Factor XIa inhibitors

Patent metadata

Field	Value
Publication number	US-10143681-B2
Application number	US-201715681478-A
Country	US
Kind code	B2
Filing date	Aug 21, 2017
Priority date	Aug 22, 2016
Publication date	Dec 4, 2018
Grant date	Dec 4, 2018

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 X is

R 1 is CF 2 H, CF 3 , OCF 2 H, O(C 1-3 alkyl) or OCH 2 (cyclopropyl);
R 2 is chloro or fluoro;
R 3 is hydrogen, chloro or fluoro;
R 4 is hydrogen, C 1-3 alkyl or O(C 1-3 alkyl), wherein said alkyl groups are optionally substituted with one to three groups independently selected from the group consisting of halo and hydroxyl;
R 5 is (C═O)OH or (C═O)O(C 1-6 alkyl), wherein said alkyl groups are optionally substituted with one to three groups independently selected from the group consisting of halo and hydroxyl;
each R x is independently selected from halo, hydroxyl, cyano, oxo, methyl, ethyl, CH 2 F, CHF 2 , CF 3 or CH 2 OH;
R y is halo or methyl;
m is zero, one or two;
n is one, two, three or four;
p is zero or one;
or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 of the formula:

wherein R 1 is CF 2 H, CF 3 , or OCF 2 H;
R 2 is chloro or fluoro;
R 3 is hydrogen, chloro or fluoro;
R 5 is (C═O)OH or (C═O)O(C 1-6 alkyl), wherein said alkyl groups are optionally substituted with one to three groups independently selected from the group consisting of halo and hydroxyl;
each R x is independently selected from halo, hydroxyl, cyano, oxo or methyl;
m is zero, one or two;
or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 wherein R 1 is OCF 2 H; or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 wherein R 1 is CF 2 H; or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 wherein R 2 is chloro and R 3 is fluoro; or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1 wherein R 5 is (C═O)OH; or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1 wherein m is zero; or a pharmaceutically acceptable salt thereof.

8. The compound of claim 1 selected from:

or a pharmaceutically acceptable salt thereof.

9. The compound of claim 8 selected from

or a pharmaceutically acceptable salt thereof.

10. The compound of claim 9 selected from

or a pharmaceutically acceptable salt thereof.

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

12. A method for inhibiting thrombus formation in blood or treating thrombus formation in blood comprising administering a composition of claim 11 to a mammal in need of thereof.

13. A method for preventing thrombus formation in blood comprising administering a composition of claim 11 to a mammal in need thereof.

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

15. A method of treating deep vein thrombosis in a mammal comprising administering a composition of claim 11 to a mammal in need thereof.

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

Assignees

• Merck Sharp & Dohme

Inventors

• Shen Dong-Ming
• Kuang Rongze
• Kumar Puneet
• Duffy Joseph L
• Zhu Cheng
• Ali Amjad
• Yang Meng
• Debenham John S

Classifications

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P7/04

  Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents · CPC title

• A61P7/02

  Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors · CPC title

• A61K31/435 Primary

  having six-membered rings with one nitrogen as the only ring hetero atom · CPC title

• C07D213/89

  with hetero atoms directly attached to the ring nitrogen atom · CPC title