Pyrimidinones as factor xia inhibitors

Patent metadata

Field	Value
Publication number	US-2016368923-A1
Application number	US-201615221142-A
Country	US
Kind code	A1
Filing date	Jul 27, 2016
Priority date	Oct 1, 2014
Publication date	Dec 22, 2016
Grant date	—

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 stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof, wherein:
ring A is independently selected from 6-membered aryl and 5- to 6-membered heterocyclyl, wherein said aryl and heterocyclyl are optionally substituted with, where valence allows, one or more R 4 ;
ring B is 5- to 10-membered heterocyclyl optionally substituted with, where valence allows, one or more R 3 or 5- to 10-membered heterocyclyl comprising carbon atoms and 1-4 heteroatoms selected from N, NR 3 , O, and S(O) p and optionally substituted with, where valence allows, one or more R 3 ;
G 1 is independently selected from C 3-10 carbocyclyl and 5- to 10-membered heterocyclyl, wherein said carbocyclyl and heterocyclyl are optionally substituted with, where valence allows, one or more R 8 ;
X is independently selected from C 4-8 alkylene and C 4-8 alkenylene, wherein said alkylene and alkenylene are substituted with R 1 and R 2 ; alternatively one or more of the carbon atoms of said alkylene and alkenylene may be replaced by O, C═O, S(═O) p , S(═O) p NH, and NR 15 ;
Y is independently selected from —CR 13 NH—, —NHC(═O)—, —C(═O)NH—, —S(═O) p NH—, —NHS(═O) p —, and C 1-2 alkylene;
R 1 and R 2 are independently selected from H, D, halogen, haloalkyl, C 1-6 alkyl (optionally substituted with R 6 ), hydroxyl, and alkoxy optionally substituted with R 6 , and C 3-6 cycloalkyl optionally substituted with R 6 ; optionally, when R 1 and R 2 are attached to the same carbon atom, together they form an oxo group or C 3-6 cycloalkyl; optionally, when R 1 and R 2 are attached to carbon atoms adjacent to each other, together they form a bond or carbocyclyl; optionally, R 1 and R 15 or R 2 and R 15 taken together form a ring;
R 3 is independently selected from H, NO 2 , ═O, halogen, haloalkyl, C 1-4 alkyl (optionally substituted with R 6 ), C 2-4 alkenyl (optionally substituted with R 6 ), C 2-4 alkynyl (optionally substituted with R 6 ),

CN, —(CH 2 ) n —OR 5 , —(CH 2 ) n —NR 5 R 5 , —(CH 2 ) n —C(═O)R 5 , —(CH 2 ) n —C(═O)OR 5 , —(CH 2 ) n —NR 9 C(═O)OR 5 , —(CH 2 ) n —NR 9 C(═O)R 5 , —(CH 2 ) n —NR 9 C(N—CN)NHR 5 , —(CH 2 ) n —NR 9 C(NH)NHR 5 , —(CH 2 ) n —N═CR 9 NR 5 R 5 , —(CH 2 ) n —NR 9 C(═O)NR 5 R 5 , —(CH 2 ) n —C(═O)NR 5 R 5 , —(CH 2 ) n —NR 9 C(═S)NR 9 C(═O)R 5 , —(CH 2 ) n —S(═O) p R 5 , —(CH 2 ) n —S(═O) p NR 5 R 5 , —(CH 2 ) n —NR 9 S(═O) p NR 5 R 5 , —(CH 2 ) n —NR 9 S(═O) p R 5 , —(CH 2 ) n —C 3-10 carbocyclyl and —(CH 2 ) n -4- to 10-membered heterocyclyl, wherein said carbocyclyl and heterocyclyl are optionally substituted with R 6 ; optionally, two adjacent R 3 groups on the heterocyclyl may form a ring optionally substituted with R 6 ;
R 3c is independently selected from H, haloalkyl, C 1-4 alkyl (optionally substituted with R 6 ), —(CH 2 ) 1-2 —OH, C(═O)C 1-4 alkyl, —(CH 2 ) 0-2 —C(═O)OH, —C(═O)OC 1-4 alkyl, S(═O) p C 1-6 alkyl, —(CH 2 ) n —C 3-10 carbocyclyl and —(CH 2 ) n -4- to 10-membered heterocyclyl, wherein said carbocyclyl and heterocyclyl are optionally substituted with R 6 ;
R 4 is independently selected from H, OH, NH 2 , halogen, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, —CH 2 OH, —C(═O)OH, —CH 2 C(═O)OH, —CO 2 (C 1-4 alkyl), —C(═O)NH 2 , —C(═O)NH(C 1-4 alkyl), —C(═O)N(C 1-4 alkyl) 2 , —S(═O) 2 C 1-4 alkyl, —S(═O) 2 NH 2 , C 3-6 cycloalkyl, aryl, and 5- to 6-membered heterocyclyl, wherein said cycloalkyl, aryl and heterocyclyl are optionally substituted with R 6 ;
R 5 is independently selected from H, C 1-4 alkyl (optionally substituted with halogen, hydroxyl, alkoxy, carboxy, hydroxycarbonyl, alkoxycarbonyl, amino, substituted amino), —(CH 2 ) n —C 3-10 carbocyclyl and —(CH 2 ) n -4- to 10-membered heterocyclyl, wherein said carbocyclyl and heterocyclyl are optionally substituted with R 6 ; alternatively, R 5 and R 5 together with the nitrogen atom to which they are both attached form a heterocyclic ring optionally substituted with R 6 ;
R 6 is independently selected from H, —(CH 2 ) n —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)NH 2 , —(CH 2 ) n —C(═O)OC 1-4 alkyl, —(CH 2 ) n —OC 1-4 alkyl, —(CH 2 ) n —C 3-10 carbocyclyl, —(CH 2 ) n -4- to 10-membered heterocyclyl, and —O-4- to 10-membered heterocyclyl, wherein said carbocyclyl and heterocyclyl are optionally substituted with R 10 ;
R 7 is independently selected from H, hydroxyl, alkoxy, halogen, amino, C 1-3 haloalkyl, and C 1-3 alkyl;
R 8 is independently selected from H, halogen, —(CH 2 ) n CN, C 1-6 alkyl, amino, aminoalkyl, haloalkyl, hydroxyl, alkoxy, haloalkoxy, alkylcarbonyl, carboxyl, carboxyl ester, amide, haloalkylaminocarbonyl, arylalkylaminocarbonyl, haloalkylaminocarbonyl, alkoxycarbonylamino, haloalkylcarbonylamino, arylamino, heteroarylamino, arylalkylcarbonyl, aryloxy, heteroaryloxy, alkylthio, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, sulfonamide, —(CH 2 ) n -aryl, —(CH 2 ) n —C 3-6 cycloalkyl, and —(CH 2 ) n -4- to 12-membered heterocyclyl, wherein said aryl, cycloalkyl, and heterocyclyl are optionally substituted with R 10 ;
alternatively, two adjacent R 8 groups taken together form a heterocyclic ring optionally substituted with R 10 ;
R 9 is H or C 1-6 alkyl;
R 10 is independently selected from H, C 1-6 alkyl (optionally substituted with R 11 ), C 2-6 alkenyl, C 2-6 alkynyl, aryl (optionally substituted with R 11 ), —(CH 2 ) n —C 3-6 cycloalkyl (optionally substituted with R 11 ), —(CH 2 ) n —O-4- to 10-membered heterocyclyl (optionally substituted with R 11 ), halogen, —(CH 2 ) n CN, NO 2 , ═O, C(═O)NR 12 R 12 , —(CH 2 ) n C(═O)OR 12 , Si(C 1-4 alkyl) 3 , —(CH 2 ) n —OR 12 , —(CH 2 ) n —NR 12 R 12 , —S(═O) p C 1-6 alkyl, NR 12 S(═O) p C 1-6 alkyl, S(═O) p NR 12 R 12 , and C(═NOH)NH 2 ;
R 11 , at each occurrence, is independently selected from H, halogen, C 1-5 alkyl, —(CH 2 ) n —OH, C 3-6 cycloalkyl, phenyl, and heterocyclyl;
R 12 , at each occurrence, is independently selected from H, C 1-5 alkyl optionally substituted with R 11 , C 3-6 cycloalkyl, phenyl, and heterocyclyl, or R 12 and R 12 together with the nitrogen atom to which they are both attached form a heterocyclic ring optionally substituted with C 1-4 alkyl;
R 13 is, independently at each occurrence, selected from H, C 1-4 haloalkyl, C 1-4 alkyl, C(═O)OH, C(═O)O(C 1-4 alkyl), C(═O)O(CH 2 ) 2 O(C 1-4 alkyl), C(═O)O(C 1-4 haloalkyl), CH 2 C(═O)OH, CH 2 C(═O)O(C 1-4 alkyl), C(═O)NH 2 , C(═O)NH(C 1-4 alkyl), C(═O)N(C 1-4 alkyl) 2 , and —C(═O)NH(C 1-4 alkoxy);
R 15 is H or C 1-6 alkyl;
n, at each occurrence, is an integer independently selected from 0, 1, 2, 3, and 4; and
p, at each occurrence, is an integer independently selected from 0, 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 6-membered aryl and 5- to 6-membered heterocyclyl;
ring B is 5- to 10-membered heterocyclyl or 5- to 10-membered heterocyclyl comprising carbon atoms and 1-4 heteroatoms selected from N, NR 3c , O, and S(O) p ;
G 1 is independently selected from C 3-6 carbocyclyl and 5- to 10-membered heterocyclyl, wherein said carbocyclyl and heterocyclyl are substituted with 1-4 R 8 ;
W is independently selected from (CR 1 R 2 ) 1-2 , O, NH, and N(C 1-4 alkyl);
Y is independently selected from —CR 13 NH—, —NHC(═O)— and —C(═O)NH—;
R 1 and R 2 are independently selected from H, halogen, haloalkyl, C 1-4 alkyl (optionally substituted with R 6 ), hydroxyl, and alkoxy (optionally substituted with

Assignees

• Bristol Myers Squibb Co

Inventors

• Dilger Andrew K
• Corte James R
• De Lucca lndawati
• 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

• C07D471/08

  Bridged systems · CPC title

• C07D487/08

  Bridged systems · CPC title

• C07D471/18 Primary

  Bridged systems · CPC title

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• C07F7/0814

  said ring is substituted at a C ring atom by Si · CPC title