6-((5-methyl-1H-pyrazol-3-yl) amino)isonicotinic acid 552 476. [00729] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((4-(dimethylcarbamoyl)- 3,5-difluoro-6-((5-methyl-1H- pyrazol-3-yl)amino)pyridin-2-yl) methyl)-2-methylpiperidine-4- carboxylic acid 579 477. [00730] embedded image (2R,4R)-4-((4-(azetidine-1-carbonyl)- 3,5-difluoro-6-((5-methyl- 1H-pyrazol-3-yl)amino)pyridin- 2-yl)methyl)-1-(3-chloro-2- fluorobenzyl)-2-methylpiperidine-4- carboxylic acid 591 478. [00731] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((3,5-difluoro-6-((5-methyl- 1H-pyrazol-3-yl)amino)-4- (morpholine-4-carbonyl)pyridin-2- yl)methyl)-2-methylpiperidine-4- carboxylic acid 621 479. [00732] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((3,5-difluoro-6-((5-methyl- 1H-pyrazol-3-yl)amino)-4-(4- methylpiperazine-1-carbonyl) pyridin-2-yl)methyl)-2- methylpiperidine-4-carboxylic acid 634 480. [00733] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((3,5-difluoro-4-isobutyryl- 6-((5-methyl-1H-pyrazol-3-yl) amino)pyridin-2-yl)methyl)-2- methylpiperidine-4-carboxylic acid 578 481. [00734] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((3,5-difluoro-6-((5-methyl- 1H-pyrazol-3-yl)amino)-4- pivaloylpyridin-2-yl)methyl)-2- methylpiperidine-4-carboxylic acid 592 482. [00735] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((3-fluoro-4-((R)-1-fluoro ethyl)-6-((5-methyl-1H-pyrazol- 3-yl)amino)pyridin-2-yl)methyl)- 2-methylpiperidine-4-carboxylic acid 536 483. [00736] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((3-fluoro-4-((S)-1-fluoro ethyl)-6-((5-methyl-1H-pyrazol- 3-yl)amino)pyridin-2-yl)methyl)- 2-methylpiperidine-4-carboxylic acid 536 484. [00737] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((3′-fluoro-6′-((5-methyl- 1H-pyrazol-3-yl)amino)-[3,4′- bipyridin]-2′-yl)methyl)-2-methyl piperidine-4-carboxylic acid 567 485. [00738] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((3-fluoro-6-((5-methyl-1 H-pyrazol-3-yl)amino)-4-(pyridazin- 3-yl)pyridin-2-yl)methyl)-2- methylpiperidine-4-carboxylic acid 568 486. [00739] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((3-fluoro-6-((5-methyl-1 H-pyrazol-3-yl)amino)-4-(oxazol- 2-yl)pyridin-2-yl)methyl)-2- methylpiperidine-4-carboxylic acid 557 487. [00740] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((3-fluoro-6-((5-methyl-1 H-pyrazol-3-yl)amino)-4-(thiazol- 2-yl)pyridin-2-yl)methyl)-2- methylpiperidine-4-carboxylic acid 573 488. [00741] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((3-fluoro-4-(1-methyl-1 H-imidazol-2-yl)-6-((5-methyl-1 H-pyrazol-3-yl)amino)pyridin-2- yl)methyl)-2-methylpiperidine-4- carboxylic acid 570 489. [00742] embedded image (2R,4R)-4-((4-(azetidine-1-carbonyl)- 3-fluoro-6-((5-methyl-1H- pyrazol-3-yl)amino)pyridin-2-yl) methyl)-1-(3-chloro-2-fluorobenzyl)- 2-methylpiperidine-4- carboxylic acid 573 490. [00743] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((3-fluoro-6-((5-methyl-1 H-pyrazol-3-yl)amino)-4- pivaloylpyridin-2-yl)methyl)-2-methyl piperidine-4-carboxylic acid 574 491. [00744] embedded image 1-(3-chloro-2-fluorobenzyl)-4-((4- (1,1-difluoroethyl)-3-fluoro-6- ((5-methyl-1H-pyrazol-3-yl)amino) pyridin-2-yl)methyl)piperidine- 4-carboxylic acid 540 492. [00745] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((3,4-difluoro-6-((5-methyl- 1H-pyrazol-3-yl)amino)pyridin- 2-yl)methyl)-2-methylpiperidine- 4-carboxylic acid 508 493. [00746] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((4-hydroxy-6-((3-methyl- 1H-pyrazol-5-yl)amino)pyridin- 2-yl)methyl)-2-methylpiperidine- 4-carboxylic acid 508 494. [00747] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((3-fluoro-6-((5-methyl-1 H-pyrazol-3-yl)amino)-4-(2,2,2- trifluoroacetyl)pyridin-2-yl)methyl)- 2-methylpiperidine-4-carboxylic acid 586 495. [00748] embedded image (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-((3-fluoro-6-((5-methyl-1 H-pyrazol-3-yl)amino)-4-(oxetane- 3-carbonyl)pyridin-2-yl)methyl)- 2-methylpiperidine-4-carboxylic acid 574 496. [00749] (2R,4R)-1-(3-chloro-2-fluorobenzyl)- 4-(2-fluoro-5-((5-methyl-1 H-1,2,4-triazol-3-yl)amino) benzyl)-2-methylpiperidine-4- carboxylic acid 490

Pharmacological Testing

[0767] Note that an Aurora A selective inhibitor, LY3295668, presently under clinical development was used as a control compound.

Example A: Evaluation of Aurora a and Aurora B Inhibitory Effect—Kinase Assay

[0768] The inhibitory activities of a test compound against Aurora A and Aurora B were measured according to the following method.

[0769] The IC.sub.50 value of Aurora A and Aurora B kinase was performed by Sundia MediTech Co. Ltd. using Mobility shift assay. And the results are shown in Table A.

Experimental Methods:

[0770] (1) Prepare a 1× kinase buffer [50 mM 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES), PH 7.5, 0.01% Brij-35, 10 mM MgCl.sub.2, 2 mM dithiothreitol (DTT)]. [0771] (2) Prepare compound:

[0772] The testing compound was dissolved with DMSO. The testing compound was diluted up to 100× final concentration in a 384-well plate. Transfer 250 nL of the compound dilution to a 384-well assay plate using Echo 550. 100% DMSO of 250 nL was added to the negative control well and the positive control well. [0773] (3) Prepare a 2.5× enzyme solution using the above 1× kinase buffer. [0774] (4) Add 10 μL of the 2.5× enzyme solution to the compound well and the positive control well of the 384-well assay plate. Add 10 μL of the 1× kinase buffer to the negative control well. [0775] (5) The 384-well plate was centrifuged at 1000 rpm for 30 seconds and incubated at room temperature for 10 min. [0776] (6) A mixture of ATP and Kinase substrate 21 with a final concentration of 25/15× was prepared by the 1× kinase buffer. [0777] (7) Add 15 L of the mixture of 25/15×ATP and kinase substrate solution 21 to start reaction. [0778] (8) The 384-well plate was centrifuged at 1000 rpm for 30 seconds and incubated at room temperature. [0779] (9) 30 L of the stop and detection buffer was added to stop the kinase reaction and centrifuged at 1000 rpm for 30 seconds. [0780] (10) Collect data on Caliper EZ ReaderII.

Data Analysis:

Formula:

[0781] [00001] $Inhibition % = \frac{Conversion %_{-} \max - Conversion %_{-} sample}{Conversion %_{\max} - Conversion %_{-} \min} \times 1 0 0$

Conversion %_sample is conversion rate data of samples. Conversion %_min is mean value of negative control (conversion rate data without enzyme activation). Conversion %_max is mean positive control (conversion rate data without compound).

Curve Fitting:

[0782] The log of concentration is on the X axis, and the percentage inhibition is on the Y axis. Fit the Quantitative effect curves with log (inhibitor) vs. response −Variable slope in GraphPad Prism5 obtain IC.sub.50 values. Equation used is Y=Bottom+(Top-Bottom)/(1+10{circumflex over ( )}((LogIC.sub.50−X)*HillSlope)).

TABLE-US-00019 TABLE A Aurora A IC.sub.50 Ratio Example IC.sub.50/nM Aur B/Aur A 1 1.3 2288 2 2.9 1236 5 0.59 1311 6 0.33 6112 8 1.2 1288 10 1.0 979 11 0.64 2264 12 2.4 2560 15 0.55 1755 16 1.7 1812 17 3.2 2974 21 3.1 1789 23 0.91 613 26 2.9 1499 27 0.81 622 29 1.4 586 30 1.1 782 33 1.5 3757 35 1.9 2403 38 0.85 986 39 0.57 3019 41 2.7 3682 45 0.88 523 49 0.7 443 50 0.52 845 51 0.22 2833 52 1.3 1285 53 0.55 562 54 0.43 2041 55 0.88 3835 66 0.57 716 67 1.6 759 69 0.91 1444 72 0.64 582 73 0.76 779 74 0.67 3358 78 0.37 1219 79 0.61 2036 81 0.77 1353 84 1.4 4026 90 0.54 1479 91 1.1 451 92 0.74 4393 102 0.93 804 LY3295668 1.0 741

[0783] As a result, the compound of the invention exhibited high inhibitory activity against Aurora A and low inhibitory activity Aurora B, compared to a control compound, LY3295668. It was demonstrated that the compound of the invention has selectivity for Aurora A.

Example B: Cell Proliferation Assay

[0784] NCI-H2171 and NCI-H446 cell proliferation analysis were conducted by CellTiter-Glo (Promega, Cat #G1111). The cells will be harvested respectively during the logarithmic growth period and counted with hemocytometer. The cell viability is over 90% by trypan blue exclusion. Adjust NCI-H2171 and NCI-H446 cells concentrations to 1.0×10.sup.5 cells/mL with complete medium (RPMI-1640 medium supplemented with 10% (v/v) fetal bovine serum). 100 μL/cell suspensions were added to 96-well plates, and the final cell densities were 1.0×10.sup.4 cells/well. The plate will be cultured overnight in 5% CO.sub.2 and 95% humidity at 37° C. The next day, the test compound was dissolved in DMSO as stock solution. Then the different concentrations of compound were added into 96-well plates. The plates will be cultured for 5 days, then measured by means of CellTiter-Glo assay. 50 μL/cell CellTiter-Glo reagent was added into 96-well plates. Shock incubation for 5 min and then stand incubation for 10 min at room temperature. Record the Luminosity values using an microplate spectrophotometer (Spark, Tecan). Fit the data using GraphPad 8.0 and obtain IC.sub.50 values.

[0785] Formula:

Survival (%)=(Lum.sub.test−Lum.sub.media control)/(Lum.sub.cell control−Lum.sub.media control)×1000

[0786] The IC.sub.50 results of the compounds of the invention are shown by Table B.

TABLE-US-00020 TABLE B NCI-H2171 NCI-H446 Example IC.sub.50/nM IC.sub.50/nM 5 30 80 6 55 103 8 75 119 30 62 128 49 18 24 50 25 73 53 57 154 69 41 87 72 23 56 73 27 63 78 13 32 LY3295668 47 67

[0787] As a result, the compound according to the invention exhibited excellent cell growth inhibitory effect.

Example C: In Vivo Assay

[0788] This study is to examine the anti-tumor efficacy of test compounds in NCI-H446 and NCI-H69 human small cell lung cancer xenograft model in BALB/c nude mice. Each mouse was inoculated subcutaneously at the right flank region with NCI-H446 (3×10.sup.6) and NCI-H69 cells (5×10.sup.6) in 0.1 mL of PBS and Matrigel (1:1) for tumor development. The mouse were randomized according to tumor size and weight, the treatment began when the mean tumor size reached 100-200 mm.sup.3. Anti-tumor activity was assessed according to relative tumor inhibition rate (TGI).

[0789] Tumor volumes were measured in two dimensions using a caliper, and the volume was expressed in mm.sup.3 using the formula: V=0.5a×b.sup.2 where a and bare the long and short diameters of the tumor, respectively. Statistical analysis of difference in tumor volume among the groups were performed using one-way ANOVA. All data was analyzed using SPSS 22.0 software. p<0.05 was considered to be statistically significant.

[0790] The results are shown as in Table C.

TABLE-US-00021 TABLE C Dose Administration TGI Example mg/kg Administration frequency Treatment/days TV (mm.sup.3).sup.a .sub.TV(%) p.sup.b Vehicle — po. BID × 10 days, 29 1551 ± 126 — — 5 15 po. QD × 19 days 29 27 ± 5 98 0.000 49 15 po. 29 160 ± 26 90 0.000 72 15 po. 29 176 ± 25 89 0.000 78 15 po. 29 65 ± 14 96 0.000 LY3295668 15 po. 29 245 ± 27 84 0.000 Note: a. mean ± sem; b. vs. Vehicle

Example D: PK in Rat

[0791] The compounds were dissolved into 10% DMSO, 30% PEG400, and 60% saline to obtain a solution. SD male rats were given the compound orally and intravenously. Then plasma samples were collected at 0 hour (pre-dose), 0.25, 0.5, 1, 2, 4, 7, 24 hours post-dose. Plasma drug concentration was detected by LC-MS/MS. Pharmacokinetic parameters were calculated using WinNonlin's software with non-compartmental model.

[0792] The results are shown in Table D.

TABLE-US-00022 TABLE D IV: 3 mg/kg PO: 10 mg/kg CL Vss C.sub.max AUC.sub.last Example (mL/min/kg) (L/kg) (ng/mL) (h * ng/mL) F % t½ (h) 5 2.74 0.56 26600 179482 168 4.25 6 0.67 0.18 34900 215445 86 6.3 49 1.05 0.22 21033 201715 127 2.95 50 1.45 0.26 16100 172609 140 3.62 78 0.585 0.22 28900 235572 85.8 4.61 LY3295668 1.52 0.29 15033 91211 81 3.37

[0793] From the above, the compound according to the invention is believed to be useful as an antitumor agent since it exhibits not only excellent cell growth inhibitory action based on Aurora A selective inhibitory activity. They also showed a great anti-tumor efficacy in vivo modles.

[0794] The compounds of the present invention are preferably formulated as pharmaceutical compositions administered by a variety of routes. Most preferably, such compositions are for oral administration. Such pharmaceutical compositions and processes for preparing the same are well known in the art. See, e.g., REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY (A. Gennaro, et al, eds., 19.sup.th ed., Mack Publishing Co., 1995). The compounds of Formula I, II, III, IV, V, VI or VII are generally effective over a wide dosage range.

[0795] For example, dosages per day normally fall within the range of about 1 mg to about 200 mg total daily dose, preferably 0.2 mg to 50 mg total daily dose, more preferably 0.2 mg to 20 mg total daily dose. 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 employed. The above dosage range is not intended to limit the scope of the invention in any way. It will be understood that the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound or compounds administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms.

NOVEL HETEROCYCLIC COMPOUNDS USEFUL AS AURORA A SELECTIVE INHIBITORS

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Cpc classification

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A61K31/4545

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C07D401/14

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C07D409/14

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A61K45/06

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A61K2300/00

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C07D405/14

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A61K2300/00

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C07D407/14

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A61K31/4545

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C07D417/14

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C07D413/14

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A61P35/00

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C07D401/12

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C07D401/12

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C07D405/14

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C07D409/14

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C07D413/14

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C07D417/14

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Abstract

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