BICYCLIC HETEROARYL SUBSTITUTED COMPOUNDSThe present invention disclose compounds of Formula (I) to (IV): [insert chemical structure here] 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, andare useful for the treatment of a thromboembolic disorder or the primary prophylaxis of a thromboembolic disorder.A kind of compound of formula (i) to (iv):its stereoisomer or salt；wherein:r1it is 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), (c1-3fluoroalkyloxy)-(c1-3fluorine alkylidene), (c1-3deuterated alkoxy)-(c1-3deuterated alkylene base), (c1-3fluoroalkyloxy)-(c1-3alkylidene) ,-(ch2)no (phenyl) ,-(ch2)nnrara、-c(o)o(c1-6alkyl) ,-c (o) nrara、-c(o)nrbrb、-nh2、-nh(c1-6alkyl) ,-n (c1-6alkyl)2、-nh(c1-6hydroxy alkyl), heterocyclic butane group, pyrrolidinyl, furyl, pyranose, piperidyl, morpholinyl, piperazinyl ,-s (o)2(c1-3alkyl) ,-s (o)2nrara、c1-3alkane sulfenyl or c1-3fluoroalkylthio；r2it is independently h, f, cl, br ,-oh ,-cn, c at each occurrence1-4alkyl, c1-4fluoroalkyl, c1-4hydroxy alkyl, c1-3 aminoalkyl, c2-4alkenyl, c2-4alkynyl, c3-7naphthenic base, c3-7fluorine naphthenic base, c1-6alkoxy, c1-3fluoroalkyloxy, c1-3alkane sulphur base, c1-3fluoroalkylthio, (c1-3alkoxy)-(c1-3alkylidene), (c1-3fluoroalkyloxy)-(c1-3alkylidene) ,-c (o) nh2、-c (o)nh(c1-6alkyl) ,-c (o) n (c1-6alkyl)2、-c(o)o(c1-6alkyl) ,-c (o) nh (ch2ch2o(c1-3alkyl)) ,-c (o)nrbrb,-c (o) (piperidyl) ,-ch (oh) (c3-6naphthenic base) ,-ch (oh) (phenyl) ,-ch (oh) (pyridyl group) ,-s (o)2 (c1-3alkyl) ,-s (o)2nraraor selected from phenyl, 5 yuan to 6 unit's heteroaryls and 5 yuan of cyclic groups to 7 circle heterocyclic ring bases, described in cyclic group replaced by zero to 5 substituent group, the substituent group is independently selected from f, cl, hydroxyl, c1-4alkyl, c1-4fluothane base, c1-3alkoxy, c1-3fluoroalkyloxy, cyclopropyl and-cn；r3it is:withr4it is h, f, cl, hydroxyl, c1-4alkyl, c1-4fluoroalkyl, c1-4hydroxy alkyl, c1-3alkoxy, c1-3fluoroalkyloxy, c1-3alkane sulfenyl, cyclopropyl or-cn；ring b with it attached by two carbon atoms together be 3 yuan to 7 yuan naphthenic base or with 1 nitrogen, oxygen or sulphur atom 5 member is to 7 circle heterocyclic rings, and wherein the naphthenic base and the heterocycle are by 0-4 rdreplace；r5it is h or c (o) nrar6；r6it is h, c1-4alkyl, phenyl or the 5- or 6-membered heteroaryl containing 1 to 3 nitrogen-atoms and 0-1 oxygen or sulphur atom, should phenyl or the heteroaryl are by 0-2 r7replace；r7it is cn, hydroxyl, nrara, halogen, c1-4alkyl, c1-4fluoroalkyl, c1-4-hydroxy alkyl, c1-4-hydroxyl fluoroalkyl, c (o) ra、c(o)ora、c(o)nrarc、s(o)2nrarcand s (o)2ra、-o-c1-4alkyl ,-s-c1-4alkyl ,-o-c1-4hydroxyl alkane base ,-o-c1-4aminoalkyl ,-o-c1-4hydroxyl fluoroalkyl, o-c1-4fluoroalkyl, o-po3-2、-c1-4alkyl-o-po3-2、-c1-4 fluoroalkyl-o-po3-2、-o-c1-4alkyl-o-po3-2、-o-c1-4fluoroalkyl-o-po3-2、-n(ra)-c1-4hydroxy alkyl or-n (ra)-c1-4hydroxyl fluoroalkyl；r8it is h, f, cl or ch3；r9it is h, cn, hydroxyl, c1-4alkyl, c1-4fluoroalkyl, cyclopropyl or halogen；rait is h, c1-4alkyl or c1-4fluoroalkyl；two rb4 yuan with 1 to 2 nitrogen-atoms and 0-1 oxygen or sulphur atom are formed together with the nitrogen-atoms attached by them to 7 circle heterocyclic rings；rcit is h, c1-4alkyl or c1-4hydroxy alkyl；rdit is f, cl, hydroxyl, c1-4alkyl, c1-4fluoroalkyl, c1-4hydroxy alkyl, c1-3alkoxy, c1-3fluoroalkyloxy, c1-3alkane sulphur base, cyclopropyl ,-cn, c (o) ra、c(o)ora、c(o)nrarc、s(o)2nrarcor s (o)2ra；andn is 1 to 3.
비시클릭 헤테로아릴 치환된 화합물화학식 (I) 내지 (IV)의 화합물 또는 그의 입체이성질체, 호변이성질체, 제약상 허용되는 염, 용매화물 또는 전구약물이 개시된다. 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 (IV)의 화합물, 그의 입체이성질체 또는 염.[이미지]여기서,R1은 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 플루오로알콕시)-(C1-3 플루오로알킬렌), (C1-3 듀테로알콕시)-(C1-3 듀테로알킬렌), (C1-3 플루오로알콕시)-(C1-3 알킬렌), -(CH2)nO(페닐), -(CH2)nNRaRa, -C(O)O(C1-6 알킬), -C(O)NRaRa, -C(O)NRbRb, -NH2, -NH(C1-6 알킬), -N(C1-6 알킬)2, -NH(C1-6 히드록시알킬), 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)O(C1-6 알킬), -C(O)NH(CH2CH2O(C1-3 알킬)), -C(O)NRbRb, -C(O)(피페리디닐), -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, C1-4 알킬, C1-4 플루오로알킬, C1-3 알콕시, C1-3 플루오로알콕시, 시클로프로필, 및 -CN으로부터 독립적으로 선택된 0 내지 5개의 치환기로 치환되고;R3은[이미지]이고;R4는 H, F, Cl, 히드록시, C1-4 알킬, C1-4 플루오로알킬, C1-4 히드록시알킬, C1-3 알콕시, C1-3 플루오로알콕시, C1-3 알킬티오, 시클로프로필, 또는 -CN이고;고리 B는 이것이 부착되어 있는 2개의 탄소 원자와 함께, 3 내지 7원 시클로알킬, 또는 1개의 질소, 산소, 또는 황 원자를 갖는 5 내지 7원 헤테로사이클이고, 여기서 시클로알킬 및 헤테로사이클은 0-4개의 Rd로 치환되고;R5는 H, 또는 C(O)NRaR6이고;R6은 H, C1-4 알킬, 페닐, 또는 1 내지 3개의 질소 원자 및 0-1개의 산소 또는 황 원자를 함유하는 5 또는 6원 헤테로아릴이고, 상기 페닐 또는 헤테로아릴은 0-2개의 R7로 치환되고;R7은 CN, 히드록시, NRaRa, 할로겐, C1-4알킬, C1-4플루오로알킬, C1-4-히드록시알킬, C1-4-히드록시플루오로알킬, C(O)Ra, C(O)ORa, C(O)NRaRc, S(O)2NRaRc, 및 S(O)2Ra, -O-C1-4알킬, -S-C1-4알킬, -O-C1-4-히드록시알킬, -O-C1-4-아미노알킬, -O-C1-4-히드록시플루오로알킬, O-C1-4플루오로알킬, O-PO3-2, -C1-4알킬-O-PO3-2, -C1-4플루오로알킬-O-PO3-2, -O-C1-4알킬-O-PO3-2, -O-C1-4플루오로알킬-O-PO3-2, -N(Ra)-C1-4히드록시알킬, 또는 -N(Ra)-C1-4히드록시플루오로알킬이고;R8은 H, F, Cl, 또는 CH3이고;R9는 H, CN, 히드록실, C1-4알킬, C1-4플루오로알킬, 시클로프로필, 또는 할로겐이고;Ra는 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;Rc는 H, C1-4알킬, 또는 C1-4히드록시알킬이고;Rd는 F, Cl, 히드록시, C1-4 알킬, C1-4 플루오로알킬, C1-4 히드록시알킬, C1-3 알콕시, C1-3 플루오로알콕시, C1-3 알킬티오, 시클로프로필, -CN, C(O)Ra, C(O)ORa, C(O)NRaRc, S(O)2NRaRc, 또는 S(O)2Ra이고;n은 1 내지 3이다.