[发明专利]作为泛素特异性蛋白酶7抑制剂的吡咯并嘧啶和吡唑并嘧啶

摘要

本发明涉及可用于治疗以下疾病的USP7抑制剂：癌症、神经退行性疾病、免疫病症、炎性病症、心血管疾病、局部缺血性疾病、病毒性感染和疾病，和细菌性感染和疾病，其具有式(I)：

主权项

1.化合物，其选自由以下组成的组：/n5-{[4-羟基-1-(3-苯基丁酰基)哌啶-4-基]甲基}-1-甲基-1H,4H,5H-吡唑并[3,4-d]嘧啶-4-酮；/n4-({4-[4-羟基-4-({1-甲基-4-氧代-1H,4H,5H-吡唑并[3,4-d]嘧啶-5-基}甲基)哌啶-1-羰基]苯基}甲氧基)苯甲腈；/n1-(4-氟苯基)-5-((4-羟基-1-(4-(5-甲基-5,6-二氢吡咯并[3,4-c]吡唑-1(4H)-基)苯甲酰基)哌啶-4-基)甲基)-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮；/n1-(4-氟苯基)-5-{[4-羟基-1-(4-{5-甲基-2H,4H,5H,6H-吡咯并[3,4-c]吡唑-2-基}苯甲酰基)哌啶-4-基]甲基}-1H,4H,5H-吡唑并[3,4-d]嘧啶-4-酮；/n2-(4-(4-(4-((1-(4-氟苯基)-4-氧代-1H-吡唑并[3,4-d]嘧啶-5(4H)-基)甲基)-4-羟基哌啶-1-羰基)苯基)-1H-吡唑-1-基)乙酰胺；/n5-((1-((2R,4S)-1-丙烯酰基-4-甲基氮杂环丁烷-2-羰基)-4-羟基哌啶-4-基)甲基)-1-(4-氟苯基)-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮；/n5-{[1-(4-{2,5-二氮杂双环[2.2.1]庚-2-基}苯甲酰基)-4-羟基哌啶-4-基]甲基}-1-(4-氟苯基)-1H,4H,5H-吡唑并[3,4-d]嘧啶-4-酮；/n1-(4-氟苯基)-5-[(4-羟基-1-{4-[1-(2-羟基乙基)-1H-吡唑-4-基]苯甲酰基}哌啶-4-基)甲基]-1H,4H,5H-吡唑并[3,4-d]嘧啶-4-酮；/n5-((1-(4-氟苯甲酰基)-4-羟基哌啶-4-基)甲基)-1-(4-(2-(1-甲基哌啶-2-基)乙基)苯基)-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮；/n1-(3-(3-(二甲基氨基)丙基)苯基)-5-((1-(4-氟苯甲酰基)-4-羟基哌啶-4-基)甲基)-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮；/n3-((1-(环丙烷羰基)-4-羟基哌啶-4-基)甲基)-7-(3-(哌啶-1-基甲基)苯基)-3H-吡咯并[2,3-d]嘧啶-4(7H)-酮；/n3-[(1-环丙烷羰基-4-羟基哌啶-4-基)甲基]-7-[4-氟-3-(哌啶-1-基甲基)苯基]-3H,4H,7H-吡咯并[2,3-d]嘧啶-4-酮；/n(S)-5-(1-(1-(4-氟苯甲酰基)-4-羟基哌啶-4-基)乙基)-1-(4-氟苯基)-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮；/n6-{[(1r,4r)-4-(4-{[1-(4-氟苯基)-4-氧代-1H,4H,5H-吡唑并[3,4-d]嘧啶-5-基]甲基}-4-羟基哌啶-1-羰基)环己基]氧基}吡啶-3-甲腈；/n1-(4-氟苯基)-5-({4-羟基-1-[(1r,4r)-4-[(6-甲基吡嗪-2-基)氧基]环己烷羰基]哌啶-4-基}甲基)-1H,4H,5H-吡唑并[3,4-d]嘧啶-4-酮；/n1-(4-氟苯基)-5-({4-羟基-1-[(1r,4r)-4-[(2-甲基嘧啶-4-基)氧基]环己烷羰基]哌啶-4-基}甲基)-1H,4H,5H-吡唑并[3,4-d]嘧啶-4-酮；/n5-({4-羟基-1-[(1r,4r)-4-[(2-氟吡啶-3-基)氧基]环己烷羰基]哌啶-4-基}甲基)-1-苯基-1H,4H,5H-吡唑并[3,4-d]嘧啶-4-酮；/n1-(4-氟苯基)-5-({4-羟基-1-[(1r,4r)-4-{[6-(氮杂环丁烷-1-基)吡啶-2-基]氧基}环己烷羰基]哌啶-4-基}甲基)-1H,4H,5H-吡唑并[3,4-d]嘧啶-4-酮；/n1-(4-氟苯基)-5-({4-羟基-1-[(1r,4r)-4-[(5-甲氧基吡啶-2-基)氧基]环己烷羰基]哌啶-4-基}甲基)-1H,4H,5H-吡唑并[3,4-d]嘧啶-4-酮；/n5-({4-羟基-1-[(1r,4r)-4-[(5-甲氧基吡啶-2-基)氧基]环己烷羰基]哌啶-4-基}甲基)-1-苯基-1H,4H,5H-吡唑并[3,4-d]嘧啶-4-酮；/n1-(4-氟苯基)-5-({4-羟基-1-[(1s,4s)-4-(吡嗪-2-基氧基)环己烷羰基]哌啶-4-基}甲基)-1H,4H,5H-吡唑并[3,4-d]嘧啶-4-酮；/n1-(4-氟苯基)-5-({4-羟基-1-[(1r,4r)-4-[(2-甲基嘧啶-5-基)氧基]环己烷羰基]哌啶-4-基}甲基)-1H,4H,5H-吡唑并[3,4-d]嘧啶-4-酮；/n1-(4-氟苯基)-5-({4-羟基-1-[(1s,4s)-4-[(6-氟吡啶-2-基)氨基]环己烷羰基]哌啶-4-基}甲基)-1H,4H,5H-吡唑并[3,4-d]嘧啶-4-酮；/n1-(4-氟苯基)-5-({4-羟基-1-[(1r,4r)-4-[(6-氟吡啶-2-基)氨基]环己烷羰基]哌啶-4-基}甲基)-1H,4H,5H-吡唑并[3,4-d]嘧啶-4-酮；/n1-(4-氟苯基)-5-({4-羟基-1-[1-甲基-3-(1-苯基乙基)-1H-吡唑-4-羰基]哌啶-4-基}甲基)-1H,4H,5H-吡唑并[3,4-d]嘧啶-4-酮；/n5-({1-[(3R)-3-(3-氟-1H-吡唑-1-基)丁酰基]-4-羟基哌啶-4-基}甲基)-1-(4-氟苯基)-1H,4H,5H-吡唑并[3,4-d]嘧啶-4-酮；/n5-({1-[(3S)-3-(3-氟-1H-吡唑-1-基)丁酰基]-4-羟基哌啶-4-基}甲基)-1-(4-氟苯基)-1H,4H,5H-吡唑并[3,4-d]嘧啶-4-酮；/n5-({4-羟基-1-[2-(1,2,3,4-四氢萘-1-基)乙酰基]哌啶-4-基}甲基)-1-甲基-1H,4H,5H-吡唑并[3,4-d]嘧啶-4-酮；/n1-(4-氟苯基)-5-({4-羟基-1-[(1s,3s)-3-[(吡啶-3-基)氨基]环丁烷羰基]哌啶-4-基}甲基)-1H,4H,5H-吡唑并[3,4-d]嘧啶-4-酮；/n1-(4-氟苯基)-5-({4-羟基-1-[(1r,3r)-3-[(吡啶-3-基)氨基]环丁烷羰基]哌啶-4-基}甲基)-1H,4H,5H-吡唑并[3,4-d]嘧啶-4-酮；/n1-(4-氟苯基)-5-({4-羟基-1-[(1s,3s)-3-[(5-氟吡啶-2-基)氨基]环丁烷羰基]哌啶-4-基}甲基)-1H,4H,5H-吡唑并[3,4-d]嘧啶-4-酮；/n1-(4-氟苯基)-5-({4-羟基-1-[(1r,3r)-3-[(5-氟吡啶-2-基)氨基]环丁烷羰基]哌啶-4-基}甲基)-1H,4H,5H-吡唑并[3,4-d]嘧啶-4-酮；/n1-(4-氟苯基)-5-({4-羟基-1-[(1s,3s)-3-[(吡啶-2-基)氨基]环丁烷羰基]哌啶-4-基}甲基)-1H,4H,5H-吡唑并[3,4-d]嘧啶-4-酮；/n1-(4-氟苯基)-5-({4-羟基-1-[(1r,3r)-3-[(吡啶-2-基)氨基]环丁烷羰基]哌啶-4-基}甲基)-1H,4H,5H-吡唑并[3,4-d]嘧啶-4-酮；/n5-({1-[(3R)-4,4-二氟-3-(3-氟-1H-吡唑-1-基)丁酰基]-4-羟基哌啶-4-基}甲基)-1-[4-(三氟甲基)苯基]-1H,4H,5H-吡唑并[3,4-d]嘧啶-4-酮；/n5-({1-[(3S)-4,4-二氟-3-(3-氟-1H-吡唑-1-基)丁酰基]-4-羟基哌啶-4-基}甲基)-1-[4-(三氟甲基)苯基]-1H,4H,5H-吡唑并[3,4-d]嘧啶-4-酮；/n7-(4-氟苯基)-3-({4-羟基-1-[(1s,4s)-4-(吡啶-2-基氧基)环己烷羰基]哌啶-4-基}甲基)-3H,4H,7H-吡咯并[2,3-d]嘧啶-4-酮；/n顺-5-((1-(4-((2-氟吡啶-3-基)氨基)环己烷-1-羰基)-4-羟基哌啶-4-基)甲基)-1-苯基-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮，异构体A(I-1039a)；/n反-5-((1-(4-((2-氟吡啶-3-基)氨基)环己烷-1-羰基)-4-羟基哌啶-4-基)甲基)-1-苯基-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮，异构体B(I-1039b)；/n5-({4-羟基-1-[4-(苯氧基甲基)苯甲酰基]哌啶-4-基}甲基)-1-甲基-1H,4H,5H-吡唑并[3,4-d]嘧啶-4-酮；/n7-(4-氟苯基)-3-({4-羟基-1-[(1s,4s)-4-[(1-甲基-1H-吡唑-3-基)氨基]环己烷羰基]哌啶-4-基}甲基)-3H,4H,7H-吡咯并[2,3-d]嘧啶-4-酮；/n7-(4-氟苯基)-3-({4-羟基-1-[(1r,4r)-4-[(1-甲基-1H-吡唑-3-基)氨基]环己烷羰基]哌啶-4-基}甲基)-3H,4H,7H-吡咯并[2,3-d]嘧啶-4-酮；/n1-[3-(3-氟-1H-吡唑-1-基)苯基]-5-{[4-羟基-1-(1-甲基环丙烷羰基)哌啶-4-基]甲基}-1H,4H,5H-吡唑并[3,4-d]嘧啶-4-酮；/n5-{[4-羟基-1-(1-甲基环丙烷羰基)哌啶-4-基]甲基}-1-{4-[4-(三氟甲基)-1H-吡唑-1-基]苯基}-1H,4H,5H-吡唑并[3,4-d]嘧啶-4-酮；/n1-[4-(4-氯-1H-吡唑-1-基)苯基]-5-{[4-羟基-1-(1-甲基环丙烷羰基)哌啶-4-基]甲基}-1H,4H,5H-吡唑并[3,4-d]嘧啶-4-酮；/n1-(3-((3,3-二氟环丁基)甲氧基)苯基)-5-((4-羟基-1-(1-甲基环丙烷-1-羰基)哌啶-4-基)甲基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮；/n1-{3-[(4,4-二氟环己基)氧基]苯基}-5-{[4-羟基-1-(1-甲基环丙烷羰基)哌啶-4-基]甲基}-1H,4H,5H-吡唑并[3,4-d]嘧啶-4-酮；/n5-({4-羟基-1-[3-(1H-吡咯-1-基)丁酰基]哌啶-4-基}甲基)-1-甲基-1H,4H,5H-吡唑并[3,4-d]嘧啶-4-酮；/n5-({4-羟基-1-[(3S)-3-(1H-吡唑-1-基)丁酰基]哌啶-4-基}甲基)-1-{4-[(3R)-3-羟基-3-甲基吡咯烷-1-基]苯基}-1H,4H,5H-吡唑并[3,4-d]嘧啶-4-酮；/n5-({1-[4-(二氟甲氧基)苯甲酰基]-4-羟基哌啶-4-基}甲基)-1-(4-甲基苯基)-1H,4H,5H-吡唑并[3,4-d]嘧啶-4-酮；/n5-[(4-羟基-1-{4-[(1-甲基吡咯烷-3-基)氧基]苯甲酰基}哌啶-4-基)甲基]-1-(4-甲基苯基)-1H,4H,5H-吡唑并[3,4-d]嘧啶-4-酮；/n4-[4-羟基-4-({1-甲基-4-氧代-1H,4H,5H-吡唑并[3,4-d]嘧啶-5-基}甲基)哌啶-1-羰基]-N-苯基苯-1-磺酰胺；/n5-({1-[(3R)-4,4-二氟-3-(1H-吡唑-1-基)丁酰基]-4-羟基哌啶-4-基}甲基)-1-(4-甲基苯基)-1H,4H,5H-吡唑并[3,4-d]嘧啶-4-酮；/n5-({1-[(3S)-4,4-二氟-3-(1H-吡唑-1-基)丁酰基]-4-羟基哌啶-4-基}甲基)-1-(4-甲基苯基)-1H,4H,5H-吡唑并[3,4-d]嘧啶-4-酮；/n5-[(4-羟基-1-{4-[(1-甲基哌啶-4-基)氧基]苯甲酰基}哌啶-4-基)甲基]-1-(4-甲基苯基)-1H,4H,5H-吡唑并[3,4-d]嘧啶-4-酮；/n5-({4-羟基-1-[4-(嘧啶-2-基氧基)苯甲酰基]哌啶-4-基}甲基)-1-(4-甲基苯基)-1H,4H,5H-吡唑并[3,4-d]嘧啶-4-酮；/n5-({4-羟基-1-[(1s,3s)-3-(吡啶-2-基氧基)环丁烷羰基]哌啶-4-基}甲基)-1-(4-甲基苯基)-1H,4H,5H-吡唑并[3,4-d]嘧啶-4-酮；/n1-(3-{5-[(1-环丙烷羰基-4-羟基哌啶-4-基)甲基]-4-氧代-1H,4H,5H-吡唑并[3,4-d]嘧啶-1-基}苯基)-3-环丙基脲；/n4-[(1-{5-[(环丙基甲基)氨基]吡啶-3-基}-4-氧代-1H,4H,5H-吡唑并[3,4-d]嘧啶-5-基)甲基]-4-羟基-N,N-二甲基哌啶-1-甲酰胺；/n7-(4-氟苯基)-3-({4-羟基-1-[(1r,4r)-4-[(1-甲基-1H-吡唑-3-基)氧基]环己烷羰基]哌啶-4-基}甲基)-3H,4H,7H-吡咯并[2,3-d]嘧啶-4-酮；/nN-[(1r,4r)-4-[(4-[[1-(4-氟苯基)-4-氧代-1H,4H,5H-吡唑并[3,4-d]嘧啶-5-基]甲基]-4-羟基哌啶-1-基)羰基]环己基]乙酰胺；/n5-((4-羟基-1-((1r,4r)-4-(吡啶-2-基氧基)环己烷羰基)哌啶-4-基)甲基)-1-(4-(羟基甲基)苯基)-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮；/n4-[4-羟基-4-({1-甲基-4-氧代-1H,4H,5H-吡唑并[3,4-d]嘧啶-5-基}甲基)哌啶-1-羰基]-N-甲基-N-苯基苯-1-磺酰胺；/n1-(4-溴苯基)-5-{[1-(4-氟苯甲酰基)-4-羟基哌啶-4-基]甲基}-1H,4H,5H-吡唑并[3,4-d]嘧啶-4-酮；/n5-{[4-羟基-1-(6-甲氧基吡啶-3-羰基)哌啶-4-基]甲基}-1-[4-(三氟甲基)苯基]-1H,4H,5H-吡唑并[3,4-d]嘧啶-4-酮；/n1-(4-氟苯基)-5-({4-羟基-1-[(1s,4s)-4-(环丙基氨基)环己烷羰基]哌啶-4-基}甲基)-1H,4H,5H-吡唑并[3,4-d]嘧啶-4-酮；/n1-(4-氟苯基)-5-({4-羟基-1-[(1r,4r)-4-[(环丙基甲基)氨基]环己烷羰基]哌啶-4-基}甲基)-1H,4H,5H-吡唑并[3,4-d]嘧啶-4-酮；/n1-(4-氟苯基)-5-({4-羟基-1-[(1s,4s)-4-[(环丙基甲基)氨基]环己烷羰基]哌啶-4-基}甲基)-1H,4H,5H-吡唑并[3,4-d]嘧啶-4-酮；/nN-[(1r,4r)-4-(4-{[1-(4-氟苯基)-4-氧代-1H,4H,5H-吡唑并[3,4-d]嘧啶-5-基]甲基}-4-羟基哌啶-1-羰基)环己基]环丙烷甲酰胺；/nN-(3-{5-[(1-环丙烷羰基-4-羟基哌啶-4-基)甲基]-4-氧代-1H,4H,5H-吡唑并[3,4-d]嘧啶-1-基}苯基)吡啶-3-甲酰胺；/n7-(4-氟苯基)-3-{[4-羟基-1-(2-甲基-1,3-噁唑-5-羰基)哌啶-4-基]甲基}-3H,4H,7H-吡咯并[2,3-d]嘧啶-4-酮；/n7-(4-氟苯基)-3-{[4-羟基-1-(1-甲基-1H-吡唑-4-羰基)哌啶-4-基]甲基}-3H,4H,7H-吡咯并[2,3-d]嘧啶-4-酮；/n3-{[1-(1-环丙基-1H-吡唑-4-羰基)-4-羟基哌啶-4-基]甲基}-7-(4-氟苯基)-3H,4H,7H-吡咯并[2,3-d]嘧啶-4-酮；/n4-[4-羟基-4-({1-甲基-4-氧代-1H,4H,5H-吡唑并[3,4-d]嘧啶-5-基}甲基)哌啶-1-羰基]-N-甲基-N-苯基苯甲酰胺；/n1-[3-(4-乙酰基哌嗪-1-基)苯基]-5-[(1-环丙烷羰基-4-羟基哌啶-4-基)甲基]-1H,4H,5H-吡唑并[3,4-d]嘧啶-4-酮；/n4-(3-{5-[(1-环丙烷羰基-4-羟基哌啶-4-基)甲基]-4-氧代-1H,4H,5H-吡唑并[3,4-d]嘧啶-1-基}苯基)-1λ