TRICYCLIC HETEROARYL-SUBSTITUTED QUINOLINE AND AZAQUINOLINE COMPOUNDS AS PAR4 INHIBITORSDisclosed are compounds of Formula (I) to (VIII) or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R3 is a tricyclic heteroaryl group substituted withR3a and zero to two R3b; and R1, R2, R3a, R3b, R4, and n are defined herein. Also disclosed are methods of using the compounds as PAR4 inhibitors, and pharmaceutical compositions comprising the 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.Formula 1. (I) to (VIII) compound or its salt:Wherein:R1For F, Cl ,-OH, C1-4Alkyl, C1-4Fluoroalkyl, C2-4Alkenyl, C2-4Alkynyl, C3-7Naphthenic base, C3-7Fluorine naphthenic base, C1-4Alkane Oxygroup, C1-4Fluoroalkyloxy, C2-4Hydroxy alkoxy base, C3-6Cycloalkyloxy, (C1-3Alkoxy)-(C1-3Alkylidene), (C1-3Alcoxyl Base)-(C1-3Fluorine alkylidene), (C1-3Deuterated alkoxy)-(C1-3Deuterated alkylidene), (C1-3Fluoroalkyloxy)-(C1-3Alkylidene), (C1-3Fluoroalkyloxy)-(C1-3Fluorine alkylidene) ,-(CH2)1-3O (phenyl) ,-(CH2)1-3NRaRa、-C(O)O(C1-6Alkyl) ,-C (O)NRaRa、-C(O)NRbRb、-NH2、-NH(C1-6Alkyl) ,-N (C1-6Alkyl)2, azetidinyl, pyrrolidinyl, furans Base, pyranose, piperidyl, morpholinyl, piperazinyl ,-S (O)2(C1-3Alkyl) ,-S (O)2NRaRa、C1-3Alkyl sulfenyl or C1-3Fluorine Alkyl sulfenyl；R2, at each occurrence, it independently is H, F, Cl, Br ,-OH ,-CN, C1-4Alkyl, C1-4Fluoroalkyl, C1-4Hydroxy alkyl, C1-3Aminoalkyl, C2-4Alkenyl, C2-4Alkynyl, C3-7Naphthenic base, C3-7Fluorine naphthenic base, C1-6Alkoxy, C1-3Fluoroalkyloxy, C1-3Alkane Base sulfenyl, C1-3Fluoroalkyl sulfenyl, (C1-3Alkoxy)-(C1-3Alkylidene), (C1-3Fluoroalkyloxy)-(C1-3Alkylidene) ,-C (O) NH2、-C(O)NH(C1-6Alkyl) ,-C (O) N (C1-6Alkyl)2、-C(O)NRbRb、-CH(OH)(C3-6Naphthenic base) ,-CH (OH) (benzene Base), CH (OH) (pyridyl group) ,-S (O)2(C1-3Alkyl) ,-S (O)2NRaRa, or extremely selected from phenyl, 5- to 6- unit's heteroaryl and 5- The cyclic group of 7- circle heterocyclic ring base, wherein cyclic group substitution has 0 to 5 to be independently selected from substituent group below: F, Cl, hydroxyl Base, C1-3Alkyl, C1-3Alkoxy, cyclopropyl and-CN；R3Are as follows:(i)X1For N and X2For S, O or NH；(ii)X1For O and X2For CH or N；(iii)X1For NH and X2For CH；Or(iv)X1For CH and X2For S or NH；And dotted line indicate double bond variable position to keep armaticity,Each R3Substitution has R3aWith 0 to 3 R3b；R3aAre as follows:(i)H、C1-6Hydroxy alkyl, C1-6Hydroxyl fluoroalkyl ,-C (O) O (C1-6Alkyl) ,-CRaRaNHC(O)(C1-6Alkyl) ,- CRaRaNHC(O)(C1-6Fluoroalkyl) ,-CRaRaNHC(O)O(C1-6Alkyl) ,-CRaRaNHC(O)O(CH2)1-3(C1-3Alkoxy) ,- CRaRaNHC(O)O(C1-4Fluoroalkyl) ,-CRaRaNaS(O)2(C1-3Alkyl), CRaRaNaS(O)2(C1-3Fluoroalkyl) ,-CRaRaOP (O)(OH)2、-CRaRaNHC(O)Rx、-CRaRaNHC(O)ORx、-CRaRaNHC(O)CH2Rx、-CRaRaNHC(O)OCH2Rx、- CRaRaOC(O)NHRx、-CRaRaNHC(O)NHRx、-CRaRaORxOr-CRaRaOC(O)Rx；(ii)-CH(OH)CRhRiRj, wherein RhAnd RiIt independently is H, F, C1-4Alkyl, C1-4Fluoroalkyl, C1-3Alkoxy or C1-3Fluorine Alkoxy, or C is formed together with the carbon atom connecting with them3-8Naphthenic base or 4- are to 7- circle heterocyclic ring basic ring；And RjFor H, C1-6 Alkyl, C1-5Fluoroalkyl, (C1-3Alkoxy)-(C1-3Alkyl), C3-8Naphthenic base, C3-8Heterocycle, aryl or heteroaryl；RxFor C3-6Naphthenic base, phenyl, pyridyl group, pyridazinyl, pyrimidine radicals, pyrazinyl, benzo [d] oxazolyl, benzo [d] thiazole Base, pyrrolopyridinyl, tetrahydro isoquinolyl, tetrahydrofuran base, THP trtrahydropyranyl, imidazopyridyl or oxo-dihydro benzene And [d] oxazolyl, respectively replacing has 0 to 2 to be independently selected from substituent group below: F, Cl, Br ,-CN ,-OH ,-CH3、-CF3、C1-3 Alkoxy, C1-3Fluoroalkyl, C1-6Hydroxy alkyl, C1-6Hydroxy alkoxy base, C1-6Hydroxyl-Fluoroalkyloxy, phenoxy group ,-NRaRa、-C (O)NRaRa、-C(O)NH(C1-6Alkyl) ,-C (O) N (C1-6Alkyl)2、-C(O)NRbRb、-C(O)NRa(C1-6Hydroxy alkyl) ,-C (O)O(C1-6Alkyl) ,-C (O) OC1-4Alkyl ,-C (O) (morpholinyl) ,-S (O)2NRaRa、-CH(OH)CH2OH ,-CH=CH2、- NHC(O)CH3、-OCH2CH2N(CH3)2、-OCH2CH2OH、-OCH2CH (Me) OH, isoxazolyl, phenoxy group, phenyl, pyrrolidines Base, thienyl and methyl-triazole base；R3b, at each occurrence, it independently is H, F, Cl, Br ,-CN, C1-3Alkyl, C1-3Fluoroalkyl, C1-3Hydroxy alkyl ,- OCHF2、C3-6Naphthenic base, C3-6Fluorine naphthenic base, C2-4Alkenyl, C2-4Alkynyl, C1-3Alkoxy, C1-3Alkyl sulfenyl or C1-3Fluothane oxygen Base；R4For H, F, Cl or-CH3；Ra, at each occurrence, it independently is H, C1-4Alkyl or C1-4Fluoroalkyl；Two RbThe 4- with 1 to 2 nitrogen-atoms and 0 to 1 oxygen or sulphur atom is formed together extremely with the nitrogen-atoms connecting with them 7- circle heterocyclic ring；AndN is 0,1 or 2.
PAR4 억제제로서의 트리시클릭 헤테로아릴-치환된 퀴놀린 및 아자퀴놀린 화합물화학식 (I) 내지 (VIII)의 화합물 또는 그의 입체이성질체, 호변이성질체, 제약상 허용되는 염, 용매화물 또는 전구약물이 개시되고, 여기서 R3은 R3a 및 0 내지 2개의 R3b로 치환된 트리시클릭 헤테로아릴 기이고; R1, R2, R3a, R3b, R4, 및 n은 제1 측면에 정의되어 있다. 이러한 화합물을 PAR4 억제제로서 사용하는 방법, 및 이러한 화합물을 포함하는 제약 조성물이 또한 개시된다. 이들 화합물은 혈소판 응집을 억제 또는 방지하는데 유용하며, 혈전색전성 장애의 치료 또는 혈전색전성 장애의 1차 예방에 유용하다.[이미지]화학식 (I) 내지 (VIII)의 화합물 또는 그의 염.[이미지]여기서R1은 F, Cl, -OH, C1-4 알킬, C1-4 플루오로알킬, C2-4 알케닐, C2-4 알키닐, C3-7 시클로알킬, C3-7 플루오로시클로알킬, C1-4 알콕시, C1-4 플루오로알콕시, C2-4 히드록시알콕시, C3-6 시클로알콕시, (C1-3 알콕시)-(C1-3 알킬렌), (C1-3 알콕시)-(C1-3 플루오로알킬렌), (C1-3 듀테로알콕시)-(C1-3 듀테로알킬렌), (C1-3 플루오로알콕시)-(C1-3 알킬렌), (C1-3 플루오로알콕시)-(C1-3 플루오로알킬렌), -(CH2)1-3O(페닐), -(CH2)1-3NRaRa, -C(O)O(C1-6 알킬), -C(O)NRaRa, -C(O)NRbRb, -NH2, -NH(C1-6 알킬), -N(C1-6 알킬)2, 아제티디닐, 피롤리디닐, 푸라닐, 피라닐, 피페리디닐, 모르폴리닐, 피페라지닐, -S(O)2(C1-3 알킬), -S(O)2NRaRa, C1-3 알킬티오, 또는 C1-3 플루오로알킬티오이고;R2는 각 경우에 독립적으로 H, F, Cl, Br, -OH, -CN, C1-4 알킬, C1-4 플루오로알킬, C1-4 히드록시알킬, C1-3 아미노알킬, C2-4 알케닐, C2-4 알키닐, C3-7 시클로알킬, C3-7 플루오로시클로알킬, C1-6 알콕시, C1-3 플루오로알콕시, C1-3 알킬티오, C1-3 플루오로알킬티오, (C1-3 알콕시)-(C1-3 알킬렌), (C1-3 플루오로알콕시)-(C1-3 알킬렌), -C(O)NH2, -C(O)NH(C1-6 알킬), -C(O)N(C1-6 알킬)2, -C(O)NRbRb, -CH(OH)(C3-6 시클로알킬), -CH(OH)(페닐), CH(OH)(피리딜), -S(O)2(C1-3 알킬), -S(O)2NRaRa, 또는 페닐, 5- 내지 6-원 헤테로아릴, 및 5- 내지 7-원 헤테로시클릴로부터 선택된 시클릭 기이고, 여기서 상기 시클릭 기는 F, Cl, 히드록시, C1-3 알킬, C1-3 알콕시, 시클로프로필, 및 -CN으로부터 독립적으로 선택된 0 내지 5개의 치환기로 치환되고;R3은[이미지]이고;(i) X1은 N이고 X2는 S, O, 또는 NH이거나;(ii) X1은 O이고 X2는 CH 또는 N이거나;(iii) X1은 NH이고 X2는 CH이거나; 또는(iv) X1은 CH이고 X2는 S 또는 NH이고;파선은 방향족성을 유지하기 위한 이중 결합의 가변 위치를 나타내고,각각의 R3은 R3a 및 0 내지 3개의 R3b로 치환되고;R3a는(i) H, C1-6 히드록시알킬, C1-6 히드록시플루오로알킬, -C(O)O(C1-6 알킬), -CRaRaNHC(O)(C1-6 알킬), -CRaRaNHC(O)(C1-6 플루오로알킬), -CRaRaNHC(O)O(C1-6 알킬), -CRaRaNHC(O)O(CH2)1-3(C1-3 알콕시), -CRaRaNHC(O)O(C1-4 플루오로알킬), -CRaRaNaS(O)2(C1-3 알킬), CRaRaNaS(O)2(C1-3 플루오로알킬), -CRaRaOP(O)(OH)2, -CRaRaNHC(O)Rx, -CRaRaNHC(O)ORx, -CRaRaNHC(O)CH2Rx, -CRaRaNHC(O)OCH2Rx, -CRaRaOC(O)NHRx, -CRaRaNHC(O)NHRx, -CRaRaORx, 또는 -CRaRaOC(O)Rx이거나;(ii) -CH(OH)CRhRiRj이며, 여기서 Rh 및 Ri는 독립적으로 H, F, C1-4 알킬, C1-4 플루오로알킬, C1-3 알콕시 또는 C1-3 플루오로알콕시이거나, 또는 이들이 부착되어 있는 탄소 원자와 함께 C3-8 시클로알킬 또는 4- 내지 7-원 헤테로시클릴 고리를 형성하고; Rj는 H, C1-6 알킬, C1-5 플루오로알킬, (C1-3 알콕시)-(C1-3 알킬), C3-8 시클로알킬, C3-8 헤테로시클릴, 아릴, 또는 헤테로아릴이고;Rx는 C3-6 시클로알킬, 페닐, 피리디닐, 피리다지닐, 피리미디닐, 피라지닐, 벤조[d]옥사졸릴, 벤조[d]티아졸릴, 피롤로피리디닐, 테트라히드로이소퀴놀리닐, 테트라히드로푸라닐, 테트라히드로피라닐, 모르폴리닐, 이미다조피리디닐 또는 옥소-디히드로벤조[d]옥사졸릴이고, 각각은 F, Cl, Br, -CN, -OH, -CH3, -CF3, C1-3 알콕시, C1-3플루오로알킬, C1-6 히드록시알킬, C1-6 히드록시알콕시, C1-6 히드록시-플루오로알콕시, 페녹시, -NRaRa, -C(O)NRaRa, -C(O)NH(C1-6 알킬), -C(O)N(C1-6 알킬)2, -C(O)NRbRb, -C(O)NRa(C1-6히드록시알킬), -C(O)O(C1-6 알킬), -C(O)OC1-4알킬, -C(O)(모르폴리닐), -S(O)2NRaRa, -CH(OH)CH2OH, -CH=CH2, -NHC(O)CH3, -OCH2CH2N(CH3)2, -OCH2CH2OH, -OCH2CH(Me)OH, 이속사졸릴, 페녹시, 페닐, 피롤리디닐, 티오페닐 및 메틸 트리아졸릴로부터 독립적으로 선택된 0 내지 2개의 치환기로 치환되고;R3b는 각 경우에 독립적으로 H, F, Cl, Br, -CN, C1-3 알킬, C1-3 플루오로알킬, C1-3 히드록시알킬, -OCHF2, C3-6 시클로알킬, C3-6 플루오로시클로알킬, C2-4 알케닐, C2-4 알키닐, C1-3 알콕시, C1-3 알킬티오, 또는 C1-3 플루오로알콕시이고;R4는 H, F, Cl, 또는 -CH3이고;Ra는 각 경우에 독립적으로 H, C1-4알킬, 또는 C1-4플루오로알킬이고;2개의 Rb는 이들이 부착되어 있는 질소 원자와 함께, 1 내지 2개의 질소 원자 및 0-1개의 산소 또는 황 원자를 갖는 4- 내지 7-원 헤테로시클로 고리를 형성하고;n은 0, 1, 또는 2이다.