Macrocycles as factor xia inhibitors

Patent metadata

Field	Value
Publication number	US-12404274-B2
Application number	US-202117493516-A
Country	US
Kind code	B2
Filing date	Oct 4, 2021
Priority date	Feb 11, 2010
Publication date	Sep 2, 2025
Grant date	Sep 2, 2025

Abstract

The present invention provides compounds of Formula (I):

or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein all the variables are as defined herein. These compounds are selective Factor XIa inhibitors or dual inhibitors of fXIa and plasma kallikrein. This invention also relates to pharmaceutical compositions comprising these compounds and methods of treating thromboembolic and/or inflammatory disorders using the same.

First claim

What is claimed is:

1. A compound of Formula (I):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof, wherein:
ring A is phenyl;
ring B is a 6-membered heteroaryl comprising: carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) p ;
ring C is a 6-membered heteroaryl comprising: carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) p ;
L 1 is —CR 5 ═CR 5 —;
L is C 3-8 alkylene; wherein said alkylene is substituted with 0-2 R 7 ;
Y is —CONH—;
R 1 is, independently at each occurrence, selected from the group consisting of: halogen, C 1-6 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, and C 1-4 haloalkyl;
R 2 is independently a 5- to 7-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NH, N (C 1-4 alkyl), O, and S(O) p , wherein said heterocycle is substituted with 0-2 R 2a ;
R 2a is, independently at each occurrence, selected from the group consisting of: halogen, C 1-4 alkyl, —CH 2 OH, C 1-4 alkoxy, OH, CF 3 , OCF 3 , CN, NH 2 , CO 2 H, CO 2 (C 1-4 alkyl), COC 1-4 alkyl, —CONH 2 , —CONH (C 1-4 alkyl), —CON(C 1-4 alkyl) 2 , —SO 2 (C 1-4 alkyl), —SO 2 NH 2 , —SO 2 NH(C 1-4 alkyl), and —SO 2 N(C 1-4 alkyl) 2 ;
R 3 is independently selected from the group consisting of: H, halogen, and CN;
R 4 is independently selected from the group consisting of: H, and C 1-4 alkyl;
R 5 is, independently at each occurrence, selected from the group consisting of: H, halogen, OH, and C 1-4 alkyl;
R 6 is, independently at each occurrence, selected from the group consisting of: halogen, C 1-4 alkyl, CN, OH, and CF 3 ;
R 7 is, independently at each occurrence, selected from the group consisting of: halogen, C 1-4 haloalkyl, OCH 2 F, OCHF 2 , OCF 3 , and C 1-4 alkoxy; and
p is, independently at each occurrence, selected from the group consisting of: 0, 1, and 2.

2. The compound of claim 1 , wherein:
ring B is independently selected from the group consisting of: pyridine, pyridazine, and pyrimidine; and
ring C is pyridine.

3. The compound of claim 2 , wherein:

is independently selected from the group consisting of:

is independently selected from the group consisting of:

4. The compound of claim 1 , wherein:
L 1 is —CH═CH—;
L is C 3-7 alkylene;
R 1 is, independently at each occurrence, selected from: halogen and CN;
R 3 is independently selected from the group consisting of: H and halogen; and
R 6 is, independently at each occurrence, halogen.

5. The compound of claim 1 , wherein:
L 1 is —CH═CH—;
L is —(CH 2 ) 3-6 ;
R 1 is, independently at each occurrence, halogen;
R 3 is H; and
R 6 is, independently at each occurrence, halogen.

6. The compound according to claim 1 , which is selected from:

(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-N—((S)-9-oxo-5,8,16-triaza-tricyclo[13.3.1.02,7]nonadeca-1(19),2,4,6,15,17-hexaen-14-yl)-acrylamide, 2 TFA salt;

(E)-3-(5-Chloro-2-tetrazol-1-yl-phenyl)-N—((S)-9-oxo-6,8,16-triaza-tricyclo[13.3.1.0 2,7 ]nonadeca-1(19),2,4,6,15,17-hexaen-14-yl)-acrylamide, 2 TFA salt; and,

(S,E)-3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-N-(4-oxo-3-aza-1(4,2),2(2,3)-dipyridinacyclononaphane-9-yl)acrylamide.

7. A pharmaceutical composition comprising one or more compounds of claim 1 and a pharmaceutically acceptable carrier or diluent.

8. A method for the treatment of a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 , or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

Assignees

• Bristol Myers Squibb Co

Inventors

• Corte James R
• Fang Tianan
• Decicco Carl P
• Pinto Donald J P
• Rossi Karen A
• Hu Zilun
• Jeon Yoon
• Quan Mimi L
• Smallheer Joanne M
• Wang Yufeng
• Yang Wu

Classifications

• C07D498/04

  Ortho-condensed systems · CPC title

• C07D487/14

  Ortho-condensed systems · CPC title

• C07D471/14

  Ortho-condensed systems · CPC title

• C07D487/18

  Bridged systems · CPC title

• C07D471/18

  Bridged systems · CPC title