US 2019/0292176 A1 · BICYCLIC HETEROARYL SUBSTITUTED COMPOUNDS

Abstract

Disclosed are compounds of Formula (I) to (VIII): (I) (II) (III) (IV) (V) (VI) (VII) (VIII); or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R3 is a bicyclic heteroaryl group substituted with zero to 3 R3a; and R1, R2, R3a, R4, 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.

A compound of Formula (I) to (VIII):

or a salt thereof;
wherein:
R1 is F, Cl, —OH, C1-4 alkyl, C1-4 fluoroalkyl, C2-4alkenyl, C2-4alkynyl, C3-7 cycloalkyl, C3-7 fluorocycloalkyl, C1-4 alkoxy, C1-4 fluoroalkoxy, C2-4 hydroxyalkoxy, C3-6 cycloalkoxy, (C1-3 alkoxy)-(C1-3 alkylene), (C1-3 alkoxy)-(C1-3 fluoroalkylene), (C1-3 deuteroalkoxy)-(C1-3 deuteroalkylene), (C1-3 fluoroalkoxy)-(C1-3 alkylene), (C1-3 fluoroalkoxy)-(C1-3 fluoroalkylene), —(CH2)1-3O(phenyl), —(CH2)1-3NRaRa, —C(O)O(C1-6 alkyl), —C(O)NRaRa, —C(O)NRbRb, —NH2, —NH(C1-6 alkyl), —N(C1-6 alkyl)2, —NH(C1-6 hydroxyalkyl), azetidinyl, pyrrolidinyl, furanyl, pyranyl, piperidinyl, morpholinyl, piperazinyl, —S(O)2(C1-3 alkyl), —S(O)2NRaRa, C1-3 alkylthio, or C1-3 fluoroalkylthio;
R2, at each occurrence, is independently H, F, Cl, Br, —OH, —CN, C1-4 alkyl, C1-4 fluoroalkyl, C1-4 hydroxyalkyl, C1-3 aminoalkyl, C2-4 alkenyl, C2-4 alkynyl, C3-7 cycloalkyl, C3-7 fluorocycloalkyl, C1-6 alkoxy, C1-3 fluoroalkoxy, C1-3 alkylthio, C1-3 fluoroalkylthio, (C1-3 alkoxy)-(C1-3 alkylene), (C1-3 fluoroalkoxy)-(C1-3 alkylene), —C(O)NH2, —C(O)NH(C1-6 alkyl), —C(O)N(C1-6 alkyl)2, —C(O)O(C1-6 alkyl), —C(O)NH(CH2CH2O(C1-3 alkyl)), —C(O)NRbRb, —C(O)(piperidinyl), —CH(OH)(C3-6 cycloalkyl), —CH(OH)(phenyl), —CH(OH)(pyridyl), —S(O)2(C1-3 alkyl), —S(O)2NRaRa, 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, C1-3 alkyl, C1-3 alkoxy, cyclopropyl, and —CN;
R3 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 R3a;
R3a, at each occurrence, is independently:
(i) F, Cl, —CN, —OH, C1-3 alkyl, C1-6 fluoroalkyl, C1-6 hydroxyalkyl, C1-6 hydroxy-deuteroalkyl, C1-6 hydroxy-fluoroalkyl, C1-6 alkoxy, C1-3 fluoroalkoxy, C3-6 cycloalkyl, C3-6 fluorocycloalkyl, 4-to 7-membered heterocyclyl, —CH(OH)Ry wherein Ry is C3-6 cycloalkyl, aryl, heteroaryl, or 4-to 7-membered heterocyclyl;
(C1-3 alkoxy)-(C1-3 alkylene), —(CH2)1-3NRaRa, —(CH2)1-3NHS(O)2(aryl), —O(CH2)1-3(aryl), —O(CH2)1-3(thiazolyl), —O(CH2)1-3(oxazolidinonyl), —O(CH2)1-3(amino isoxazolyl), —O(CH2)1-3(imidazolyl substituted with phenyl), C1-6 hydroxyalkoxy, (C1-3 alkoxy)-(C1-6 alkoxy), —O(CH2)1-4O(aryl), —O(CH2)1-4O(CH2)1-3(aryl), —O(CH2)1-4NRaRa, —O(CH2)1-3CHRaNRa(methoxy pyrimidinyl), —O(CH2)1-4NHS(O)2(C1-3 alkyl), —O(CH2)1-4NHS(O)2(aryl), —O(CH2)1-4C(O)OH, —O(CH2)1-4C(O)O(C1-6 alkyl), —O(CH2)1-4C(O)NRa(CH2)0-3(aryl), —O(CH2)1-4C(O)NRa(CH2)0-3(heteroaryl), —O(CH2)1-4C(O)(morpholinyl), —O(CH2)1-4OC(O)O(C1-3 alkyl), —O(CH2)1-3CHRaOC(O)NRa(CH2)1-4C(O)NRaRa, —CH2CHRdOC(O)NRa(heteroaryl), —O(CH2)1-4OC(O)NRa(heteroaryl), —O(imidazolyl substituted with aryl), —C(O)OH, —C(O)O(C1-6 alkyl), —NRaC(O)(furanyl), —NRaC(O)(pyranyl), —NRaC(O)O(C1-6 alkyl), —NRaC(O)O(CH2)1-4(aryl), —O(CH2)1-4NRaC(O)O(C1-6 alkyl), —O(CH2)1-4NRaC(O)O(CH2)0-4(tetrahydropyranyl), —O(CH2)1-4NRaC(O)O(CH2)0-4(aryl), —O(CH2)1-4NRaC(O)O(CH2)0-4(heteroaryl), or —O(CH2)1-4NRaC(O)O(CH2)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, C1-3 alkyl, C1-3 fluoroalkyl, C1-4 hydroxyalkyl, C1-3 alkoxy, —OCF3, —OCHF2, —NH2, —NH(C1-6 alkyl), —N(C1-6 alkyl)2, —C(O)O(C1-3 alkyl), C1-3 hydroxyalkoxy, phenyl, —CONRcRc, and —S(O)2NRcRc;
(ii) —CH(OH)CRhRiRj wherein Rh and Ri are independently H, F, C1-4 alkyl, C1-4 fluoroalkyl, C1-3 alkoxy, C1-3 fluoroalkoxy, or taken together with the carbon atom to which they are attached, form C3-8 cycloalkyl or 4- to 7-membered heterocyclyl ring;
and Rj is H, C1-6 alkyl, C1-5 fluoroalkyl, (C1-3 alkoxy)-(C1-3 alkylene), C3-8 cycloalkyl, C3-8 heterocyclyl, aryl, or heteroaryl;
(iii) —O(CH2)1-4NRaS(O)2(C1-4 alkyl) or —O(CH2)1-4NRaS(O)2Rw, wherein Rw is aryl or heteroaryl, each substituted with zero to 2 substituents independently selected from F, Cl, cyano, C1-3 alkyl, C1-3 alkoxy, —OCF3, —OCHF2, and C1-3 fluoroalkyl;
or
(iv) —O(CH2)1-4OC(O)NRaRx, —OCH(Rd)(CH2)1-3OC(O)NRaRx, —OCRdRd(CH2)1-3OC(O)NRaRx, —O(CH2)1-3CH(Rd)OC(O)NRaRx, —O(CH2)1-3CRdRdOC(O)NRaRx, —OCH(Rd)CH(Rd)(CH2)0-2OC(O)NRaRx, or —OCRdRdCRdRd(CH2)0-2OC(O)NRaRx, wherein Rx is selected from H, C1-4 alkyl, C1-4 fluoroalkyl, aryl, heteroaryl, and —CH2(heteroaryl), each aryl and heteroaryl substituted with zero to 2 substituents independently selected from F, Cl, Br, —CN, —OH, C1-3 alkyl, C1-3 fluoroalkyl, C1-6 hydroxyalkyl, C1-6 hydroxy-deuteroalkyl, C1-6 hydroxyalkoxy, C1-6 hydroxy-fluoroalkoxy, C1-3 alkoxy, —C(O)OH, —(CH2)0-3C(O)O(C1-3 alkyl), —(CH2)1-3OP(O)(OH)2, —CH2(morpholinyl), —C(O)NH2, —C(O)NH(C1-6 alkyl), —C(O)N(C1-6 alkyl)2, —C(O)NRa(C1-6 hydroxyalkyl), —C(O)NRbRb, —S(O)2NRaRa, —NH2, —NH(C1-6 alkyl), —NRa(C1-6 hydroxyalkyl), —N(C1-6 alkyl)2, —NRaC(O)(C1-6 alkyl), —NRaC(O)(chloro, fluorophenyl), —NRaS(O)2(C1-3 alkyl), —C(O)NRa(CH2)0-1 (hydroxymethyloxetanyl), —C(O)NRa(CH2)0-1 (hydroxymethyl C3-6 cycloalkyl), —C(O)NRa(CH2)0-1 (hydroxy C3-6 cycloalkyl), —C(O)NHCH2C(CH3)2OP(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;
R4 is H, F, Cl, or —CH3;
Ra, at each occurrence, is independently H, C1-4alkyl, or C1-4 fluoroalkyl;
two Rb 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;
Rc, at each occurrence, is independently C1-3 alkyl or C1-3 hydroxyalkyl, or two Rc along with the nitrogen atom to which they are attached form a heterocyclyl or bicyclic heterocyclyl;
Rd, at each occurrence, is independently C1-6 alkyl, C1-4 fluoroalkyl, C1-6 hydroxyalkyl, (C1-4 alkoxy)-(C1-3 alkylene), (C1-2 fluoroalkoxy)-(C1-2 alkylene), (C3-6 cycloalkyl)-(C0-2 alkylene), aryl-(C1-2 alkylene), heteroaryl-(C1-2 alkylene), aryloxy-(C1-2 alkylene), aryl-CH2O—(C1-2 alkylene), or heteroaryloxy-(C1-2 alkylene);
and
n is zero, 1, or 2.

17 more elements

Bicyclic heteroaryl substituted compounds

Life of this patent

Bicyclic heteroaryl substituted compounds

Life of this patent

Abstract

Claims14