Factor XIa macrocyclic inhibitors bearing alkyl or cycloalkyl P2' moieties

Patent metadata

Field	Value
Publication number	US-10287288-B2
Application number	US-201615747818-A
Country	US
Kind code	B2
Filing date	Jul 28, 2016
Priority date	Jul 29, 2015
Publication date	May 14, 2019
Grant date	May 14, 2019

Abstract

The present invention provides compounds of Formula (I): 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 (I):

or a pharmaceutically acceptable salt thereof, wherein:
L is independently selected from

---- is an optional bond;
Q is independently selected from O, NH, and CH 2 ;
Y is independently selected from N and CR 7 ;
W is independently selected from —C(O)NH, —NHC(O)—, and —NHC(O)CH 2 —;
ring A is independently selected from

each R 1 is independently selected from H, halogen, C 1-4 alkyl substituted with 0-4 R e , OR b , and C 3-6 cycloalkyl substituted with 1-4 R 6 ;
each R 2 is independently selected from H, halogen, C 1-4 alkyl substituted with 0-4 R e , OR b , and C 3-6 cycloalkyl substituted with 1-4 R 6 ; or
alternatively, two adjacent R 1 groups form a bond;
R 3 is independently selected from H, C 1-4 alkyl substituted with 1-5 R 5 , C 2-4 alkenyl substituted with 1-5 R 5 , C 2-4 alkynyl substituted with 1-5 R 5 , —(CH 2 ) n —CN, —(CH 2 ) n —OR b , —(CH 2 ) n —OC(═O)NR a R a , —(CH 2 ) n —NR a R a , —(CH 2 ) n —C(═O)R b , —(CH 2 ) n —C(═O)OR b , —(CH 2 ) n —NR a C(═O)OR b , —(CH 2 ) n —NR a C(═O)R b , —(CH 2 ) n —NR a C(N—CN)NR a R a , —(CH 2 ) n —NR a C(NH)NR a R a , —(CH 2 ) n —N═CR b NR a R a , —(CH 2 ) n —NR a C(═O)NR a R a , —(CH 2 ) n —C(═O)NR a R a , —(CH 2 ) n —NR a C(═S)NR a C(═O)R b , —(CH 2 ) n —S(═O) p R c , —(CH 2 ) n —S(═O) p NR a R a , —(CH 2 ) n —NR a S(═O) p NR a R a , —(CH 2 ) n —NR a S(═O) p R c , —(CR d R d ) n —C 3-10 carbocyclyl substituted with 1-5 R 5 , and —(CR d R d ) n -4- to 10-membered heterocyclyl
substituted with 1-5 R 5 ; or
optionally, two adjacent R 3 groups on the carbocyclyl and heterocyclyl may form a ring substituted with 1-5 R 5 ;
R 3a is independently selected from H and C 1-4 alkyl; or
alternatively, R 3a and R 3 are taken together to form a saturated C 3-6 carbocyclic ring, wherein the carbocyclic ring is substituted with R 3c ; or
alternatively, R 3a and R 11 are taken together to form a C 3-6 carbocyclic ring or a heterocyclic ring comprising carbon atoms and 1-3 heteroatoms selected from N, NR 3b , O, and S, wherein the carbocyclic ring or heterocyclic ring is substituted with R 3c ;
R 3b is independently selected from H, C 1-4 alkyl substituted with 1-5 R 5 , —(CH 2 ) n —C(═O)R b , —(CH 2 ) n —C(═O)OR b , —(CH 2 ) n —C(═O)NR a R a , —(CH 2 ) n —NHC(═O)OR b , —(CH 2 ) n —S(═O) p R c , —(CH 2 ) n —S(═O) p NR a R a , —(CR d R d ) n —C 3-10 carbocyclyl substituted with 1-5 R 5 , and —(CR d R d ) n -4- to 10-membered heterocyclyl substituted with 1-5 R 5 ;

R 3c is independently selected from H, NO 2 , ═O, halogen, C 1-4 alkyl substituted with 1-5 R 5 , C 2-4 alkenyl substituted with 1-5 R 5 , C 2-4 alkynyl substituted with 1-5 R 5 , CN, —(CH 2 ) n —OR b , —(CH 2 ) n —NR a R a , —(CH 2 ) n —C(═O)R b , —(CH 2 ) n —C(═O)OR b , —(CH 2 ) n —NR a C(═O)OR b , —(CH 2 ) n —NR a C(═O)R b , —(CH 2 ) n —NR a C(N—CN)NR a R a , —(CH 2 ) n —NR a C(NH)NR a R a , —(CH 2 ) n —N═CR b NR a R a , —(CH 2 ) n —NR a C(═O)NR a R a , —(CH 2 ) n —C(═O)NR a R a , —(CH 2 ) n —NR a C(═S)NR a C(═O)R b , —(CH 2 ) n —S(═O) p R c , —(CH 2 ) n —S(═O) p NR a R a , —(CH 2 ) n —NR a S(═O) p NR a R a , —(CH 2 ) n —NR a S(═O) p R c , —(CR d R d ) n —C 3-10 carbocyclyl substituted with 1-5 R 5 , and —(CR d R d ) n -4- to 10-membered heterocyclyl substituted with 1-5 R 5 ;
R 4 is independently selected from H, halogen, CN, —(CH 2 ) n NR a R a , C 1-6 alkyl substituted with 1-5 R 10 , —(CH 2 ) n OR b , —(CH 2 ) n C(═O)R b , —(CH 2 ) n C(═O)OR b , —(CH 2 ) n —NR a C(═O)OR b , —(CH 2 ) n —NR a C(═O)R b , —(CH 2 ) n —NR a C(N—CN)NR a R a , —(CH 2 ) n —NR a C(NH)NR a R a , —(CH 2 ) n —N═CR b NR a R a , —(CH 2 ) n —NR a C(═O)NR a R a , —(CH 2 ) n —C(═O)NR a R a , —(CH 2 ) n —NR a C(═S)NR a C(═O)R b , —(CH 2 ) n —S(═O) p R c , —(CH 2 ) n —S(═O) p NR a R a , —(CH 2 ) n —NR a S(═O) p NR a R a , —(CH 2 ) n —NR a S(═O) p R c , —(CH 2 ) n -aryl substituted with 1-5 R 10 , —(CH 2 ) n —C 3-6 cycloalkyl substituted with 1-5 R 10 , and —(CH 2 ) n -4-6 membered heterocyclyl substituted with 1-5 R 10 ;
R 5 , at each occurrence, is independently selected from H, deuterium, —(CH 2 ) n —OR, ═O, —(CH 2 ) n NH 2 , —(CH 2 ) n CN, halogen, C 1-6 alkyl, —(CH 2 ) n —C(═O)OR b , —(CH 2 ) n —OR b , —(CH 2 ) n —C 3-10 carbocyclyl substituted with 0-5 R e , —(CH 2 ) n -4- to 10-membered heterocyclyl substituted with 0-5 R e , and —O-4- to 10-membered heterocyclyl substituted with 0-5 R e ;
R 6 is independently selected from H, OH, ═O, —(CH 2 ) n NH 2 , —(CH 2 ) n CN, halogen, C 1-6 alkyl, —(CH 2 ) n —C(═O)OH, —(CH 2 ) n —C(═O)OC 1-4 alkyl, —(CH 2 ) n —OC 1-4 alkyl, —(CH 2 ) n —C 3-10 carbocycle substituted with 0-5 R e , —(CH 2 ) n -4- to 10-membered heterocycle substituted with 0-5 R e , and —(CH 2 ) n -4- to 10-membered heterocycle substituted with 0-5 R e ;
R 7 is independently selected from H, CN, OR b , halogen, NR a R a , and C 1-3 alkyl substituted with 0-5 R e ;
R 8 is independently selected from H, OH, F, Cl, Br, C 1-4 alkyl, C 1-4 alkoxy, CF 3 , CN, C 3-6 cycloalkyl, aryl, and 5- to 6-membered heterocycle;
R 10 , at each occurrence, is independently selected from H, halogen, CN, NO 2 , ═O, C(═O)NR a R a , C(═O)OR b , —(CH 2 ) n —OR b , —(CH 2 ) n —NR a R a , C(═NOH)NH 2 , C 1-6 alkyl substituted with 0-5 R e , C 2-6 alkenyl substituted with 0-5 R e , C 2-6 alkynyl substituted with 0-5 R e , aryl substituted with 0-5 R e , —(CH 2 ) n —C 3-6 cycloalkyl substituted with 0-5 R e , and —(CH 2 ) n —O-4- to 10-membered heterocyclyl substituted with 0-5 R e ;
R 11 is independently selected from H, C 1-4 alkyl, and aryl;
R a , at each occurrence, is independently selected from H, C 1-6 alkyl substituted with 0-5 R e , C 2-6 alkenyl substituted with 0-5 R e , C 2-6 alkynyl substituted with 0-5 R e , —(CH 2 ) n —C 3-10 carbocyclyl substituted with 0-5 R e , and —(CH 2 ) n -heterocyclyl substituted with 0-5 R e ; or
Ra and Ra, together with the nitrogen atom to which they are both attached, form a heterocyclic ring substituted with 0-5 R e ;
R b , at each occurrence, is independently selected from H, C 1-6 alkyl substituted with 0-5 R e , C 2-6 alkenyl substituted with 0-5 R e , C 2-6 alkynyl substituted with 0-5 R e , —(CH 2 ) n —C 3-10 carbocyclyl substituted with 0-5 R e , and —(CH 2 ) n -heterocyclyl substituted with 0-5 R e ;
R c , at each occurrence, is independently selected from C 1-6 alkyl substituted with 0-5 R e , C 2-6 alkenyl substituted with 0-5 R e , C 2-6 alkynyl substituted with 0-5 R e , C 3-6 carbocyclyl, and heterocyclyl;
R d , at each occurrence, is independently selected from H and C 1-4 alkyl substituted with 0-5 R e ;
R e , at each occurrence, is independently selected from F, Cl, Br, CN, NO 2 , ═O, C 1-6 alkyl substituted with 0-5 R f , C 2-6 alkenyl, C 2-6 alkynyl, —(CH 2 ) n —C 3-6 cycloalkyl, —(CH 2 ) n -aryl, —(CH 2 ) n -heterocyclyl, CO 2 H, —(CH 2 ) n OR f , SR f , and —(CH 2 ) n NR f R f ;
R f , at each occurrence, is independently selected from H or C 1-5 alkyl substituted with F, Cl, Br, C 3-6 cycloalkyl, and phenyl; or
R f and R f , together with the nitrogen atom to which they are both attached, form a heterocyclic ring optionally substituted with C 1-4 alkyl;
n, at each occurrence, is an integer independently selected from 0, 1, 2, 3, and 4;
p, at each occurrence, is an integer independently selected from 0, 1, and 2; and
q, at each occur

Assignees

• Bristol Myers Squibb Co
• Bristol Myers Squibb

Inventors

• Pabbisetty Kumar Balashanmuga
• Corte James R
• Dilger Andrew K
• Ewing William R
• Zhu Yeheng

Classifications

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• C07D403/14

  containing three or more hetero rings · CPC title

• A61K31/4353

  ortho- or peri-condensed with heterocyclic ring systems · CPC title

• C07D471/06

  Peri-condensed systems · CPC title

• C07D471/20

  Spiro-condensed systems · CPC title