FACTOR XIa INHIBITORS

Patent metadata

Field	Value
Publication number	US-2016347757-A1
Application number	US-201515116659-A
Country	US
Kind code	A1
Filing date	Feb 6, 2015
Priority date	Feb 11, 2014
Publication date	Dec 1, 2016
Grant date	—

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

1 . A compound of the formula:

wherein

is heteroaryl, which is optionally substituted with one to three groups independently selected from the group consisting of halo, methyl and cyano;
Z is CH 2 , C═O or CHC(O)OH;
R 1 is hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, halo, cyano or hydroxy, wherein said alkyl and cycloalkyl groups are optionally substituted with one to three groups independently selected from the group consisting of halo and hydroxy;
each R 2 is independently selected from the group consisting of halo, cyano, hydroxy, OR 3 , C 1-6 alkyl, CO 2 H, CO 2 R 3 , (R 3 )CO 2 H, (R 3 )CO 2 R 4 , NR 5 R 6 , (R 3 )NR 5 R 6 , NHCOR 3 , NHC(O)OR 3 , NHCO 2 (R 3 )OR 4 , NHCO 2 (R 3 )CO 2 H, (R 3 )NHCO 2 R 4 , NHCONR 5 R 6 , NHSO 2 R 3 , CONR 5 R 6 , CH 2 CONR 5 R 6 and NHCONH(R 3 )heterocyclyl;
R 3 is hydrogen or C 1-6 alkyl, wherein said alkyl is optionally substituted with hydroxy or one to three halo;
R 4 is hydrogen or C 1-6 alkyl, wherein said alkyl is optionally substituted with one to three halo;
R 5 is hydrogen or C 1-6 alkyl,
R 6 is hydrogen or C 1-6 alkyl,
R 7 is hydrogen or C 1-6 alkyl, CO 2 H, COR 3 , CONR 5 R 6 , wherein said alkyl is optionally substituted with one to three halo;
x is an integer between zero and three;
y is an integer between zero and three;
z is an integer between zero and three;

or a pharmaceutically acceptable salt thereof.

2 . The compound of claim 1 wherein

is a nitrogen-containing heteroaryl, which is optionally substituted with one to three groups independently selected from the group consisting of halo, methyl and cyano; or a pharmaceutically acceptable salt thereof.

3 . The compound of claim 1 wherein

is a selected from the group consisting of pyrrolyl, pyrazolyly, imidazolyl, triazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl, wherein said groups are optionally substituted with one to three groups independently selected from the group consisting of halo, methyl and cyano; or a pharmaceutically acceptable salt thereof.

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

5 . The compound of claim 1 wherein R 2 is NHC(O)OR 3 ; or a pharmaceutically acceptable salt thereof.

6 . The compound of claim 1 wherein x is 1; or a pharmaceutically acceptable salt thereof.

7 . The compound of claim 1 selected from:

or a pharmaceutically acceptable salt thereof.

8 . A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

9 . A method for inhibiting thrombus formation in blood or treating thrombus formation in blood comprising administering a composition of claim 8 to a mammal in need of thereof.

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

11 . A method of treating venous thromboembolism and pulmonary embolism in a mammal comprising administering a composition of claim 8 to a mammal in need thereof.

12 . A method of treating deep vein thrombosis in a mammal comprising administering a composition of claim 8 to a mammal in need thereof.

13 . A method of treating thromboembolic stroke in a human comprising administering a composition of claim 8 to a mammal in need thereof.

14 . (canceled)

15 . (canceled)

Assignees

• Neelamkavil Santhosh F
• Edmondson Scott D
• Guo Zhuyan
• Hruza Alan W
• Hussain Zahid
• Lesburg Charles A
• Moningka Remond
• Ogawa Anthony K
• Mal Rudrajit
• Merck Sharp & Dohme
• Merck Sharp & Dohme

Inventors

• Neelamkavil Santhosh F
• Edmondson Scott D
• Guo Zhuyan
• Hruza Alan W
• Hussain Zahid
• Lesburg Charles A
• Moningka Remond
• Ogawa Anthony K
• Mal Rudrajit

Classifications

• A61P7/02

  Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors · CPC title

• C07D487/08 Primary

  Bridged systems · CPC title

• C07D471/08

  Bridged systems · CPC title