Bicyclic heteroaryl substituted compounds

Patent metadata

Field	Value
Publication number	US-12060347-B2
Application number	US-202017123265-A
Country	US
Kind code	B2
Filing date	Dec 16, 2020
Priority date	Jul 14, 2016
Publication date	Aug 13, 2024
Grant date	Aug 13, 2024

Abstract

Disclosed are compounds of Formula (I) to (VIII):

or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R 3 is a bicyclic 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) to (IV):

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 , —NH(C 1-6 hydroxyalkyl), azetidinyl, pyrrolidinyl, furanyl, pyranyl, piperidinyl, morpholinyl, piperazinyl, —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)O(C 1-6 alkyl), —C(O)NH(CH 2 CH 2 O(C 1-3 alkyl)), —C(O)NR b R b , —C(O)(piperidinyl), —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 heterocyclyl, wherein said cyclic group is substituted with zero to 5 substituents independently selected from F, Cl, hydroxy, C 1-3 alkyl, C 1-3 alkoxy, cyclopropyl, and —CN;
R 3 is a bicyclic group selected from indolyl, benzofuranyl, benzo[b]thiophenyl, benzo[d]imidazolyl, benzo[d]oxazolyl, benzo[d]thiazolyl, imidazol[1,2-a]pyridinyl, thiazolo[4,5-b]pyridinyl, thiazolo[4,5-c]pyridinyl, thiazolo[5,4-b]pyridinyl, thiazolo[5,4-c]pyridinyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl, 4,5,6,7-tetrahydrobenzofuranyl, 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridinyl, 5,6,7,8-tetrahydro-4H-cyclohepta[d]thiazolyl, 5,6-dihydro-4H-cyclopenta[d]thiazolyl, indolizinyl, pyrrolo[1,2-a]pyrimidinyl, 6,7-dihydrothiazolo[5,4-c]pyridinyl, 6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazinyl, 4,5,6,7-tetrahydrobenzothiophenyl, furo[3,2-b]pyridinyl, and furo[2,3-b]pyridinyl, each bicyclic group substituted with zero to 3 R 3a ;
R 3a , at each occurrence, is independently:

(i) F, Cl, —CN, —OH, C 1-3 alkyl, C 1-6 fluoroalkyl, C 1-6 hydroxyalkyl, C 1-6 hydroxy-deuteroalkyl, C 1-6 hydroxy-fluoroalkyl, C 1-6 alkoxy, C 1-3 fluoroalkoxy, C 3-6 cycloalkyl, C 3-6 fluorocycloalkyl, 4- to 7-membered heterocyclyl, —CH(OH)R y wherein R y is C 3-6 cycloalkyl, aryl, heteroaryl, or 4- to 7-membered heterocyclyl; (C 1-3 alkoxy)-(C 1-3 alkylene), —(CH 2 ) 1-3 NR a R a , —(CH 2 ) 1-3 NHS(O) 2 (aryl), —O(CH 2 ) 1-3 (aryl), —O(CH 2 ) 1-3 (thiazolyl), —O(CH 2 ) 1-3 (oxazolidinonyl), —O(CH 2 ) 1-3 (amino isoxazolyl), —O(CH 2 ) 1-3 (imidazolyl substituted with phenyl), C 1-6 hydroxyalkoxy, (C 1-3 alkoxy)—(C 1-6 alkoxy), —O(CH 2 ) 1-4 O(aryl), —O(CH 2 ) 1-4 O(CH 2 ) 1-3 (aryl), —O(CH 2 ) 1-4 NR a R a , —O(CH 2 ) 1-3 CHR a NR a (methoxy pyrimidinyl), —O(CH 2 ) 1-4 NHS(O) 2 (C 1-3 alkyl), —O(CH 2 ) 1-4 NHS(O) 2 (aryl), —O(CH 2 ) 1-4 C(O)OH, —O(CH 2 ) 1-4 C(O)O(C 1-6 alkyl), —O(CH 2 ) 1-4 C(O)NR a (CH 2 ) 0-3 (aryl), —O(CH 2 ) 1-4 C(O)NR a (CH 2 ) 0-3 (heteroaryl), —O(CH 2 ) 1-4 C(O)(morpholinyl), —O(CH 2 ) 1-4 OC(O)O(C 1-3 alkyl), —O(CH 2 ) 1-3 CHR a OC(O)NR a (CH 2 ) 1-4 C(O)NR a R a , —CH 2 CHR d OC(O)NR a (heteroaryl), —O(CH 2 ) 1-4 OC(O)NR a (heteroaryl), —O(imidazolyl substituted with aryl), —C(O)OH, —C(O)O(C 1-6 alkyl), —NR a C(O)(furanyl), —NR a C(O)(pyranyl), —NR a C(O)O(C 1-6 alkyl), —NR a C(O)O(CH 2 ) 1-4 (aryl), —O(CH 2 ) 1-4 NR a C(O)O(C 1-6 alkyl), —O(CH 2 ) 1-4 NR a C(O)O(CH 2 ) 0-4 (tetrahydropyranyl), —O(CH 2 ) 1-4 NR a C(O)O(CH 2 ) 0-4 (aryl), —O(CH 2 ) 1-4 NR a C(O)O(CH 2 ) 0-4 (heteroaryl), or —O(CH 2 ) 1-4 NR a C(O)O(CH 2 ) 0-4 (tetrahydrofuranyl), wherein each of said aryl, heteroaryl, and 3- to 6-membered heterocyclyl is substituted with zero to 5 substituents independently selected from F, Cl, —CN, C 1-3 alkyl, C 1-3 fluoroalkyl, C 1-4 hydroxyalkyl, C 1-3 alkoxy, —OCF 3 , —OCHF 2 , —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , —C(O)O(C 1-3 alkyl), C 1-3 hydroxyalkoxy, phenyl, —CONR c R c , and —S(O) 2 NR c R c ;
(ii) —CH(OH)CR h R i R j wherein R h and R i are independently H, F, C 1-4 alkyl, C 1-4 fluoroalkyl, C 1-3 alkoxy, C 1-3 fluoroalkoxy, or taken together with the carbon atom to which they are attached, form C 3-8 cycloalkyl or 4- to 7-membered heterocyclyl ring; and R j is H, C 1-6 alkyl, C 1-5 fluoroalkyl, (C 1-3 alkoxy)—(C 1-3 alkylene), C 3-8 cycloalkyl, C 3-8 heterocyclyl, aryl, or heteroaryl;
(iii) —O(CH 2 ) 1-4 NR a S(O) 2 (C 1-4 alkyl) or —O(CH 2 ) 1-4 NR a S(O) 2 R w , wherein R w is aryl or heteroaryl, each substituted with zero to 2 substituents independently selected from F, Cl, cyano, C 1-3 alkyl, C 1-3 alkoxy, —OCF 3 , —OCHF 2 , and C 1-3 fluoroalkyl; or
(iv) —O(CH 2 ) 1-4 OC(O)NR a R x , —OCH(R d )(CH 2 ) 1-3 OC(O)NR a R x , —OCR d R d (CH 2 ) 1-30 C(O)NR a R x , —O(CH 2 ) 1-3 CH(R d )OC(O)NR a R x , —O(CH 2 ) 1-3 CR d R d OC(O)NR a R x , —OCH(R d )CH(R d )(CH 2 ) 0-2 OC(O)NR a R x , or —OCR d R d CR d R d (CH 2 ) 0-2 OC(O)NR a R x , wherein R x is selected from H, C 1-4 alkyl, C 1-4 fluoroalkyl, aryl, heteroaryl, and —CH 2 (heteroaryl), each aryl and heteroaryl substituted with zero to 2 substituents independently selected from F, Cl, Br, —CN, —OH, C 1-3 alkyl, C 1-3 fluoroalkyl, C 1-6 hydroxyalkyl, C 1-6 hydroxy-deuteroalkyl, C 1-6 hydroxyalkoxy, C 1-6 hydroxy-fluoroalkoxy, C 1-3 alkoxy, —C(O)OH, —(CH 2 ) 0-3 C(O)O(C 1-3 alkyl), —(CH 2 ) 1-3 OP(O)(OH) 2 , —CH 2 (morpholinyl), —C(O)NH 2 , —C(O)NH(C 1-6 alkyl), —C(O)N(C 1-6 alkyl) 2 , —C(O)NR a (C 1-6 hydroxyalkyl), —C(O)NR b R b , —S(O) 2 NR a R a , —NH 2 , —NH(C 1-6 alkyl), —NR a (C 1-6 hydroxyalkyl), —N(C 1-6 alkyl) 2 , —NR a C(O)(C 1-6 alkyl), —NR a C(O)(chloro, fluorophenyl), —NR a S(O) 2 (C 1-3 alkyl), —C(O)NR a (CH 2 ) 0-1 (hydroxymethyloxetanyl), —C(O)NR a (CH 2 ) 0-1 (hydroxymethyl C 3-6 cycloalkyl), —C(O)NR a (CH 2 ) 0-1 (hydroxy C 3-6 cycloalkyl), —C(O)NHCH 2 C(CH 3 ) 2 OP(O)(OH) 2 , —C(O)(hydroxypiperidinyl), —C(O)(hydroxypyrrolidinyl), —C(O)(hydroxymethylpyrrolidinyl), —C(O)(morpholinyl), —C(O)(hydroxymethylmorpholinyl), pyrrolidinyl, morpholinyl, thiophenyl, methyl triazolyl, and oxazolidinonyl;
R 4 is H, F, Cl, or —CH 3 ;
R a , at each occurrence, is independently H, C 1-4 alkyl, or C 1-4 fluoroalkyl;
two R b along with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclo ring having 1 to 2 nitrogen atoms and 0-1 oxygen or sulfur atoms;
R c , at each occurrence, is independently C 1-3 alkyl or C 1-3 hydroxyalkyl, or two R c along with the nitrogen atom to which they are attached form a heterocyclyl or bicyclic heterocyclyl;
R d , at each occurrence, is independently C 1-6 alkyl, C 1-4 fluoroalkyl, C 1-6 hydroxyalkyl, (C 1-4 alkoxy)—(C 1-3 alkylene), (C 1-2 fluoroalkoxy)—(C 1-2 alkylene), (C 3-6 cycloalkyl)—(C 0-2 alkylene), aryl-(C 1-2 alkylene), heteroaryl-(C 1-2 alkylene), aryloxy-(C 1-2 alkylene), aryl-CH 2 O-(C 1-2 alkylene), or heteroaryloxy-(C 1-2 alkylene); and
n is zero, 1, or 2.

2. The compound according to claim 1 or a salt thereof; wherein:
R 1 is —OH, C 1-2 alkyl, —CHFCH 3 , —CH═CH 2 , C 1-3 alkoxy, C 1-2 fluoroalkoxy, —OCH 2 CH 2 OH, —CH 2 O(C 1-2 alkyl), —CD 2 OCD 3 , —CH 2 OCHF 2 , —CF 2 OCH 3 , —CH 2 O(phenyl), § -CH(CH 3 )OCH 3 , —NH(CH 3 )

Assignees

• Bristol Myers Squibb Co

Inventors

• Zhang Xiaojun
• Priestley Eldon Scott
• Bates J Alex
• Halpern Oz Scott
• Reznik Samuel Kaye
• Richter Jeremy M

Classifications

• C07D403/04

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

• C07D513/04

  Ortho-condensed systems · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title