MONOCYCLIC HETEROARYL SUBSTITUTED COMPOUNDSDisclosed are compounds of Formulas (I), (II), (III), (IV), (V), (VI), (VII), or (VIII): (I) (II) (III) (IV) (V) (VI) (VII) (VIII) or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R3 is a monocyclic 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 kind of compound of formula (i) to (viii):or its 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), (c1-3deuterated 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, azetidine -1- base, pyrrolidin-1-yl, furyl, pyranose, piperidin-1-yl, morpholine -4- base, piperazine -1- base,-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)nrbrb、-ch(oh)(c3-6naphthenic base) ,-ch (oh) (phenyl) ,- ch (oh) (pyridyl group) ,-s (o)2(c1-3alkyl) ,-s (o)2nraraor it is selected from phenyl, 5 yuan to 6 unit's heteroaryls and 5 yuan to 7 the cyclic group of circle heterocyclic ring, wherein the cyclic group is by 0 to 5 independently selected from f, cl, c1-3the substitution of alkoxy and-cn base replaces；r3it is monocyclic groups selected from the following: thio-phenyl, pyrazolyl, thiazolyl, isothiazolyl, thiadiazolyl group, pyridyl group, miaow oxazolyl, furyl, oxazolyl, pyrrole radicals, pyrimidine radicals, pyridazinyl, pyrazinyl, tetrazole radical, triazolyl, oxadiazoles base, isoxazole base, different thiadiazolyl group and different oxadiazoles base, each monocyclic groups are by 0 to 3 r3areplace；r3ait is independently h, f, cl ,-cn ,-oh, c at each occurrence1-6alkyl, c2-6alkenyl, c1-6fluoroalkyl, c1-6hydroxyl alkane base, c1-6alkoxy, c1-3fluoroalkyloxy, c1-6alkylthio group ,-(ch2)m-c3-7naphthenic base ,-(ch2)maryl ,-(ch2)mheteroaryl base ,-(ch2)mheterocycle ,-(ch2)1-3nrara、-(ch2)1-3nhs(o)2(aryl), (c1-3alkoxy)-(c1-6alkoxy) ,- c(o)oh、-c(o)o(c1-6alkyl) ,-c (o) nrara、-c(o)nrbrb、-s(o)2nrara、-s(o)2nrbrb、-c(o)(c1-4alkane base) ,-c (o) aryl ,-c (o) heteroaryl ,-c (o) (c3-7naphthenic base) ,-s (o)2(c1-4alkyl) ,-s (o)2aryl ,-s (o)2it is miscellaneous aryl ,-s (o)2(c3-7naphthenic base) ,-nraraor-nrbrb, wherein in the naphthenic base, heterocycle, aryl and heteroaryl each is replaced by 0 to 5 substituent group, and the substituent group is independently selected from f, cl ,-oh, oxo ,-cn, c1-3alkyl, c1-3fluothane base, c1-4hydroxy alkyl, c1-3alkoxy, c1-3fluoroalkyloxy, c1-6alkylthio group ,-nh2、-nhc(o)(c1-6alkyl), c1-3hydroxyl alkoxy, cooh ,-c (o) o (c1-6alkyl)-c (o) nrara、-c(o)nrbrb、-s(o)2nrara、-s(o)2nrbrb、-c(o) (c1-4alkyl) ,-c (o) aryl ,-c (o) heteroaryl ,-c (o) (c3-7naphthenic base) ,-s (o)2(c1-4alkyl) ,-s (o)2aryl ,-s (o)2heteroaryl ,-s (o)2(c3-7naphthenic base) ,-nraraor-nrbrb；r4it is h, f, cl or-ch3；rait is independently h, c at each occurrence1-3alkyl, c1-3fluoroalkyl, c3-6naphthenic base, aryl or heteroaryl；two rb4 yuan are formed together to 7 circle heterocyclic rings with the nitrogen-atoms attached by them；m is zero, 1 or 2 at each occurrence；andn is zero, 1 or 2 at each occurrence.
모노시클릭 헤테로아릴 치환된 화합물화학식 (I), (II), (III), (IV), (V), (VI), (VII) 또는 (VIII)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] 여기서 R3은 0 내지 3개의 R3a로 치환된 모노시클릭 헤테로아릴 기이고; R1, R2, R3a, R4 및 n은 본원에 정의되어 있다.화학식 (I) 내지 (VIII)의 화합물 또는 그의 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 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, 아제티딘-1-일, 피롤리딘-1-일, 푸라닐, 피라닐, 피페리딘-1-일, 모르폴린-4-일, 피페라진-1-일, -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 헤테로사이클로부터 선택된 시클릭 기이고, 여기서 상기 시클릭 기는 F, Cl, C1-3 알콕시, 및 -CN으로부터 독립적으로 선택된 0 내지 5개의 치환기로 치환되고;R3은, 티오페닐, 피라졸릴, 티아졸릴, 이소티아졸릴, 티아디아졸릴, 피리디닐, 이미다졸릴, 푸릴, 옥사졸릴, 피롤릴, 피리미디닐, 피리다지닐, 피라지닐, 테트라졸릴, 트리아졸릴, 옥사디아졸릴, 이속사졸릴, 이소티아디아졸릴, 및 이속사디아졸릴로부터 선택된 모노시클릭 기이고, 각각의 모노시클릭 기는 0 내지 3개의 R3a로 치환되고;R3a는 각 경우에 독립적으로 H, F, Cl, -CN, -OH, C1-6 알킬, C2-6 알케닐, C1-6 플루오로알킬, C1-6 히드록시알킬, C1-6 알콕시, C1-3 플루오로알콕시, C1-6 알킬티오, -(CH2)m-C3-7 시클로알킬, -(CH2)m-아릴, -(CH2)m-헤테로아릴, -(CH2)m-헤테로시클릴, -(CH2)1-3NRaRa, -(CH2)1-3NHS(O)2(아릴), (C1-3 알콕시)-(C1-6 알콕시), -C(O)OH, -C(O)O(C1-6 알킬), -C(O)NRaRa, -C(O)NRbRb, -S(O)2NRaRa, -S(O)2NRbRb, -C(O)(C1-4 알킬), -C(O)아릴, -C(O)헤테로아릴, -C(O)(C3-7 시클로알킬), -S(O)2(C1-4 알킬), -S(O)2아릴, -S(O)2헤테로아릴, -S(O)2 (C3-7 시클로알킬), -NRaRa, 또는 -NRbRb이고, 여기서 각각의 상기 시클로알킬, 헤테로시클릴, 아릴, 및 헤테로아릴은 F, Cl, -OH, 옥소, -CN, C1-3 알킬, C1-3 플루오로알킬, C1-4 히드록시알킬, C1-3 알콕시, C1-3 플루오로알콕시, C1-6 알킬티오, -NH2, -NHC(O)(C1-6 알킬), C1-3 히드록시알콕시, COOH, -C(O)O(C1-6 알킬) -C(O)NRaRa, -C(O)NRbRb, -S(O)2NRaRa, -S(O)2NRbRb, -C(O)(C1-4 알킬), -C(O)아릴, -C(O)헤테로아릴, -C(O)(C3-7 시클로알킬), -S(O)2(C1-4 알킬), -S(O)2아릴, -S(O)2헤테로아릴, -S(O)2 (C3-7 시클로알킬), -NRaRa, 또는 -NRbRb로부터 독립적으로 선택된 0 내지 5개의 치환기로 치환되고;R4는 H, F, Cl, 또는 -CH3이고;Ra는 각 경우에 독립적으로 H, C1-3 알킬, C1-3 플루오로알킬, C3-6 시클로알킬, 아릴, 또는 헤테로아릴이고;2개의 Rb는 이들이 부착되어 있는 질소 원자와 함께, 4- 내지 7-원 헤테로시클로 고리를 형성하고;m은 각 경우에 0, 1, 또는 2이고;n은 각 경우에 0, 1, 또는 2이다.