Macrocyclic factor XIa inhibitors bearing heterocyclic groups

Patent metadata

Field	Value
Publication number	US-10273236-B2
Application number	US-201815946837-A
Country	US
Kind code	B2
Filing date	Apr 6, 2018
Priority date	Jan 31, 2014
Publication date	Apr 30, 2019
Grant date	Apr 30, 2019

Abstract

The present invention provides compounds of Formula (Ia):

or stereoisomers, tautomers, or pharmaceutically acceptable salts 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 (Ia):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof, wherein:
--- is an optional bond;
ring A is independently selected from

R 1 is independently selected from H, F, OH, and C 1-4 alkyl;
R 2 is independently selected from H, F, and OH;
R 3 is absent or independently selected from H, C 1-4 alkyl,

C 1-4 haloalkyl, —(CH 2 ) n —OR 5 , —(CH 2 ) n —C(O)OR 5 , C 3-6 cycloalkyl optionally substituted with halogen, and 5- to 6-membered heteroaryl comprising carbon atoms and 1-2 nitrogen atoms and optionally substituted with R 1 ; provided only one R 3 group is present on the ring;
R 4 is independently selected from H, OH, F, OC 1-4 alkyl, C 1-4 alkyl, and CN;
R 5 is independently selected from H and C 1-4 alkyl;
R 6 is independently selected from H, F, Cl, Br, CN, OCH 3 , CH 3 , C(O)CH 3 , CHF 2 , CCH 3 F 2 , CF 3 , OCHF 2 , NHC(O)C 1-4 alkyl, C 3-6 cycloalkyl, and 5-membered heterocycle substituted with R 9 ;
R 7 is independently selected from H and F;
R 8 is independently selected from H, F, Cl, and OCH 3 ;
R 9 is independently selected from H, cyano, C 1-4 alkyl, haloalkyl, and halogen; and
n, at each occurrence, is an integer selected from 1 and 2.

2. The compound of claim 1 having Formula (IIa):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof, wherein:
ring A is independently selected from

R 1 is independently selected from H and C 1-3 alkyl;
R 2 is independently selected from H and F;
R 3 is independently selected from H, C 1-3 alkyl,

C 1-3 haloalkyl, —(CH 2 ) n —OR 5 , —(CH 2 ) n —C(O)OR 5 , and C 3-4 cycloalkyl optionally substituted with halogen;
R 4 is independently selected from H and F;
R 5 is independently selected from H and C 1-4 alkyl;
R 6 is independently selected from H, F, Cl, Br, CN, CF 3 , C(O)CH 3 , CHF 2 , CCH 3 F 2 , CF 3 , OCHF 2 ,

R 7 is independently selected from H and F;
R 8 is independently selected from H, F, Cl, and OCH 3 ;
R 9 is independently selected from H, CHF 2 , and CF 3 ;
R 9′ is independently selected from H, F, Cl, CN, CHF 2 , and CF 3 ; and
n, at each occurrence, is an integer selected from 1 and 2.

3. The compound of claim 2 , or a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof, wherein:
R 1 is independently selected from H, CH 3 , and CH(CH 3 ) 2 ;
R 2 is independently selected from H and F;
R 3 is independently selected from H, CH 3 , CD 3 ,

CH 2 CH 3 , —CHF 2 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CH 2 OH, CH 2 CH 2 OC(CH 3 ) 3 , —CH 2 C(O)OH, cyclopropyl optionally substituted with F, and cyclobutyl;
R 6 is independently selected from H, F, Cl, Br, CN, CF 3 , C(O)CH 3 , CHF 2 , CCH 3 F 2 , CF 3 , OCHF 2 ,

R 7 is independently selected from H and F;
R 8 is independently selected from H, F, Cl, and OCH 3 ;
R 9 is independently selected from H, CHF 2 , and CF 3 ; and
R 9′ is independently selected from H, F, Cl, CN, CHF 2 , and CF 3 .

4. The compound of claim 1 having Formula (IIIa):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof, wherein:
ring A is independently selected from

R 1 is independently selected from H, CH 3 , and CH(CH 3 ) 2 ;
R 2 is independently selected from H and F;
R 3 is independently selected from H, CH 2 C(═O)OH, CH 2 C(═O)OCH 2 CH 3 ,

R 4 is independently selected from H and F;
R 6 is independently selected from H, F, Cl, Br, CN, CF 3 , C(O)CH 3 , CHF 2 , CCH 3 F 2 , CF 3 , OCHF 2 ,

R 7 is independently selected from H and F;
R 8 is independently selected from H, F, Cl, and OCH 3 ;
R 9 is independently selected from H, CHF 2 , and CF 3 ; and
R 9′ is independently selected from H, F, Cl, CN, CHF 2 , and CF 3 .

5. The compound of claim 1 , or a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof, wherein:
R 3 is independently selected from H, CH 3 , CD 3 ,

CH 2 CH 3 , —CHF 2 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CH 2 OH, CH 2 CH 2 OC(CH 3 ) 3 , —CH 2 C(O)OH, CH 2 C(═O)OH, CH 2 C(═O)OCH 2 CH 3 , cyclopropyl optionally substituted with F, and cyclobutyl,

R 6 is independently selected from H, F, Cl, Br, CN, CF 3 , C(O)CH 3 , CHF 2 , CCH 3 F 2 , CF 3 , OCHF 2 ,

R 7 is independently selected from H and F;
R 8 is Cl;
R 9 is independently selected from H, CHF 2 , and CF 3 ; and
R 9′ is independently selected from H, F, Cl, CN, CHF 2 , and CF 3 .

6. A compound having Formula (IV):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof, wherein:
ring A is independently selected from

R 1 is independently selected from H and C 1-3 alkyl;
R 2 is independently selected from H and F;
R 3 is independently selected from H, CD 3 , CHF 2 , and CH 3 ;
R 4 is independently selected from H and halogen;
R 7 is independently selected from H and F;
R 8 is independently selected from H, F, Cl, and OCH 3 ; and
R 9 is independently selected from H, F, Cl, CN, and CF 3 .

7. A compound having Formula (V):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof, wherein:
ring A is independently selected from

R 1 is independently selected from H and C 1-3 alkyl;
R 2 is independently selected from H and F;
R 3 is independently selected from H, CD 3 , CHF 2 , and CH 3 ;
R 4 is independently selected from H and halogen;
R 6 is independently selected from H, F, Cl, Br, CN, CF 3 , C(O)CH 3 , CHF 2 , CCH 3 F 2 , CF 3 , OCHF 2 ,

R 7 is independently selected from H and F;
R 8 is independently selected from H, F, Cl, and OCH 3 ;
R 9 is independently selected

Assignees

• Bristol Myers Squibb Co
• Bristol Myers Squibb

Inventors

• Dilger Andrew K
• Corte James R
• De Lucca Indawati
• Fang Tianan
• Yang Wu
• Wang Yufeng
• Pabbisetty Kumar Balashanmuga
• Ewing William R
• Zhu Yeheng
• Wexler Ruth R
• Pinto Donald J P
• Orwat Michael J
• Smith Ii Leon M

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• 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

• A61P9/06

  Antiarrhythmics · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P7/02

  Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors · CPC title