Monocyclic heteroaryl substituted compounds

Patent metadata

Field	Value
Publication number	US-10815224-B2
Application number	US-201716317232-A
Country	US
Kind code	B2
Filing date	Jul 13, 2017
Priority date	Jul 14, 2016
Publication date	Oct 27, 2020
Grant date	Oct 27, 2020

Abstract

Disclosed are compounds of Formulas (I), (II), (III), (IV), (V), (VI), (VII), or (VIII): (I) (II) (III) (IV) (V) (VI) (VII) (VIII) or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R 3 is a monocyclic heteroaryl group substituted with zero to 3 R 3a ; and R 1 , R 2 , R 3a , R 4 , and n are defined herein. Also disclosed are methods of using such compounds as PAR4 inhibitors, and pharmaceutical compositions comprising such compounds. These compounds are useful in inhibiting or preventing platelet aggregation, and are useful for the treatment of a thromboembolic disorder or the primary prophylaxis of a thromboembolic disorder.

First claim

What is claimed is:

1. A compound of Formula (I):

or a salt thereof; wherein:
R 1 is F, Cl, —OH, C 1-4 alkyl, C 1-4 fluoroalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-7 cycloalkyl, C 3-7 fluorocycloalkyl, C 1-4 alkoxy, C 1-4 fluoroalkoxy, C 2-4 hydroxyalkoxy, C 3-6 cycloalkoxy, (C 1-3 alkoxy)-(C 1-3 alkylene), (C 1-3 alkoxy)-(C 1-3 fluoroalkylene), (C 1-3 deuteroalkoxy)-(C 1-3 deuteroalkylene), (C 1-3 fluoroalkoxy)-(C 1-3 alkylene), (C 1-3 fluoroalkoxy)-(C 1-3 fluoroalkylene), —(CH 2 ) 1-3 O(phenyl), —(CH 2 ) 1-3 NR a R a , —C(O)O(C 1-6 alkyl), —C(O)NR a R a , —C(O)NR b R b , —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , azetidin-1-yl, pyrrolidin-1-yl, furanyl, pyranyl, piperidin-1-yl, morpholin-4-yl, piperazin-1-yl, —S(O) 2 (C 1-3 alkyl), —S(O) 2 NR a R a , C 1-3 alkylthio, or C 1-3 fluoroalkylthio;
R 2 , at each occurrence, is independently H, F, Cl, Br, —OH, —CN, C 1-4 alkyl, C 1-4 fluoroalkyl, C 1-4 hydroxyalkyl, C 1-3 aminoalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-7 cycloalkyl, C 3-7 fluorocycloalkyl, C 1-6 alkoxy, C 1-3 fluoroalkoxy, C 1-3 alkylthio, C 1-3 fluoroalkylthio, (C 1-3 alkoxy)-(C 1-3 alkylene), (C 1-3 fluoroalkoxy)-(C 1-3 alkylene), —C(O)NH 2 , —C(O)NH(C 1-6 alkyl), —C(O)N(C 1-6 alkyl) 2 , —C(O)NR b R b , —CH(OH)(C 3-6 cycloalkyl), —CH(OH)(phenyl), —CH(OH)(pyridyl), —S(O) 2 (C 1-3 alkyl), —S(O) 2 NR a R a , or a cyclic group selected from phenyl, 5- to 6-membered heteroaryl, and 5- to 7-membered heterocycle, wherein said cyclic group is substituted with zero to 5 substituents independently selected from F, Cl, C 1-3 alkoxy, and —CN;
R 3 is:

R 3a , at each occurrence, is independently H, F, Cl, —CN, —OH, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 fluoroalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-3 fluoroalkoxy, C 1-6 alkylthio, —(CH 2 ) m —C 3-7 cycloalkyl, —(CH 2 ) m -aryl, —(CH 2 ) m -heteroaryl, —(CH 2 ) m -heterocyclyl, —(CH 2 ) 1-3 NR a R a , —(CH 2 ) 1-3 NHS(O) 2 (aryl), (C 1-3 alkoxy)-(C 1-6 alkoxy), —C(O)OH, —C(O)O(C 1-6 alkyl), —C(O)NR a R a , —C(O)NR b R b , —S(O) 2 NR a R a , —S(O) 2 NR b R b , —C(O)(C 1-4 alkyl), —C(O)aryl, —C(O)heteroaryl, —C(O)(C 3-7 cycloalkyl), —S(O) 2 (C 1-4 alkyl), —S(O) 2 aryl, —S(O) 2 heteroaryl, —S(O) 2 (C 3-7 cycloalkyl), —NR a R a , or —NR b R b , wherein each of said cycloalkyl, heterocyclyl, aryl, and heteroaryl is substituted with zero to 5 substituents independently selected from F, Cl, —OH, oxo, —CN, C 1-3 alkyl, C 1-3 fluoroalkyl, C 1-4 hydroxyalkyl, C 1-3 alkoxy, C 1-3 fluoroalkoxy, C 1-6 alkylthio, —NH 2 , —NHC(O)(C 1-6 alkyl), C 1-3 hydroxyalkoxy, COOH, —C(O)O(C 1-6 alkyl) —C(O)NR a R a , —C(O)NR b R b , —S(O) 2 NR a R a , —S(O) 2 NR b R b , —C(O)(C 1-4 alkyl), —C(O)aryl, —C(O)heteroaryl, —C(O)(C 3-7 cycloalkyl), —S(O) 2 (C 1-4 alkyl), —S(O) 2 aryl, —S(O) 2 heteroaryl, —S(O) 2 (C 3-7 cycloalkyl), —NR a R a , or —NR b R b ;
R 4 is H, F, Cl, or —CH 3 ;
R a , at each occurrence, is independently H, C 1-3 alkyl, C 1-3 fluoroalkyl, C 3-6 cycloalkyl, aryl, or heteroaryl;
two R b along with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclo ring;
m, at each occurrence, is zero, 1, or 2;
n, at each occurrence, is zero, 1, or 2; and q is zero or 1.

2. The compound according to claim 1 or a salt thereof; wherein:
R 1 is methyl, —OCH 3 , —OCHF 2 , —OCH 2 CH 3 , or —CH 2 OCH 3 ;
R 2 is H, F, Cl, Br, —OH, —CN, C 1-3 alkyl, C 1-3 fluoroalkyl, C 1-3 hydroxyalkyl, or C 1-3 aminoalkyl; and
R 3a , at each occurrence, is independently H, —CH 3 , —C(CH 3 ) 3 , —CF 3 , —CH 2 OH, —CH═CH 2 , cyclopropyl, cyclohexyl, —CH 2 (phenyl), —C(O)(hydroxymethyl piperidinyl), —C(O)(cyclohexyl), —C(O)NHCH 2 CH 3 , —C(O)NH(methoxy phenyl), piperidinyl, pyrazolyl, methyl pyrazolyl, indole, phenyl substituted with zero to 3 substituents independently selected from F, Cl, —OH, —CH 3 , —CHF 2 , —CF 3 , and —OCF 3 ; or pyridinyl substituted with zero to 2 substituents independently selected from —OH, —CH 3 , and —OCH 3 .

3. The compound according to claim 2 , wherein
R 1 is —OCH 3 , —OCF 2 , or —CH 2 OCH 3 ;
n is zero or 1; and
q is zero or 1.

4. The compound according to claim 3 having the structure of Formula (Ia):

or a salt thereof.

5. The compound according to claim 4 or a salt thereof, wherein R 3 is:

6. The compound according to claim 1 or a salt thereof, wherein said compound is selected from: 5-(2-methoxy-7-methylquinoxalin-5-yl)-3-phenylisoxazole (1); 2-(difluoromethoxy)-7-methyl-5-(1-phenyl-1H-pyrazol-4-yl)quinoxaline (2); 5-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-2-phenylthiazole (3); 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-5-methylthiazole (4); 3-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)isothiazole (5); 3-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylthiazol-5-yl)phenol (6); 5-benzyl-2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)thiazole (7); 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-vinylthiazole (8); 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methyl-5-(1H-pyrazol-5-yl)thiazole (9); 4-cyclopropyl-2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)thiazole (10); 2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylthiazol-5-yl)-4-fluorophenol (11); 2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylthiazol-5-yl)-3-fluorophenol (12); 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-5-(piperidin-1-yl)thiazole (13); 5-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)thiazol-5-yl)pyridin-3-ol (14); 2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylthiazol-5-yl)phenol (15); 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-5-(2-(trifluoromethyl)phenyl)thiazole (16); 5-cyclohexyl-2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)thiazole (17); 2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-5-phenylthiazole (18); 2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)thiazol-5-yl)-6-fluorophenol (19); 2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)thiazol-5-yl)-4-methylphenol (20); 2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)thiazol-5-yl)-4-fluorophenol (21); 2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)thiazol-5-yl)-4-chlorophenol (22); 2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)thiazol-5-yl)-6-chlorophenol (23); 2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)thiazol-5-yl)-3-fluorophenol (24); 3-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)thiazol-5-yl)-4-fluorophenol (25); 3-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)thiazol-5-yl)-5-fluorophenol (26); 3-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)thiazol-5-yl)-4-(trifluoromethoxy)phenol (27); 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-5-phenylthiazole (28); 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-5-(pyridin-3-yl)thiazole (29); 2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)thiazol-5-yl)phenol (30); N-ethyl-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazole-5-carboxamide (31); 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-N-(4-methoxyphenyl)thiazole-4-carboxamide (32); (2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)thiazol-4-yl)(4-(hydroxymethyl)piperidin-1-yl)methanone (33); 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)thiazole (34); 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-5-phenyl-1,3,4-thiadiazole (35); 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylthiazole (36); 2-(2-(difluorometh

Assignees

• Bristol Myers Squibb Co

Inventors

• Richter Jeremy M
• Zhang Xiaojun
• Priestley Eldon Scott

Classifications

• C07D403/04 Primary

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D417/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D413/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D413/10 Primary

  linked by a carbon chain containing aromatic rings · CPC title