Factor XI activation inhibitors

Patent metadata

Field	Value
Publication number	US-12492187-B2
Application number	US-202117914826-A
Country	US
Kind code	B2
Filing date	Mar 26, 2021
Priority date	Apr 1, 2020
Publication date	Dec 9, 2025
Grant date	Dec 9, 2025

Abstract

The present invention provides a compound of Formula (I) and pharmaceutical compositions comprising one or more said compounds, and methods for using said compounds for treating or preventing thromboses, embolisms, hypercoagulability or fibrotic changes. The compounds are selective Factor XI activation inhibitors.

First claim

What is claimed is:

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.

Assignees

• Merck Sharp & Dohme Llc

Inventors

• Hicks Jacqueline D
• Ali Amjad
• Debenham John S
• Donofrio Anthony
• Fu Wenlang
• Gao Ying-Duo
• Hruza Alan
• Lim Yeon-Hee
• Lombardo Matthew J
• Nizner Peter
• So Sung-Sau
• Tan Zheng
• Tatosian Daniel A
• Xiao Dong
• Yang Dexi
• Yu Yang

Classifications

• C07D491/048

  the oxygen-containing ring being five-membered · CPC title

• C07D471/08

  Bridged systems · CPC title

• C07D417/14

  containing three or more hetero rings · CPC title

• C07D401/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• A61P7/02

  Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors · CPC title