Granted Patent B2

US 12,492,187 · App. 17/914,826 · Granted Dec 9, 2025

Inventors: Jacqueline D. Hicks (Watchung, NJ); Amjad Ali (Freehold, NJ); John S. Debenham (South Plainfield, NJ); Anthony Donofrio (Cambridge, MA); Wenlang Fu (Madison, NJ); Ying-Duo Gao (Middletown, NJ); Alan Hruza (Hackettstown, NJ); Yeon-Hee Lim (South San Francisco, CA); Matthew J. Lombardo (Flemington, NJ); Peter Nizner (Fanwood, NJ); Sung-Sau So (Verona, NJ); Zheng Tan (Westfield, NJ); Daniel A. Tatosian (Berkeley Heights, NJ); Dong Xiao (Warren, NJ); Dexi Yang (Livingston, NJ); Yang Yu (Edison, NJ)

Assignee: Merck Sharp & Dohme LLC

C07D401/14A61P7/02C07D401/06C07D417/14C07D471/08C07D491/048

Abstract

Claims (53)

1 . A compound of the formula:

wherein

R 1 is N (C 3-6 cycloalkyl) (R 8 ) or a nitrogen-containing ring system, which may be monocyclic, bicyclic or tricyclic, wherein said nitrogen-containing ring system is optionally substituted with one to three substituents independently selected from the group consisting of halo, oxo, cyano, R 6 , OR 6 , R 7 , (C 1-3 alkyl) R 7 and (C 3-6 cycloalkyl) R 7 ;

R 2 is hydrogen, halo, cyano, C 1-6 alkyl or C 3-6 cycloalkyl, wherein said alkyl group is optionally substituted with one to three halo;

R 3 is hydrogen or C 1-6 alkyl, wherein said alkyl group is optionally substituted with one to three halo;

R 4 is cyano;

R 5 is phenyl;

R 6 is hydrogen or C 1-6 alkyl, which is optionally substituted with one to three halo;

R 7 is phenyl, C 3-6 cycloalkyl, heterocyclyl or heteroaryl, wherein said phenyl and heterocyclyl groups are optionally substituted with one to three substituents independently selected from the group consisting of C 1-6 alkyl and halo;

R 8 is C 1-6 alkyl, which is optionally substituted with one or two substituents independently selected from the group consisting of halo, hydroxyl and C 3-6 cycloalkyl;

or a pharmaceutically acceptable salt thereof.

2 . The compound of claim 1 wherein R 1 is piperidinyl, hexahydrobenzofuropyridinyl, azetidinyl, piperazinyl or azabicycloheptanyl, wherein said groups are optionally substituted with one or two substituents independently selected from the group consisting of halo, oxo, cyano, R 6 , OR 6 , R 7 , (C 1-3 alkyl) R 7 and (C 3-6 cycloalkyl) R 7 ; or a pharmaceutically acceptable salt thereof.

3 . The compound of claim 1 wherein R 2 is methyl, trifluoromethyl or cyano; or a pharmaceutically acceptable salt thereof.

4 . The compound of claim 1 wherein R 3 is hydrogen or methyl; or a pharmaceutically acceptable salt thereof.

5 . The compound of claim 1 selected from

1-(4-(4-(3,3-difluoropyrrolidin-1-yl) piperidine-1-carbonyl)-5-methylpicolinoyl)-4-phenylpiperidine-4-carbonitrile, 2,2,2-trifluoroacetate salt,

1-(4-((4aR,9aS)-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridine-2-carbonyl)-5-methylpicolinoyl)-4-phenylpiperidine-4-carbonitrile and 1-(4-((4aS,9aR)-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridine-2-carbonyl)-5-methylpicolinoyl)-4-phenylpiperidine-4-carbonitrile,

1-(4-(4-(3,3-difluoropyrrolidin-1-yl)-4-methylpiperidine-1-carbonyl)-5-methylpicolinoyl)-4-phenylpiperidine-4-carbonitrile,

1-(4-(3-(3-fluorophenyl) azetidine-1-carbonyl)-5-methylpicolinoyl)-4-phenylpiperidine-4-carbonitrile,

1-(5-methyl-4-(4-phenylpiperidine-1-carbonyl) picolinoyl)-4-phenylpiperidine-4-carbonitrile,

1-(5-methyl-4-(4-phenethylpiperidine-1-carbonyl) picolinoyl)-4-phenylpiperidine-4-carbonitrile,

2-(4-cyano-4-phenylpiperidine-1-carbonyl)-N-cyclobutyl-N-(2-(1-hydroxycyclopentyl) ethyl)-5-methylisonicotinamide,

1-(5-methyl-4-(3-phenylazetidine-1-carbonyl) picolinoyl)-4-phenylpiperidine-4-carbonitrile,

1-(4-(3-(4-fluorophenyl) azetidine-1-carbonyl)-5-methylpicolinoyl)-4-phenylpiperidine-4-carbonitrile,

1-(4-(4-benzylpiperidine-1-carbonyl)-5-methylpicolinoyl)-4-phenylpiperidine-4-carbonitrile,

1-(4-(4-cyclopentyl-3-oxopiperazine-1-carbonyl)-5-methylpicolinoyl)-4-phenylpiperidine-4-carbonitrile,

1-(4-(6-fluoro-6-phenyl-3-azabicyclo [3.1.1] heptane-3-carbonyl)-5-methylpicolinoyl)-4-phenylpiperidine-4-carbonitrile,

1-(5-methyl-4-(6-phenyl-3-azabicyclo [3.1.1] heptane-3-carbonyl) picolinoyl)-4-phenylpiperidine-4-carbonitrile,

1-(4-(6-fluoro-1,2,3,4,4a,9a-hexahydrobenzofuro [2,3-c]pyridine-2-carbonyl)-5-methylpicolinoyl)-4-phenylpiperidine-4-carbonitrile,

1-(4-(4-(tert-butyl) piperidine-1-carbonyl)-5-cyclopropylpicolinoyl)-4-phenylpiperidine-4-carbonitrile, 2,2,2-trifluoroacetate salt,

1-(4-(1,2,3,4,4a,9a-hexahydrobenzofuro [2,3-c]pyridine-2-carbonyl)-5-(trifluoromethyl) picolinoyl)-4-phenylpiperidine-4-carbonitrile,

1-(4-(3-(4-fluorophenyl) azetidine-1-carbonyl)-5-(trifluoromethyl) picolinoyl)-4-phenylpiperidine-4-carbonitrile,

1-[4-[4-(3,3-difluoropyrrolidin-1-ium-1-yl) piperidine-1-carbonyl]-5-(trifluoromethyl) pyridine-2-carbonyl1-4-phenyl-piperidine-4-carbonitrile; 2,2,2-trifluoroacetate,

1-(4-(5,7-difluoro-1,2,3,4,4a,9a-hexahydrobenzofuro [2,3-c]pyridine-2-carbonyl)-5-methylpicolinoyl)-4-phenylpiperidine-4-carbonitrile,

1-[4-(7-fluoro-3,4,4a,9a-tetrahydro-1H-benzofuro [2,3-c]pyridine-2-carbonyl)-5-methyl-pyridin-1-ium-2-carbonyl]-4-phenyl-piperidine-4-carbonitrile; 2,2,2-trifluoroacetate,

1-[4-(7-methoxy-3,4,4a,9a-tetrahydro-1H-benzofuro [2,3-c]pyridine-2-carbonyl)-5-methyl-pyridin-1-ium-2-carbonyl]-4-phenyl-piperidine-4-carbonitrile; 2,2,2-trifluoroacetate,

2-[2-(4-cyano-4-phenyl-piperidine-1-carbonyl)-5-methyl-pyridin-1-ium-4-carbonyl]-3,4,4a,9a-tetrahydro-1H-benzofuro [2,3-c]pyridine-7-carbonitrile; 2,2,2-trifluoroacetate,

1-[4-(7-chloro-3,4,4a,9a-tetrahydro-1H-benzofuro [2,3-c]pyridine-2-carbonyl)-5-methyl-pyridin-1-ium-2-carbonyl1-4-phenyl-piperidine-4-carbonitrile; 2,2,2-trifluoroacetate,

1-[4-(6,7-difluoro-3,4,4a,9a-tetrahydro-1H-benzofuro [2,3-c]pyridine-2-carbonyl)-5-methyl-pyridin-1-ium-2-carbonyl]-4-phenyl-piperidine-4-carbonitrile; 2,2,2-trifluoroacetate,

4-(4-tert-butylpiperidine-1-carbonyl)-6-(4-cyano-4-phenyl-piperidine-1-carbonyl) pyridin-1-ium-3-carbonitrile; 2,2,2-trifluoroacetate,

1-[4-[4-(3,3-difluoropyrrolidin-1-ium-1-yl) piperidine-1-carbonyl]-5,6-dimethyl-pyridine-2-carbonyl]-4-phenyl-piperidine-4-carbonitrile; 2,2,2-trifluoroacetate,

1-[4-(4-tert-butylpiperidine-1-carbonyl)-5,6-dimethyl-pyridine-2-carbonyl]-4-phenyl-piperidine-4-carbonitrile,

1-[5,6-dimethyl-4-[4-(thiazol-2-ylmethyl) piperidine-1-carbonyl] pyridine-2-carbonyl]-4-phenyl-piperidine-4-carbonitrile,

1-[5,6-dimethyl-4-[4-(1-phenylcyclopropyl) piperazine-1-carbonyl] pyridine-2-carbonyl]-4-phenyl-piperidine-4-carbonitrile,

1-[4-(4-benzylpiperidine-1-carbonyl)-5,6-dimethyl-pyridine-2-carbonyl]-4-phenyl-piperidine-4-carbonitrile,

1-[5,6-dimethyl-4-(4-methyl-4-phenyl-piperidine-1-carbonyl) pyridine-2-carbonyl]-4-phenyl-piperidine-4-carbonitrile, and

1-[5,6-dimethyl-4-(4-phenylpiperidine-1-carbonyl) pyridine-2-carbonyl]-4-phenyl-piperidine-4-carbonitrile, or a pharmaceutically acceptable salt thereof.

6 . A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

7 . A method for inhibiting thrombus formation in blood or treating thrombus formation in blood comprising administering a composition of claim 6 to a mammal in need of thereof.

8 . A method for preventing thrombus formation in blood comprising administering a composition of claim 6 to a mammal in need thereof.

9 . A method of treating venous thromboembolism or pulmonary embolism in a mammal comprising administering a composition of claim 6 to a mammal in need thereof.

10 . A method of treating deep vein thrombosis in a mammal comprising administering a composition of claim 6 to a mammal in need thereof.

11 . A method of treating thromboembolic stroke in a mammal comprising administering a composition claim 6 to a mammal in need thereof.

Assignments (2)

Continuity (2)

References Cited (16)