ARYL SUBSTITUTED BICYCLIC HETEROARYL COMPOUNDSThe present invention discloses a compound of Formula (I) or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate or prodrug thereof, wherein one R3 is H and the other R3 is an aryl group substituted with zero to 3 R3a; and R1, R2, and R3a are defined herein. Also disclosed are methods of using such compounds as PAR4 inhibitors for the inhibition or prevention of platelet aggregation, and the treatment of a thromboembolic disorder or the primary prophylaxis of a thromboembolic disorder. Also disclosed are methods of using such compounds for the treatment of human papillomavirus.Additionally, the present invention further provides pharmaceutical compositions comprising at least one compound of Formula (I).A kind of pharmaceutical composition, it includes pharmaceutically acceptable carriers and formula (i) compound：or its pharmaceutically acceptable salt, wherein：one r1for h and another r1for h, f, cl ,-oh, c1-4alkyl, c1-4fluoroalkyl, c2-4alkenyl, c2-4alkynyl, c3-7cycloalkanes base, c3-7fluorine cycloalkyl, c1-3alkoxy, c1-3fluoroalkyloxy, c2-4hydroxy alkoxy base, c3-6cycloalkyloxy, (c1-3alkoxy)- (c1-3alkylidene), (c1-3alkoxy)-(c1-3fluorine alkylidene), (c1-3deuterated alkoxy)-(c1-3deuterated alkylidene), (c1-3fluorine alkoxy)-(c1-3alkylidene) ,-(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, azetidin -1- bases, pyrrolidin-1-yl, furyl, pyrans base, piperidin-1-yl, morpholine -4- bases, piperazine -1- bases,-s (o)2(c1-3alkyl) ,-s (o)2nraraor c1-3alkyl sulfenyl；one r2for h and another r2for h, f, cl, br ,-oh ,-cn, c1-4alkyl, c1-4fluoroalkyl, c1-4hydroxy alkyl, c1-3ammonia base alkyl, c2-4alkenyl, c2-4alkynyl, c3-7cycloalkyl, c3-7fluorine cycloalkyl, c1-6alkoxy, c1-3fluoroalkyloxy, c1-3alkyl sulfide base, (c1-3alkoxy)-(c1-3alkylidene), (c1-3fluoroalkyloxy)-(c1-3alkylidene) ,-c (o) nh2、-c(o)nh(c1-6alkane base) ,-c (o) n (c1-6alkyl)2、-c(o)nrbrb、-c(o)o(c1-6alkyl) ,-ch (oh) (c3-6cycloalkyl) ,-ch (oh) (benzene base) ,-s (o)2(c1-3alkyl) ,-s (o)2nraraor the cyclic group selected from phenyl, 5 to 6 unit's heteroaryls and 5 to 7 circle heterocyclic rings, wherein described cyclic group substitution has 0 to 5 to be independently selected from following substituent group：f、cl、c1-3alkoxy and-cn；one r3for h and another r3there is 0 to 3 r for substitution3aaryl；r3a, at each occurrence, it independently is：(i)h、f、cl、br、-cn、-oh、c1-3alkyl, c1-3fluoroalkyl, c1-6hydroxy alkyl, c1-6alkoxy, c1-3fluoroalkyloxy, c3-6cycloalkyl, c3-6fluorine cycloalkyl, 3 to 6 circle heterocyclic ring bases ,-ch (oh) (c3-6cycloalkyl) ,-ch (oh) (aryl) ,-ch (oh) (heteroaryl), (c1-3alkoxy)-(c1-3alkylidene) ,-(ch2)1-3nrara、-(ch2)1-3nhs(o)2(aryl) ,-o (ch2)1-3 (aryl) ,-o (ch2)1-3(thiazolyl) ,-o (c1-6hydroxy alkyl), (c1-3alkoxy)-(c1-6alkoxy) ,-o (ch2)1-4o (virtues base) ,-o (ch2)1-4o(ch2)1-3(aryl) ,-o (ch2)1-4nrara、-o(ch2)1-4nhs(o)2(c1-3alkyl) ,-o (ch2)1-4nhs(o)2(aryl) ,-o (ch2)1-4c(o)oh、-o(ch2)1-4c(o)o(c1-6alkyl) ,-o (ch2)1-4c(o)nra(ch2)0-3 (aryl) ,-o (ch2)1-4c (o) (morpholinyl) ,-o (ch2)1-4oc(o)o(c1-3alkyl) ,-o (ch2)1-3chraoc(o)nra (ch2)1-4c(o)nrara、-o(ch2)1-4oc(o)nra(heteroaryl) ,-o (substitution has the imidazole radicals of aryl) ,-c (o) oh ,-c (o) o(c1-6alkyl) ,-nrac (o) (furyl) ,-nrac (o) (pyranose) ,-nrac(o)o(c1-6alkyl) ,-nrac(o)o (ch2)1-4(aryl) ,-o (ch2)1-4nrac(o)o(c1-6alkyl) ,-o (ch2)1-4nrac(o)o(ch2)0-4(pyranose) ,-o (ch2)1-4nrac(o)o(ch2)0-4(aryl) or-o (ch2)1-4nrac(o)o(ch2)0-4(furyl), wherein the aryl or miscellaneous each substitution in aryl has 0 to 5 to be independently selected from following substituent group：f、cl、-cn、c1-3alkyl, c1-3fluoroalkyl, c1-4 hydroxy alkyl, c1-3alkoxy ,-ocf3、-ochf2、-nh2、-nh(c1-6alkyl) ,-n (c1-6alkyl)2、c1-3hydroxy alkoxy base ,- conrcrcwith-s (o)2nrcrc；(ii)-o(ch2)1-4nras(o)2rw, wherein rwthere is 0 to 2 aryl or heteroaryl for being independently selected from following substituent group for substitution base：f、cl、-cn、c1-3alkyl, c1-3alkoxy ,-ocf3、-ochf2and c1-3fluoroalkyl；or(iii)-o(ch2)1-4oc(o)nrarx、-och(rd)(ch2)1-3oc(o)nrarx、-o(ch2)1-3ch(rd)oc(o)nrarx or-och (rd)ch(rd)(ch2)0-2oc(o)nrarx, wherein rxselected from h, c1-4alkyl, c1-4fluoroalkyl, aryl and-ch2(heteroaryl base), each aryl or heteroaryl substitution have 0 to 2 to be independently selected from following substituent group：f、cl、-cn、c1-3alkyl, c1-3fluothane base, c1-6hydroxy alkyl, c1-6hydroxy alkoxy base, c1-3alkoxy ,-c (o) o (c1-3alkyl) ,-c (o) nh2、-c(o)nh(c1-6alkane base) ,-c (o) n (c1-6alkyl)2、-c(o)nra(c1-6hydroxy alkyl) ,-c (o) nrara、-c(o)nrbrb、-s(o)2nraraand first base triazolyl；ra, at each occurrence, it independently is h or-ch3；two rbthe nitrogen-atoms connected together with them forms 4 to 7 circle heterocyclic rings；rc, at each occurrence, it independently is c1-3alkyl or c1-3hydroxy alkyl or two rcthe nitrogen-atoms connected together with them monocyclic or bicyclic heterocycles base is formed together；andrd, at each occurrence, it independently is c1-6alkyl, fluoroalkyl, c1-6hydroxy alkyl, (c1-3alkoxy)-(c1-3alkylene base), (c1-2fluoroalkyl)-o- (c1-2alkylidene), (c3-6cycloalkyl)-(c0-2alkylidene), aryl (c1-2alkylidene), heteroaryl (c1-2alkylidene), aryl-o- (c1-2alkylidene) or heteroaryl-o- (c1-2alkylidene).
아릴 치환된 비시클릭 헤테로아릴 화합물 화학식 (I)의 화합물 또는 그의 입체이성질체, 호변이성질체, 제약상 허용되는 염, 용매화물 또는 전구약물이 기재된다.[이미지] 여기서 1개의 R3은 H이고, 다른 R3은 0 내지 3개의 R3a로 치환된 아릴 기이고; R1, R2, 및 R3a는 본원에 정의되어 있다. 또한, 혈소판 응집의 억제 또는 예방, 및 혈전색전성 장애의 치료 또는 혈전색전성 장애의 1차 예방을 위한 PAR4 억제제로서의 이러한 화합물을 사용하는 방법이 기재된다. 또한, 인간 유두종바이러스의 치료를 위한 이러한 화합물을 사용하는 방법이 기재된다. 추가적으로, 화학식 (I)의 적어도 1종의 화합물을 포함하는 제약 조성물이 기재된다.제약상 허용되는 담체, 및 화학식 (I)의 화합물 또는 그의 제약상 허용되는 염을 포함하는 제약 조성물.[이미지]여기서1개의 R1은 H이고, 다른 R1은 H, F, Cl, -OH, C1-4 알킬, C1-4 플루오로알킬, C2-4 알케닐, C2-4 알키닐, C3-7 시클로알킬, C3-7 플루오로시클로알킬, C1-3 알콕시, C1-3 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), -(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, 또는 C1-3 알킬티오이고;1개의 R2는 H이고, 다른 R2는 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 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, -C(O)O(C1-6 알킬), -CH(OH)(C3-6 시클로알킬), -CH(OH)(페닐), -S(O)2(C1-3 알킬), -S(O)2NRaRa, 또는 페닐, 5- 내지 6-원 헤테로아릴, 및 5- 내지 7-원 헤테로사이클로부터 선택된 시클릭 기이며, 여기서 상기 시클릭 기는 F, Cl, C1-3 알콕시, 및 -CN으로부터 독립적으로 선택된 0 내지 5개의 치환기로 치환되고;1개의 R3은 H이고, 다른 R3은 0 내지 3개의 R3a로 치환된 아릴 기이고;R3a는, 각 경우에, 독립적으로(i) H, F, Cl, Br, -CN, -OH, C1-3 알킬, C1-3 플루오로알킬, C1-6 히드록시알킬, C1-6 알콕시, C1-3 플루오로알콕시, C3-6 시클로알킬, C3-6 플루오로시클로알킬, 3- 내지 6-원 헤테로시클릴, -CH(OH)(C3-6 시클로알킬), -CH(OH)(아릴), -CH(OH)(헤테로아릴), (C1-3 알콕시)-(C1-3 알킬렌), -(CH2)1-3NRaRa, -(CH2)1-3NHS(O)2(아릴), -O(CH2)1-3(아릴), -O(CH2)1-3(티아졸릴), -O(C1-6 히드록시알킬), (C1-3 알콕시)-(C1-6 알콕시), -O(CH2)1-4O(아릴), -O(CH2)1-4O(CH2)1-3(아릴), -O(CH2)1-4NRaRa, -O(CH2)1-4NHS(O)2(C1-3 알킬), -O(CH2)1-4NHS(O)2(아릴), -O(CH2)1-4C(O)OH, -O(CH2)1-4C(O)O(C1-6 알킬), -O(CH2)1-4C(O)NRa(CH2)0-3(아릴), -O(CH2)1-4C(O)(모르폴리닐), -O(CH2)1-4OC(O)O(C1-3 알킬), -O(CH2)1-3CHRaOC(O)NRa(CH2)1-4C(O)NRaRa, -O(CH2)1-4OC(O)NRa(헤테로아릴), -O(아릴로 치환된 이미다졸릴), -C(O)OH, -C(O)O(C1-6 알킬), -NRaC(O)(푸라닐), -NRaC(O)(피라닐), -NRaC(O)O(C1-6 알킬), -NRaC(O)O(CH2)1-4(아릴), -O(CH2)1-4NRaC(O)O(C1-6 알킬), -O(CH2)1-4NRaC(O)O(CH2)0-4(피라닐), -O(CH2)1-4NRaC(O)O(CH2)0-4(아릴), 또는 -O(CH2)1-4NRaC(O)O(CH2)0-4(푸라닐) (여기서, 각각의 상기 아릴 또는 헤테로아릴은 F, Cl, -CN, C1-3 알킬, C1-3 플루오로알킬, C1-4 히드록시알킬, C1-3 알콕시, -OCF3, -OCHF2, -NH2, -NH(C1-6 알킬), -N(C1-6 알킬)2, C1-3 히드록시알콕시, -CONRcRc, 및 -S(O)2NRcRc로부터 독립적으로 선택된 0 내지 5개의 치환기로 치환됨);(ii) -O(CH2)1-4NRaS(O)2Rw (여기서 Rw는 F, Cl, -CN, C1-3 알킬, C1-3 알콕시, -OCF3, -OCHF2, 및 C1-3 플루오로알킬로부터 독립적으로 선택된 0 내지 2개의 치환기로 치환된 아릴 또는 헤테로아릴임); 또는(iii) -O(CH2)1-4OC(O)NRaRx, -OCH(Rd)(CH2)1-3OC(O)NRaRx, -O(CH2)1-3CH(Rd)OC(O)NRaRx, 또는 -OCH(Rd)CH(Rd)(CH2)0-2OC(O)NRaRx (여기서, Rx는 H, C1-4 알킬, C1-4 플루오로알킬, 아릴, 및 -CH2(헤테로아릴)로부터 선택되고, 각각의 아릴 및 헤테로아릴은 F, Cl, -CN, C1-3 알킬, C1-3 플루오로알킬, C1-6 히드록시알킬, C1-6 히드록시알콕시, C1-3 알콕시, -C(O)O(C1-3 알킬), -C(O)NH2, -C(O)NH(C1-6 알킬), -C(O)N(C1-6 알킬)2, -C(O)NRa(C1-6 히드록시알킬), -C(O)NRaRa, -C(O)NRbRb, -S(O)2NRaRa, 및 메틸 트리아졸릴로부터 독립적으로 선택된 0 내지 2개의 치환기로 치환됨)이고;Ra는, 각 경우에, 독립적으로 H 또는 -CH3이고;2개의 Rb는 이들이 부착되어 있는 질소 원자와 함께 4- 내지 7-원 헤테로시클로 고리를 형성하고;Rc는, 각 경우에, 독립적으로 C1-3 알킬 또는 C1-3 히드록시알킬이거나 또는 2개의 Rc는 이들이 부착되어 있는 질소 원자와 함께 모노시클릭 또는 비시클릭 헤테로시클릴을 형성하고;Rd는, 각 경우에, 독립적으로 C1-6 알킬, 플루오로알킬, C1-6 히드록시알킬, (C1-3 알콕시)-(C1-3 알킬렌), (C1-2 플루오로알킬)-O-(C1-2 알킬렌), (C3-6 시클로알킬)-(C0-2 알킬렌), 아릴(C1-2 알킬렌), 헤테로아릴(C1-2 알킬렌), 아릴-O-(C1-2 알킬렌), 또는 헤테로아릴-O-(C1-2 알킬렌)이다.