Factor XIA inhibitors

Patent metadata

Field	Value
Publication number	US-10214512-B2
Application number	US-201615771538-A
Country	US
Kind code	B2
Filing date	Oct 24, 2016
Priority date	Oct 29, 2015
Publication date	Feb 26, 2019
Grant date	Feb 26, 2019

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 XIa inhibitors or dual inhibitors of Factor XIa and plasma Kallikrein.

First claim

What is claimed is:

1. A compound of the formula:

wherein
 is aryl or heteroaryl, which is optionally substituted with one to three groups independently selected from the group consisting of halo, oxo, cyano, R 6 , OR 6 , C(O)OR 6 , C 1-3 alkyl-C(O)OR 6 , NR 6 R 7 , NH 3 + , C 1-3 alkyl-NR 7 R 8 , NHC(O)R 6 , NHC(O)OR 6 , NHC(O)OC 3-6 cycloalkyl, NHC(O)O—C 1-3 alkyl-OR 7 , NHC(O)O—C 1-3 alkyl-C(O)OH, C 1-3 alkyl-NHC(O)OR 7 , NHC(O)NR 7 R 8 , NHSO 2 R 6 , C(O)NR 7 R 8 , CH 2 C(O)NR 7 R 8 and NHCONH—C 1-3 alkyl-heterocyclyl;
 is aryl or heteroaryl, which is optionally substituted with one to three groups independently selected from the group consisting of halo, cyano, oxido, oxo, cyclopropyl, R 6 , OR 6 , C(O)OR 6 , C 1-3 alkyl- C(O)OR 6 , C(O)NR 6 R 7 and NR 6 R 7 ;
W is N or N + O − ;
Y—X is —C(O)NR 6 —, —C(O)O—, —CHC(O)OR 7 —NR 6 —, —CR 6 R 7 —C(O)NR 6 —, —CHC(O)R 7 —NR 6 —, —CHC(O)OR 7 —CH 2 —, —CHC(O)NR 6 R 7 —NR 6 —, —CHCR 6 R 7 OR 8 —NR 6 —, —CHCR 6 R 7 —NR 6 R 7 —NR 6 —, —OC(O)NR 6 —, —NR 6 C(O)NR 6 - or -SO 2 NR 6 —;
Z is C 3-8 alkylene or C 3-8 alkenylene, wherein one or two of the carbon atoms in said alkylene and alkenylene may be replaced with O, NR 6 , C═O, C(O)NR 6 , NR 6 C(O), S, SO or SO 2;
R 1 is aryl, heteroaryl, C 3-6 cycloalkyl or heteroalkyl, wherein said aryl, heteroaryl, cycloalkyl and heterocyclyl groups are optionally substituted with one to four substituents independently selected from the group consisting of halo, nitro, cyano, oxo, R 6 , OR 6 , C(O)R 6 , C(O)OR 6 , NR 6 R 7 , C 1-3 alkyl-NR 6 R 7 , NHC(O)R 7 , NHC(O)OR 7 , C(NH)NR 6 R 7 , C 3-6 cycloalkyl and heteroaryl (which is optionally substituted with halo, cyano, cyclopropyl, C(O)OH, C(O)NR 6 R 7 or R 6 );
R 2 is hydrogen, cyano, halo, R 6 or OR 6 ;
R 3 is hydrogen, cyano, halo, R 6 or OR 6 ;
each R 4 is independently C 1-6 alkyl, CO 2 R 6 , COR 6 or CONR 7 R 8 , wherein said alkyl is optionally substituted with one to three halo;
R 5 is hydrogen, halo or C 1-6 alkyl;
or one of R 4 and R 5 can be taken together with the atoms between them to form a 3 to 6 membered ring;
each R 6 is independently hydrogen or C 1-6 alkyl, which is optionally substituted with one to three groups independently selected from the group consisting of halo and hydroxy;
each R 7 is independently hydrogen, C 1-6 alkyl, heteroaryl or heterocyclyl, wherein said alkyl group is optionally substituted with one to three groups independently selected from the group consisting of halo and hydroxy;
each R 8 is independently hydrogen or C 1-6 alkyl;
R a is hydrogen, hydroxy or O(C 1-6 alkyl);
n is an integer between zero and three;
or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 of the formula

wherein
 is aryl or heteroaryl, which is optionally substituted with one to three groups independently selected from the group consisting of halo, oxo, cyano, R 6 , OR 6 , C(O)OR 6 , C 1-3 alkyl-C(O)OR 6 , NR 6 R 7 , NH 3 + , C 1-3 alkyl-NR 7 R 8 , NHC(O)R 6 , NHC(O)OR 6 , NHC(O)OC 3-6 cycloalkyl, NHC(O)O—C 1-3 alkyl-OR 7 , NHC(O)O—C 1-3 alkyl-C(O)OH, C 1-3 alkyl-NHC(O)OR 7 , NHC(O)NR 7 R 8 , NHSO 2 R 6 , C(O)NR 7 R 8 , CH 2 C(O)NR 7 R 8 and NHCONH—C 1-3 alkyl-heterocyclyl;
 is aryl or heteroaryl, which is optionally substituted with one to three groups independently selected from the group consisting of halo, cyano, oxido, oxo, cyclopropyl, R 6 , OR 6 , C(O)OR 6 , C 1-3 alkyl-C(O)OR 6 , C(O)NR 6 R 7 and NR 6 R 7 ;
R 1 is aryl, heteroaryl, C 3-6 cycloalkyl or heteroalkyl, wherein said aryl, heteroaryl, cycloalkyl and heterocyclyl groups are optionally substituted with one to four substituents independently selected from the group consisting of halo, nitro, cyano, oxo, R 6 , OR 6 , C(O)R 6 , C(O)OR 6 , NR 6 R 7 , C 1-3 alkyl-NR 6 R 7 , NHC(O)R 7 , NHC(O)OR 7 , C(NH)NR 6 R 7 , C 3-6 cycloalkyl and heteroaryl (which is optionally substituted with halo, cyano, cyclopropyl, C(O)OH, C(O)NR 6 R 7 or R 6 );
R 2 is hydrogen, cyano, halo, R 6 or OR 6 ;
R 3 is hydrogen, cyano, halo, R 6 or OR 6 ;
R 4 is C 1-6 alkyl, CO 2 R 6 , COR 6 or CONR 7 R 8 , wherein said alkyl is optionally substituted with one to three halo;
R 6 is hydrogen or C 1-6 alkyl, which is optionally substituted with one to three groups independently selected from the group consisting of halo and hydroxy;
R 7 is hydrogen or C 1-6 alkyl, which is optionally substituted with one to three groups independently selected from the group consisting of halo and hydroxy;
R 8 is hydrogen or C 1-6 alkyl;
R a is hydrogen, hydroxy or O(C 1-6 alkyl);
n is an integer between zero and three;
or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 wherein
 is a selected from the group consisting of phenyl, imidazolyl, pyridinyl and pyrimidinyl, wherein said groups are optionally substituted with one to three groups independently selected from the group consisting of halo, oxido, R 6 and cyclopropyl.or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 wherein
 is phenyl, which is optionally substituted with one to three groups independently selected from the group consisting of halo, C(O)OR 6 and NHC(O)OR 6 ; or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 wherein R 1 is aryl, which optionally is substituted with one to four substituents independently selected from the group consisting of chloro, fluoro, iodo, methyl, cyclopropyl, OCF 3 , OCF 2 , CF 3 , CF 2 , and heteroaryl (which is optionally substituted with halo, cyano, cyclopropyl, C(O)OH, methyl, CF 3 or CF 2 ); or a pharmaceutically acceptable salt thereof.

6. The compound of any of claim 1 wherein R 1 is phenyl, which optionally is substituted with one to three substituents independently selected from the group consisting of halo, cyclopropyl and tetrazolyl; or a pharmaceutically acceptable salt thereof.

7. The compound of any of claim 1 wherein R a is hydrogen or hydroxy; or a pharmaceutically acceptable salt thereof.

8. The compound of claim 1 selected from:

Assignees

• Merck Sharp & Dohme

Inventors

• Xu Jiayi
• Ali Amjad
• Zhou Wei
• Gao Ying-Duo
• Edmondson Scott D
• Mertz Eric
• Neelamkavil Santhosh F
• Liu Weiguo
• Sun Wanying
• Shen Dong-Ming
• Harper Bart
• Zhu Cheng
• Bara Thomas
• Lim Yeon-Hee
• Yang Meng

Classifications

• A61P7/02

  Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors · CPC title

• A61K31/4427

  containing further heterocyclic ring systems · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title