Bicyclic heteroaryl substituted compounds

Patent metadata

Field	Value
Publication number	US-10730868-B2
Application number	US-201716317218-A
Country	US
Kind code	B2
Filing date	Jul 13, 2017
Priority date	Jul 14, 2016
Publication date	Aug 4, 2020
Grant date	Aug 4, 2020

Abstract

Disclosed are compounds of Formula (I) to (IV): or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate or prodrug thereof. 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):

stereoisomer, or 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 fluoroalkoxy)-(C 1-3 fluoroalkylene), (C 1-3 deuteroalkoxy)-(C 1-3 deuteroalkylene), (C 1-3 fluoroalkoxy)-(C 1-3 alkylene), —(CH 2 ) n O(phenyl), —(CH 2 ) n 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 16 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 1-4 alkyl, C 1-4 fluoroalkyl, C 1-3 alkoxy, C 1-3 fluoroalkoxy, cyclopropyl, and —CN;
R 3 is:

R 4 is H, F, Cl, hydroxy, C 1-4 alkyl, C 1-4 fluoroalkyl, C 1-4 hydroxyalkyl, C 1-3 alkoxy, C 1-3 fluoroalkoxy, C 1-3 alkylthio, cyclopropyl, or —CN;
Ring B, along with the two carbon atoms through which it is attached, is a 3 to 7 membered cycloalkyl, or a 5 to 7 membered heterocycle having 1 nitrogen, oxygen, or sulphur atom, wherein the cycloalkyl and heterocycle are substituted with 0-4 R d ;
R 5 is H, or C(O)NR a R 6 ;
R 6 is H, C 1-4 alkyl, phenyl, or a 5 or 6 membered heteroaryl, containing 1 to 3 nitrogen atoms and 0-1 oxygen or sulphur atoms, the phenyl or heteroaryl being substituted with 0-2 R 7 ;
R 7 is CN, hydroxy, NR a R a , halogen, C 1-4 alkyl, C 1-4 fluoroalkyl, C 1-4 -hydroxyalkyl, C 1-4 -hydroxyfluoroalkyl, C(O)R a , C(O)OR a , C(O)NR a R c , S(O) 2 NR a R c , and S(O) 2 R a , —O—C 1-4 alkyl, —S—C 1-4 alkyl, —O—C 1-4 -hydroxyalkyl, —O—C 1-4 -aminoalkyl, —O—C 1-4 -hydroxyfluoroalkyl, O—C 1-4 fluoroalkyl, O—PO 3 −2 , —C 1-4 alkyl-O—PO 3 −2 , —C 1-4 fluoroalkyl-O—PO 3 −2 , —O—C 1-4 alkyl-O—PO 3 −2 , —O—C 1-4 fluoroalkyl-O—PO 3 −2 , —N(R a )—C 1-4 hydroxyalkyl, or —N(R a )—C 1-4 hydroxyfluoroalkyl;
R 8 is H, F, Cl, or CH 3 ;
R 9 is H, CN, hydroxyl, C 1-4 alkyl, C 1-4 fluoroalkyl, cyclopropyl, or halogen;
R a is 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 is H, C 1-4 alkyl, or C 1-4 hydroxyalkyl;
R d is F, Cl, hydroxy, C 1-4 alkyl, C 1-4 fluoroalkyl, C 1-4 hydroxyalkyl, C 1-3 alkoxy, C 1-3 fluoroalkoxy, C 1-3 alkylthio, cyclopropyl, —CN, C(O)R a , C(O)OR a , C(O)NR a R c , S(O) 2 NR a R c , or S(O) 2 R a ; and
n is 1 to 3.

2. A compound of claim 1 , stereoisomer or salt thereof, wherein
R 1 is methyl, methoxy, ethoxy, OCHF 2 , or —CH 2 OCH 3 ;
R 2 is F, Cl, CN, methyl, hydroxymethyl, methoxy, or difluoromethyl;
R 3 is

R 4 is H or F;
Ring B, along with the two carbon atoms through which it is attached, is cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, or piperadinyl, each of these being substituted with 0-3 R d ;
R 5 is C(O)NHR 6 ;
R 6 is phenyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl, each of these being substituted with 0-2 R 7 ;
R 7 is F, Cl, CN, hydroxy, C 1-4 alkyl, C 1-4 fluoroalkyl C 1-4 -hydroxyalkyl, C(O)OR a , C(O)NR a R c , —O—C 1-4 alkyl, —S—C 1-4 alkyl, —O—C 1-4 -hydroxyalkyl, O—C 1-4 fluoroalkyl, —O—PO 3 −2 , —C 1-4 alkyl-O—PO 3 −2 , or —O—C 1-4 alkyl-O—PO 3 −2 ;
R 8 is H or F;
R 9 is H, F, Cl, CH 3 , or CHF 2 ;
R a is H, or C 1-4 alkyl;
R c is H, C 1-4 alkyl, C 1-4 hydroxyalkyl; and
R d is F, C 1-4 alkyl, C(O)O—C 1-4 alkyl, C 1-4 fluoroalkyl, C 1-3 alkoxy, or C 1-3 fluoroalkoxy.

3. A compound of claim 2 , stereoisomer or salt thereof, wherein
R 1 is methoxy, or ethoxy;
R 2 is F, Cl, CN, or methyl;
R 3 is

R 4 is H or F;
Ring B, along with the two carbon atoms through which it is attached, is a cyclobutyl, cyclopentyl, or cyclohexyl, each of these being substituted with 0-2 R d ;
R 5 is C(O)NHR 6 ;
R 6 is pyridinyl, or pyrimidinyl, each of these being substituted with 0-2 R 7 ;
R 7 is F, Cl, CN, hydroxy, methyl, CF 3 , CHF 2 , CH 2 OH, CH 2 CH 2 OH, —OCH 2 CH 2 OH, —OCH 3 , —OCF 3 —OCHF 2 , —CH 2 CH(CH 3 )OH, —O—CH 2 CH(CH 3 )OH, —O—PO 3 −2 , CH 2 O—PO 3 −2 , CH 2 CH 2 O—PO 3 −2 , —OCH 2 CH 2 O—PO 3 −2 , CH 2 CH(CH 3 )O—PO 3 −2 , or —O—CH 2 CH(CH 3 )O—PO 3 −2 ;
R 8 is H or F;
R 9 is H; and
R d is F, or methyl.

4. A compound of claim 3 , stereoisomer or salt thereof, wherein
R 3 is

5. A compound of claim 4 , stereoisomer or salt thereof, wherein the compound is of formula (I)

6. A compound of claim 1 , stereoisomer or salt thereof, wherein the compound is of formula

7. The compound of claim 6 , stereoisomer or salt thereof, wherein
R 1 is methoxy, or ethoxy;
R 2 is F, Cl, CN, or methyl;
R 4 is F;
R 5 is C(O)NHR 6 ;
R 6 is pyridinyl, or pyrimidinyl, each of these being substituted with 0-2 R 7 ;
R 7 is F, Cl, CN, hydroxy, methyl, CF 3 , CHF 2 , CH 2 OH, CH 2 CH 2 OH, —OCH 2 CH 2 OH, —OCH 3 , —OCF 3 —OCHF 2 , —CH 2 CH(CH 3 )OH, or —O—CH 2 CH(CH 3 )OH;
R 8 is H;
R 9 is H; and
R d is H, methyl, or C(O)O—C 1-4 alkyl.

8. The compound of claim 5 , stereoisomer or salt thereof, wherein
R 3 is

9. A compound of claim 8 , stereoisomer or salt thereof, wherein
R 7 is F, Cl, CN, hydroxy, methyl, CF 3 , CHF 2 , CH 2 OH, CH 2 CH 2 OH, —OCH 2 CH 2 OH, —OCH 3 , —OCF 3 —OCHF 2 , —CH 2 CH(CH 3 )OH, or —O—CH 2 CH(CH 3 )

Assignees

• Bristol Myers Squibb Co

Inventors

• Fu Qinghong
• Zhang Xiaojun
• Priestley Eldon Scott
• Halpern Oz Scott
• Reznik Samuel Kaye
• Richter Jeremy M

Classifications

• C07D417/04

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

• C07D513/04

  Ortho-condensed systems · 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

• A61K31/498

  Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine · CPC title

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title