CN101687876A - 氨基杂环化合物 - Google Patents
氨基杂环化合物 Download PDFInfo
- Publication number
- CN101687876A CN101687876A CN200880024273A CN200880024273A CN101687876A CN 101687876 A CN101687876 A CN 101687876A CN 200880024273 A CN200880024273 A CN 200880024273A CN 200880024273 A CN200880024273 A CN 200880024273A CN 101687876 A CN101687876 A CN 101687876A
- Authority
- CN
- China
- Prior art keywords
- pyrazolo
- dihydro
- pyrimidin
- methyl
- tetramethyleneimine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 150000001875 compounds Chemical class 0.000 claims abstract description 233
- 150000003839 salts Chemical class 0.000 claims abstract description 43
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 20
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- 101100407341 Drosophila melanogaster Pde9 gene Proteins 0.000 claims abstract 3
- -1 sec.-propyl Chemical group 0.000 claims description 209
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 169
- 239000000203 mixture Substances 0.000 claims description 47
- 241000124008 Mammalia Species 0.000 claims description 37
- 238000000034 method Methods 0.000 claims description 36
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 24
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 24
- 239000003795 chemical substances by application Substances 0.000 claims description 23
- 229910052739 hydrogen Inorganic materials 0.000 claims description 21
- 125000001072 heteroaryl group Chemical group 0.000 claims description 19
- 239000001257 hydrogen Substances 0.000 claims description 19
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 14
- 201000010099 disease Diseases 0.000 claims description 13
- 125000002769 thiazolinyl group Chemical group 0.000 claims description 13
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 12
- 125000003545 alkoxy group Chemical group 0.000 claims description 11
- 125000003118 aryl group Chemical group 0.000 claims description 11
- 125000004076 pyridyl group Chemical group 0.000 claims description 11
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 10
- AYDQIZKZTQHYIY-UHFFFAOYSA-N OC(=O)C1(C)CC(C(O)=O)=CC=C1 Chemical compound OC(=O)C1(C)CC(C(O)=O)=CC=C1 AYDQIZKZTQHYIY-UHFFFAOYSA-N 0.000 claims description 10
- 125000001188 haloalkyl group Chemical group 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 10
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- 125000003226 pyrazolyl group Chemical group 0.000 claims description 9
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- 239000003937 drug carrier Substances 0.000 claims description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- USPWKWBDZOARPV-UHFFFAOYSA-N pyrazolidine Chemical compound C1CNNC1 USPWKWBDZOARPV-UHFFFAOYSA-N 0.000 claims description 8
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 7
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 7
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 7
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 7
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- HGUFODBRKLSHSI-UHFFFAOYSA-N 2,3,7,8-tetrachloro-dibenzo-p-dioxin Chemical compound O1C2=CC(Cl)=C(Cl)C=C2OC2=C1C=C(Cl)C(Cl)=C2 HGUFODBRKLSHSI-UHFFFAOYSA-N 0.000 claims description 6
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- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 5
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- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 4
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- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 4
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- STXRQVNFUFZKSJ-DNVCBOLYSA-N chembl572747 Chemical compound C([C@H]([C@@H](C1)C=2NC(=O)C=3C=NN(C=3N=2)C2CCCC2)C)N1CC1=CC=CC=C1 STXRQVNFUFZKSJ-DNVCBOLYSA-N 0.000 claims description 3
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- 125000004598 dihydrobenzofuryl group Chemical group O1C(CC2=C1C=CC=C2)* 0.000 claims description 3
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- 230000006872 improvement Effects 0.000 claims description 3
- 125000001624 naphthyl group Chemical group 0.000 claims description 3
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 claims description 3
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- 125000002098 pyridazinyl group Chemical group 0.000 claims description 3
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- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 2
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- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 2
- NLUPGGKMPPBLIC-RDTXWAMCSA-N 1-cyclopentyl-6-[(3S,4S)-1-[[2-(dimethylamino)pyrimidin-4-yl]methyl]-4-methylpyrrolidin-3-yl]-5H-pyrazolo[3,4-d]pyrimidin-4-one Chemical compound C([C@H]([C@@H](C1)C=2NC(=O)C=3C=NN(C=3N=2)C2CCCC2)C)N1CC1=CC=NC(N(C)C)=N1 NLUPGGKMPPBLIC-RDTXWAMCSA-N 0.000 claims description 2
- ALUQMCBDQKDRAK-UHFFFAOYSA-N 2,3,3a,4-tetrahydro-1,3-benzothiazole Chemical compound C1C=CC=C2SCNC21 ALUQMCBDQKDRAK-UHFFFAOYSA-N 0.000 claims description 2
- BQDJLAWUTBCDHK-UHFFFAOYSA-N 2-(trifluoromethyl)pyrimidine Chemical compound FC(F)(F)C1=NC=CC=N1 BQDJLAWUTBCDHK-UHFFFAOYSA-N 0.000 claims description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 2
- 125000003282 alkyl amino group Chemical group 0.000 claims description 2
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- 125000005946 imidazo[1,2-a]pyridyl group Chemical group 0.000 claims description 2
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- 230000001737 promoting effect Effects 0.000 claims description 2
- ASUTZQLVASHGKV-JDFRZJQESA-N galanthamine Chemical compound O1C(=C23)C(OC)=CC=C2CN(C)CC[C@]23[C@@H]1C[C@@H](O)C=C2 ASUTZQLVASHGKV-JDFRZJQESA-N 0.000 claims 2
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- 230000002401 inhibitory effect Effects 0.000 abstract description 2
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- DNCYBUMDUBHIJZ-UHFFFAOYSA-N 1h-pyrimidin-6-one Chemical class O=C1C=CN=CN1 DNCYBUMDUBHIJZ-UHFFFAOYSA-N 0.000 description 70
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- 239000011541 reaction mixture Substances 0.000 description 40
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Abstract
本发明提供一种式(I)的PDE9抑制化合物,或其药学上可接受盐,其中R、R1、R2和R3如本文所定义。还提供了含有式I化合物的药物组合物及其在治疗神经退行失调症和认知失调症(诸如阿尔茨海默氏症和精神分裂症)中的用途。
Description
相关申请
本申请根据35U.S.C.§119(e)要求于2007年6月11日递交的美国临时申请60/917,333的优先权。
技术领域
本发明涉及一系列新型化合物,它们是9型磷酸二酯酶(PDE9)的选择性抑制剂。更具体地,本发明涉及一种用于治疗和预防神经退行疾病和其他受PDE9调节影响的疾病和失调症的吡唑并[3.4-d]嘧啶酮化合物。
背景技术
环核苷环鸟苷单磷酸酯(cGMP)和环腺苷单磷酸酯(cAMP)是重要的第二信使,因而是控制和调节各种器官中的多数细胞事件(生理学上和病理生理学上)的关键因素。
环状GMP由GTP通过鸟苷酸环化酶(GC)的催化反应而形成,其通过一氧化氮(NO)活化。之后,环状GMP使cGMP依赖型蛋白激酶活化,从而介导局部和全身信号发送。心血管、神经系统和免疫系统中的各种生理学过程通过NO/cGMP通路控制,这种通路包括离子通道传导、肝糖分解、细胞凋亡和平滑肌松弛。在血管中,血管平滑肌的松弛导致血管舒张和血流增加。
磷酸二酯酶(PDE)家族的酶使cGMP和cAMP水解。PDE9酶被认为是PDE酶家族中新的一员,其对cGMP而非cAMP选择性水解。参见Fisher等人的J.Biol.Chem.,273(25),15559-15564(1998)。已发现PDE9存在于各种人体组织中,即存在于睾丸、大脑、小肠、骨骼肌、心脏、肺、胸腺和脾中以及存在于各种人体组织的脉管系统的平滑肌细胞中。
近来的研究直接暗示了阿尔茨海默氏症(Alzheimer′s Disease)中NO/cGMP/cGK信号发送功能紊乱。例如,研究表明,淀粉样-β肽对长时程增强效应(LTP,一种与认知和记忆力相关的生理现象)的破坏源自NO/cGMP信号发送功能失调。Puzzo等人J.Neurosci.,25(29):6887-6897(2005)。此外,在大鼠中的研究表明,由于前脑乙酰胆碱脂酶的损耗因而记忆力损耗(这与阿尔茨海默氏症相关),服用一氧化氮模拟剂使GC活性提高并且扭转记忆力中的认知不足。Bennett等人Neuropsychopharmacology,32:505-513(2007)。因此,人们认为能够增强GC/NO/cGMP/cGK信号级联的治疗剂可被用作治疗阿尔茨海默氏症和其它神经退行失调症的新途径。
通过降低或抑制通过PDE9的cGMP水解,PDE9抑制剂提高了细胞内的cGMP水平,因而增强或延长了其作用。还发现,提高大鼠中cGMP的浓度导致在社交和物体识别测试中的学习和记忆能力改善。参见例如Boess等人的Neuropharmacology,47:1081-1092(2004)。研究表明抑制PDE9使LTP增加。Hendrix,BMC Pharmacol.,5(Supp 1):55(2005)。
因此,需要一种PDE9抑制剂,其可以有效治疗通过抑制PDE9来调节或正常化的病症。
发明内容
本发明涉及一种式(I)化合物,
及其药学上可接受盐,其中R、R1、R2和R3如本文所定义。
本发明还涉及一种组合物,其包含式(I)化合物或其药学上可接受盐以及药学上可接受载体、载剂或稀释剂,并且可选进一步包含第二药学试剂。
本发明进一步涉及一种用于抑制哺乳动物中的PDE9的方法,所述哺乳动物需要上述抑制,所述方法包括如下步骤:施予所述哺乳动物PDE9抑制量的a)式I化合物或其药学上可接受盐或b)药物组合物,该药物组合物包含式I化合物或其药学上可接受盐以及药学上可接受载体、载剂或稀释剂。
本发明进一步涉及一种用于治疗哺乳动物中的神经退行疾病的方法,所述哺乳动物需要上述治疗,所述方法包括如下步骤:施予所述哺乳动物治疗有效量的式I化合物或其药学上可接受盐。
本发明进一步涉及一种用于促进哺乳动物中的神经恢复的方法,所述哺乳动物需要上述神经恢复,所述方法包括如下步骤:施予所述哺乳动物治疗有效量的式I化合物或其药学上可接受盐。
本发明进一步还涉及一种用于改善哺乳动物中的认知缺陷和治疗哺乳动物中的认知受损的方法,所述哺乳动物需要上述改善和治疗,所述方法包括如下步骤:施予所述哺乳动物治疗有效量的式I化合物或其药学上可接受盐。
通过参照以下对本发明的详细描述以及所附权利要求书可以更清楚地理解本发明的性质,其中本发明的前述优点和特征和其它优点和特征在此后会变得显而易见。
具体实施方式
本发明包括一种式(I)的新型的选择性PDE9抑制,
及其药学上可接受盐,其中:
R选自由(C1-C6)烷基、(C2-C6)烯基、(C2-C6)炔基、(C3-C8)环烷基、杂环烷基、芳基和杂芳基组成的组,各个基团可选被1至3个取代基取代,所述取代基独立地选自由(C1-C4)烷基、(C1-C4)烷氧基、卤素和(C1-C4)卤代烷基组成的组;
R1选自由氢、(C1-C4)烷基、(C2-C4)烯基、(C2-C4)炔基、(C1-C4)卤代烷基和环丙基组成的组;
R2选自由(C1-C6)烷基、(C2-C6)烯基、(C2-C6)炔基、(C1-C6)卤代烷基、杂芳基(选自由吡啶基、哒嗪基、嘧啶基和吡嗪基组成的组)和ER5组成的组,其中所述杂芳基可选被1至3个取代基取代,所述取代基独立地选自由(C1-C4)烷基和(C1-C4)卤代烷基组成的组;
R3选自由氢、(C1-C4)烷基、(C2-C4)烯基、(C2-C4)炔基、(C3-C6)环烷基和(C1-C4)卤代烷基组成的组;
E选自由-CH2-、-CH2CH2-、-CH2CH2CH2-和-C(O)-组成的组;
R5选自由(C3-C8)环烷基、杂环烷基、芳基、芳氧基和杂芳基组成的组,这些基团中的任意一个可选被1至3个取代基取代,所述取代基独立地选自由(C1-C4)烷基、(C2-C4)烯基、(C2-C4)炔基、(C1-C4)羟烷基、(C1-C4)卤代烷基、(C1-C4)烷氧基、(C1-C4)卤代烷氧基、(C3-C8)环烷基、卤素、氰基、苯基、吗啉基、(C1-C4)烷氨基、吡唑基、三唑基和咪唑基组成的组。
优选地,R选自由乙基、异丙基、三氟乙基、环丁基、环戊基、二氟环己基、甲氧基苯基和四氢-2H-吡喃-4-基组成的组;R1是氢或甲基;R2是甲基、三氟乙基、三氟丁基、嘧啶基、三氟甲基嘧啶基或ER5;R3是甲基、乙基、异丙基、三氟甲基、三氟乙基或环丙基;E是-CH2-或-C(O)-;R5选自由被取代的或未被取代的环戊基、吗啉基、苯基、萘基、苄氧基、嘧啶基、吡啶基、喹啉基、喹喔啉基、吡嗪基、吡唑基、苯并咪唑基、噌啉基、萘啶基(naphthydrinyl)、吡啶并[2,3-b]吡嗪基、咪唑并[4,5-c]吡啶基、苯并噻二唑基、四氢吡唑并[1,5-a]吡啶基、二氢苯并二噁英基、咪唑基、二氢苯并呋喃基、三唑基、噁唑基、异噁唑基、苯并二噁英基、噻唑基、咪唑并[1,2-a]吡啶基、四氢苯并噻唑基、二氢苯并噁嗪基、四氢吡喃基、四氢吡唑并[1,5-a]氮杂卓基和二氢吡咯并[1,2-b]吡唑基组成的组。
更优选地,R选自由异丙基、环丁基、环戊基和四氢-2H-吡喃-4-基组成的组;R1是氢;R2是ER5;R3是甲基或乙基;E是-CH2-;R5选自由苯基、嘧啶-2-基、吡啶-2-基、吡嗪-2-基和5-甲基吡嗪-2-基组成的组。
在其它优选的实施方式中,该化合物是:
6-[(3,4-反式)-1-苄基-4-甲基吡咯烷-3-基]-1-(2-甲氧基苯基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-[(3,4-反式)-1-苄基-4-甲基吡咯烷-3-基]-1-环戊基-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-[(3S,4S)1-苄基-4-甲基吡咯烷-3-基]-1-环戊基-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-4-甲基-1-嘧啶-2-基吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-{(3,4-反式)-4-甲基-1-[4-(三氟甲基)嘧啶-2-基]吡咯烷-3-基}-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-[(3,4-反式)-1-苯甲酰基-4-甲基吡咯烷-3-基]-1-环戊基-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-4-甲基-1-(吡啶-3-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-{(3,4-反式)-4-甲基-1-[3-(三氟甲基)苄基]吡咯烷-3-基}-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-4-甲基-1-(喹啉-2-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-4-甲基-1-(喹啉-4-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-4-甲基-1-{[6-(三氟甲基)吡啶-3-基]甲基}吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-4-甲基-1-(喹喔啉-2-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-4-甲基-1-(喹喔啉-6-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-4-甲基-1-(嘧啶-5-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-1,4-二甲基吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-4-甲基-1-(2,2,2-三氟乙基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-{(3,4-反式)-4-甲基-1-[(2-甲基吡啶-3-基)甲基]吡咯烷-3-基}-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-4-甲基-1-(喹啉-8-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-4-甲基-1-(喹啉-3-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-{(3,4-反式)-4-甲基-1-[(6-甲基吡啶-3-基)甲基]吡咯烷-3-基}-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-[(3,4-反式)-1-苄基-4-异丙基吡咯烷-3-基]-1-环戊基-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-[(3,4-反式)-1-苄基-4-甲基吡咯烷-3-基]-1-环戊基-3-甲基-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3S,4S)-4-甲基-1-(喹喔啉-6-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-4-甲基-1-(2-苯基乙基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-{(3,4-反式)-1-[(6-甲氧基吡啶-3-基)甲基]-4-甲基吡咯烷-3-基}-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-4-甲基-1-(吡啶-2-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-{(3,4-反式)-4-甲基-1-[(3-甲基吡啶-2-基)甲基]吡咯烷-3-基}-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-[(3,4-反式)-1-苄基-4-乙基吡咯烷-3-基]-1-环戊基-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-[(3,4-反式)-1-苄基-4-环丙基吡咯烷-3-基]-1-环戊基-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-[(3,4-反式)-1-苄基-4-甲基吡咯烷-3-基]-1-异丙基-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-[(3S,4S)-1-苄基-4-甲基吡咯烷-3-基]-1-异丙基-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-异丙基-6-[(3,4-反式)-4-甲基-1-(喹啉-2-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-异丙基-6-[(3,4-反式)-4-甲基-1-(喹喔啉-6-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-异丙基-6-[(3,4-反式)-4-甲基-1-(喹啉-3-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-[(3,4-反式)-1-苄基-4-(三氟甲基)吡咯烷-3-基]-1-环戊基-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-异丙基-6-[(3S,4S)-4-甲基-1-(喹喔啉-6-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-异丙基-6-[(3S,4S)-4-甲基-1-(喹啉-3-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-{(3S,4S)-4-甲基-1-[(5-甲基吡嗪-2-基)甲基]吡咯烷-3-基}-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-[(3,4-反式)-1-苄基-4-乙基吡咯烷-3-基]-1-异丙基-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-[(3S,4S)-1-苄基-4-乙基吡咯烷-3-基]-1-异丙基-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-异丙基-6-{(3S,4S)-4-甲基-1-[(2-甲基嘧啶-5-基)甲基]吡咯烷-3-基}-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-(1-苄基吡咯烷-3-基)-1-环戊基-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-异丙基-6-{(3S,4S)-1-[(6-甲氧基吡啶-3-基)甲基]-4-甲基吡咯烷-3-基}-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-[(3,4-反式)-4-乙基-1-(喹啉-3-基甲基)吡咯烷-3-基]-1-异丙基-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-{(3,4-反式)-4-乙基-1-[(6-甲氧基吡啶-3-基)甲基]吡咯烷-3-基}-1-异丙基-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-[(3,4-反式)-4-乙基-1-(喹喔啉-6-基甲基)吡咯烷-3-基]-1-异丙基-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-{(3S,4S)-1-[(1,3-二甲基-1H-吡唑-5-基)甲基]-4-甲基吡咯烷-3-基}-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3S,4S)-4-甲基-1-(4,5,6,7-四氢吡唑并[1,5-a]吡啶-3-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-{(3S,4S)-4-甲基-1-[(1-甲基-1H-苯并咪唑-2-基)甲基]吡咯烷-3-基}-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-异丙基-6-{(3S,4S)-4-甲基-1-[(5-甲基吡嗪-2-基)甲基]吡咯烷-3-基}-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-[(3S,4S)-1-(噌啉-3-基甲基)-4-甲基吡咯烷-3-基]-1-环戊基-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-1-(喹喔啉-6-基甲基)-4-(三氟甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-{(3S,4S)-4-甲基-1-[(2-甲基嘧啶-4-基)甲基]吡咯烷-3-基}-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3S,4S)-1-{[2-(二甲基氨基)嘧啶-4-基]甲基}-4-甲基吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-{(3,4-反式)-4-环丙基-1-[(5-甲基吡嗪-2-基)甲基]吡咯烷-3-基}-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-4-环丙基-1-(喹喔啉-6-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-4-环丙基-1-甲基吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-[(3,4-反式)-1-苄基-4-甲基吡咯烷-3-基]-1-乙基-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-{(3,4-反式)-4-乙基-1-[(2-甲基嘧啶-5-基)甲基]吡咯烷-3-基}-1-异丙基-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-[(3,4-反式)-1-苄基-4-甲基吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-[(3S,4S)-1-苄基-4-甲基吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-[(3,4-反式)-1-苄基-4-(2,2,2-三氟乙基)吡咯烷-3-基]-1-环戊基-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-[(3,4-反式)-1-苄基-4-甲基吡咯烷-3-基]-1-(4,4-二氟环己基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-[(3,4-反式)-1-苄基-4-甲基吡咯烷-3-基]-1-(2,2,2-三氟乙基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-异丙基-6-[(3S,4S)-4-甲基-1-(1,5-萘啶-4-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-异丙基-6-[(3S,4S)-4-甲基-1-(1,8-萘啶-4-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-异丙基-6-[3S,4S]-4-甲基-1-(喹啉-4-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-异丙基-6-[(3S,4S)-4-甲基-1-(吡啶并[2,3-b]吡嗪-8-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-异丙基-6-{(3,4-反式)-1-[(6-甲氧基-1,5-萘啶-4-基)甲基]-4-甲基吡咯烷-3-基}-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-{(3,4-反式)-1-[(8-氟喹啉-2-基)甲基]-4-甲基吡咯烷-3-基}-1-异丙基-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-异丙基-6-{(v)-1-[(6-甲氧基喹啉-4-基)甲基]-4-甲基吡咯烷-3-基}-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-[(3,4-反式)-1-苄基-4-甲基吡咯烷-3-基]-1-环丁基-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-{(3S,4S)-4-甲基-1-[(2-甲基嘧啶-5-基)甲基]吡咯烷-3-基}-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-{(3,4-反式)-4-乙基-1-[(2-甲基嘧啶-5-基)甲基]吡咯烷-3-基}-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-{(3S,4S)-4-甲基-1-[(5-甲基吡嗪-2-基)甲基]吡咯烷-3-基}-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-{(3S,4S)-1-[(6-甲氧基吡啶-3-基)甲基]-4-甲基吡咯烷-3-基}-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-[(3S,4S)-4-甲基-1-(喹啉-3-基甲基)吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-{(3S,4S)-4-甲基-1-[(2-甲基嘧啶-4-基)甲基]吡咯烷-3-基}-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-{(3S,4S)-4-甲基-1-[(6-甲基吡啶-3-基)甲基]吡咯烷-3-基}-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-[(3S,4S)-4-甲基-1-{[6-(三氟甲基)吡啶-3-基]甲基}吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-{(3S,4S)-4-甲基-1-[(1-甲基-1H-咪唑并[4,5-c]吡啶-2-基)甲基]吡咯烷-3-基}-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-{(3S,4S)-1-[(1,3-二甲基-1H-吡唑-5-基)甲基]-4-甲基吡咯烷-3-基}-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环丁基-6-{(3,4-反式)-4-甲基-1-[(2-甲基嘧啶-5-基)甲基]吡咯烷-3-基}-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-[(3S,4S)-1-(2,1,3-苯并噻二唑-5-基甲基)-4-甲基吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-[(3S,4S)-4-甲基-1-(喹喔啉-2-基甲基)吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-[(3S,4S)-4-甲基-1-(喹啉-4-基甲基)吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-[(3S,4S)-4-甲基-1-(吡啶-2-基甲基)吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-[(3S,4S)-1-苄基-4-甲基吡咯烷-3-基]-3-甲基-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-[(3S,4S)-1-(3-氟苄基)-4-甲基吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-[(3S,4S)-1-(35-二氟苄基)-4-甲基吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-{(3S,4S)-4-甲基-1-[4-(三氟甲基)苄基]吡咯烷-3-基}-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-[(3,4-反式)-1-苄基-4-乙基吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-[(3S,4S)-1-苄基-4-乙基吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
3-甲基-6-[(3S,4S)-4-甲基-1-(吡啶-3-基甲基)吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
3-甲基-6-{(3S,4S)-4-甲基-1-[(2-甲基嘧啶-5-基)甲基]吡咯烷-3-基}-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-{(3S,4S)-1-[(6-甲氧基吡啶-3-基)甲基]-4-甲基吡咯烷-3-基}-3-甲基-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-{(3S,4S)-4-甲基-1-[(6-甲基吡啶-2-基)甲基]吡咯烷-3-基}-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-[(3S,4S)-1-(4-氟苄基)-4-甲基吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-[(3S,4S)-1-(2-氟苄基)-4-甲基吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-{(3S,4S)-4-甲基-1-[2-(三氟甲基)苄基]吡咯烷-3-基}-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-[(3S,4S)-1-(2,4-二氟苄基)-4-甲基吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-[(3S,4S)-1-(4-甲氧基苄基)-4-甲基吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-[(3S,4S)-1-苄基-4-甲基吡咯烷-3-基]-1-(四氢-2H-噻喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-[(3S,4S)-1-(2-甲氧基苄基)-4-甲基吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-[(3S,4S)-1-(3-甲氧基苄基)-4-甲基吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-{(3S,4S)-4-甲基-1-[3-(三氟甲基)苄基]吡咯烷-3-基}-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-[(3S,4S)-1-(26-二氟苄基)-4-甲基吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-{(3S,4S)-4-乙基-1-[(5-甲基吡嗪-2-基)甲基]吡咯烷-3-基}-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-{(3S,4S)-4-乙基-1-[(6-甲氧基吡啶-3-基)甲基]吡咯烷-3-基}-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-[(3S,4S)-4-乙基-1-(吡啶-2-基甲基)吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-[(3S,4S)-4-乙基-1-(喹喔啉-2-基羰基)吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-[(3S,4S)-4-甲基-1-(嘧啶-2-基甲基)吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
2-({(3S,4S)-3-乙基-4-[4-氧代-1-(四氢-2H-吡喃-4-基)-45-二氢-1H-吡唑并[3,4-d]嘧啶-6-基]吡咯烷-1-基}甲基)苯甲腈;
3-({(3S,4S)-3-乙基-4-[4-氧代-1-(四氢-2H-吡喃-4-基)-45-二氢-1H-吡唑并[3,4-d]嘧啶-6-基]吡咯烷-1-基}甲基)苯甲腈;
4-({(3S,4S)-3-乙基-4-[4-氧代-1-(四氢-2H-吡喃-4-基)-45-二氢-1H-吡唑并[3,4-d]嘧啶-6-基]吡咯烷-1-基}甲基)苯甲腈;
1-环戊基-6-{(3,4-反式)-4-甲基-1-[3-(1H-吡唑-1-基)苄基]吡咯烷-3-基}-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-{(3,4-反式)-4-甲基-1-[(2-甲基吡啶-4-基)甲基]吡咯烷-3-基}-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-[(3,4-反式)-1-(2-氯-6-氟苄基)-4-甲基吡咯烷-3-基]-1-环戊基-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-1-(2,3-二甲基苄基)-4-甲基吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-{(3,4-反式)-1-[2-(二氟甲氧基)苄基]-4-甲基吡咯烷-3-基}-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-{(3,4-反式)-1-[(2-乙氧吡啶-3-基)甲基]-4-甲基吡咯烷-3-基}-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-4-甲基-1-(4,5,6,7-四氢吡唑并[1,5-a]吡啶-3-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-1-(2,3-二氢-1,4-苯并二噁英-6-基甲基)-4-甲基吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-{(3,4-反式)-1-[4-(1H-咪唑-1-基)苄基]-4-甲基吡咯烷-3-基}-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-1-(2,5-二氯苄基)-4-甲基吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-1-(4-甲氧基-3-甲基苄基)-4-甲基吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-1-(2,3-二氢-1-苯并呋喃-7-基甲基)-4-甲基吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-1-(2,3-二氟苄基)-4-甲基吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-1-(5-氟-2-甲氧基苄基)-4-甲基吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-1-(2-氟-4-甲氧基苄基)-4-甲基吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-1-(3-氟-4-甲基苄基)-4-甲基吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-{(3,4-反式)-4-甲基-1-[(2-甲基-1,3-噻唑-5-基)甲基]吡咯烷-3-基}-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-{(3,4-反式)-1-[(4-异丙基-1,3-噻唑-2-基)甲基]-4-甲基吡咯烷-3-基}-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-{(3,4-反式)-1-[(1,3-二甲基-1H-吡唑-5-基)甲基]-4-甲基吡咯烷-3-基}-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-1-(2,3-二氟-4-甲基苄基)-4-甲基吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-4-甲基-1-{[6-(1H-吡唑-1-基)吡啶-2-基]甲基}吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-4-甲基-1-(4-甲基苄基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-4-甲基-1-(2-萘基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-{(3,4-反式)-1-[(2-甲氧基吡啶-3-基)甲基]-4-甲基吡咯烷-3-基}-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-1-(2-乙氧苄基)-4-甲基吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-{(3,4-反式)-4-甲基-1-[4-(1H-1,2,4-三唑-1-基)苄基]吡咯烷-3-基}-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-1-(3-甲氧基-4-甲基苄基)-4-甲基吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-4-甲基-1-(1-萘基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-1-(3-氟-4-甲氧基苄基)-4-甲基吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-1-(2,5-二甲氧基苄基)-4-甲基吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-{(3,4-反式)-4-甲基-1-[(5-甲基异噁唑-3-基)甲基]吡咯烷-3-基}-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-1-(2-氟-6-甲氧基苄基)-4-甲基吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-1-(2,4-二氟苄基)-4-甲基吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-1-(4-氟-3-甲氧基苄基)-4-甲基吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-1-(2,3-二氢-1,4-苯并二噁英-5-基甲基)-4-甲基吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-[(3,4-反式)-1-(2-氯-4-氟苄基)-4-甲基吡咯烷-3-基]-1-环戊基-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-1-(2,4-二甲基苄基)-4-甲基吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-1-(3,5-二甲氧基苄基)-4-甲基吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-1-(3-乙氧苄基)-4-甲基吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-[(3,4-反式)-1-(4-氯-2-氟苄基)-4-甲基吡咯烷-3-基]-1-环戊基-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
3-{[(3,4-反式)-3-(1-环戊基-4-氧代-4,5-二氢-1H-吡唑并[3,4-d]嘧啶-6-基)-4-甲基吡咯烷-1-基]甲基}苯甲腈;
1-环戊基-6-[(3,4-反式)-1-(2,5-二氟苄基)-4-甲基吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
2-{[(3,4-反式)-3-(1-环戊基-4-氧代-4,5-二氢-1H-吡唑并[3,4-d]嘧啶-6-基)-4-甲基吡咯烷-1-基]甲基}苯甲腈;
6-[(3,4-反式)-1-(3-氯-4-氟苄基)-4-甲基吡咯烷-3-基]-1-环戊基-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-{(3,4-反式)-1-[4-(二氟甲氧基)苄基]-4-甲基吡咯烷-3-基}-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-4-甲基-1-(3-甲基苄基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-1-(3,4-二氟苄基)-4-甲基吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-1-(2,5-二甲基苄基)-4-甲基吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-[(3,4-反式)-1-(3-氯-2-氟苄基)-4-甲基吡咯烷-3-基]-1-环戊基-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-1-(2,3-二氯苄基)-4-甲基吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-4-甲基-1-(1,3-噻唑-2-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-1-(3-氟-2-甲基苄基)-4-甲基吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-{(3,4-反式)-4-甲基-1-[(2-甲基嘧啶-5-基)甲基]吡咯烷-3-基}-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-{(3,4-反式)-1-[(2-乙基嘧啶-5-基)甲基]-4-甲基吡咯烷-3-基}-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-1-(4-异丙基苄基)-4-甲基吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-{(3,4-反式)-1-[(1-乙基-1H-吡唑-4-基)甲基]-4-甲基吡咯烷-3-基}-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-{(3,4-反式)-1-[(4-甲氧基吡啶-3-基)甲基]-4-甲基吡咯烷-3-基}-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-1-(异噁唑-5-基甲基)-4-甲基吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-1-(4-乙氧苄基)-4-甲基吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-1-{[6-(1-羟基-1-甲基乙基)吡啶-3-基]甲基}-4-甲基吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-{(3,4-反式)-1-[(2,2-二甲基-2,3-二氢-1-苯并呋喃-5-基)甲基]-4-甲基吡咯烷-3-基}-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-1-(3,4-二甲氧基苄基)-4-甲基吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-{(3,4-反式)-4-甲基-1-[(5-甲基吡嗪-2-基)甲基]吡咯烷-3-基}-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-1-(咪唑并[1,2-a]吡啶-2-基甲基)-4-甲基吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-{(3,4-反式)-4-甲基-1-[(2-苯基-1,3-噁唑-4-基)甲基]吡咯烷-3-基}-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-4-甲基-1-(2-甲基苄基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-1-(2-异丙氧苄基)-4-甲基吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-[(3,4-反式)-1-(噌啉-3-基甲基)-4-甲基吡咯烷-3-基]-1-环戊基-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-{(3,4-反式)-1-[3-(二氟甲氧基)苄基]-4-甲基吡咯烷-3-基}-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-1-(4-氟-3-甲基苄基)-4-甲基吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-{(3,4-反式)-4-甲基-1-[4-(1H-吡唑-1-基)苄基]吡咯烷-3-基}-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-{(3,4-反式)-1-[(2,7-二甲基咪唑并[1,2-a]吡啶-3-基)甲基]-4-甲基吡咯烷-3-基}-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-1-(3,5-二氯苄基)-4-甲基吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-1-(4-异丙氧苄基)-4-甲基吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-1-{[2-(1-羟基-1-甲基乙基)吡啶-4-基]甲基}-4-甲基吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-4-甲基-1-(4,5,6,7-四氢-1,3-苯并噻唑-2-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-1-(米基甲基)-4-甲基吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-1-(2,6-二氯苄基)-4-甲基吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
4-{[(3,4-反式)-3-(1-环戊基-4-氧代-4,5-二氢-1H-吡唑并[3,4-d]嘧啶-6-基)-4-甲基吡咯烷-1-基]甲基}苯甲腈;
1-环戊基-6-[(3,4-反式)-1-(2-氟-5-甲氧基苄基)-4-甲基吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-1-(2,6-二甲基苄基)-4-甲基吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-{(3,4-反式)-1-[(4-甲氧基-3,5-二甲基吡啶-2-基)甲基]-4-甲基吡咯烷-3-基}-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-1-(3,5-二甲基苄基)-4-甲基吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-1-(3,4-二甲基苄基)-4-甲基吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-{(3,4-反式)-4-甲基-1-[(1-甲基-1H-苯并咪唑-2-基)甲基]吡咯烷-3-基}-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-{(3,4-反式)-4-甲基-1-[(4-甲基-3,4-二氢-2H-1,4-苯并噁嗪-7-基)甲基]吡咯烷-3-基}-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-4-甲基-1-(3-苯基丙基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-{(3,4-反式)-4-甲基-1-[2-(三氟甲基)苄基]吡咯烷-3-基}-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-4-甲基-1-(4,4,4-三氟丁基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-1-(3-甲氧基苄基)-4-甲基吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-1-(环戊基甲基)-4-甲基吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-1-(2,4-二甲氧基苄基)-4-甲基吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-{(3,4-反式)-4-甲基-1-[4-(吗啉-4-基甲基)苄基]吡咯烷-3-基}-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-[(3,4-反式)-1-(2,1,3-苯并噻二唑-5-基甲基)-4-甲基吡咯烷-3-基]-1-环戊基-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-{(3,4-反式)-1-[2-(苄基氧)乙基]-4-甲基吡咯烷-3-基}-1-环戊基-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-1-(2,6-二氟苄基)-4-甲基吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-1-(2-甲氧基苄基)-4-甲基吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-{(3,4-反式)-4-甲基-1-[(3,5,6-三甲基吡嗪-2-基)甲基]吡咯烷-3-基}-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-1-(2,4-二氯苄基)-4-甲基吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-4-甲基-1-(5,6,7,8-四氢-4H-吡唑并[1,5-a]氮杂卓-3-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-1-(3-氟苄基)-4-甲基吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-1-(2,3-二氢-1-苯并呋喃-5-基甲基)-4-甲基吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-1-(2-甲氧基-5-甲基苄基)-4-甲基吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-1-(2-氟苄基)-4-甲基吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-[(3,4-反式)-1-(2-氯苄基)-4-甲基吡咯烷-3-基]-1-环戊基-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-1-(3,4-二氯苄基)-4-甲基吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-[(3,4-反式)-1-(2,1,3-苯并噻二唑-4-基甲基)-4-甲基吡咯烷-3-基]-1-环戊基-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-{(3,4-反式)-4-甲基-1-[(2-丙基嘧啶-5-基)甲基]吡咯烷-3-基}-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-{(3,4-反式)-1-[(1-乙基-1H-吡唑-5-基)甲基]-4-甲基吡咯烷-3-基}-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-{(3,4-反式)-4-甲基-1-[2-(三氟甲氧基)苄基]吡咯烷-3-基}-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-{(3,4-反式)-4-甲基-1-[4-(三氟甲基)苄基]吡咯烷-3-基}-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-{(3,4-反式)-4-甲基-1-[(1-甲基-1H-咪唑并[4,5-c]吡啶-2-基)甲基]吡咯烷-3-基}-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3,4-反式)-1-(3,5-二氟苄基)-4-甲基吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮或
1-环戊基-6-[(3,4-反式)-1-(5,6-二氢-4H-吡咯并[1,2-b]吡唑-3-基甲基)-4-甲基吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;或
其药学上可接受盐。
我们令人惊讶地发现,本发明的化合物具有药理学活性(包括选择性抑制PDE9),这使得它们适于治疗、预防和/或控制可以通过抑制PDE9来调节或正常化的病症。
可以根据IUPAC(国际纯粹与应用化学联合会)或CAS(化学文摘社,Columbus,OH)的命名体系对本发明的化合物和中间体进行命名。
定义
本文所用某些术语通常如下定义:
本文中各种含有碳氢的片段中的碳原子含量可以通过前缀表示,该前缀表示该片段中碳原子的最少个数和最多个数。因此,例如(C1-C6)烷基指具有1至6个碳原子的烷基,包括两个端点。
术语“烷氧基”指结合有氧原子的直链的或支化的一价饱和脂族烃基,该氧原子被连接到核心结构上。烷氧基的实例包括甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、叔丁氧基、戊氧基等等。
术语“烷基”指饱和的一价直链或支链脂族烃基。烷基的实例包括甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、仲丁基、戊基、异戊基、新戊基、己基、异己基等等。
术语“烯基”指具有1个或更多个双键的部分不饱和的直链或支链脂族烃基。烯基的实例包括乙烯基、烯丙基、1-丙烯基、异丙烯基、正丁烯基、正戊烯基等等。术语“烯基”涵盖了具有“顺式”方向和“反式”方向的基团,或者具有“Z”方向和“E”方向的基团。
术语“炔基”指具有1个或更多个双键的部分不饱和的直链或支链脂族烃基。炔基的实例包括1-丙炔基、2-丙炔基(也被称为炔丙基)、1-丁炔基、2-丁炔基、1-戊炔基等等。
术语“芳基”指单环或多环芳族环系,例如为蒽基、苄基、芴基、茚基、萘基、苯并蒽基、苯基等等。术语“芳基”还包含上述环系的部分氢化衍生物,例如1,2,3,4-四氢萘基。
术语“芳基氧”指结合有氧原子的芳基,该氧原子连接到核心部分,诸如苄基氧。
术语“环烷基”指饱和的单环或双环环烷基。环烷基的实例包括环丙基、环丁基、环戊基、环己基、环庚基、环辛基等等。
术语“卤素”或“卤”表示氯、溴、氟和碘的原子和基团。
术语“卤代烷基”指其中至少一个氢基被卤素基团替代的烷基和环烷基。在一个以上氢被卤素替代时,这些卤素可以是相同的或不同的。卤代烷基的实例包括三氟甲基、2,2,2-三氟乙基、4,4,4-三氟丁基、4,4-二氟环己基、氯甲基、二氯甲基、三氯甲基、1-溴甲基等等。
术语“卤代烷氧基”指其中至少一个氢基被卤素基团替代的烷氧基。在一个以上氢被卤素替代时,这些卤素可以是相同的或不同的。卤代烷氧基的实例包括二氟甲氧基、三氟甲氧基、2,2,2-三氟乙氧基、氯代甲氧基、溴代甲氧基等等。
本文所用术语“杂芳基”包括含有一个或多个杂原子(诸如氮、氧和硫)的杂环不饱和环系。如果该杂芳基包含一个以上杂原子,那么这些杂原子可以是相同的或不同的。该杂芳基可以通过碳原子或杂原子结合。术语“杂芳基”还包括上述环系的部分氢化衍生物。杂芳基的实例包括呋喃基、咪唑啉基、咪唑基(也被称为“1,3-二唑基”)、吲哚基、噁二唑基、噁嗪基、噁唑基、异噁唑基、吡喃基、吡嗪基(也被称为1,4-二嗪基)、吡唑基(也被称为“1,2-二唑基”)、吡唑啉基、pyrazyl、、哒嗪基(也称为1,2-二嗪基)、吡啶基、嘧啶基(也被称为“1,3-二嗪基”)、吡咯基、噻二嗪基、噻二唑基、噻三唑基、噻唑基、异噻唑基、噻吩基、硫代呋喃基(thiofuranyl)(也被称为“苯硫基”)、噻喃基(thiopyranyl)、三嗪基、三唑基等等。
术语“杂芳基”还涵盖了其中2个或3个环稠合到一起的基团,其中这些环中至少一个环包含杂原子作为环原子,其包括其中(a)杂环烷基环与芳基或杂芳基环稠合的基团或者(b)环烷基环与杂芳基环稠合的基团。2-稠合杂芳基环的实例包括苯并二噁英基、二氢苯并二噁英基、苯并呋喃基、二氢苯并呋喃基、异苯并呋喃基、苯并咪唑基、苯并噻二唑基、四氢苯并噻二唑基、苯并噻唑基、苯并噻吩基(benzothienyl)(也被称为“苯并苯硫基”、“硫萘基”和“苯并硫代呋喃基”)、苯并噁嗪基、二氢苯并噁嗪基、苯并噁唑基、苯并二氢吡喃基(chromanyl)、异苯并二氢吡喃基(isochromanyl)、苯并吡喃基(chromenyl)、噌啉基(也被称为“1,2-苯并二嗪基”)、咪唑并吡啶基(例如咪唑并[1,2-a]吡啶基或咪唑并[4,5-c]吡啶基)、吲唑基、二氢吲哚基、异二氢吲哚基、中氮茚基(indolizinyl)、吲哚基、异吲哚基、萘啶基、氧硫杂环并吡咯基(oxathiolopyrrolyl)、蝶啶基、pthalazinyl、嘌呤基(也被称为“咪唑并[4,5-d]嘧啶基”)、吡喃并吡咯基、吡唑并氮杂卓基、四氢吡唑并氮杂卓基(例如四氢吡唑并[1,5-a]氮杂卓基)、吡唑并吡啶基、四氢吡唑并吡啶基(例如四氢吡唑并[1,5-a]吡啶基)、吡唑并嘧啶基(例如吡唑并[3,4-d]嘧啶基)、吡啶并吡嗪基(例如吡啶并[2,3-b]吡嗪基)、吡啶并吡啶基、吡咯并吡唑基、二氢吡咯并吡唑基(例如二氢吡咯并[1,2-b]吡唑基)、喹唑啉基(也被称为“1,3-苯并二嗪基”)、喹啉基(也被称为“1-benzazinyl”)、异喹啉基(也被称为“2-benzazinyl”)、喹嗪基(quinolizinyl)、醌醇基(quinolyl)、异醌醇基(isoquinolyl)、喹喔啉基、二硫萘二基(dithianaphthalenyl)、噻吩并呋喃基(例如噻吩并[3,2-b]呋喃基)等等。
三稠合杂芳基环的实例包括吖啶基、二吖蒽基、三吖菲基、咔唑基、咔唑啉基、糠并噌啉基(furocinnolinyl)、萘嵌间二氮(杂)苯基(perimidinyl)、菲啶基、菲咯啉基、吩嗪基、吩噻嗪基、phenoxathiinyl、吩噁嗪基(phenoxazinyl)、噻蒽基、占吨基(xanthenyl)等等。
术语“杂环烷基”指其中碳原子中的至少一个被诸如氮、氧或硫的杂原子替代的饱和单环或多环环烷基。如果杂环包含一个以上杂原子,那么这些杂原子可以是相同的或不同的。杂环烷基可以通过碳原子或杂原子结合。杂环烷基的实例包括氮杂环丁基、二氧杂环己基、1,3-二氧杂环戊基、咪唑烷基、吗啉基、哌嗪基、哌啶基、吡唑烷基、吡咯烷基、四氢呋喃基、四氢吡喃基、四氢噻喃基、噻嗪烷基等等。
环状基团可以以一种以上的方式结合其它基团。如果没有特别说明结合方式,那么意指所有可能的排列方式。例如术语“吡啶基”包含2-、3-或4-吡啶基。
术语“哺乳动物”指包括例如狗、猫、牛、绵羊、山羊、马和人类的动物。优选的哺乳动物包括人类。
术语“氧代”指通过碳原子和氧原子组合而形成的羰基。
术语“患者”包括人类患者和非人类患者。
短语“药学上可接受”表示,所指定的载剂、载体、稀释剂和/或盐通常在化学上和/或物理学上与包含在制剂中的其它成分相容并且在生理学上与其受体相容。
术语“盐”指式(I)化合物的有机盐和无机盐。上述盐可以在最终分离和纯化化合物期间原位制成,或者可以通过如下制成:单独地将式(I)化合物、前药或立体异构体与适当的有机或无机酸或件进行反应,然后分离所形成的盐。具有代表性的阴离子盐包括氢溴酸盐、氢氯酸盐、氢碘酸盐、硫酸盐、硫酸氢盐、硝酸盐、乙酸盐、三氟乙酸盐、草酸盐、苯磺酸盐(besylate)、棕榈酸盐、扑酸盐(pamoate)、丙二酸盐、硬脂酸盐、月桂酸盐、苹果酸盐、硼酸盐、苯甲酸盐、乳酸盐、磷酸盐、六氟磷酸盐、苯磺酸盐(benzene sulfonate)、甲苯磺酸盐、甲酸盐、柠檬酸盐、马来酸盐、富马酸盐、琥珀酸盐、酒石酸盐、萘酸盐、甲磺酸盐、葡庚酸盐、乳糖酸盐和月桂基磺酸盐等等。具有代表性的阳离子盐包括钠盐、钾盐、钙盐和镁盐等等。通常参见例如Berge等人的J.Pharm.Sci.,66,1-19(1977)。
式(I)化合物的盐可以通过如下容易地制成:将式(I)化合物的溶液和适当的酸或碱混合到一起。该盐可由溶液沉淀并通过过滤收集或者可以通过蒸发溶剂回收。
术语“基团”指一组原子,其在化学反应中以单一反应物的形式起作用,例如有机基团是赋予包含该基团的化合物特定性质或者在一系列反应或转化期间保持不变的一组原子。
符号“-”表示共价键。
短语“反应惰性溶剂”或“惰性溶剂”指不会以对所需性质产生不利影响的方式与原料、试剂、中间体或产物相互作用的溶剂或溶剂混合物。
本文所用术语“治疗”、“治疗的”、“被治疗的”或“治疗作用”包括预防性(例如预防疾病的)、缓解性或治愈性应用或结果。
式(I)化合物可以包含不对称或手性中心,因而以不同立体异构形式存在。除非另有声明,本领域技术人员将认识到本文所描述、阐述和/或讨论的新型化合物的所有立体异构体(例如对映异构体和非对映异构体及其外消旋混合物)都包含在本发明的范围内。此外,除非另有声明,本发明涵盖了所有几何异构体和位置异构体。优选的是核心吡咯烷基的构象为(3S,4S)对映异构体。
可以基于非对映异构混合物的物理化学差异通过本领域普通技术人员公知的方法(诸如色谱分离和/或分级结晶)将该混合物分离成单独的非对映异构体。对映异构体可以通过如下分离:使对映异构体的混合物与适当光学活性化合物(例如醇)进行反应从而将其转化成非对映异构体的混合物;分离该对映异构体;然后将单独的非对映异构体转化(例如水解)成相应的纯对映异构体。其它方法包括采用手性盐以及手性色谱拆分外消旋混合物。
本领域技术人员将进一步认识到,式(I)化合物可以以如下结晶形式存在,诸如以水合物(其中水分子结合到该化合物的结晶结构中)形式存在和以溶剂化物(其中溶剂分子结合到其中)形式存在。所有上述水合物和溶剂化物形式被认为是本发明的一部分。
从业人员将认识到式(I)化合物可以以互变异构体形式存在,即两种异构体(它们彼此间处于快速平衡状态)之间存在平衡。常见的互变实例是酮-烯醇互变,即
一种互变异构体超过其它互变异构体的程度取决于各种因素,包括取代形式和溶剂类型。本领域普通技术人员根据本发明将认识到其它实例。式(I)的所有互变异构形式都包含在本发明的范围内,除非另有声明。
本发明还包括本发明化合物的前药。术语“前药”指在施用后通过化学或生理学过程(例如当遇到生理pH时或通过酶作用)在体内释放药物的药物前驱体。前药本身在其保留在体内期间可以具有生物学活性或者可以转化成生物活性化合物(例如通过代谢或水解)。关于前药制备和使用的讨论由Higuchi和Stella的“Pro-drugs as Novel Delivery Systems”,Vol.14,ACS Symposium Series和“Bioreversible Carriers in Drug Design”,E.B.Roche编辑,American Pharmaceutical Association and Pergamon Press,1987提供。各种式(I)化合物的所有前药都包含在本发明的范围内。
本发明还涵盖了经同位素标记的式(I)化合物,其与本文所述那些化合物相同,不同之处在于:一个或多个原子被原子量或质量数不同于在自然界中占主导的原子量或质量数的原子替换。可以掺入式(I)化合物中的同位素的实例包括氢、碳、氮、氧、磷、氟和氯的同位素,诸如分别为2H、3H、13C、14C、15N、18O、17O、31P、32P、35S、18F和36Cl。含有上述同位素和/或其它原子的其它同位素的式(I)化合物及其药学上可接受盐都包含在本发明的范围内。
某些经同位素标记的式(I)化合物,例如,掺入了放射性同位素(诸如3H和14C)的那些,可用于药物和/或底物的组织分布研究。氚(即3H)和14C特别有利于,因为它们易于制备并且容易检测。此外,用较重的同位素(例如氘,即2H)进行取代可提供某些治疗好处(由于更好的代谢稳定性),例如,增加的体内半衰期或者降低的剂量需求,因此,在某些情况下这可能是优选的。经同位素标记的式(I)化合物及其药学上可接受盐通常通过如下制成:实施与以下示意图和/或实施例中公开的那些类似的工艺,但用容易得到的经同位素标记的试剂代替未经同位素标记的试剂。
本发明还包括药物组合物,其包含一定量的式(I)化合物或该化合物的药学上可接受盐,可选包含药学上可接受载体、载剂或稀释剂。在优选的实施方式中,药物组合物具有有效抑制哺乳动物中的酶PDE9的用量。在另一优选实施方式中,哺乳动物是人类。
本发明包括组合使用式(I)所提供的PDE9抑制剂化合物和一种或多种额外的药学上可接受活性试剂。如果组合施用活性试剂,那么它们可以以单独剂型形式顺序施用或同时施用,或者可以以单一剂型形式组合施用。因此,本发明还包含一种药物组合物,其包含一定量的(a)第一试剂,该第一试剂包含式(I)化合物或该化合物的药学上可接受盐;和(b)第二药学上活性试剂;和(c)药学上可接受载剂、载体或稀释剂。
根据待治疗的疾病、失调症或病症,可选选择各种药学活性试剂与式(I)化合物结合使用。可与本发明的组合物组合使用的药学活性试剂包括但不限于:
(i)乙酰胆碱酯酶抑制剂,诸如多萘哌齐盐酸盐(donepezilhydrochloride,E2020,ARICEPT,MEMAC)、毒扁豆碱水杨酸盐(physostigmine salicylate,ANTILIRIUM)、毒扁豆碱硫酸盐(physostigmine sulfate,ESERINE)、美曲磷酯(metrifonate)、新斯的明(neostigmine)、溴比斯的明(MESTINON)、阿伯斯的明(ambenonium,MYTELASE)、demarcarium、Debio992(也被称为ZT-1)、利凡斯的明(rivastigmine,EXELON)、拉多替吉(ladostigil,也被称为TV3326)、NP-0361、氢溴酸加兰他敏(galantamine hydrobromide,RAZADYNE,RIMINYL,NIVALIN)、他可林(tacrine,COGNEX)、维吖啶马来酸酯(velnacrine maleate)、memoquin、石杉碱甲A(huperzineA,HUP-A)、苯羟基丙氨酸(phenserine)和氯化腾喜龙(edrophonium,ENLON,TENSILON);
(ii)淀粉样蛋白-β(或其片段),诸如与pan HLA DR-结合抗原(PADRE)共轭的Aβ1-15、ACC-001、ACI-01、ACI-24、AN-1792、Affitope AD-01、CAD106和V-950;
(iii)淀粉样蛋白-β(或其片段)的抗体,诸如Bapineuzumab(也被称为AAB-001)、AAB-002、ACI-01-Ab7、BAN-2401、静脉内Ig(GAMMAGARD)、LY2062430(人性化m266)、PF-04360365(也被称为RN-1219)、RN-6G、R-1450、ACU-5A5、huC091以及国际专利公开WO04/032868、WO05/025616、WO06/036291、WO06/069081、WO06/118959、美国专利公开US2003/0073655、US2004/0192898、US2005/0048049、US2005/0019328、欧洲专利公开EP0994728和1257584和美国专利5,750,349中公开的那些;
(iv)淀粉样蛋白的降低或抑制试剂(包括用于降低淀粉样堆积和纤维溶解的那些试剂),诸如Bisnorcymserine(也被称为BNC)、比格列酮(pioglitazone)、PBT2、氟比洛芬(flurbiprofen ANSAID,FROBEN)及其R-异构体、Tarenflurbil(也被称为MPC-7869;FLURIZAN)、硝基氟吡洛芬(nitroflurbiprofen)、菲诺洛芬(fenoprofen,FENOPRON,NALFON)、布洛芬(ibuprofen,ADVIL,MOTRIN,NUROFEN)、布洛芬赖氨酸盐(ibuprofen lysinate)、甲氯芬那酸(meclofenamic acid)、甲氯芬那酸钠(meclofenamate sodium,MECLOMEN)、吲哚美辛(indomethacin,INDOCIN)、双氯芬酸钠(diclofenac sodium,VOLTAREN)、双氯芬酸钾(diclofenac potassium)、舒林酸(sulindacCLINORIL)、舒林酸硫化物(sulindac sulfide)、二氟尼柳(diflusinal,DOLOBID)、萘普生(Naproxen,NAPROSYN)、萘普生钠(ANAPROX,ALEVE)、胰岛素降解酶(也被称为胰岛素抵抗细胞)、白果萃取物Egb-761(ROKAN,TEBONIN)、高牛磺酸(tramiprosate,NC-758,CEREBRIL,ALZHEMED)、Eprodisate(NC-503,FIBRILLEX,KIACTA)、化合物W(3,5-双(4-硝基苯氧基)苯甲酸)、NGX-96992、脑菲肽酶(也被称为中性肽链内切酶NEP)、青蟹肌醇(也被称为鲨肌醇,ELND005,AZD-103)、阿托伐他汀(atorvastatin LIPITOR)、辛伐他汀(simvastatin,ZOCOR)、KLVFF-(EEX)3和RAGE(高度糖基化终产物的受体)抑制剂;
(v)α-肾上腺素受体拮抗剂,诸如氯压定(clonidine,CATAPRES)、间羟胺(ARAMINE)、甲基多巴(ALDOMET,DOPAMET,NOVOMEDOPA)、替扎尼定(tizanidine,ZANAFLEX)、苯肾上腺素(也被称为去氧肾上腺素)、甲氧胺(methoxamine)、西拉唑林(cirazoline)、胍法辛(guanfacine,INTUNIV)、洛非西定(lofexidine)、甲苯噻嗪、莫达非尼(modafinil PROVIGIL)、艾捉非尼(adrafinil)和阿莫达非尼(armodafinil,NUVIGIL);
(vi)β-肾上腺素受体阻断剂(β阻断剂),诸如卡替洛尔(carteolol)、艾司洛尔(esmolol,BREVIBLOC)、拉贝洛尔(labetalol,NORMODYNE,TRANDATE)、氧烯洛尔(oxprenolol,LARACOR,TRASACOR)、吲哚洛尔(pindolol,VISKEN)、普萘洛尔(propanolol,INDERAL)、索他洛尔(sotalol,BETAPACE,SOTALEX,SOTACOR)、噻吗洛尔(timolol,BLOCADREN,TIMOPTIC)、醋丁洛尔(acebutolol,SECTRAL,PRENT)、纳多洛尔(nadolol,CORGARD)、酒石酸美托洛尔(LOPRESSOR)、琥珀酸美托洛尔(TOPROL-XL)、阿替洛尔(atenolol,TENORMIN)、丁氧胺和SR59230A(Sanofi);
(vii)抗胆碱能药,诸如阿米替林(amitriptyline,ELAVIL,ENDEP)、布替林(butriptyline)、甲磺酸苯扎托品(benztropinemesylate,COGENTIN)、苯海索(trihexyphenidyl,ARTANE)、苯海拉明(diphenhydramine,BENADRYL)、奥芬那君(orphenadrine,NORFLEX)、天仙子胺(hyoscyamine)、阿托品(ATROPEN)、车莨菪碱(反式DERM-SCOP)、车莨菪碱甲基溴化物(PARMINE)、双环维林(dicycloverine(BENTYL,BYCLOMINE,DIBENT,DILOMINE)、托特罗定(tolterodine,DETROL)、奥昔布宁(oxybutynin DITROPAN,LYRINEL XL,OXYTROL)、喷噻溴胺(penthienate bromide)、丙胺太林(propantheline,PRO-BANTHINE)、苯甲嗪(cyclizine)、丙咪嗪盐酸盐(imipramine hydrochloride,TOFRANIL)、丙咪嗪马来酸盐(SURMONTIL)、洛非帕明(lofepramine)、地昔帕明(desipramine,NORPRAMIN)、多塞平(doxepin,SINEQUAN,ZONALON)、曲米帕明(trimipramine,SURMONTIL)和甘罗溴胺(glycopyrrolate,ROBINUL);
(viii)抗惊厥药,诸如卡巴咪嗪(carbamazepine,TEGRETOL,CARBATROL)、奥卡西平(oxcarbazepine,TRILEPTAL)、苯妥英钠(phenytoin sodium,PHENYTEK)、磷苯妥英(fosphenytoin,CEREBYX,PRODILANTIN)、双丙戊酸钠(divalproex sodium,DEPAKOTE)、加巴喷丁(gabapentin,NEURONTIN)、普瑞巴林(pregabalin LYRICA)、托吡酯(topirimate TOPAMAX)、丙戊酸(DEPAKENE)、丙戊酸钠(DEPACON)、1-苄基-5-溴尿嘧啶、普罗加比(progabide)、苄氯丙酰胺和普里米酮(MYSOLINE);
(ix)安定药,诸如Lurasidone(也被称为SM-13496)、阿立哌唑(aripiprazole ABILIFY)、氯丙嗪(chlorpromazine,THORAZINE)、氟哌丁苯(haloperidol,HALDOL)、癸酸(DEPIXOL,FLUANXOL)、利血平(reserpine,SERPLAN)、哌迷清(pimozide,ORAP)、氟非那嗪癸酸(fluphenazine decanoate)、氟非那嗪盐酸、普鲁氯嗪(COMPRO)、阿莫沙平(asenapine)、洛沙平(loxapineLOXITANE)、美索达嗪(mesoridazine)、吗吲酮(molindone,MOBAN)、奋乃静(perphenazine)、Thiothixine、硫利达嗪(thiothixine)、三氟拉嗪(trifluoperazine STELAZINE)、氯氮平(clozapine CLOZARIL)、去甲基氯氮平(norclozapine ACP-104)、利培酮(risperidone RISPERDAL)、帕潘立酮(paliperidone INVEGA)、Melperone、奥氮平(olanzapine ZYPREXA)、喹硫平(quetiapineSEROQUEL)、舍吲哚(sertindole)、舒必利(sulpiride MERESA,DOGMATYL,SULPITIL)、氨磺必利(amisulpride)、齐拉西酮(ziprasidone GEODON)、Blonanserin(LONASEN)和Bifepurnox;
(x)钙通道阻断剂,诸如尼伐地平(nilvadipine ESCOR,NIVADIL)、氨氯地平(amlodipine,NORVASC,ISTIN,AMLODIN)、非洛地平(felodipine PLENDIL)、尼卡地平(nicardipineCARDENE)、硝苯地平(nifedipine ADALAT,PROCARDIA)、MEM1003及其母体化合物尼莫地平(nimodipine NIMOTOP)、尼索地平(nisoldipine SULAR)、尼群地平(nitrendipine)、拉西地平(lacidipineLACIPIL,MOTENS)、乐卡地平(lercanidipine CARDENE)、地尔硫(diltiazem CARDIZEM)、维拉帕米(CALAN,VERELAN)和enecadin(也被称为NS-7);
(xi)儿茶酚-O转甲基酶(COMT)抑制剂,诸如托卡朋(tolcaponeTASMAR),恩他卡朋(ntacapone COMTAN)和环庚三烯酚酮(tropolone);
(xii)中枢神经系统刺激剂,诸如咖啡因、苯甲吗啉、苯甲曲秦(phendimetrazine)、匹莫林(pemoline)、Fencamfamine(GLUCOENERGAN,REACTIVAN)、fen乙基line(CAPTAGON)、pipradol(MERETRAN)、deanol(也被称为二甲氨基乙醇)、利他林(Methylphenidate DAYTRANA)、盐酸利他林(RITALIN),Dexmethylphenidate(FOCALIN),安非他明(amphetamine,单独或与其他CNS刺激剂组合,如Adderall(安非他明天门冬氨酸,硫酸安非他明,右旋安非他明糖酸盐和右旋安非他明硫酸盐))、右旋安非他明硫酸盐(DEXEDRINE,DEXTROSTAT)、甲基安非他明(DESOXYN)、Lisdexamfetamine(VYVANSE)和苄非他明(DIDREX);
(xiii)皮质类固醇,诸如强的松(prednisone STERAPRED,DELTASONE)、泼尼松(prednisolone PRELONE)、醋酸泼尼松(OMNIPRED,PRED MILD,PRED FORTE)、泼尼松磷酸钠(ORAPREDODT)、甲泼尼松(Methylprednisolone MEDROL)、醋酸甲基泼尼松(DEPO-MEDROL)和甲泼尼松琥珀酸钠(A-METHAPRED,SOLU-MEDROL);
(xiv)多巴胺受体激动剂,诸如阿朴吗啡(apomorphineAPOKYN)、溴麦角隐亭(bromocriptine PARLODEL)、卡麦角林(cabergoline DOSTINEX)、Dihydrexidine、Dihydrexidine、非诺多泮(fenoldopam CORLOPAM)、Lisuride(DOPERGIN)、培高利特(pergolide PERMAX)、吡贝地尔(piribedil TRIVASTAL,TRASTAL)、普拉克索(pramipexole MIRAPEX)、Quinpirole、罗匹尼罗(ropinirole REQUIP、)和罗替戈汀(NEUPRO);
(xv)多巴受体拮抗剂,诸如四苯喹嗪(tetrabenazine NITOMAN,XENAZINE)、7-羟基阿莫沙平(7-hydroxyamoxapine)、氟哌利多(droperidol INAPSINE,DRIDOL,DROPLETAN)、多潘立酮(domperidone MOTILIUM)、L-741742、L-745870、氯雷必利(Raclopride)、SCH-23390、Ecopipam、SKF-83566和胃复安(metoclopramide REGLAN);
(xvi)多巴胺再摄入抑制剂,诸如来酸诺米芬新马(nomifensinemaleate MERITAL)、伐诺司林(vanoxerine也被称为GBR-12909)和其癸酸酯DBL-583和阿米庚酸(amineptine);
(xvii)γ-氨基丁酸(GABA)受体激动剂,诸如巴氯芬(baclofenLIORESAL,KEMSTRO)、戊巴比妥(pentobarbital NEMBUTAL)、普罗加比(progabide GABRENE)和氯美噻唑(clomethiazole);
(xviii)免疫调节剂,诸如醋酸格拉默(也称为共聚物-1;COPAXONE)、MBP-8298(髓鞘碱性蛋白合成肽)、富马酸二甲酯、芬戈莫德(fingolimod,也被称为FTY720)、,罗喹美克(roquinimexLINOMIDE)、拉喹莫德(laquinimod,也被称为ABR-215062和SAIK-MS)、ABT-874(人抗IL-12抗体)、美罗华(RITUXAN)、阿来组单抗(alemtuzumab CAMPATH)、赛尼哌(daclizumab ZENAPAX)和那他珠单抗(natalizumab TYSABRI);
(xix)免疫抑制剂,诸如甲氨蝶呤(TREXALL,RHEUMATREX),米托蒽醌(mitoxantrone NOVANTRONE),吗替麦考酚酯(mycophenolate mofetil CELLCEPT)、麦考酚钠(MYFORTIC)、咪唑硫嘌呤(AZASAN,IMURAN)、巯基嘌呤(PURI-NETHOL)、环磷酰胺(NEOSAR,CYTOXAN)、苯丁酸氮芥(LEUKERAN)、克拉曲滨(cladribine LEUSTATIN,MYLINAX)、α-胎蛋白、益塞普(ENBREL)、4-苄基氧-5-((5-十一烷基-2H-吡咯-2-亚基)甲基)-2,2′-二-1H-吡咯(也被称作PNU-156804);
(xx)干扰素,包括干扰素β-1a(AVONEX,REBIF)和干扰素β-1b(BETASERON,BETAFERON);
(xxi)左旋多巴(或其甲基或乙酯),单独或与DOPA脱羧酶抑制剂(如卡比多巴(SINEMET,CARBILEV,PARCOPA,V1512)、苄丝肼(benserazide MADOPAR)、α-甲基多巴、一氟甲基多巴、二氟甲基多巴、溴克利那(brocresine)或m-羟基苄基肼)组合;
(xxii)N-甲基-D天冬氨酸(NMDA)受体拮抗剂,诸如美金胺(memantine NAMENDA,AXURA,EBIXA)、金刚烷胺(SYMMETREL)、阿坎酸钙(acamprosate CAMPRAL)、Besonprodil(也称为PD-196,860或CI-1041)、克他命(Ketamine KETALAR)、Delucemine(也称为NPS 1506)、地塞米诺(Dexanabinol也被称为HU-211)、右旋美沙芬(dextromethorphan)、右啡烷(dextrorphan)、曲索罗地(traxoprodil,也被称为CP-101,606)、Himantane、Idantadol(也称为V-3381)、Lancicemine(也称为AR-R 15896)、左啡诺(levorphanol DROMORAN)、美沙酮(DOLOPHINE)、Neramexane(也被称为MRZ 2/579)、Perzinfotel、苯环己哌啶、塞奈普汀(tianeptineSTABLON)、地卓西平(也称为MK-801)、伊菠加因(ibogaine)、伏康京碱(voacangine)、替来他明(tiletamine)、利鲁唑(riluzoleRILUTEK)、阿替加萘(aptiganel CERESTAT)、加维斯替奈(gavestinel)和Remacimide;
(xxiii)单胺氧化酶(MAO)抑制剂,诸如司来吉兰(selegilineEMSAM)、盐酸司来吉兰(1-deprenyl,ELDEPRYL,ZELAPAR)、二甲基司来吉兰、溴法罗明(brofaromine)、苯乙肼(phenelzine NARDIL)、双苯胺(tranylcypromine PARNATE)、吗氯贝胺(moclobemideAURORIX,MANERIX)、贝氟沙通(befloxatone)、沙芬酰胺(safinamide,也被称为PNU-151774E)、异唑阱(isocarboxazidMARPLAN)、烟阱酰胺(nialamide NIAMID)、Rasageline(AZILECT)、异丙异烟阱(iproniazide MARSILID,IPROZID,IPRONID)、异丙氯阱(iproclozide)、托洛沙酮(toloxatone HUMORYL,PERENUM)、二苯美仑(bifemelane)、Desoxypeganine、骆驼蓬碱(也被称为南美卡皮根碱或banasterine)、二氢骆驼蓬碱(harmaline)、雷奈佐利(linezolid ZYVOX,ZYVOXID)和巴吉林(pargyline EUDATIN,SUPIRDYL);
(xxiv)毒蕈碱受体(特别是M1亚型)激动剂,诸如乌拉胆碱盐酸盐(DUVOID,URECHOLINE)、匹鲁卡品(SALAGEN)、NGX267、槟榔碱、L-687306、L-689660、呋索碘铵(furtrethonium iodide FURAMON,FURANOL)、呋索苯磺酸铵、呋索对甲苯磺酸铵、McN-A-343、氧化震颤素和卡巴可(CARBASTAT,MIOSTAT,CARBOPTIC);
(xxv)烟碱受体激动剂,诸如地棘蛙素(epibatidine)、ABT-089、ABT-594、AZD-0328、R-4996(也被称为MEM-63908)、TC-5619和EVP-6124;
(xxvi)神经保护药物,诸如2,3,4,9-四氢-1H-咔唑-3-酮肟、AL-108、ACD3480(也被称为TC-1734)、双(4-β-D-吡喃葡萄糖醛羧基苄基)-2-β-D-吡喃葡萄糖醛酸吉-2-异丁基酒石酸(也被称为dactylorhin B或DHB)、扎利罗登(Xaliproden XAPRILA)、Dimeboline盐酸盐(DIMEBON)、Disufenton(NXY-059,CEROVIVE)、Arundic酸(ONO-2506,PROGLIA,CEREACT)、胞二磷胆碱(也被称为胞啶5′-二磷胆碱)、依达拉奉(RADICUT)、AEOL-10150、AGY-94806(也被称维SA-450和Msc-1)、粒细胞克隆刺激因子(AX-200)、BAY-387271(也被称为KN-387271)、DP-b99、HF-0220(17-β-羟基表雄甾酮)、HF-0420(也称为oligotropin)、吡哆醛5′-磷酸(也被称为MC-1)、微纤溶酶(microplasmin)、S-18986、Piclozotan(也被称为SUN-N4057)、NP031112、L-丝氨酰基-L-甲硫基-L-丙氨酰基-L-赖氨酸基-L-谷氨酰甘氨酰-L-缬氨酸和SUN-N8075;
(xxvii)降肾上腺素(去甲肾上腺素)再摄入抑制剂,诸如阿托莫西汀(atomoxetine Strattera)、多塞平(doxepin APONAL,ADAPIN,SINEQUAN)、去甲替林(AVENTYL,PAMELOR,NORTRILEN)、阿莫沙平(ASENDIN,DEMOLOX,MOXIDIL)、瑞波西汀(EDRONAX,VESTRA)、维洛沙秦(VIVALAN)、马普替林(DEPRILEPT,LUDIOMIL,PSYMION)、安非他酮(WELLBUTRIN)和Radaxafine;
(xxviii)其它PDE9抑制剂,诸如BAY 73-6691和美国专利公开US2003/0195205、US2004/0220186、US2006/0111372和US2006/0106035中公开的那些;
(xxix)其它磷酸二酯酶(PDE)抑制剂,其包括(a)PDE1抑制剂(例如长春乙酯(vinpocetine CAVINTON,CERACTIN,INTELECTOL)和美国专利No 6,235,742中公开的那些;(b)PDE2抑制剂(例如赤型-9-(2-羟基-3-壬基)腺嘌呤(EHNA)、BAY 60-7550和美国专利6,174,884中描述的那些);(c)PDE4抑制剂(例如咯利普兰(rolipram)、Ro20-1724、异丁司特(ibudilast KETAS)、吡拉米特(piclamilast也被称为RP73401)、CDP840、西洛司特(cilomilast ARIFLO)、罗氟司特(roflumilast)、妥非司特(tofimilast)、Oglemilast(也被称为GRC3886)、替托司特(tetomilast,也被称为OPC-6535)、Lirimifast、茶碱(UNIPHYL,THEOLAIR)、阿罗茶碱(arofylline,也被称为LAS-31025)、多索茶碱、RPR-122818或松叶菊碱(mesembrine));和(d)PDE5抑制剂(例如西地那非(sildenafil VIAGRA,REVATIO)、他达拉非(tadalafil CIALIS)、伐地那非(vardenafil LEVITRA VIVANZA)、Udenafil、阿伐那非(avanafil)、双嘧达莫(dipyridamolePERSANTINE)、E-4010、E-4021、E-8010、敏喘宁(zaprinast)、PF-489791、UK-357903、DA-8159和国际专利申请WO05/049616、WO06/120552和WO07/122466中公开的那些);
(xxx)喹啉类,诸如奎宁(包括其盐酸盐、二盐酸盐、硫酸盐、硫酸氢盐和葡萄糖酸盐)、氯喹、羟基氯喹(PLAQUENIL)、甲氟喹(mefloquine LARIAM)和阿莫地喹(amodiaquine CAMOQUIN,FLAVOQUINE);
(xxxi)β-分泌酶抑制剂(β-secretase inhibitors),诸如WY-25105、(+)-苯羟基丙氨酸(POSIPHEN)、LSN-2434074(也被称为LY-2434074)、PNU-33312、KMI-574、SCH-745966、Ac-rER(N2-乙酰基-D-精氨酰基-L-精氨酸)、Loxistatin(也被称为E64d)和CA074Me;
(xxxii)γ-分泌酶抑制剂,诸如LY-411、575、LY-685、458、ELAN-G、ELAN-Z、4-氯-N-[2-乙基-1(S)-(羟甲基)丁基]苯磺酰胺;
(xxxiii)血清素(5-羟色胺)1A(5-HT1A)受体拮抗剂,诸如螺哌隆(spiperone)、左旋心得乐(levo-pindolol)、BMY 7378、NAD-299、S(-)-UH-301、NAN 190、WAY 100635、Lecozotan(也被称为SRA-333);
(xxxiv)血清素(5-羟色胺)6(5-HT6)受体拮抗剂,诸如米安色林(mianserin TORVOL,BOLVIDON,NORVAL)、Methiothepin(也被称为甲替平)、利坦丝林(ritanserin)、ALX-1161、ALX-1175、MS-245、LY-483518(也被称为SGS518)、MS-245、Ro 04-6790、RO 43-68544、Ro63-0563、RO 65-7199、Ro 65-7674、SB-399885、SB-214111、SB-258510、SB-271046、SB-357134、SB-699929、SB-271046、SB-742457和PRX-07034;
(xxxv)血清素(5-HT)再摄入抑制剂,诸如阿拉丙酯(alaproclate)、西酞普兰(CELEXA,CIPRAMIL)、依他普仑(LEXAPRO,CIPRALEX)、氯米帕明(ANAFRANIL),度洛西汀(CYMBALTA)、非莫西汀(femoxetine MALEXIL)、芬氟拉明(fenfluramine PONDIMIN)、去乙芬氟拉明(norfenfluramine)、氟西汀(PROZAC)、氟伏沙明(LUVOX)、茚达品(indalpine)、米那普仑(milnacipran IXEL)、帕罗西汀(PAXIL,SEROXAT)、舍曲林(ZOLOFT,LUSTRAL)、曲唑酮(DESYREL,MOLIPAXIN)、文拉法辛(EFFEXOR)、齐美利定(zimelidine NORMUD,ZELMID)、比西发定(bicifadine)、去甲文拉法辛(desvenlafaxine PRISTIQ)、Brasofensine和Tesofensine;
(xxxvi)营养因子,诸如神经生长因子(NGF)、碱性成纤维细胞生长因子(bFGF)、神经营养因子-3(NT-3)、脑源性神经营养因子(BDNF)和神经胶质源性神经营养因子(GDNF)和刺激营养因子局部生成的试剂,诸如丙戊茶碱(propentofylline)、艾地苯醌(idebenone)和AIT-082(NEOTROFIN);等等。
本发明还包含一种用于抑制哺乳动物中的PDE9的方法,所述方法包括:向需要上述抑制的哺乳动物施予PDE9抑制量的(a)式(I)化合物或其药学上可接受盐或(b)一种药物组合物,该药物组合物包含在药学上可接受载体、载剂或稀释剂中的式(I)化合物或其药学上可接受盐;以上试剂单独施用或者与上述第二试剂组合施用。
本发明还包含一种用于治疗哺乳动物中通过PDE9抑制作用介导的病症的方法,所述方法包括:向需要上述治疗的哺乳动物施予治疗有效量的(a)式(I)化合物或其药学上可接受盐或(b)一种药物组合物,该药物组合物包含在药学上可接受载体、载剂或稀释剂中的式(I)化合物或其药学上可接受盐;以上试剂单独施用或者与上述第二试剂组合施用。
可通过本发明的方法治疗、控制或预防的疾病包括与神经退行相关的疾病和失调症,诸如:亚历山大病(Alexander disease)、阿尔珀氏病(alper’s disease)、阿尔茨海默氏症(Alzheimer’s disease)、肌萎缩性脊髓侧索硬化症(ALS,也被称为Lou Gehrig病或运动神经疾病)、共济失调毛细血管扩张症、Batten疾病(又称Spielmeyer-Vogt-Sjogren-Batten症)、Binswanger老年痴呆症(皮层下动脉硬化性脑病)、双相情感障碍、牛海绵状脑病(BSE)、Canavan疾病、化疗引起的痴呆、Cockayne综合征、皮质基底节变性(corticobasal degeneration)、Creutzfeldt-Jakob病、抑郁症、唐氏综合症、颞叶病变(包括额颞叶痴呆、语义性痴呆、进行性失语)、Gerstmann-Straüssler-Scheinker病、青光眼、Huntington氏病(舞蹈病)、HIV相关老年痴呆症、运动机能亢奋、Kennedy氏病、Korsakoff综合征(健忘-虚构综合征)、Krabbe病、Lewy体痴呆、Logopenic进行性失语、Machado-Joseph病(3型脊髓小脑共济失调)、多发性硬化症、多系统萎缩(橄榄体脑桥小脑萎缩)、重症肌无力、帕金森氏症、Pelizaeus-Merzbacher病、Pick病、前期老年性痴呆(轻度认知功能损害)、原发性侧索硬化症、原发性进行性失语、辐射诱发痴呆症、Refsum病(植烷酸贮积病)、Sandhoff病、Schilder病、精神分裂症、语义性痴呆、老年性痴呆、Shy-Drager综合征、脊髓小脑共济失调、脊髓性肌萎缩、Steele-Richardson-Olszewski病(进行性核上性麻痹)、脊髓痨、迟发性运动障碍、血管淀粉样变性、血管性痴呆(多梗死性痴呆)。
优选地,神经退行疾病或失调症是阿尔茨海默氏症。
可以通过本发明的方法治疗或控制的与PDE9相关的其它病症和失调症包括泌尿生殖系统失调症(诸如性功能障碍),注意力缺乏(ADD),注意力缺乏多动症(ADHD),糖尿病,心血管失调症或疾病(如全身性高血压、肺动脉高压、充血性心力衰竭、冠心病、动脉硬化、中风、血栓形成、低血管通畅病症(如后经皮冠状动脉腔内成形术)),外周血管疾病,肾病,心绞痛(包括稳定的、不稳定和变异(Prinzmetal)心绞痛)以及改善血流会导致改善终端器官功能的任何病症。
本发明还涉及一种用于促进下述患者神经恢复和功能恢复的方法,这些患者的头部、脊髓或外周神经遭受创伤性或非创伤性伤害。创伤性脑损伤包括闭合性头部受伤(其中头骨没有损坏)和开放性或穿透性头部受伤(其中物体刺入头骨并破坏硬脑膜),其中突发性外伤(例如事故、摔倒、受袭击)通过撕裂、拉伸、撞击或肿胀对脑组织造成破坏。非创伤性脑损伤的起因包括动脉瘤,中风、脑膜炎,由于缺氧症、组织缺氧或缺血造成的缺氧,脑肿瘤,感染(如脑炎),中毒,药物滥用等等。本发明可用于治疗由脑损伤引起的以及由神经退行疾病和失调症引起的认知受损和认知功能失调。
本发明还涉及一种用于预防哺乳动物(包括人类)中的上述病症的方法,所述方法包括如下步骤:向哺乳动物施予一定量的(a)式(I)化合物或其药学上可接受盐或(b)一种药物组合物,该药物组合物包含在药学上可接受载体、载剂或稀释剂中的式(I)化合物或其药学上可接受盐;以上试剂单独施用或者与上述第二试剂组合施用,作为为了预防上述病症而设计的适当剂型。
本发明还涉及一种改善认知不足的方法,所述认知不足包括理解不足、注意力不足、学习力不足、记忆力不足、交流不足、推理不足和解决问题不足。
适当的剂型、所施予的每次剂量以及两个化合物剂量之间的间隔取决于所使用的本发明的式(I)化合物、所使用的药物组合物的类型、所治疗的对象的特性以及所治疗的病症的严重程度。一般而言,式(I)化合物或其药学上可接受盐的有效剂量在每天约0.1mg至约3500mg的范围内。对于体重约70kg的正常成人来说,每kg体重约0.01mg至约50mg的剂量通常是足够的,优选剂量为每kg约0.2至2.5mg,一天一次或一天多次。施予可以以单一剂量(例如一天一次)或多剂量形式进行或者可以通过持续输液形式进行。
通常的剂量范围内可能需要一些变化,这取决于受治对象的年龄和体重、所需施予途径、所施予的具体化合物等等。确定具体哺乳动物对象的用量范围和最佳用量在本领域技术人员的能力范围内。
式(I)化合物可以通过各种常规施予途径施予,包括口用、颊用、舌下、眼用、局部用(例如透皮)、胃肠外(例如静脉内、肌肉或皮下)、直肠、脑池内、叶鞘内、腹腔内、膀胱内、局部(例如粉、膏、或液滴)、鼻用和/或吸入剂型;或使用“快速”剂型,即,使药物在口腔内溶解,而无需使用水。如本领域普通技术人员所认识到的,适当的剂型、所施予的每次剂量以及两个化合物剂量之间的间隔取决于所用的式(I)化合物或其前药、所使用的药物组合物的类型、所治疗的对象的特性和/或所治疗的病症的严重程度。
具有不同量活性成分的各种药物组合物的制备方法是已知的,且根据本发明公开的内容对本领域技术人员来说是显然的。参见例如Remington′sPharmaceutical Sciences,Mack Publishing Co.,Easton,PA,第19版(1995)。
对于上述组合物来说,适当的药物载剂、载体和稀释剂包括惰性固体稀释剂或填料、无菌水溶液和各种有机溶剂。通过组合本发明的化合物和药学上可接受载剂、载体或稀释剂而形成的药物组合物易于通过各种剂型(诸如片剂、散剂、锭剂、糖浆、可注射溶液等等)形式施用。
口服用固体剂型包括胶囊、片剂、散剂和颗粒。在上述固体剂型中,活性化合物与如下组合:至少一种惰性常规药物赋形剂(或载剂),诸如柠檬酸钠、碳酸钙或磷酸二钙;或(a)填料或增量剂,诸如淀粉、乳糖、蔗糖、甘露醇和硅酸;(b)结合剂,诸如羧甲基纤维素、海藻酸盐、明胶、聚乙烯基甲基酮、蔗糖和阿拉伯胶;(c)保湿剂,诸如丙三醇;(d)绷解剂,诸如琼脂(agar-agar)、碳酸钙、土豆或木薯淀粉、海藻酸、某些复合硅酸盐和碳酸钠;(e)溶解阻滞剂(solution retarder),诸如石蜡;(f)吸收促进剂,诸如季铵化合物;(g)润湿剂,诸如鲸蜡醇和丙三醇一硬脂酸酯;(h)吸附剂,诸如高岭土和斑脱土,和/或(i)润滑剂,诸如滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、月桂基硫酸钠或其混合物。在胶囊和片剂中,剂型可以进一步包含缓冲剂。
固体剂型可以配制成修饰释放剂型和脉冲释放剂型,这些剂型包含诸如以上详细描述的立即释放剂型用赋形剂以及起到释放速率调节剂作用的额外赋形剂,其中额外赋形剂包覆在剂型体上和/或包含在剂型体中。释放速率调节剂包括但不限于羟丙基甲基纤维素、甲基纤维素、羧甲基纤维素钠、乙基纤维素、醋酸纤维素、聚氧乙烯、黄原胶、氨基甲基丙烯酸酯共聚物、氢化蓖麻油、巴西棕榈蜡、固体石蜡、醋酸纤维素邻苯二甲酸酯、羟丙基甲基纤维素邻苯二甲酸酯、甲基丙烯酸共聚物及其混合物。修饰释放剂型和脉冲释放剂型可以包含一种或组合的释放速率调节赋形剂。
本发明的药物组合物可以进一步包含快速分解或溶解的剂型(FDDF)。本文所用于描述FDDF的术语“分散或溶解”取决于所用药物的溶解性,即在药物不可溶时,可以制备快速分散剂型;在药物可溶时,可以制备快速溶解剂型。
类似类型的固体组合物还可以用作软质或硬质填充明胶的胶囊的填料,该胶囊使用乳糖或牛奶糖以及高分子量聚乙二醇等等作为上述赋形剂。
固体剂型(诸如片剂、糖衣丸、胶囊和颗粒)可以采用包衣和壳(诸如肠衣以及本领域普通技术人员已知的其它包衣)来制备。它们还可以包含浊化剂,并且还可以是以延迟、持续或可控方式释放活性化合物的组合物。可以采用的包埋组合物的实例是聚合物质和蜡。活性化合物还可以为微胶囊形式,如果需要其具有上述赋形剂中一种或多种。
口服用液体剂型包括药学上可接受乳液、溶液、悬浮液、糖浆和酏剂。除了活性化合物以外,液体剂型可以包含本领域常用的惰性稀释剂(诸如水或其它溶剂)、增溶剂和乳化剂,诸如乙醇、异丙醇、碳酸乙酯、苯甲酸苄酯、丙二醇、1,3-丁二醇、油(具体为棉花子油、花生油、玉米芽油、橄榄油、蓖麻油和芝麻子油)、丙三醇、四氢糠醇、聚乙二醇和山梨聚糖的脂肪酸酯,或者这些物质的混合物等等。
除了活性化合物以外,药物组合物可以进一步包含悬浮剂,诸如乙氧基化的异硬脂醇、聚氧乙烯山梨糖醇和山梨聚糖酯、微晶纤维素、偏氢氧化铝(aluminum metahydroxide)、斑脱土、琼脂和黄芪胶,或者这些物质的混合物等等。还可以包含甜味剂、调味剂和香味剂。
本发明的药物组合物可以进一步包含如下佐剂,诸如防腐剂、润湿剂、乳化剂和分散剂。可采用各种抗菌剂和抗真菌剂防止本发明的组合物受到微生物的污染,所述抗菌剂和抗真菌剂例如为对羟基苯甲酸酯、氯丁醇、苯酚、山梨酸等等。还可能希望包含等压试剂,诸如糖、氯化钠等等。通过使用能够延长吸收的试剂(例如单硬脂酸铝和明胶)可以使可注射药物组合物的长期吸收受到影响。
对于胃肠外施用,可以采用在蓖麻油或花生油、水性丙二醇或者在无菌水溶液中的溶液。如果需要,上述水性溶液应当适当缓冲,并且首先用足够的盐水或葡萄糖对液体稀释剂进行等压处理。这些水溶液尤其适于静脉内施用、肌肉施用、皮下施用和腹膜内施用。在上下文中,所用无菌水性介质都可以通过本领域普通技术人员已知的标准技术容易地得到。
对于鼻内施用或通过吸入施用,式(I)化合物便于以溶液或悬浮液形式从患者挤压或抽吸的泵喷容器输送或者作为气溶胶喷雾从加压容器或喷雾器输送,使用合适的推进剂,例如二氯二氟甲烷、三氯氟甲烷、二氯四氟乙烷、二氧化碳或其它合适气体。在加压气溶胶的情况下,通过递送计量量的阀来确定剂量单位。加压容器或喷雾器可以包含本发明化合物的溶液或悬浮液。用于吸入器或吹药器(insufflator)的胶囊或药筒(cartridges)可被配制为含有本发明的化合物和合适的粉末基底(例如,乳糖或淀粉)的粉末混合物。
本发明的药物组合物还可以配制成用于兽用治疗,其中本发明的化合物或其兽医学上可接受盐或其兽医学上可接受溶剂化合物或前药根据常规兽医实践以适于接受的制剂形式施用,并且兽医能确定最适于具体动物的剂型和施予途径。
一般而言,式(I)化合物或其药学上可接受盐可以根据以下示意图和实例中公开的示例性途径以及通过其他本领域普通技术人员已知或由本发明公开的内容而明显的常规制备过程制备。这些方法形成本发明的其他方面。
示意图和实例中描述的反应用起始化合物中的一些根据本文所述制备。所有其他起始化合物可由一般性商业来源(诸如Sigma-AldrichCorporation,St.Louis,MO)得到。
除非另有声明,以下实验中的缩写具有如下含义:
μL-微升 | m-多重态 |
bd-宽双峰 | MHz-兆赫兹 |
bm-宽多峰 | Min(s)-分钟 |
BOC-t-丁氧羰基 | MeOH-甲醇 |
bs-宽单峰 | Mg-毫克 |
CDCl3-氘代氯仿 | ml-毫升 |
CD3OD-氘代甲醇 | mmol-毫摩尔 |
dd-双二重峰 | MPLC-中压液相色谱 |
DMF-二甲基甲酰胺 | MS-质谱 |
DMSO-二甲基亚砜 | NMR-核磁共振 |
dt-双三重峰 | ppm-百万分之一份 |
EtOAc-乙酸乙酯 | psi-磅每平方英寸 |
EtOH-乙醇 | s-单线态 |
h(例如1h,2h)-小时 | SPA-邻近闪烁分析 |
H(例如1H,2H)-氢 | t-三重态 |
Hz-赫兹 | THF-四氢呋喃 |
IPA-异丙醇 | Tris-三(羟甲基)氨基甲烷 |
J-自旋-自旋耦合常数 | |
LC-液相色谱 |
本发明的示意图和实例公开的方法仅仅为了阐述本发明的实例,但并不构成对其限制。
示意图1举例说明多个用于形成脂族肼的方法,该脂族肼可用于制备本发明的化合物。酮可以转换成酰肼酰亚胺并被硼烷或氰基硼氢化钠还原。还可以使用其他还原剂。然后可以用酸除去Boc基团从而形成所希望的肼中间体。或者可以用三苯基膦和二氮杂羧酸二叔丁酯对脂族醇进行处理从而转换成boc保护的肼。然后可以用酸除去Boc基团,从而释放肼。文献中已知通过如下合成芳族肼:使苯胺先后通过重氮化化学反应和还原反应从而转化成肼。
示意图1
吡咯烷中间体可以通过如下形成:通过用酸催化使α-β不饱和酯与在商业上可获得的N-(甲氧基甲基)(苯基)-N-((三甲基甲硅烷基)甲基)甲胺偶联。这个化学反应在以下实验部分举例说明,还通过若干文献实例(诸如Hosomi等人的Chem.Lett.13(7)1117-1120,1984)举例说明。吡咯烷还通过如下以对映异构纯的方式合成:对酯使用手性佐剂(参见Nichols等人Org.Lett.,8(7),1495-1498,2006)或者在环加成化学反应中使用手性苄基胺(参见Haight等人Org.Proc.Res.Dev.,8(6),897-902,2004)。
示意图2
然后,肼可以在诸如甲氧化钠或三乙胺的碱的存在下与2-(乙氧基亚甲基)丙二腈或其取代变体偶联,从而得到所需氨基氰基吡唑。氰基可以通过各种试剂氧化,但使用两种条件来制备本专利的化合物。用浓硫酸或过氧化氢和氢氧化铵进一步处理,从而得到氨基-酰胺吡唑。然后,在加热下,使氨基-酰胺-吡唑在诸如叔丁氧化钾的碱的存在下与酯偶联。这个反应选择的溶剂是四氢呋喃,在一些情况下,可以采用诸如分子筛的脱水剂来改善偶联产率。
示意图3
然后,通过标准氢化条件除去苄基,从而得到仲胺,该仲胺备用于进一步的官能化。胺可以在碱的存在下用烷基卤化物烷基化,或者利用各种氢化物还原剂进行还原氨化化学反应作用从而得到所需化合物。
示意图4
实例
以下实例意欲说明本发明的具体实例和其制备方法,但并不意欲以任何方式限制本说明书(包括权利要求书)。除非另有声明,所使用的所有试剂商购。
实例1
(a)5-氨基-1-(2-甲氧基苯基)-1H-吡唑-4-甲腈
向1-(2-甲氧基苯基)肼氯化氢(3g,0.017mol)在乙醇(50mL)中的溶液添加2-(甲氧基亚甲基)丙二腈(1.89g,0.9当量)和甲醇钠(1.92g,2.1当量)。将反应混合物在回流下加热18小时,并浓缩。将反应混合物在盐水和乙酸乙酯中进行分配。将有机层分离,用硫酸镁干燥,过滤并浓缩。用20-60%乙酸乙酯/己烷洗脱的MPLC Biotage色谱得到53%产率的标题化合物。400MHz 1H NMR(CDCl3)δ7.64(m,1H),7.40(m,2H),7.08(m,2H),4.51(bs,2H),3.87(s,3H);MS:(M+H m/z=215.2)。
(b)5-氨基-1-(2-甲氧基苯基)-1H-吡唑-4-甲酰胺
向5-氨基-1-(2-甲氧基苯基)-1H-吡唑-4-甲腈(1.53g)在饱和氢氧化铵(30mL)中的溶液添加30%的过氧化氢溶液(6mL)。将反应在环境温度下搅拌18小时,并用60mL的饱和硫酸钠溶液缓缓猝灭。将水层用乙酸乙酯萃取,在硫酸镁上干燥,过滤并浓缩。用20-60%甲醇/二氯甲烷洗脱的MPLC Biotage色谱得到标题化合物1.38g(84%)。400MHz 1H NMR(DMSO)δ7.79(s,1H),7.42(m,1H),7.25(d,J=7.5Hz,2H),7.19(d,J=8.3Hz,2H),7.03(t,J=6.2Hz,1H),5.83(s,2H),3.76(s,3H);MS:(M+H m/z=233.2)。
(c)(3,4-反式)-1-苄基-4-甲基吡咯烷-3-羧酸甲酯
向(E)-丁-2-烯酸甲酯(1.6g)的溶液中添加甲苯(30mL)、N-(甲氧基甲基)(苯基)-N-((三甲基甲硅烷基)甲基)甲胺(3.7g)和三氟乙酸(1.5g)。将反应混合物在50℃下加热18小时。将反应混合物浓缩,用饱和碳酸氢钠猝灭,用二氯甲烷萃取,在硫酸镁上干燥,过滤并浓缩。用20-30%乙酸乙酯/己烷洗脱通过MPLC色谱纯化得到标题化合物(1.5g)。400MHz 1H NMR(CDCl3)δ7.33-7.20(m,5H),4.15-4.08(m,1H),3.66-3.53(m,2H),2.87-2.74(m,2H),2.53-2.44(m,2H),2.23-2.19(m,1H),1.23(t,J=7.1Hz,3H),1.11(d,J=6.6Hz,3H)。
(d)6-[(3,4-反式)-1-苄基-4-甲基吡咯烷-3-基]-1-(2-甲氧基苯基)-1,5-二氢-4H- 吡唑并[3,4-d]嘧啶-4-酮
(Rac表示外消旋,下同)
向(3,4-反式)-1-苄基-4-甲基吡咯烷-3-羧酸甲酯(241mg)和5-氨基-1-(2-甲氧基苯基)-1H-吡咯-4-甲酰胺(200mg)中添加叔丁醇钾在THF中的溶液(1M,4.31mL,5当量)。将反应混合物在回流下加热16小时,并倒入饱和碳酸氢钠中。将水层用乙酸乙酸萃取,在硫酸镁上干燥,过滤并浓缩。采用1-4%甲醇/二氯甲烷(具有0.5%饱和氢氧化铵)洗脱的MPLC Biotage色谱得到79mg标题化合物。400MHz 1H NMR(DMSO)δ8.16(d,J=7.9Hz,1H),7.92(s,1H),7.34(m,5H),7.09(m,1H),6.92(m,2H),3.89(s,3H),3.84(m,1H),3.71(m,1H),3.37(t,J=9.1Hz,1H),3.09(m,1H),2.85(m,1H),2.65(m,1H),2.47(m,1H),2.03(m,2H),1.19(d,J=7.1Hz,3H);MS:(M+Hm/z=416.1)。
实例2
6-[(3,4-反式)-1-苄基-4-甲基吡咯烷-3-基]-1-环戊基-1,5-二氢-4H-吡唑并[3,4-
d]嘧啶-4-酮
遵循6-[(3,4-反式)-1-苄基-4-甲基吡咯烷-3-基]-1-(2-甲氧基苯基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用5-氨基-1-环戊基-1H-吡唑-4-甲酰胺替换,从而得到标题化合物。400MHz 1H NMR(CD3OD)δ8.00(s,1H),7.38-7.23(m,5H),5.14-5.10(m,1H),3.80-3.57(m,2H),3.34(t,J=8.3Hz,1H),2.97(d,J=9.9Hz,1H),2.80-2.78(m,1H),2.53-2.49(m,1H),2.41-2.38(m,1H),2.10-1.89(m,7H),1.70-1.66(m,2H),1.17(d,J=6.6Hz,3H)。MS:(M+H m/z=378.1)。
实例3
6-[(3S,4S)1-苄基-4-甲基吡咯烷-3-基]-1-环戊基-1,5-二氢-4H-吡唑并[3,4-d]
嘧啶-4-酮
在Chiralcel OD手性HPLC柱上分离外消旋物,移动相90/10庚烷/EtOH,TR=6.807,从而得到对映异构体。400MHz 1H NMR(CDCl3)δ8.00(s,1H),7.38-7.22(m,5H),5.27-5.10(m,1H),3.78(d,J=12.5Hz,1H),3.6(d,J=12.5Hz,1H),3.34(t,J=8.3Hz,1H),2.97(d,J=9.9Hz,1H),2.80-2.78(m,1H),2.52-2.48(m,1H),2.41-2.38(m,1H),2.10-1.89(m,7H),1.70-1.66(m,2H),1.18(d,J=6.6Hz,3H)。MS:(M+H m/z=378.1)。
Chiralcel OD,移动相90/10庚烷/IPA,TR=9.433
实例4
(a)1-环戊基-6-[(3,4-反式)-4-甲基吡咯烷-3-基]-1H-吡唑并[3,4-d]嘧啶- 4(5H)-酮
将6-[(3,4-反式)-1-苄基-4-甲基吡咯烷-3-基]-1-环戊基-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮(970mg)在乙醇250mL中的溶液加入Parr瓶中。添加乙酸(2.5mL)和Pd(OH)2(500mg)。将反应混合物放置在氢化器中在40PSI下16小时。将反应混合物过滤通过硅藻土并浓缩。将反应混合物在饱和碳酸氢盐溶液和二氯甲烷中分配。将各层分离,并将水层用二氯甲烷萃取6x。将有机层在硫酸镁上干燥、过滤并浓缩,从而得到429mg的标题化合物。400MHz 1H NMR(CD3OD)δ9.25(brs,1H),8.02(s,1H),5.20-5.17(m,1H),3.91(m,1H),3.77-3.68(m,2H),3.46-3.44(m,1H),3.10(m,1H),2.89(m,1H),2.13-1.87(m,6H),1.74-1.65(m,2H),1.20(d,J=6.2Hz,3H)。MS:(M+H m/z=288.1)。
(b)1-环戊基-6-{(3,4-反式)-4-甲基-1-[4-(三氟甲基)嘧啶-2-基]吡咯烷-3-基}- 1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
向1-环戊基-6-[(3,4-反式)-4-甲基吡咯烷-3-基]-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮(40mg)在二甲基甲酰胺(1ml)中的溶液添加碳酸铯(2当量)和2-氯-4-(三氟甲基)嘧啶(1.2当量),并将反应混合物在60℃下加热90分钟。将反应混合物倒入饱和碳酸氢钠中,用二氯甲烷萃取,在硫酸镁上干燥,过滤并浓缩。通过MPLC Biotage色谱仪采用20-60%乙酸乙酯/己烷洗脱纯化,从而得到40mg的标题化合物。400MHz 1H NMR(CDCl3)δ8.51(d,J=5.0Hz,1H),8.02(m,1H),6.79(d,J=4.6Hz,1H),5.16-5.08(m,1H),4.243.97(m,3H),3.37-3.32(m,1H),3.20-3.14(m,1H),2.09-2.05(m,3H),1.96-1.90(m,1H),1.73-1.56(m,5H),1.24(d,J=6.6Hz,3H)。MS:(M+Hm/z=434.1)。
实例5
1-环戊基-6-[(3,4-反式)-4-甲基-1-嘧啶-2-基吡咯烷-3-基]-1,5-二氢-4H-吡唑并
[3,4-d]嘧啶-4-酮
遵循1-环戊基-6-{(3,4-反式)-4-甲基-1-[4-(三氟甲基)嘧啶-2-基]吡咯烷-3-基}-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用2-氯嘧啶替换,从而得到标题化合物。400MHz 1H NMR(CD3OD)δ8.29(d,J=5.0Hz,2H),7.96(s,1H),6.60(t,J=5.0Hz,1H),5.08-5.04(m,1H),4.06-3.87(m,3H),3.23-3.18(m,1H),3.12(q,J=7.9Hz,1H),2.80-2.76(m,1H),2.05-1.98(m,4H),1.90-1.82(m,2H),1.66-1.61(m,2H),1.17(d,J=7.1Hz,3H)。MS:(M+H m/z=366.1)。
实例6
6-[(3,4-反式)-1-苯甲酰基-4-甲基吡咯烷-3-基]-1-环戊基-1,5-二氢-4H-吡唑并
[3,4-d]嘧啶-4-酮
向1-环戊基-6-[(3,4-反式)-4-甲基吡咯烷-3-基]-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮(40mg)在二氯甲烷(1ml)中的溶液添加三乙胺(2.5当量)和苯甲酰氯(1.2当量),然后将反应混合物在环境温度下搅拌1小时。将反应混合物倒入饱和的碳酸氢钠中,用二氯甲烷萃取,在硫酸镁上干燥,过滤并浓缩。通过Biotage MPLC色谱仪采用2-4%甲醇/二氯甲烷洗脱纯化,从而得到标题化合物(27mg)。400MHz 1H NMR(CDCl3)δ8.06-8.03(m,1H),7.57-7.50(m,2H),7.43-7.37(m,3H),5.20-5.13(m,1H),4.16-4.03(m,1H),3.92(d,J=8.3Hz,1H),3.81-3.76(m,1H),3.47-3.29(m,1H),3.17-3.03(m,1H),2.84-2.67(m,1H),2.11-1.80(m,3H),1.79-1.72(m,1H),1.56-1.30(m,4H),1.21-1.11(m,3H)。MS:(M+H m/z=392.1)。
实例7
1-环戊基-6-[(3,4-反式)-4-甲基-1-(吡啶-3-基甲基)吡咯烷-3-基]-1,5-二氢-4H-
吡唑并[3,4-d]嘧啶-4-酮
向1-环戊基-6-[(3,4-反式)-4-甲基吡咯烷-3-基]-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮(40mg)的1,2-二氯乙烷(2mL)溶液中添加乙酸(2当量)、烟醛(1.5当量)和三乙酰氧基硼氢化钠(58mg)。将反应混合物在40℃下加热4小时,然后倒入饱和碳酸氢钠中,在二氯甲烷中萃取,在硫酸镁上干燥,过滤并浓缩。通过Biotage MPLC色谱仪采用1-4%甲醇/二氯甲烷/0.5%氢氧化铵洗脱纯化,从而得到标题化合物(47mg)。400MHz 1H NMR(CDCl3)δ8.55(m,2H),2.02(s,1H),7.84(m,1H),7.36(m,1H),5.16-5.09(m,1H),3.82-3.60(m,2H),3.36(m,1H),3.05-2.38(m,4H),2.13-1.89(m,7H),1.73-1.68(m,2H),1.21(m,J=7.1Hz,3H)。MS:(M+H m/z=379.1)。
实例8
1-环戊基-6-{(3,4-反式)-4-甲基-1-[3-(三氟甲基)苄基]吡咯烷-3-基}-1,5-二氢-
4H-吡唑并[3,4-d]嘧啶-4-酮
遵循1-环戊基-6-{(3,4-反式)-4-甲基-1-(吡啶-3-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用3-(三氟甲基)苯甲醛替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ8.02(s,1H),7.66(s,1H),7.53-7.50(m,3H),5.16-5.09(m,1H),3.80(m,1H),3.69-3.66(m,1H),3.35(m,1H),2.99(m,1H),2.83(m,1H),2.42(m,1H),2.12-1.93(m,7H),1.74-1.68(m,2H),1.56(m,1H),1.21(d,J=6.6Hz,3H)。MS:(M+H m/z=446.0)。
实例9
1-环戊基-6-[(3,4-反式)-4-甲基-1-(喹啉-2-基甲基)吡咯烷-3-基]-1,5-二氢-4H-
吡唑并[3,4-d]嘧啶-4-酮
遵循1-环戊基-6-[(3,4-反式)-4-甲基-1-(吡啶-3-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用喹啉-2-甲醛替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ8.22-8.15(m,2H),8.07(s,1H),7.80(d,J=7.9Hz,1H),7.71(t,J=8.3Hz,1H),7.69-7.50(m,2H),5.18-5.11(m,1H),4.25(m,1H),3.91(m,1H),3.71(m,1H),3.49(m,1H),3.17(m,1H),2.87(m,1H),2.73-2.45(m,2H),2.13-1.94(m,6H),1.75-1.68(m,2H),1.23(d,J=7.1Hz,3H)。MS:(M+H m/z=429.1)。
实例10
1-环戊基-6-[(3,4-反式)-4-甲基-1-(喹啉-4-基甲基)吡咯烷-3-基]-1,5-二氢-4H-
吡唑并[3,4-d]嘧啶-4-酮
遵循1-环戊基-6-[(3,4-反式)-4-甲基-1-(吡啶-3-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用喹啉-4-甲醛替代,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ8.92-8.89(m,1H),8.27-8.25(m,1H),8.18-8.16(m,1H),8.00(s,1H),7.80-7.74(m,2H),7.63-7.50(m,1H),5.14-5.07(m,1H),4.18(m,2H),3.37(m,1H),3.10-2.30(m,5H),2.15-1.93(m,6H),1.74-1.64(m,2H),1.21(d,J=6.6Hz,3H)。MS:(M+H m/z=429.1)。
实例11
1-环戊基-6-[(3,4-反式)-4-甲基-1-{[6-(三氟甲基)吡啶-3-基]甲基}吡咯烷-3-
基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
遵循1-环戊基-6-[(3,4-反式)-4-甲基-1-(吡啶-3-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用6-(三氟甲基)烟醛替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ8.63(m,1H),8.01(s,1H),7.7(d,J=7.80Hz,1H),5.12(m,1H),4.82(m,1H),3.79(q,J=13.2,16.2,Hz,2H),3.32(t,J=8.5Hz,1H),3.02(m,1H),2.86(m,1H),2.63(m,1H),2.45(m,1H),2.12-2.88(m,6H),),1.74-1.64(m,3H),1.32(d,J=7.05Hz,3H)。MS:(M+H m/z=447.0)。
实例12
1-环戊基-6-[(3,4-反式)-4-甲基-1-(喹喔啉-2-基甲基)吡咯烷-3-基]-1,5-二氢-
4H-吡唑并[3,4-d]嘧啶-4-酮
遵循1-环戊基-6-[(3,4-反式)-4-甲基-1-(吡啶-3-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用喹喔啉-2-甲醛替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ8.86(s,1H),8.31-8.29(m,1H),8.05-8.08(m,2H),7.79-7.70(m,2H),5.16-5.12(m,1H),4.32-4.28(m,1H),3.94-3.98(m,1H),3.46(t,J=8.3Hz,1H),3.26(d,J=9.5Hz,1H),2.90-2.88(m,1H),2.64-2.60(m,1H),2.50-2.47(m,1H),2.18(t,J=8.3Hz,1H),2.11-1.91(m,6H),1.71-1.66(m,2H),1.23(d,J=7.05Hz,3H)。MS:(M+H m/z=430.1)。
实例13
1-环戊基-6-[(3,4-反式)-4-甲基-1-(喹喔啉-6-基甲基)吡咯烷-3-基]-1,5-二氢-
4H-吡唑并[3,4-d]嘧啶-4-酮
遵循1-环戊基-6-[(3,4-反式)-4-甲基-1-(吡啶-3-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用喹喔啉-6-甲醛替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ8.82(s,2H),8.14(d,J=8.3Hz,1H),8.07-7.93(m,3H),5.15-5.08(m,1H),4.00-3.87(m,2H),3.37(t,J=8.7Hz,1H),3.04(d,J=9.5Hz,1H),2.85-2.84(m,1H),2.66-2.62(m,1H),2.46-2.42(m,1H),2.11-1.92(m,7H),1.71-1.63(m,2H),1.20(d,J=7.05Hz,3H)。MS:(M+H m/z=430.1)。
实例14
1-环戊基-6-[(3,4-反式)-4-甲基-1-(嘧啶-5-基甲基)吡咯烷-3-基]-1,5-二氢-4H-
吡唑并[3,4-d]嘧啶-4-酮
遵循1-环戊基-6-[(3,4-反式)-4-甲基-1-(吡啶-3-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用嘧啶-5-甲醛替换,从而得到标题化合物。400MHz 1H NMR,(CDCl3)δ9.16(s,1H),8.76(s,2H),8.02(s,1H),5.17-5.10(m,1H),3.78-3.69(m,2H),3.27(t,J=8.7Hz,1H),3.07(d,J=9.5Hz,1H),2.89(m,1H),2.69(m,1H),2.48-2.46(m,1H),2.12-1.89(m,6H),1.74-1.63(m,3H),1.26-1.19(m,3H)。MS:(M+H m/z=380.1)。
实例15
1-环戊基-6-[(3,4-反式)-1,4-二甲基吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]
嘧啶-4-酮
遵循1-环戊基-6-[(3,4-反式)-4-甲基-1-(吡啶-3-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮,但用甲醛替换,从而得到标题化合物。400MHz 1H NMR,(CDCl3)δ8.04(s,1H),5.18-5.11(m,1H),3.39(m,1H),3.15(m,1H),3.03-2.96(m,1H),2.70(m,1H),2.51(m,4H),2.15-1.90(m,7H),1.75-1.66(m,2H),1.20(d,J=6.6Hz,3H)。MS:(M+H m/z=302.2)。
实例16
1-环戊基-6-[(3,4-反式)-4-甲基-1-(2,2,2-三氟乙基)吡咯烷-3-基]-1,5-二氢-4H-
吡唑并[3,4-d]嘧啶-4-酮
向1-环戊基-6-[(3,4-反式)-4-甲基吡咯烷-3-基]-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮(40mg)在二甲基甲酰胺(1.5mL)中的溶液添加碳酸钠(30mg)和1,1,1-三氟-2-碘代乙烷(1.1当量)。将反应混合物在40℃下加热3天。将额外3当量的1,1,1-三氟-2-碘代乙烷以及碳酸铯(2当量)和反应混合物在60℃下加热3天。将反应混合物倒入饱和碳酸氢钠中,用二氯甲烷萃取,在硫酸镁上干燥,过滤并浓缩。通过MPLC Biotage采用0.5-2%甲醇/二氯甲烷/0.5%氢氧化铵洗脱纯化,从而得到标题化合物(9mg)。400MHz 1H NMR,(CDCl3)δ8.03(s,1H),5.16-5.10(m,1H),3.50-3.48(m,1H),3.30-3.25(m,2H),2.52(m,1H),2.25(m,1H),2.13-1.94(m,5H),1.72-1.57(m,6H),1.22(d,J=7.1Hz,3H)。MS:(M+H m/z=370.1)。
实例17
1-环戊基-6-{(3,4-反式)-4-甲基-1-[(2-甲基吡啶-3-基)甲基]吡咯烷-3-基}-1,5-
二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
遵循1-环戊基-6-[(3,4-反式)-4-甲基-1-(吡啶-3-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用2-甲基烟醛替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ8.40-8.39(m,1H),7.99(s,1H),7.62-7.60(m,1H),7.12-7.09(m,1H),5.15-5.08(m,1H),3.73-3.65(m,2H),3.30(t,J=8.7Hz,1H),3.04(d,J=9.95Hz,1H),2.86-2.84(m,1H),2.66-2.62(m,4H),2.46-2.39(m,1H),2.11-1.89(m,7H),1.71-1.64(m,2H),1.19(d,J=7.05Hz,3H)。MS:(M+H m/z=393.2)。
实例18
1-环戊基-6-[(3,4-反式)-4-甲基-1-(喹啉-8-基甲基)吡咯烷-3-基]-1,5-二氢-4H-
吡唑并[3,4-d]嘧啶-4-酮
遵循1-环戊基-6-[(3,4-反式)-4-甲基-1-(吡啶-3-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用喹啉-5-甲醛替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ9.10-9.09(m,1H),8.13(dd,J=8.3,1.6Hz,1H),7.98(s,1H),7.76-7.74(d,J=7.88Hz,2H),7.50(t,J=7.88Hz,1H),7.45-7.42(m,1H),5.14-5.07(m,1H),4.52(d,J=12.40Hz,1H),4.21(d,J=12.40Hz,1H),3.34(t,J=8.3Hz,1H),3.1(d,J=9.95Hz,1H),2.8-2.79(m,1H),2.71-2.67(m,1H),2.37-2.31(m,1H),2.10-1.88(m,7H),1.72-1.62(m,2H),1.17(d,J=6.64Hz,3H)。MS:(M+H m/z=429.2)。
实例19
1-环戊基-6-[(3,4-反式)-4-甲基-1-(喹啉-3-基甲基)吡咯烷-3-基]-1,5-二氢-4H-
吡唑并[3,4-d]嘧啶-4-酮
遵循1-环戊基-6-[(3,4-反式)-4-甲基-1-(吡啶-3-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用喹啉-3-甲醛替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ8.87(s,1H),8.29(s,1H),8.07(d,J=7.8Hz,1H),8.02(s,1H),7.89(d,J=7.9Hz,1H),7.70-7.66(m,1H),7.54(t,J=7.5Hz,1H),5.16-5.08(m,1H),4.02-3.98(m,1H),3.86-3.83(m,1H),3.47(s,1H),3.40(t,J=8.3Hz,1H),3.07(d,J=8.5Hz,1H),2.85(m,1H),2.65-2.61(m,1H),2.47-2.46(m,1H),2.15-1.87(m,6H),1.73-1.63(m,2H),1.20(d,J=7.1Hz,3H)。MS:(M+H m/z=429.2)。
实例20
1-环戊基-6-{(3,4-反式)-4-甲基-1-[(6-甲基吡啶-3-基)甲基]吡咯烷-3-基}-1,5-
二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
遵循1-环戊基-6-[(3,4-反式)-4-甲基-1-(吡啶-3-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用6-甲基烟醛替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ8.37(d,J=1.2Hz,1H),8.00(s,1H),7.73(dd,J=7.9,2.1Hz,1H),7.18(d,J=8.3Hz,1H),5.16-5.08(m,1H),3.76-3.72(m,1H),3.61-3.57(m,1H),3.32(t,J=8.71Hz,1H),2.98(d,J=9.9Hz,1H),2.83-2.81(m,1H),2.57-2.51(m,4H),2.42-2.38(m,1H),2.11-1.89(m,7H),1.72-1.64(m,2H),1.19(d,J=7.1Hz,3H)。MS:(M+H m/z=393.2)。
实例21
(a)(3,4-反式)-1-苄基-4-异丙基吡咯烷-3-羧酸甲酯
遵循(3,4-反式)-1-苄基-4-甲基吡咯烷-3-羧酸甲酯的制备方法,但用(E)-4-甲基戊-2-烯酸甲酯替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ7.31-7.20(m,5H),3.66(s,3H),3.62-3.49(m,2H),2.79-2.69(m,3H),2.31-2.27(m,2H),1.61-1.56(m,1H),1.27-4.25(m,1H),0.86(t,J=2.9Hz,6H)。MS:(M+H m/z=262.2)。
(b)6-[(3,4-反式)-1-苄基-4-异丙基吡咯烷-3-基]-1-环戊基-1,5-二氢-4H- 吡唑并[3,4-d]嘧啶-4-酮
遵循6-[(3,4-反式)-1-苄基-4-甲基吡咯烷-3-基]-1-(2-甲氧基苯基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用5-氨基-1-环戊基-1H-吡唑-4-甲酰胺和(3,4-反式)-1-苄基-4-异丙基吡咯烷-3-羧酸甲酯替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ8.00(s,1H),7.38-7.32(m,4H),7.27-7.24(m,1H),5.13-5.05(m,1H),3.78(d,J=12.5Hz,1H),3.6(d,J=12.5Hz,1H),3.27-3.21(m,1H),2.98-2.96(m,2H),2.37(m,1H),2.10-1.88(m,7H),1.69-1.60(m,3H),0.98(d,J=6.6Hz,3H),0.86(d,J=6.6Hz,3H)。MS:(M+H m/z=406.1)。
实例22
(a)5-氨基-1-环戊基-3-甲基-1H-吡唑-4-甲腈
遵循5-氨基-1-(2-甲氧基苯基)-1H-吡唑-4-甲腈的制备方法,但用1-环戊基肼和2-(1-甲氧基亚乙基)丙二腈替换,从而得到标题化合物。1H NMR(300MHz,CDCl3):δ4.24(m,3H),2.24(s,3H),2.01(m,4H),1.90(m,2H),1.67(m,2H)。
(b)5-氨基-1-环戊基-3-甲基-1H-吡唑-4-甲酰胺
遵循5-氨基-1-(2-甲氧基苯基)-1H-吡唑-4-甲酰胺的制备方法,但用5-氨基-1-环戊基-3-甲基-1H-吡唑-4-甲腈替换,从而得到标题化合物。1HNMR(300MHz,CDCl3):δ5.39(br,2H),5.32(br,2H),4.26(m,1H),2.38(s,3H),2.04(m,4H),1.9(m,2H),1.66(m,2H)。
(c)6-[(3,4-反式)-1-苄基-4-甲基吡咯烷-3-基]-1-环戊基-3-甲基-1,5-二 氢-4H-吡唑并[3,4-d]嘧啶-4-酮
遵循6-[(3,4-反式)-1-苄基-4-甲基吡咯烷-3-基]-1-(2-甲氧基苯基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用5-氨基-1-环戊基-3-甲基-1H-吡唑-4-甲酰胺替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ7.45-7.20(m,5H),5.13-4.96(m,1H),3.85-3.61(m,2H),3.45-3.30(m,1H),3.08-2.98(m,1H),2.82-2.74(m,1H),2.60-2.45(m,4H),2.45-2.30(m,1H),2.18-1.80(m,6H),1.79-1.50(m,3H),1.2-1.1(m,3H)。MS:(M+H m/z=392.5)。
实例23
(a)1-环戊基-6-[(3S,4S)-4-甲基吡咯烷-3-基]-1H-吡唑并[3,4-d]嘧啶- 4(5H)-酮
将6-[(3S,4S)1-苄基-4-甲基吡咯烷-3-基]-1-环戊基-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮(9.25g)在乙醇100mL中的溶液添加到Parr瓶中。先后添加2mL的浓HCl和3g的氢氧化钯。将反应混合物放置在氢化器中45psi的H2气体下4小时。将反应混合物在硅藻土上过滤并浓缩,从而得到HCl盐形式的标题化合物。400MHz 1H NMR(CDCl3)δ8.00(s,1H),5.14-5.10(m,1H),4.89-3.84(m,1H),3.72-3.67(m,1H),3.38-3.31(m,1H),3.03-2.98(m,1H),2.85-2.81(m,1H),2.08-1.85(m,7H),1.69-1.61(m,2H),1.19-1.10(m,3H)。MS:(M+H m/z=288.2)。
(b)1-环戊基-6-[(3S,4S)-4-甲基-1-(喹喔啉-6-基甲基)吡咯烷-3-基]-1,5- 二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
遵循1-环戊基-6-[(3,4-反式)-4-甲基-1-(吡啶-3-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用1-环戊基-6-[(3S,4S)-4-甲基吡咯烷-3-基]-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮和喹喔啉-6-甲醛替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ8.82(s,2H),8.14(d,J=8.3Hz,1H),8.07-7.93(m,3H),5.15-5.08(m,1H),4.00-3.87(m,2H),3.37(t,J=8.7Hz,1H),3.04(d,J=9.5Hz,1H),2.85-2.84(m,1H),2.66-2.62(m,1H),2.46-2.42(m,1H),2.11-1.92(m,7H),1.71-1.63(m,2H),1.20(d,J=7.05Hz,3H)。MS:(M+H m/z=430.1)。
实例24
1-环戊基--6-[(3,4-反式)-4-甲基-1-(2-苯基乙基)吡咯烷-3-基]-1,5-二氢-4H-吡
唑并[3,4-d]嘧啶-4-酮
遵循1-环戊基-6-[(3,4-反式)-4-甲基-1-(吡啶-3-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用2-苯基乙醛替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ8.03(s,1H),7.32-7.19(m,5H),5.18-5.11(m,1H),3.44(t,J=8.7Hz,1H),3.14(d,J=9.9Hz,1H),2.90-2.78(m,5H),2.56-2.52(m,1H),2.40-2.39(m,1H),2.14-1.89(m,7H),1.73-1.67(m,2H),1.19(d,J=7.05Hz,3H)。MS:(M+H m/z=392.1)。
实例25
1-环戊基-6-{(3,4-反式)-1-[(6-甲氧基吡啶-3-基)甲基]-4-甲基吡咯烷-3-基}-
1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
遵循1-环戊基-6-[(3,4-反式)-4-甲基-1-(吡啶-3-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用6-甲氧基烟醛替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ8.01(dd,J=31.5,2.5Hz,1H),8.00(s,1H),7.69(dd,J=8.3,2.5Hz,1H),6.76(d,J=8.3Hz,1H),5.16-5.09(m,1H),3.90(s,3H),3.68(d,J=12.9Hz,1H),3.55(d,J=12.9Hz,1H),3.31(t,J=8.7Hz,1H),2.98(d,J=9.9Hz,1H),2.81-2.79(m,1H),2.54-2.50(m,1H),2.41-2.36(m,1H),2.12-1.87(m,7H),1.73-1.64(m,2H),1.18(d,J=7.05Hz,3H)。MS:(M+H m/z=409.1)。
实例26
1-环戊基-6-[(3,4-反式)-4-甲基-1-(吡啶-2-基甲基)吡咯烷-3-基]-1,5-二氢-4H-
吡唑并[3,4-d]嘧啶-4-酮
遵循1-环戊基-6-[(3,4-反式)-4-甲基-1-(吡啶-3-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用比考啉醛(picolinaldehyde)替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ8.63-8.62(m,1H),8.02(s,1H),7.72-7.67(m,1H),7.41(d,J=7.9Hz,1H),7.20-7.17(m,1H),5.18-5.10(m,1H),4.03(d,J=13.7Hz,1H),3.75(d,J=13.7Hz,1H),3.41(t,J=8.3Hz,1H),3.07(d,J=9.9Hz,1H),2.83-2.82(m,1H),2.58(m,1H),2.46-2.40(m,1H),2.13-1.89(m,7H),1.74-1.64(m,2H),1.21(d,J=7.1Hz,3H)。MS:(M+H m/z=379.1)。
实例27
1-环戊基-6-{(3,4-反式)-4-甲基-1-[(3-甲基吡啶-2-基)甲基]吡咯烷-3-基}-1,5-
二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
遵循1-环戊基-6-[(3,4-反式)-4-甲基-1-(吡啶-3-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用3-甲基比考啉醛替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ8.02(s,1H),7.57(t,J=7.5,1H),7.22(d,J=7.8Hz,1H),7.02(d,J=7.5Hz,1H),5.17-5.09(m,1H),3.97(d,J=13.3Hz,1H),3.68(d,J=13.3Hz,1H),3.42(t,J=8.3Hz,1H),3.05(d,J=9.9Hz,1H),2.82-2.80(m,1H),2.57-2.53(m,1H),5.54(s,3H),2.44-2.38(m,1H),2.12-1.89(m,7H),1.72-1.64(m,2H),1.19(d,J=7.05Hz,3H)。MS:(M+H m/z=393.1)。
实例28
(a)(3,4-反式)-1-苄基-4-乙基吡咯烷-3-羧酸乙酯
遵循(3,4-反式)-1-苄基-4-甲基吡咯烷-3-羧酸甲酯的制备方法,但用(E)-戊-2-烯酸甲酯替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ7.33-7.19(m,5H),4.15-4.08(m,2H),3.65-3.52(m,2H),2.82-2.71(m,3H),2.60-2.55(m,1H),2.38-2.24(m,2H),1.59-1.50(m,1H),1.47-1.38(m,1H),1.23(t,J=7.5Hz,3H),0.87(t,J=7.1Hz,3H)。MS:(M+H m/z=262.2)。
(b)6-[(3,4-反式)-1-苄基-4-乙基吡咯烷-3-基]-1-环戊基-1,5-二氢-4H-吡唑并 [3,4-d]嘧啶-4-酮
遵循6-[(3,4-反式)-1-苄基-4-甲基吡咯烷-3-基]-1-(2-甲氧基苯基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用5-氨基-1-环戊基-1H-吡唑-4-甲酰胺和(3,4-反式)-1-苄基-4-乙基吡咯烷-3-羧酸甲酯替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ8.00(s,1H),7.39-7.24(m,5H),5.13-5.07(m,1H),3.78(d,J=13.3Hz,1H),3.58(d,J=12.9Hz,1H),3.42(t,J=12.9Hz,1H),3.33(t,J=8.7Hz,1H),2.98(d,J=9.9Hz,1H),2.86(m,1H),2.46-2.42(m,1H),2.19-1.44(m,11H),0.92(t,J=7.05Hz,3H)。MS:(M+H m/z=392.1)。
实例29
(a)(3,4-反式)-1-苄基-4-环丙基吡咯烷-3-羧酸甲酯
遵循(3,4-反式)-1-苄基-4-甲基吡咯烷-3-羧酸甲酯的制备方法,但用(E)-3-环丙基丙烯酸酯甲酯替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ7.33-7.20(m,5H),3.66(s,3H),3.64-3.54(m,2H),2.87-2.81(m,2H),2.77-2.70(m,2H),2.47-2.43(m,1H),1.84-1.78(m,1H),0.87-0.79(m,1H),0.45-0.36(m,2H),0.20-0.06(m,2H)。MS:(M+H m/z=260.2)。
(b)6-[(3,4-反式)-1-苄基-4-环丙基吡咯烷-3-基]-1-环戊基-1,5-二氢-4H-吡唑 并[3,4-d]嘧啶-4-酮
遵循6-[(3,4-反式)-1-苄基-4-甲基吡咯烷-3-基]-1-(2-甲氧基苯基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用5-氨基-1-环戊基-1H-吡唑-4-甲酰胺和(3,4-反式)-1-苄基-4-环丙基吡咯烷-3-羧酸甲酯替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ7.99(s,1H),7.38-7.31(m,4H),7.27-7.23(m,1H),5.14-5.10(m,1H),3.78(d,J=12.4Hz,1H),3.63(d,J=12.4Hz,1H),3.32(t,J=8.7Hz,1H),3.12-3.10(m,1H),3.01(d,J=9.9Hz,1H),2.59-2.57(m,1H),2.20-1.87(m,8H),1.71-1.65(m,2H),0.86-0.84(m,1H),0.52-0.48(m,2H),0.19-0.09(m,2H)。MS:(M+H m/z=393.1)。
实例30
(a)5-氨基-1-异丙基-1H-吡唑-4-甲腈
遵循5-氨基-1-(2-甲氧基苯基)-1H-吡唑-4-甲腈的制备方法,但用1-异丙基肼替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ7.50(s,1H),4.22-4.16(m,3H),1.45(d,J=6.6Hz,6H)。MS:(M+H m/z=151.1)。
(b)5-氨基-1-异丙基-1H-吡唑-4-甲酰胺
遵循5-氨基-1-(2-甲氢基苯基)-1H-吡唑-4-甲酰胺的制备方法,但用5-氨基-1-异丙基-1H-吡唑-4-甲腈替换,从而得到标题化合物。400MHz 1HNMR(CDCl3)δ7.67(s,1H),4.40-4.33(m,1H),1.37(d,J=6.6Hz,6H)。MS:(M+H m/z=169.1)。
(c)6-[(3,4-反式)-1-苄基-4-甲基吡咯烷-3-基]-1-异丙基-1,5-二氢-4H-吡唑并 [3,4-d]嘧啶-4-酮
遵循6-[(3,4-反式)-1-苄基-4-甲基吡咯烷-3-基]-1-(2-甲氧基苯基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用5-氨基-1-异丙基-1H-吡唑-4-甲酰胺替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ7.98(s,1H),7.38-7.22(m,5H),5.07-5.04(m,1H),3.77-3.64(m,2H),3.12-3.08(m,1H),2.99-2.91(m,3H),2.67-2.63(m,1H),2.27-2.25(m,1H),1.48(d,J=7.1Hz,6H),1.14(d,J=6.6Hz,3H)。MS:(M+H m/z=352.1)。
实例31
6-[(3S,4S)-1-苄基-4-甲基吡咯烷-3-基]-1-异丙基-1,5-二氢-4H-吡唑并[3,4-d]
嘧啶-4-酮
在Chiralcel OD手性HPLC柱上分离外消旋物,移动相90/10庚烷/EtOH,TR=8.917,从而得到对映异构体。400MHz 1H NMR(CD3OD)δ7.98(s,1H),7.38-7.33(m,2H),7.33-7.29(m,2H),7.26-7.22(m,1H),5.07-5.02(m,1H),3.77-3.64(m,2H),3.12-3.07(m,1H),2.99-2.91(m,3H),2.67-2.63(m,1H),2.29-2.25(m,1H),1.48(d,J=6.6Hz,6H),1.14(d,J=6.6Hz,3H)。MS:(M+H m/z 352.1)。
实例32
(a)1-异丙基-6-[(3,4-反式)-4-甲基吡咯烷-3-基]-1H-吡唑并[3,4-d]嘧啶- 4(5H)-酮
遵循1-环戊基-6-[(3S,4S)-4-甲基吡咯烷-3-基]-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮的制备方法,但用6-[(3,4-反式)-1-苄基-4-甲基吡咯烷-3-基]-1-异丙基-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮替换,从而得到标题化合物。400MHz 1H NMR(CD3OD)δ8.02(s,1H),5.11-5.08(m,1H),3.80-3.74(m,2H),3.64-3.57(m,1H),3.30-3.22(m,1H),3.07-3.02(m,1H),2.75-2.71(m,1H),1.49(dd,J=6.6,1.7Hz,6H),1.15(d,J=7.1Hz,3H)。MS:(M+H m/z=262.2)。
(b)1-异丙基-6-[(3,4-反式)-4-甲基-1-(喹啉-2-基甲基)吡咯烷-3-基]-1,5-二氢- 4H-吡唑并[3,4-d]嘧啶-4-酮
遵循1-环戊基-6-[(3,4-反式)-4-甲基-1-(吡啶-3-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用1-异丙基-6-[(3,4-反式)-4-甲基吡咯烷-3-基]-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮和喹啉-2-甲醛替换,从而得到标题化合物。400MHz 1H NMR(CD3OD)δ8.31(d,J=8.7Hz,1H),8.02(d,J=8.7Hz,1H),7.98(s,1H),7.95(d,J=7.9Hz,1H),7.75-7.68(m,2H),7.58-7.54(m,1H),5.07-5.04(m,1H),4.11-3.96(m,2H),3.22-3.18(m,1H),3.14-3.11(m,1H),3.05-2.96(m,2H),2.71-2.68(m,1H),2.42-2.37(m,1H),1.49(q,J=6.6Hz,6H),1.17(d,J=7.1Hz,3H)。MS:(M+Hm/z 403.1)。
实例33
1-异丙基-6-[(3,4-反式)-4-甲基-1-(喹喔啉-6-基甲基)吡咯烷-3-基]-1,5-二氢-
4H-吡唑并[3,4-d]嘧啶-4-酮
遵循1-环戊基-6-[(3,4-反式)-4-甲基-1-(吡啶-3-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用1-异丙基-6-[(3,4-反式)-4-甲基吡咯烷-3-基]-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮和喹喔啉-6-甲醛替换,从而得到标题化合物。400MHz 1H NMR(CD3OD)δ8.84-8.81(m,2H),8.04-8.00(m,2H),7.96(s,1H),7.91-7.88(m,1H),5.09-5.02(m,1H),4.01-3.87(m,2H),3.14-3.93(m,4H),2.72-2.66(m,1H),2.39-2.34(m,1H),1.47(dd,J=6.6,1.2Hz,6H),1.15(d,J=6.6Hz,3H)。MS:(M+H m/z 404.1)。
实例34
1-异丙基-6-[(3,4-反式)-4-甲基-1-(喹啉-3-基甲基)吡咯烷-3-基]-1,5-二氢-4H-
吡唑并[3,4-d]嘧啶-4-酮
遵循1-环戊基-6-[(3,4-反式)-4-甲基-1-(吡啶-3-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用1-异丙基-6-[(3,4-反式)-4-甲基吡咯烷-3-基]-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮和喹啉-3-甲醛替换,从而得到标题化合物。400MHz 1H NMR(CD3OD)δ8.87(d,J=2.1Hz,1H),8.30(d,J=1.2Hz,1H),7.99(d,J=8.7Hz,1H),7.97(s,1H),7.90(d,J=7.5Hz,1H),7.74-7.69(m,1H),7.60-7.56(m,1H),5.06-4.99(m,1H),3.97-3.87(m,2H),3.13-3.09(m,1H),3.05-3.02(m,2H),2.97-2.93(m,1H),2.73-2.66(m,1H),2.39-2.35(m,1H),1.46(dd,J=6.6,2.3Hz,6H),1.15(d,J=7.1Hz,3H)。MS:(M+H m/z 403.1)。
实例35
(a)(3,4-反式)-1-苄基-4-(三氟甲基)吡咯烷-3-羧酸乙酯
遵循(3,4-反式)-1-苄基-4-甲基吡咯烷-3-羧酸甲酯的制备方法,但用(E)-4,4,4-三氟丁-2-烯酸甲酯替换,从而得到标题化合物。400MHz 1HNMR(CDCl3)δ7.33-7.22(m,5H),4.16(q,J=7.1Hz,2H),3.65-3.56(m,2H),3.40-3.32(m,1H),3.12-3.07(m,1H),2.90-2.76(m,3H),2.70-2.66(m,1H),1.24(t,J=7.1Hz,3H)。MS:(M+H m/z=302.1)。
(b)6-[(3,4-反式)-1-苄基-4-(三氟甲基)吡咯烷-3-基]-1-环戊基-1,5-二氢-4H- 吡唑并[3,4-d]嘧啶-4-酮
遵循6-[(3,4-反式)-1-苄基-4-甲基吡咯烷-3-基]-1-(2-甲氧基苯基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用5-氨基-1-环戊基-1H-吡唑-4-甲酰胺和(3,4-反式)-1-苄基-4-(三氟甲基)吡咯烷-3-羧酸甲酯替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ8.02(s,1H),7.38-7.26(m,5H),5.15-5.11(m,1H),3.83(d,J=12.5Hz,1H),3.64(d,J=12.5Hz,1H),3.44-3.41(m,1H),3.34(t,J=9.1Hz,1H),3.12-3.10(m,1H),3.03(d,J=9.9Hz,1H),2.70-2.65(m,1H),2.55-5.50(m,1H),2.11-1.93(m,4H),1.72-1.66(m,2H),0.86-0.83(m,2H)。MS:(M+H m/z=432.0)。
实例36
(a)1-异丙基-6-[(3S,4S)-4-甲基吡咯烷-3-基]-1H-吡唑并[3,4-d]嘧啶-4(5H)酮
遵循1-环戊基-6-[(3S,4S)-4-甲基吡咯烷-3-基]-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮的制备方法,但用6-[(3S,4S)-1-苄基-4-甲基吡咯烷-3-基]-1-异丙基-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮替换,从而得到标题化合物。400MHz 1H NMR(CD3OD)δ8.02(s,1H),5.11-5.08(m,1H),3.80-3.74(m,2H),3.64-3.57(m,1H),3.30-3.22(m,1H),3.07-3.02(m,1H),2.75-2.71(m,1H),1.49(dd,J=6.6,1.7Hz,6H),1.15(d,J=7.1Hz,3H)。MS:(M+H m/z=262.2)。
(b)1-异丙基-6-[(3S,4S)-4-甲基-1-(喹喔啉-6-基甲基)吡咯烷-3-基]-1,5-二氢- 4H-吡唑并[3,4-d]嘧啶-4-酮
(Abs表示绝对构型,下同)
遵循1-环戊基-6-[(3,4-反式)-4-甲基-1-(吡啶-3-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用1-异丙基-6-[(3S,4S)-4-甲基吡咯烷-3-基]-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮和喹喔啉-6-甲醛替换,从而得到标题化合物。400MHz1H NMR(CD3OD)δ11.0(brs,1H),8.81(s,2H),8.13(d,J=8.7,1H),8.01-7.92(m,3H),5.01-4.94(m,1H),4.01-3.88(m,2H),3.37(t,J=8.3,1H),3.05(d,J=9.9,1H),2.86-2.85(m,1H),2.70-2.68(m,1H),2.49-2.44(m,1H),2.07-2.01(m,1H),1.48(dd,J=15.3,6.6Hz,6H),1.20(d,J=7.05Hz,3H)。MS:(M+H m/z 404.1)。
实例37
1-异丙基-6-[(3S,4S)-4-甲基-1-(喹啉-3-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡
唑并[3,4-d]嘧啶-4-酮
遵循1-环戊基-6-[(3,4-反式)-4-甲基-1-(吡啶-3-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用1-异丙基-6-[(3S,4S)-4-甲基吡咯烷-3-基]-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮和喹啉-3-甲醛替换,从而得到标题化合物。400MHz 1H NMR(CD3OD)δ11.0(brs,1H),8.87(d,J=2.1Hz,1H),8.29(s,1H),8.07(d,J=8.3Hz,1H),8.02(s,1H),7.90-7.88(m,1H),7.70-7.66(m,1H),7.56-7.51(m,1H),5.01-4.92(m,1H),4.03-3.83(m,2H),3.40(t,J=8.7Hz,1H),3.07(d,J=9.5Hz,1H),2.89-2.86(m,1H),2.68-2.67(m,1H),2.48-2.47(m,1H),2.08-2.02(m,1H),1.48(dd,J=6.6,16.59Hz,6H),1.20(d,J=7.1Hz,3H)。MS:(M+H m/z 403.1)。
实例38
1-环戊基-6-{(3S,4S)-4-甲基-1-[(5-甲基吡嗪-2-基)甲基]吡咯烷-3-基}-1,5-二
氢-4H-吡唑并[3,4-d]嘧啶-4-酮
遵循1-环戊基-6-[(3,4-反式)-4-甲基-1-(吡啶-3-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用1-环戊基-6-[(3S,4S)-4-甲基吡咯烷-3-基]-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮和5-甲基吡嗪-2-甲醛替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ8.53(s,1H),8.53(s,1H),8.01(s,1H),5.16-5.05(m,1H),4.02(d,J=14.1Hz,1H),3.74(dJ=14.1Hz,1H),3.45-3.41(m,1H),3.38(t,J=8.3Hz,1H),3.08(d,J=9.9Hz,1H),2.84-2.83(m,1H),2.62-2.54(m,1H),2.52(s,3H),2.47-2.40(m,1H),2.14-1.89(m,6H),1.71-1.64(m,2H),1.24-1.16(m,3H)。MS:(M+Hm/z=394.1)。
实例39
6-[(3,4-反式)-1-苄基-4-乙基吡咯烷-3-基]-1-异丙基-1,5-二氢-4H-吡唑并[3,4-
d]嘧啶-4-酮
遵循6-[(3,4-反式)-1-苄基-4-甲基吡咯烷-3-基]-1-(2-甲氧基苯基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用5-氨基-1-异丙基-1H-吡唑-4-甲酰胺和(3,4-反式)-1-苄基-4-乙基吡咯烷-3-羧酸甲酯替换,从而得到标题化合物。400MHz 1H NMR(CD3OD)δ8.01(s,1H),7.38-7.22(m,5H),5.06-5.01(m,1H),3.76-3.64(m,2H),3.12(t,J=8.71Hz,1H),3.00-2.91(m,2H),2.87-2.82(m,1H),2.51-2.47(m,1H),2.30-2.26(m,1H),1.60-1.50(m,2H),1.49(d,J=7.05Hz,6H),3.08(d,J=7.5Hz,3H)。MS:(M+H m/z=366.1)。
实例40
6-[(3S,4S)-1-苄基-4-乙基吡咯烷-3-基]-1-异丙基-1,5-二氢-4H-吡唑并[3,4-d]
嘧啶-4-酮
在Chiralcel OJ手性HPLC柱上分离外消旋物,移动相80/20庚烷/EtOH,TR=9.177,从而得到对映异构体。400MHz 1H NMR(CD3OD)δ8.01(s,1H),7.38-7.22(m,5H),5.06-5.01(m,1H),3.76-3.64(m,2H),3.12(t,J=8.71Hz,1H),3.00-2.91(m,2H),2.87-2.82(m,1H),2.51-2.47(m,1H),2.30-2.26(m,1H),1.60-1.50(m,2H),1.49(d,J=7.05Hz,6H),3.08(d,J=7.5Hz,3H)。MS:(M+H m/z=366.2)。
实例41
1-异丙基-6-{(3S,4S)-4-甲基-1-[(2-甲基嘧啶-5-基)甲基]吡咯烷-3-基}-1,5-二
氢-4H-吡唑并[3,4-d]嘧啶-4-酮
遵循1-环戊基-6-[(3,4-反式)-4-甲基-1-(吡啶-3-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用1-异丙基-6-[(3S,4S)-4-甲基吡咯烷-3-基]-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮和2-甲基嘧啶-5-甲醛替换,从而得到标题化合物。400MHz 1H NMR(CD3OD)δ8.68(s,2H),7.97(s,1H),5.08-5.01(m,1H),3.78-3.68(m,2H),3.08-2.92(m,4H),2.74-2.67(m,1H),2.65(s,3H),2.36-2.32(m,1H),1.48(d,J=6.6Hz,6H),1.15(d,J=7.1Hz,3H)。MS:(M+H m/z=368.1)。
实例42
6-(1-苄基吡咯烷-3-基)-1-环戊基-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
遵循6-[(3,4-反式)-1-苄基-4-甲基吡咯烷-3-基]-1-(2-甲氧基苯基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用5-氨基-1-环戊基-1H-吡唑-4-甲酰胺和1-苄基吡咯烷-3-羧酸甲酯替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ8.01(s,1H),7.39-7.32(m,4H),7.27-7.23(m,1H),5.12-5.09(m,1H),3.84(d,J=12.4Hz,1H),3.61(d,J=12.4Hz,1H),3.30-3.26(m,1H),3.18-3.14(m,1H),3.01(d,J=9.9Hz,1H),2.45-2.32(m,3H),2.11-1.90(m,7H),1.71-1.65(m,2H)。MS:(M+H m/z=364.1)。
实例43
1-异丙基-6-{(3S,4S)-1-[(6-甲氧基吡啶-3-基)甲基]-4-甲基吡咯烷-3-基}-1,5-
二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
遵循1-环戊基-6-[(3,4-反式)-4-甲基-1-(吡啶-3-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用1-异丙基-6-[(3S,4S)-4-甲基吡咯烷-3-基]-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮和6-甲氧基烟醛替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ8.02(s,2H),7.72(m,1H),6.77(d,J=8.3Hz,1H),3.90(s,3H),3.73-3.53(m,2H),3.39-3.33(m,1H),3.30(m,1H),2.8(m,1H),2.55-2.40(m,1H),1.9(m,1H),1.57-1.53(m,2H),1.52-1.47(m,6H),1.19(d,J=6.6Hz,3H)。MS:(M+H m/z=383.2)。
实例44
(a)6-((3,4-反式)-4-乙基吡咯烷-3-基)-1-异丙基-1H-吡唑并[3,4-d]嘧啶- 4(5H)-酮
遵循1-环戊基-6-[(3S,4S)-4-甲基吡咯烷-3-基]-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮的制备方法,但用6-[(3,4-反式)-1-苄基-4-乙基吡咯烷-3-基]-1-异丙基-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮替换,从而得到标题化合物。400MHz 1H NMR(CD3OD)δ8.02(s,1H),5.10(m,1H),3.78-3.60(m,3H),3.32-3.28(m,1H),3.10(m,1H),2.62(m,1H),1.65(m,1H),1.58(m,1H),1.49(dd,J=6.6,1.7Hz,6H),0.97(t,J=7.5Hz,3H)。MS:(M+H m/z=276.1)。
(b)6-[(3,4-反式)-4-乙基-1-(喹啉-3-基甲基)吡咯烷-3-基]-1-异丙基-1,5-二氢- 4H-吡唑并[3,4-d]嘧啶-4-酮
遵循1-环戊基-6-[(3,4-反式)-4-甲基-1-(吡啶-3-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用6-((3,4-反式)-4-乙基吡咯烷-3-基)-1-异丙基-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮和喹啉-3-甲醛替换,从而得到标题化合物。400MHz 1H NMR(CD3OD)δ8.86(d,J=2.1Hz,1H),8.29(d,J=1.7Hz,1H),7.98(d,J=8.3Hz,1H),7.97(s,1H),7.89(d,J=8.3Hz,1H),7.73-7.68(m,1H),7.59-7.55(m,1H),5.05-4.98(m,1H),3.94-3.85(m,2H),3.13-3.09(m,1H),3.02-2.94(m,3H),2.57-2.52(m,1H),2.39-2.34(m,1H),1.58-1.48(m,2H),1.48(d,J=6.6Hz,6H)10.87(t,J=7.05Hz,3H)。MS:(M+H m/z=417.0)。
实例45
6-{(3,4-反式)-4-乙基-1-[(6-甲氧基吡啶-3-基)甲基]吡咯烷-3-基}-1-异丙基-
1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
遵循1-环戊基-6-[(3,4-反式)-4-甲基-1-(吡啶-3-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用6-((3,4-反式)-4-乙基吡咯烷-3-基)-1-异丙基-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮和6-甲氧基烟醛替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ10.83(brs,1H),8.02(d,J=2.1Hz,1H),8.00(s,1H),7.69(dd,J=8.7,2.1Hz,1H),6.77(d,J=8.3Hz,1H),4.98-4.94(m,1H),3.89(s,3H),3.69-3.54(m,2H),3.29(t,J=8.5Hz,1H),2.98(d,J=9.9Hz,1H),2.88-2.87(m,1H),2.55(m,1H),2.18(m,1H),1.91(m,1H),1.60-1.55(m,1H),1.51-1.47(m,7H),0.91(t,J=7.5Hz,3H)。MS:(M+H m/z=397.0)。
实例46
6-[(3,4-反式)-4-乙基-1-(喹喔啉-6-基甲基)吡咯烷-3-基]-1-异丙基-1,5-二氢-
4H-吡唑并[3,4-d]嘧啶-4-酮
遵循1-环戊基-6-[(3,4-反式)-4-甲基-1-(吡啶-3-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用6-((3,4-反式)-4-乙基吡咯烷-3-基)-1-异丙基-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮和喹喔啉-6-甲醛替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ10.83(brs,1H),8.81(s,2H),7.79(d,J=2.5Hz,1H),8.15-7.92(m,3H),4.99-4.92(m,1H),3.98-3.86(m,2H),3.35(t,J=8.7Hz,1H),3.04(d,J=9.9Hz,1H),2.92-2.91(m,1H),2.61-2.57(m,1H),2.25-2.2(m,1H),2.02(t,J=8.7Hz,1H),1.64-1.52(m,1H),1.50-1.45(m,7H),0.91(t,J=7.5Hz,3H)。MS:(M+H m/z=418.1)。
实例47
1-环戊基-6-{(3S,4S)-1-[(1,3-二甲基-1H-吡唑-5-基)甲基]-4-甲基吡咯烷-3-
基}-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
遵循1-环戊基-6-[(3,4-反式)-4-甲基-1-(吡啶-3-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用1-环戊基-6-[(3S,4S)-4-甲基吡咯烷-3-基]-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮和1,3-二甲基-1H-吡唑-5-甲醛替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ7.99(s,1H),5.95-5.94(m,1H),5.14-5.09(m,1H),3.87(s,3H),3.81(s,1H),3.66(q,J=14.5Hz,2H),3.33(t,J=8.3Hz,1H),3.03(d,J=9.9Hz,1H),2.84-2.82(m,1H),2.59-2.55(m,1H),2.44-2.41(m,1H),2.20-2.19(m,3H),2.12-1.90(m,5H),1.70-1.65(m,2H),1.25-1.18(m,3H)。MS:(M+H m/z=396.1)。
实例48
1-环戊基-6-[(3S,4S)-4-甲基-1-(4,5,6,7-四氢吡唑并[1,5-a]吡啶-3-基甲基)吡
咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
遵循1-环戊基-6-[(3,4-反式)-4-甲基-1-(吡啶-3-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用1-环戊基-6-[(3S,4S)-4-甲基吡咯烷-3-基]-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮和4,5,6,7-四氢吡唑并[1,5-a]吡啶-3-甲醛替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ7.99(s,1H),7.35(s,1H),5.16-5.09(m,1H),4.11-4.06(m,2H),3.68(d,J=13.3Hz,1H),3.57(d,J=13.3Hz,1H),3.32(t,J=8.7Hz,1H),3.00(d,J=9.9Hz,1H),2.94-2.80(m,2H),2.78-2.77(m,1H),2.49-2.45(m,1H),2.38-2.33(m,1H),2.11-1.83(m,11H),1.73-1.61(m,2H),1.17(d,J=7.1Hz,3H)。MS:(M+H m/z=422.1)。
实例49
1-环戊基-6-{(3S,4S)-4-甲基-1-[(1-甲基-1H-苯并咪唑-2-基)甲基]吡咯烷-3-
基}-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
遵循1-环戊基-6-[(3,4-反式)-4-甲基-1-(吡啶-3-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用1-环戊基-6-[(3S,4S)-4-甲基吡咯烷-3-基]-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮和1-甲基-1H-苯并[d]咪唑-2-甲醛替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ7.98(s,1H),7.73(m,1H),7.35(dd,J=7.1,1.2Hz,1H),7.29-7.21(m,2H),5.13-5.09(m,1H),4.11-4.06(m,2H),3.97(s,3H),3.37(t,J=8.3Hz,1H),3.06(d,J=10.4Hz,1H),2.88-2.85(m,1H),2.77-2.73(m,1H),2.16-1.92(m,8H),1.70-1.66(m,2H),1.21(d,J=7.1Hz,3H)。MS:(M+H m/z=432.1)。
实例50
1-异丙基-6-{(3S,4S)-4-甲基-1-[(5-甲基吡嗪-2-基)甲基]吡咯烷-3-基}-1,5-二
氢-4H-吡唑并[3,4-d]嘧啶-4-酮
遵循1-环戊基-6-[(3,4-反式)-4-甲基-1-(吡啶-3-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用1-异丙基-6-[(3S,4S)-4-甲基吡咯烷-3-基]-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮和5-甲基吡嗪-2-甲醛替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ11.4(brs,1H),8.49(s,1H),8.44(s,1H),7.99(s,1H),5.00-4.93(m,1H),4.00-3.97(m,1H),3.78-3.67(m,1H),3.33(t,J=8.3Hz,1H),3.04(d,J=9.9Hz,1H),2.85-2.82(m,1H),2.65-2.61(m,1H),2.49(s,3H),2.48-2.41(m,1H),2.13(t,J=8.5Hz,1H),1.46(dd,J=11.6,6.6Hz,6H),1.17(d,J=7.05Hz,3H)。MS:(M+Hm/z=368.1)。
实例51
6-[(3S,4S)-1-(噌啉-3-基甲基)-4-甲基吡咯烷-3-基]-1-环戊基-1,5-二氢-4H-吡
唑并[3,4-d]嘧啶-4-酮
遵循1-环戊基-6-[(3,4-反式)-4-甲基-1-(吡啶-3-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用1-环戊基-6-[(3S,4S)-4-甲基吡咯烷-3-基]-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮和噌啉-3-甲醛替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ8.49(d,J=8.7Hz,1H),8.16(s,1H),8.01(s,1H),7.93(d,J=7.9Hz,1H),7.83-7.81(m,1H),7.79-7.71(m,1H),5.16-5.09(m,1H),4.47-4.44(m,1H),4.35-4.32(m,1H),3.49-3.45(m,2H),3.10-3.07(m,1H),2.87-2.71(m,2H),2.49-2.48(m,1H),2.23(m,1H),2.11-1.87(m,5H),1.73-1.63(m,2H),1.22(d,J=7.1Hz,3H)。MS:(M+H m/z=430.1)。
实例52
(a)1-环戊基-6-[(3,4-反式)-4-(三氟甲基)吡咯烷-3-基]-1H-吡唑并[3,4-d]嘧 啶-4(5H)-酮
遵循1-环戊基-6-[(3S,4S)-4-甲基吡咯烷-3-基]-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮的制备方法,但用6-[(3,4-反式)-1-苄基-4-(三氟甲基)吡咯烷-3-基]-1-环戊基-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮替换,从而得到标题化合物。400MHz 1H NMR(CD3OD)δ7.98(s,1H),5.23(m,1H),3.73(m,1H),3.42(m,2H),3.10(m,2H),2.19-1.92(m,7H),1.75(m,2H),1.23-1.19(m,3H)。
(b)1-环戊基-6-[(3,4-反式)-1-(喹喔啉-6-基甲基)-4-(三氟甲基)吡咯烷-3-基]- 1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
遵循1-环戊基-6-[(3,4-反式)-4-甲基-1-(吡啶-3-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用1-环戊基-6-[(3,4-反式)-4-(三氟甲基)吡咯烷-3-基]-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮和喹喔啉-6-甲醛替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ8.80(s,1H),8.08(d,J=8.3Hz,1H),7.99(m,1H),7.86-7.83(m,1H),5.13-5.10(m,1H),4.88(s,1H),3.96-3.88(m,2H),3.50-3.35(m,2H),3.17(t,J=9.9Hz,1H),3.03-2.99(m,1H),2.92-2.88(m,1H),2.79-2.75(m,1H),2.11-1.90(m,6H),1.71-1.65(m,1H)。
实例53
1-环戊基-6-{(3S,4S)-4-甲基-1-[(2-甲基嘧啶-4-基)甲基]吡咯烷-3-基}-1,5-二
氢-4H-吡唑并[3,4-d]嘧啶-4-酮
遵循1-环戊基-6-[(3,4-反式)-4-甲基-1-(吡啶-3-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用1-环戊基-6-[(3S,4S)-4-甲基吡咯烷-3-基]-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮和2-甲基嘧啶-4-甲醛替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ8.60(d,J=5.4Hz,1H),8.03(s,1H),7.24(s,1H),5.18-5.10(m,1H),3.97-3.94(m,1H),3.72-3.68(m,1H),3.40(t,J=8.3Hz,1H),3.15(d,J=9.5Hz,1H),2.89(m,1H),2.73(s,3H),2.68-2.63(m,1H),2.53-2.47(m,1H),2.15-1.89(m,7H),1.74-1.65(m,2H),1.21(d,J=7.1Hz,3H)。MS:(M+H m/z=394.1)。
实例54
1-环戊基-6-[(3S,4S)-1-{[2-(二甲基氨基)嘧啶-4-基]甲基}-4-甲基吡咯烷-3-
基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
遵循1-环戊基-6-[(3,4-反式)-4-甲基-1-(吡啶-3-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用1-环戊基-6-[(3S,4S)-4-甲基吡咯烷-3-基]-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮和2-(二甲基氨基)嘧啶-4-甲醛替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ8.24-8.21(m,1H),8.00-7.99(m,1H),6.52-6.50(m,1H),5.13-5.10(m,1H),3.72-3.68(m,1H),3.56-3.52(m,1H),3.46-3.40(m,3H),3.17-3.11(m,7H),2.84-2.82(m,1H),2.64-2.60(m,1H),2.44-2.38(m,1H),2.06-1.92(m,5H),1.66-1.65(m,2H),1.20-1.16(m,3H)。MS:(M+H m/z=423.1)。
实例55
(a)1-环戊基-6-[(3,4-反式)-4-环丙基吡咯烷-3-基]-1H-吡唑并[3,4-d]嘧啶- 4(5H)-酮
遵循1-环戊基-6-[(3S,4S)-4-甲基吡咯烷-3-基]-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮的制备方法,但用6-[(3,4-反式)-1-苄基-4-环丙基吡咯烷-3-基]-1-环戊基-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ8.08-7.94(m,1H),5.17-5.10(m,1H),3.39-3.34(m,1H),3.29-3.28(m,2H),3.17-3.14(m,1H),2.13-1.91(m,7H),1.78-1.67(m,3H),0.82(m,1H),0.47-0.44(m,2H),0.13-0.08(m,2H)。MS:(M+H m/z=314.2)。
(b)1-环戊基-6-{(3,4-反式)-4-环丙基-1-[(5-甲基吡嗪-2-基)甲基]吡咯烷-3- 基}-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
遵循1-环戊基-6-[(3S,4S)-4-甲基吡咯烷-3-基]-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮的制备方法,但用1-环戊基-6-[(3,4-反式)-4-环丙基吡咯烷-3-基]-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮和5-甲基吡嗪-2-甲醛替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ8.52(d,J=0.8Hz,1H),8.46(s,1H),8.00(s,1H),5.14-5.10(m,1H),4.04-4.01(m,1H),3.78-3.75(m,1H),3.35(t,J=8.7Hz,1H),3.15-3.09(m,2H),2.66-2.64(m,1H),2.52(s,3H),2.38(t,J=8.7Hz,1H),2.11-2.01(m,3H),1.96-1.91(m,2H),1.73-1.65(m,2H),1.24-1.20(m,1H),0.59-0.83(m,2H),0.53-0.49(m,2H),0.23-0.11(m,2H)。MS:(M+H m/z=420.1)。
实例56
1-环戊基-6-[(3,4-反式)-4-环丙基-1-(喹喔啉-6-基甲基)吡咯烷-3-基]-1,5-二
氢-4H-吡唑并[3,4-d]嘧啶-4-酮
遵循1-环戊基-6-[(3S,4S)-4-甲基吡咯烷-3-基]-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮的制备方法,但用1-环戊基-6-[(3,4-反式)-4-环丙基吡咯烷-3-基]-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮和喹喔啉-6-甲醛替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ8.82(s,2H),8.14(d,J=8.7Hz,1H),8.00(s,2H),7.96-7.94(m,1H),5.16-5.09(m,1H),3.98-3.95(m,2H),3.35(t,J=8.3Hz,1H),3.15-3.08(m,2H),2.70(m,1H),2.27(m,1H),2.15-1.88(m,6H),1.74-1.62(m,3H),0.91-0.87(m,1H),0.55-0.47(m,2H),0.21-0.09(m,2H)。MS:(M+H m/z=456.1)。
实例57
1-环戊基-6-[(3,4-反式)-4-环丙基-1-甲基吡咯烷-3-基]-1,5-二氢-4H-吡唑并
[3,4-d]嘧啶-4-酮
遵循1-环戊基-6-[(3S,4S)-4-甲基吡咯烷-3-基]-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮的制备方法,但用1-环戊基-6-[(3,4-反式)-4-环丙基吡咯烷-3-基]-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮和甲醛替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ8.01(s,1H),5.19-5.11(m,1H),3.31(d,J=8.7Hz,1H),3.14-3.13(m,1H),3.06(d,J=9.9Hz,1H),2.57(m,1H),2.43(s,3H),2.14-1.91(m,7H),1.75-1.64(m,3H),0.91-0.82(m,1H),0.53-0.50(m,2H),0.20-0.14(m,2H)。MS:(M+H m/z=328.2)。
实例58
6-[(3,4-反式)-1-苄基-4-甲基吡咯烷-3-基]-1-乙基-1,5-二氢-4H-吡唑并[3,4-d]
嘧啶-4-酮
遵循6-[(3,4-反式)-1-苄基-4-甲基吡咯烷-3-基]-1-(2-甲氧基苯基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用5-氨基-1-乙基-1H-吡唑-4-甲酰胺替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ8.02(s,1H),7.42-7.27(m,5H),4.38-4.30(m,2H),3.83-3.80(m,1H),3.63-3.59(m,1H),3.49-3.35(m,1H),2.99(d,J=10.3Hz,1H),2.83-2.80(m,1H),2.55-2.50(m,1H),2.44-2.378(m,1H),1.95-1.90(m,1H),1.47(t,J=7.1Hz,3H),1.22(t,J=10.3Hz,3H)。MS:(M+H m/z=338.1)。
实例59
(a)6-((3S,4S)-4-乙基吡咯烷-3-基)-1-异丙基-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮
遵循1-环戊基-6-[(3S,4S)-4-甲基吡咯烷-3-基]-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮的制备方法,但用6-[(3S,4S)-1-苄基-4-乙基吡咯烷-3-基]-1-异丙基-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮替换,从而得到标题化合物。400MHz 1H NMR(CD3OD)δ8.02(s,1H),5.10(m,1H),3.78-3.60(m,3H),3.32-3.28(m,1H),3.10(m,1H),2.62(m,1H),1.65(m,1H),1.58(m,1H),1.49(dd,J=6.6,1.7Hz,6H),0.97(t,J=7.5Hz,3H)。MS:(M+H m/z=276.1)。
(b)6-{(3,4-反式)-4-乙基-1-[(2-甲基嘧啶-5-基)甲基]吡咯烷-3-基}-1-异丙基- 1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
遵循1-环戊基-6-[(3S,4S)-4-甲基吡咯烷-3-基]-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮的制备方法,但用6-((3S,4S)-4-乙基吡咯烷-3-基)-1-异丙基-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮和2-甲基嘧啶-5-甲醛替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ10.8(brs,1H),8.62(s,2H),8.01(s,1H),5.00-4.93(m,1H),3.66(s,2H),3.25-3.20(m,1H),3.02(d,J=9.9Hz,1H),2.95-2.92(m,1H),2.70(s,3H),2.62-2.58(m,1H),2.28-2.23(m,1H),1.98(t,J=8.7Hz,1H),1.62-1.52(m,1H),1.48(t,J=6.6Hz,6H),1.46-1.42(m,1H),3.08(t,J=7.5Hz,3H)。MS:(M+H m/z=382.2)。
实例60
(a)1-(四氢-2H-吡喃-4-基)肼
在环境温度下,向四氢吡喃-4-酮(71.6g,715mmol)在甲醇(2L)中的溶液中添加肼基甲酸叔丁基酯(100g,758mmol)。将混合物在环境温度下搅拌20小时。将反应混合物在减压下浓缩至干燥,从而得到白色固体(154g)。向白色固体(154g,715mmol)在水(1L)中的悬浮液中添加乙酸(500mL,8.73mol),然后将混合物搅拌30分钟从而得到澄清溶液。向该溶液中分批添加固体NaCNBH3(44.5g,708mmol)。将混合物在环境温度下搅拌2小时。然后,将混合物转移到12L烧瓶中,冷却至0℃,并用1NNaOH(8.73L,8.73mol)猝灭。将混合物用CH2Cl2(3x3L)萃取并在Na2SO4上干燥。将有机层过滤并浓缩,从而得到白色固体(164g,包含~15%的N-乙酰基-N’-Boc-肼衍生物)。色谱分离[硅石,乙酸乙酯/MeOH(95∶5]得到94g纯度90%的Boc-肼。将Boc-肼(50g,231mmol)在甲醇(500mL)中的溶液添加到HCl在二氧杂环己烷的溶液(462mL,1.85mol,4.0M)中。将混合物在环境温度下搅拌整夜。将反应混合物在减压下浓缩从而得到白色固体状标题化合物(43g,98%)。400MHz 1H NMR(DMSO)δ3.85-3.82(m,2H),3.27-3.21(m,2H),3.13-3.05(m,1H),1.88-1.84(m,2H),1.48-1.38(m,2H).MS:(M+H m/z=117.2)。
(b)5-氨基-1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-甲腈
在0℃(冰浴)下,向1-(四氢-2H-吡喃-4-基)肼二氯化氢(18g,96mmol)在200mL的EtOH中的混合物中添加Et3N(30g,40mL,288mmol)。将所得混合物搅拌1小时,然后缓缓添加2-(乙氧基亚甲基)丙二腈(12g,96mmol)在100mL的EtOH中的溶液,以将反应温度保持在5℃以下。将这个混合物在环境温度下搅拌整夜,然后加热至回流2小时。在真空下除去溶剂后,将残余物用300mL的水洗涤。将固体收集,用额外200mL的水、200mL的1∶1己烷和醚洗涤,干燥,从而得到17g黄色固体。400MHz 1H NMR(CD3OD)δ7.71(s,1H),4.29-4.21(m,1H),4.02(dd,J=11.6,4.6Hz,2H),3.28(t,J=1.7Hz,2H),2.12-2.02(m,2H),1.80-1.76(m,2H).MS:(M+H m/z=193.1).
(c)5-氨基-1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-甲酰胺
先后用35%的H2O2水溶液(100mL)和氨水(300mL)处理搅动的5-氨基-1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-甲腈(~228mmol)在乙醇(300mL)中的溶液。将反应混合物在环境温度下搅拌48小时,然后用饱和的硫代硫酸钠水溶液(800mL)猝灭,并在减压下浓缩,以除去大多数乙醇。通过过滤取出所得固体,然后将其用水(2x200mL)和醚(2x150mL)洗涤。将固体在真空下干燥至恒重(31g,2个步骤的产率65%)。400MHz 1H NMR(CD3OD)δ7.67(s,1H),4.27-4.21(m,1H),4.03(dd,J=11.6,4.6Hz,2H),3.28(t,J=1.7Hz,2H),2.14-2.04(m,2H),1.81-1.78(m,2H)。MS:(M+Hm/z=382.2)。
(d)6-[(3,4-反式)-1-苄基-4-甲基吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1,5-二 氢-4H-吡唑并[3,4-d]嘧啶-4-酮
向5-氨基-1-(四氢-2H-吡喃-4-基-1H-吡唑-4-甲酰胺(6.0g,28.54mmol)和(3,4-反式)-1-苄基-4-甲基吡咯烷-3-羧酸甲酯(13.3g,57.08mmol)的混合物中添加分子筛(小球)。向搅动的混合物中添加1.0M的t-BuOK在THF中的溶液(57.1ml,57.08mmol),然后在剧烈搅拌的同时将所得混合物在回流、氮气氛下加热整夜。通过LC/MS对反应混合物的分析表明原料的消耗。将反应混合物冷却至环境温度,并通过过滤取出固体。将固体用EtOAc(2x)洗涤,将合并的滤液在减压下浓缩。将剩余物在CH2Cl2和H2O之间进行分配,然后分离水层和有机层。将有机层用CH2Cl2(1x)萃取,然后将合并的有机萃取物在Na2SO4上干燥,过滤,减压浓缩。将剩余的残余物用色谱(硅胶,1%EtOAc中的Et3N)进行纯化,从而得到灰白色固体状标题化合物(7.8g,70%产率)。400MHz 1H NMR(CDCl3)δ8.02(s,1H),7.39-7.25(m,6H),4.83-4.75(m,1H),4.14-4.09(m,2H),3.82(m,1H),3.62-3.54(m,3H),3.39-3.37(m,1H),3.00(m,1H),2.83(m,1H),2.66-2.27(m,4H),2.10-1.83(m,3H),1.20(d,J=6.6Hz,3H)。MS:(M+H m/z=394.2)。
实例61
6-[(3S,4S)-1-苄基-4-甲基吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-
吡唑并[3,4-d]嘧啶-4-酮
在Chiralcel OD-H手性HPLC柱上分离实例60的外消旋物,移动相70/30庚烷/EtOH,TR=11.465,从而得到对映异构体。400MHz 1H NMR(CDCl3)δ8.02(s,1H),7.39-7.25(m,6H),4.82-4.76(m,1H),4.14-4.09(m,2H),3.82-3.79(m,1H),3.62-3.54(m,3H),3.37(d,J=8.7Hz,1H),3.00(d,J=9.9Hz,1H),2.79(dd,J=6.3,2.5Hz,1H),2.52-2.48(m,1H),2.42-2.30(m,3H),1.94-1.82(m,3H),1.20(d,J=6.6Hz,3H)。MS:(M+H m/z=394.2)。
实例62
(a)(3,4-反式)-1-苄基-4-(2,2,2-三氟乙基)吡咯烷-3-羧酸乙酯
遵循(3,4-反式)-1-苄基-4-甲基吡咯烷-3-羧酸甲酯的制备方法,但用(E)-5,5,5-三氟戊-2-烯酸甲酯替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ7.32-7.21(m,5H),4.18-4.10(m,2H),3.67-3.55(m,2H),2.90-2.63(m,4H),2.43-2.34(m,2H),2.24-2.15(m,1H),1.27-1.22(m,3H),0.88-0.85(m,1H)。
(b)6-[(3,4-反式)-1-苄基-4-(2,2,2-三氟乙基)吡咯烷-3-基]-1-环戊基-1,5-二氢- 4H-吡唑并[3,4-d]嘧啶-4-酮
遵循6-[(3,4-反式)-1-苄基-4-甲基吡咯烷-3-基]-1-(2-甲氧基苯基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用5-氨基-1-环戊基-1H-吡唑-4-甲酰胺和(3,4-反式)-1-苄基-4-(2,2,2-三氟乙基)吡咯烷-3-羧酸乙酯替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ8.02(s,1H),7.36-7.26(m,5H),5.12-5.08(m,1H),3.85-3.81(m,1H),3.60-3.57(m,1H),3.42(t,J=8.3Hz,1H),3.02-2.96(m,2H),2.64(m,1H),2.53-2.44(m,2H),2.34-1.89(m,6H),1.81-1.62(m,4H)。
实例63
(a)1-(4,4-二氟环己基)肼
向4,4-二氟环己醇(0.9g)在甲苯中的溶液添加三苯基膦(2.6g)和二叔丁基二氮杂草酸酯(1.82g),并将反应混合物搅拌18小时。浓缩反应混合物,并添加甲醇(13mL)。向甲醇溶液中添加在二氧杂环己烷中的HCl(4M,13mL)。将反应混合物搅拌3小时并浓缩。将反应混合物在水和乙酸乙酯之间分配。分离各层,将水层用乙酸乙酯萃取3次。将有机层在硫酸镁上干燥,过滤并浓缩。将标题化合物直接用在5-氨基-1-(4,4-二氟环己基)-1H-吡唑-4-甲腈的制备中,无需纯化。400MHz 1H NMR(CD3OD)δ2.15-2.07(m,4H),2.00-1.81(m,2H),1.68-1.58(m,2H)。(M+H m/z=279.0)。
(b)5-氨基-1-(4,4-二氟环己基)-1H-吡唑-4-甲腈
遵循5-氨基-1-(2-甲氧基苯基)-1H-吡唑-4-甲腈的制备方法,但用1-(4,4-二氟环己基)肼替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ7.5(m,1H),3.90(m,1H),2.40-1.00(m,8H)。
(c)5-氨基-1-(4,4-二氟环己基)-1H-吡唑-4-甲酰胺
遵循5-氨基-1-(2-甲氧基苯基)-1H-吡唑-4-甲酰胺的制备方法,但用5-氨基-1-(4,4-二氟环己基)-1H-吡唑-4-甲腈替换,从而得到标题化合物。400MHz 1H NMR(CD3OD)δ8.01(s,1H),4.19(m,1H),2.22-1.90(m,8H)。
(d)6-[(3,4-反式)-1-苄基-4-甲基吡咯烷-3-基]-1-(4,4-二氟环己基)-1,5-二氢- 4H-吡唑并[3,4-d]嘧啶-4-酮
遵循6-[(3,4-反式)-1-苄基-4-甲基吡咯烷-3-基]-1-(2-甲氧基苯基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用5-氨基-1-(4,4-二氟环己基)-1H-吡唑-4-甲酰胺替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ8.00(s,1H),7.40-7.25(m,5H),4.73-4.67(m,1H),3.85-3.82(m,1H),3.64-3.61(m,1H),3.38(t,J=8.7Hz,1H),3.00(m,1H),2.83(m,1H),2.56-2.52(m,1H),2.43-2.25(m,5H),2.04-1.90(m,5H),1.20(d,J=7.1Hz,3H)。MS:(M+H m/z=428.1)。
实例64
(a)5-氨基-1-(2,2,2-三氟乙基)-1H-吡唑-4-甲腈
遵循5-氨基-1-(2-甲氧基苯基)-1H-吡唑-4-甲腈的制备方法,但用1-(2,2,2-三氟乙基)肼替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ7.60(s,1H),4.59(m,2H),4.40(brs,2H)。
(b)5-氨基-1-(2,2,2-三氟乙基)-1H-吡唑-4-甲酰胺
遵循5-氨基-1-(2-甲氧基苯基)-1H-吡唑-4-甲酰胺的制备方法,但用5-氨基-1-(2,2,2-三氟乙基)-1H-吡唑-4-甲腈替换,从而得到标题化合物。400MHz 1H NMR(DMSO)δ7.75(s,1H),7.30(brs,1H),6.78(brs,1H)6.58(m,2H),4.88(m,2H)。
(c)6-[(3,4-反式)-1-苄基-4-甲基吡咯烷-3-基]-1-(2,2,2-三氟乙基)-1,5-二氢- 4H-吡唑并[3,4-d]嘧啶-4-酮]
遵循6-[(3,4-反式)-1-苄基-4-甲基吡咯烷-3-基]-1-(2-甲氧基苯基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用5-氨基-1-(2,2,2-三氟乙基)-1H-吡唑-4-甲酰胺替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ8.15(s,1H),7.59-7.57(m,2H),7.44-7.41(m,3H),4.96-4.88(m,2H),4.22-4.11(m,2H),3.57-3.37(m,4H),2.85(m,2H),1.26-1.23(m,3H)。MS:(M+Hm/z=392.1)。
实例65
1-异丙基-6-[(3S,4S)-4-甲基-1-(1,5-萘啶-4-基甲基)吡咯烷-3-基]-1,5-二氢-
4H-吡唑并[3,4-d]嘧啶-4-酮
遵循1-环戊基-6-[(3,4-反式)-4-甲基-1-(吡啶-3-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用1-异丙基-6-[(3S,4S)-4-甲基吡咯烷-3-基]-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮和1,5-萘啶-4-甲醛替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ9.09-9.08(m,1H),8.95-8.87(m,1H),8.44-8.39(m,1H),8.00(s,1H),7.73-7.70(m,1H),7.67-7.64(m,1H),5.00-4.96(m,1H),4.56-4.53(m,1H),4.33-4.29(m,1H),3.34(t,J=8.3Hz,1H),3.19(d,J=9.5Hz,1H),2.91-2.82(m,2H),2.47-2.43(m,1H),2.12(t,J=8.3Hz,1H),1.48(dd,J=9.9,6.6Hz,6H),1.18(d,J=7.1Hz,3H)。MS:(M+H m/z=404.2)。
实例66
1-异丙基-6-[(3S,4S)-4-甲基-1-(1,8-萘啶-4-基甲基)吡咯烷-3-基]-1,5-二氢-
4H-吡唑并[3,4-d]嘧啶-4-酮]
遵循1-环戊基-6-[(3,4-反式)-4-甲基-1-(吡啶-3-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用1-异丙基-6-[(3S,4S)-4-甲基吡咯烷-3-基]-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮和1,8-萘啶-4-甲醛替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ9.15(dd,J=4.1,1.7Hz,1H),9.07(d,J=4.6Hz,1H),8.69(dd,J=8.3,1.66Hz,1H),7.99(s,1H),7.69-7.65(m,1H),7.46(d,J=4.6Hz,1H),5.00-4.93(m,1H),4.14(s,3H),3.26(t,J=8.3Hz,1H),3.03(d,J=9.5Hz,1H),2.92-2.90(m,1H),2.80-2.76(m,1H),2.52-2.43(m,1H),1.50-1.46(m,6H),1.20(d,J=6.6Hz,3H)。MS:(M+H m/z=404.1)。
实例67
1-异丙基-6-[3S,4S)-4-甲基-1-(喹啉-4-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡
唑并[3,4-d]嘧啶-4-酮
遵循1-环戊基-6-[(3,4-反式)-4-甲基-1-(吡啶-3-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用1-异丙基-6-[(3S,4S)-4-甲基吡咯烷-3-基]-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮和喹啉-4-甲醛替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ10.63(brs,1H),8.85(d,J=4.6Hz,1H),8.26-8.24(m,1H),8.13-8.11(m,1H),7.99(s,1H),7.77-7.69(m,2H),7.39(d,J=4.6Hz,1H),5.00-4.94(m,1H),4.13(d,J=3.3Hz,2H),3.32(t,J=8.3Hz,1H),3.06(d,J=9.5Hz,1H),2.89-2.87(m,1H),2.74-2.70(m,1H),2.46-2.42(m,1H),2.04(t,J=8.7Hz,1H),1.48(dd,J=12.9,7.1Hz,6H),1.20(d,J=7.1Hz,3H)。MS:(M+H m/z 403.2)。
实例68
1-异丙基-6-[(3S,4S)-4-甲基-1-(吡啶并[2,3-b]吡嗪-8-基甲基)吡咯烷-3-基]-
1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
遵循1-环戊基-6-[(3,4-反式)-4-甲基-1-(吡啶-3-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用1-异丙基-6-[(3S,4S)-4-甲基吡咯烷-3-基]-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮和吡啶并[2,3-b]吡嗪-8-甲醛替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ10.00(brs,1H),9.16-9.10(m,3H),8.00(s,1H),7.78(m,1H),5.00-4.97(m,1H),4.63-4.58(m,1H),4.34-4.18(m,1H),3.30(m,1H),3.27(m,1H),2.92-2.77(m,2H),2.49-2.38(m,1H),2.09-1.97(m,1H),1.48(dd,J=10.8,6.6Hz,6H),1.20(d,J=6.6Hz,3H)。MS:(M+H m/z 405.2)。
实例69
1-异丙基-6-{(3,4-反式)-1-[(6-甲氧基-1,5-萘啶-4-基)甲基]-4-甲基吡咯烷-3-基}-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
遵循1-环戊基-6-[(3,4-反式)-4-甲基-1-(吡啶-3-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用1-异丙基-6-[(3,4-反式)-4-甲基吡咯烷-3-基]-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮和6-甲氧基-1,5-萘啶-4-甲醛替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ8.78(d,J=4.6Hz,1H),8.21(d,J=9.1Hz,1H),8.01(s,1H),7.63(m,1H),7.17(d,J=9.1Hz,1H),5.01-4.95(m,1H),4.4(m,1H),4.07(s,3H),3.48(m,1H),3.18(m,1H),2.89-2.75(m,2H),2.43(m,1H),2.10-2.08(m,2H),1.49(dd,J=11.6,6.6Hz,6H),1.21(d,J=6.6Hz,3H)。MS:(M+H m/z 434.2)。
实例70
6-{(3,4-反式)-1-[(8-氟喹啉-2-基)甲基]-4-甲基吡咯烷-3-基}-1-异丙基-1,5-二
氢-4H-吡唑并[3,4-d]嘧啶-4-酮
遵循1-环戊基-6-[(3,4-反式)-4-甲基-1-(吡啶-3-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用1-异丙基-6-[(3,4-反式)-4-甲基吡咯烷-3-基]-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮和8-氟喹啉-2-甲醛替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ8.27-8.25(m,1H),8.04(s,1H),7.86(m,1H),7.66-7.60(m,1H),7.50-7.38(m,2H),5.04-4.97(m,1H),4.30(m,1H),4.18(m,1H),3.47(m,2H),3.28(m,1H),3.00(m,1H),2.59(m,1H),2.40(m,1H),1.50(dd,J=11.2,6.6Hz,6H),1.22(d,J=7.1Hz,3H)。MS:(M+H m/z 421.2)。
实例71
1-异丙基-6-{(v)-1-[(6-甲氧基喹啉-4-基)甲基]-4-甲基吡咯烷-3-基}-1,5-二氢-
4H-吡唑并[3,4-d]嘧啶-4-酮
遵循1-环戊基-6-[(3,4-反式)-4-甲基-1-(吡啶-3-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用1-异丙基-6-[(3,4-反式)-4-甲基吡咯烷-3-基]-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮和6-甲氧基喹啉-4-甲醛替换,从而得到标题化合物。400MHz 1H NMR(CD3OD)δ8.87(d,J=5.0Hz,1H),8.08(d,J=9.5Hz,1H),8.00-7.95(m,2H),7.70(d,J=2.5Hz,1H),7.61(d,J=2.9Hz,1H),5.03-4.97(m,1H),4.08(s,3H),4.08-4.02(m,3H),3.91-3.86(m,2H),3.46-3.41(m,1H),3.33(s,1H),2.94(m,1H),1.48(d,J=7.1Hz,3H),1.42(d,J=6.6Hz,3H),1.21(d,J=6.6Hz,3H)。MS:(M+Hm/z 433.2)。
实例72
(a)5-氨基-1-环丁基-1H-吡唑-4-甲腈
遵循5-氨基-1-(2-甲氧基苯基)-1H-吡唑-4-甲腈的制备方法,但用1-环丁基肼替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ7.50(s,1H),4.48-4.40(m,1H),4.23(m,2H),2.70-2.58(m,2H),2.48-2.35(m,2H),1.97-1.79(m,2H)。MS:(M+H m/z 163.1)。
(b)5-氨基-1-环丁基-1H-吡唑-4-甲酰胺
遵循5-氨基-1-(2-甲氧基苯基)-1H-吡唑-4-甲酰胺的制备方法,但用5-氨基-1-环丁基-1H-吡唑-4-甲腈替换,从而得到标题化合物。400MHz 1HNMR(CD3OD)δ7.71(s,1H),4.71-4.55(m,1H),2.61-2.50(m,2H),2.46-2.31(m,2H),1.89-1.83(m,2H)。
(c)6-[(3,4-反式)-1-苄基-4-甲基吡咯烷-3-基]-1-环丁基-1,5-二氢-4H-吡唑并 [3,4-d]嘧啶-4-酮
遵循6-[(3,4-反式)-1-苄基-4-甲基吡咯烷-3-基]-1-(2-甲氧基苯基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用5-氨基-1-环丁基-1H-吡唑-4-甲酰胺替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ8.03(d,J=3.32Hz,1H),7.35-7.24(m,5H),5.25-5.20(m,1H),3.79-3.57(m,3H),3.36-3.32(m,1H),2.98(d,J=9.9Hz,1H),2.80-2.60(m,3H),2.53-2.38(m,3H),1.92-1.79(m,3H),1.25-1.12(m,3H)。MS:(M+H m/z 464.2)。
实例73
(a)6-[(3S,4S)-4-甲基吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d] 嘧啶-4(5H)-酮
将6-[(3S,4S)-1-苄基-4-甲基吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮(5.6g)溶于100mL的甲醇中,并加入Parr瓶中。氢氧化钯(3.76g)与3.56mL的浓盐酸一起添加。将反应混合物放置在氢化器中在40psi的H2下18小时。将反应混合物通过硅藻土过滤并浓缩,从而得到4.47g盐酸盐形式的标题化合物。400MHz 1H NMR(CD3OD)δ8.03(s,1H),4.49(m,1H),4.09-4.06(m,2H),3.74-3.57(m,4H),3.24(m,1H),3.05(m,1H),2.89(m,1H),2.77(m,1H),2.30(m,2H),1.90(m,2H),1.22(d,J=6.6Hz,3H)。MS:(M+H m/z=304.2)。
(b)6-{(3S,4S)-4-甲基-1-[(2-甲基嘧啶-5-基)甲基]吡咯烷-3-基}-1-(四氢-2H- 吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
向6-[(3S,4S)-4-甲基吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮盐酸盐(493mg)在1,2-二氯乙烷(10mL)中的溶液中添加乙酸(174mg)、2-甲基嘧啶-5-甲醛(236mg)和三乙酰氧硼氢化钠(635mg)。将反应混合物在50℃下加热整夜。将反应混合物在硅胶上浓缩并通过CombiFlash色谱纯化,从而得到标题化合物(146mg).400MHz 1H NMR(CDCl3)δ8.63(s,2H),8.01(s,1H),4.82-4.76(m,1H),4.12-4.08(m,2H),3.68(d,J=5.0Hz,3H),3.64-3.54(m,2H),3.28(t,J=8.3Hz,1H),3.04(d,J=9.9Hz,1H),2.89-2.86(m,1H),2.71(s,3H),2.66-2.62(m,1H),2.49-2.27(m,3H),1.97(t,J=7.9Hz,1H),1.91-1.83(m,2H),1.19(d,J=7.05Hz,3H)。MS:(M+H m/z 410.2)。
实例74
6-{(3,4-反式)-4-乙基-1-[(2-甲基嘧啶-5-基)甲基]吡咯烷-3-基}-1-(四氢-2H-吡
喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
遵循6-{(3S,4S)-4-甲基-1-[(2-甲基嘧啶-5-基)甲基]吡咯烷-3-基}-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用6-[(3,4-反式)-4-乙基吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮盐酸盐替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ10.55(brs,1H),8.64(s,2H),8.01(s,1H),4.81-4.73(m,1H),4.11-4.09(m,2H),3.68(s,2H),3.61-3.53(m,2H),3.28(t,J=8.7Hz,1H),3.03(d,J=9.9Hz,1H),2.94-2.92(m,1H),2.71(s,3H),2.57-2.53(m,1H),2.40-2.20(m,3H),1.96(t,J=8.7Hz,1H),1.89-1.84(m,2H),1.64-1.57(m,1H),1.52-1.44(m,1H),0.91(t,J=7.1Hz,3H)。MS:(M+H m/z 424.3)。
实例75
6-{(3S,4S)-4-甲基-1-[(5-甲基吡嗪-2-基)甲基]吡咯烷-3-基}-1-(四氢-2H-吡喃-
4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
遵循6-{(3S,4S)-4-甲基-1-[(2-甲基嘧啶-5-基)甲基]吡咯烷-3-基}-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用5-甲基吡嗪-2-甲醛替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ8.53(s,1H),8.47(s,1H),8.03(s,1H),4.83-4.79(m,1H),4.12-4.03(m,2H),3.78-3.75(m,1H),3.61-3.55(m,2H),3.46-3.40(m,1H),3.12-3.09(m,1H),2.87(m,1H),2.64(m,1H),2.53(m,2H),2.47-2.28(m,4H),2.16(m,2H),1.91-1.84(m,2H),1.23-1.20(m,3H)。MS:(M+H m/z 410.3)。
实例76
6-{(3S,4S)-1-[(6-甲氧基吡啶-3-基)甲基]-4-甲基吡咯烷-3-基}-1-(四氢-2H-吡
喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
遵循6-{(3S,4S)-4-甲基-1-[(2-甲基嘧啶-5-基)甲基]吡咯烷-3-基}-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用6-甲氧基烟醛替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ8.03(d,J=2.1Hz,1H),8.01(s,1H),7.69(dd,J=8.7,2.5Hz,1H),7.77(d,J=8.7Hz,1H),4.83-4.75(m,1H),4.14-4.08(m,2H),3.89(s,3H),3.72-3.68(m,1H),3.62-3.3.54(m,3H),3.33(t,J=8.3Hz,1H),2.99(d,J=9.9Hz,1H),2.84-2.82(m,1H),2.57-2.53(m,1H),2.43-2.27(m,3H),1.95-1.82(m,3H),1.19(d,J=6.6Hz,3H)。MS:(M+H m/z 425.3)。
实例77
6-[(3S,4S)-4-甲基-1-(喹啉-3-基甲基)吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-
1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
遵循6-{(3S,4S)-4-甲基-1-[(2-甲基嘧啶-5-基)甲基]吡咯烷-3-基}-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用喹啉-3-甲醛替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ8.86(d,J=2.1Hz,1H),8.27(d,J=1.7Hz,1H),8.08-8.06(m,1H),8.03(s,1H),7.90-7.57(m,1H),7.70-7.66(m,1H),7.56-7.52(m,1H),4.83-4.75(m,1H),4.11-4.07(m,2H),4.02-3.99(m,1H),3.85-3.82(m,1H),3.60-3.53(m,2H),3.33(t,J=8.3Hz,1H),3.05(d,J=9.9Hz,1H),2.87-2.85(m,1H),2.68-2.60(m,1H),2.53-2.40(m,1H),2.38-2.29(m,2H),2.05(m,1H),1.90-1.84(m,2H),1.19(d,J=6.6Hz,3H)。MS:(M+H m/z 445.1)。
实例78
6-{(3S,4S)-4-甲基-1-[(2-甲基嘧啶-4-基)甲基]吡咯烷-3-基}-1-(四氢-2H-
吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
遵循6-{(3S,4S)-4-甲基-1-[(2-甲基嘧啶-5-基)甲基]吡咯烷-3-基}-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用2-甲基嘧啶-4-甲醛替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ8.59(d,J=5.0Hz,1H),8.03(s,1H),7.20(d,J=5.0Hz,1H),4.84-4.76(m,1H),4.13-4.08(m,2H),3.97-3.93(m,1H),3.70-3.67(m,1H),3.61-3.53(m,2H),3.40(t,J=8.3Hz,1H),3.14(d,J=9.5Hz,1H),2.88(m,1H),2.72(s,3H),2.69-2.63(m,1H),2.47-2.27(m,3H),2.10-2.08(m,1H),1.91-1.83(m,2H),1.21(d,J=7.1Hz,3H)。MS:(M+H m/z 410.2)。
实例79
6-{(3S,4S)-4-甲基-1-[(6-甲基吡啶-3-基)甲基]吡咯烷-3-基}-1-(四氢-2H-吡喃-
4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
遵循6-{(3S,4S)-4-甲基-1-[(2-甲基嘧啶-5-基)甲基]吡咯烷-3-基}-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用6-甲基烟醛替换,从而得到标题化合物。400MHz 1H NMR(CD3OD)δ8.38(d,J=2.1Hz,1H),7.99(s,1H),7.77(d,J=2.07Hz,1H),7.75(d,J=2.07Hz,1H),4.94-4.83(m,1H),4.09-4.05(m,2H),3.78-3.57(m,4H),3.31-3.28(m,1H),3.11-3.06(m,1H),3.01-2.91(m,2H),2.72-2.65(m,1H),2.50(s,3H),2.33-2.23(m,3H),1.90-1.86(m,2H),1.14(d,J=7.1Hz,3H)。MS:(M+H m/z 409.2)。
实例80
6-[(3S,4S)-4-甲基-1-{[6-(三氟甲基)吡啶-3-基]甲基}吡咯烷-3-基]-1-(四氢-
2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
遵循6-{(3S,4S)-4-甲基-1-[(2-甲基嘧啶-5-基)甲基]吡咯烷-3-基}-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用6-(三氟甲基)烟醛替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ8.64(d,J=1.7Hz,1H),8.01(s,1H),7.99(d,J=1.7Hz,1H),7.70(d,J=8.3Hz,1H),4.83-4.77(m,1H),4.13-4.08(m,2H),3.86-3.74(m,2H),3.61-3.53(m,2H),3.30(t,J=8.7Hz,1H),3.03(d,J=9.9Hz,1H),2.92-2.89(m,1H),2.72-2.67(m,1H),2.50-2.47(m,1H),2.38-2.30(m,2H),2.07-2.03(m,1H),1.91-1.82(m,2H),1.20(d,J=7.1Hz,3H)。MS:(M+H m/z 412.2)。
实例81
6-{(3S,4S)-4-甲基-1-[(1-甲基-1H-咪唑并[4,5-c]吡啶-2-基)甲基]吡咯烷-3-
基}-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
遵循6-{(3S,4S)-4-甲基-1-[(2-甲基嘧啶-5-基)甲基]吡咯烷-3-基}-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用1-甲基-1H-咪唑并[4,5-c]吡啶-2-甲醛替换,从而得到标题化合物。400MHz1H NMR(CDCl3)δ10.83(brs 1H),9.01(s,1H),8.41(d,J=15.8Hz,1H),7.98(s,1H),7.30(d,J=4.98Hz,1H),4.79-4.75(m,1H),4.13-4.06(m,3H),4.00-3.96(s,4H),3.60-3.52(m,2H),3.30(t,J=8.7Hz,1H),3.07(d,J=9.9Hz,1H),2.92-2.89(m,1H),2.82-2.77(m,1H),2.48-2.45(m,1H),2.36-2.27(m,2H),2.19-2.17(m,1H),1.89-1.79(m,2H),1.23(d,J=6.6Hz,3H)。MS:(M+H m/z 449.2)。
实例82
6-{(3S,4S)-1-[(1,3-二甲基-1H-吡唑-5-基)甲基]-4-甲基吡咯烷-3-基}-1-(四氢-
2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
遵循6-{(3S,4S)-4-甲基-1-[(2-甲基嘧啶-5-基)甲基]吡咯烷-3-基}-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用1,3-二甲基-1H-吡唑-5-甲醛替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ7.98(s,1H),5.94(s,1H),4.81-4.75(m,1H),4.57(s,1H),4.11-4.06(m,2H),3.84(s,2H),3.77(s,1H),3.71-3.52(m,2H),3.31(t,J=8.3Hz,1H),3.01(d,J=9.9Hz,1H),2.85-2.83(m,1H),2.62-2.57(m,1H),2.46-2.25(m,2H),2.17-2.16(m,6H),1.96-1.81(m,2H),1.18(d,J=6.6Hz,3H)。MS:(M+H m/z 412.2)。
实例83
(a)1-环丁基-6-[(3,4-反式)-4-甲基吡咯烷-3-基]-1H-吡唑并[3,4-d]嘧啶- 4(5H)-酮
遵循6-[(3S,4S)-4-甲基吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮的制备方法,但用6-[(3,4-反式)-1-苄基-4-甲基吡咯烷-3-基]-1-环丁基-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮替换,从而得到标题化合物。400MHz 1H NMR(CD3OD)δ8.03(s,1H),5.39(m,1H),3.79-3.38(m,4H),3.08-2.71(m,4H),2.43(m,2H),1.92(m,2H),1.22(m,3H)。MS:(M+H m/z 464.2)。
(b)1-环丁基-6-{(3,4-反式)-4-甲基-1-[(2-甲基嘧啶-5-基)甲基]吡咯烷-3-基}- 1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
遵循6-{(3S,4S)-4-甲基-1-[(2-甲基嘧啶-5-基)甲基]吡咯烷-3-基}-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用1-环丁基-6-[(3,4-反式)-4-甲基吡咯烷-3-基]-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ10.79(brs,1H),8.63(s,2H),8.04(s,1H),5.28-5.22(m,1H),3.68(s,2H),3.24(t,J=8.3Hz,1H),3.04(d,J=9.9Hz,1H),2.89-2.87(m,1H),2.80-2.67(m,5H),2.51-2.38(m,3H),2.03-1.81(m,4H),1.18(d,J=7.1Hz,3H)。MS:(M+H m/z480.2)。
实例84
6-[(3S,4S)-1-(2,1,3-苯并噻二唑-5-基甲基)-4-甲基吡咯烷-3-基]-1-(四氢-2H-
吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
遵循6-{(3S,4S)-4-甲基-1-[(2-甲基嘧啶-5-基)甲基]吡咯烷-3-基}-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用苯并[c][1,2,5]噻二唑-5-甲醛替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ10.97(brs,1H),8.02-8.00(m,2H),7.86(s,1H),7.77(d,J=1.2Hz,1H),4.81-4.75(m,1H),4.12-4.06(m,2H),3.96-3.92(m,1H),3.81-3.78(m,1H),3.60-3.52(m,2H),3.38(t,J=8.3Hz,1H),3.03(d,J=9.9Hz,1H),2.88-2.85(m,1H),2.68-2.63(m,1H),2.47-2.45(m,1H),2.37-2.28(m,2H),2.04(t,J=8.7Hz,1H),1.90-1.80(m,2H),1.21(d,J=7.1Hz,3H)。MS:(M+H m/z 452.1)。
实例85
6-[(3S,4S)-4-甲基-1-(喹喔啉-2-基甲基)吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-
1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
遵循6-{(3S,4S)-4-甲基-1-[(2-甲基嘧啶-5-基)甲基]吡咯烷-3-基}-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用喹喔啉-2-甲醛替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ11.57(brs,1H),8.89(s,1H),8.26(dd,J=8.3,1.2Hz,1H),8.08-8.05(m,2H),7.78-7.70(m,2H),4.82(m,1H),4.32-4.28(m,1H),4.13-4.08(m,2H),4.00-3.96(m,1H),3.63-3.55(m,2H),3.44(t,J=8.3Hz,1H),3.26(d,J=9.9Hz,1H),2.93-2.91(m,1H),2.70-2.69(m,1H),2.39-2.31(m,2H),2.25-2.23(m,1H),2.04(s,1H),1.92-1.84(m,2H),1.23(d,J=7.1Hz,3H)。MS:(M+Hm/z 446.2)。
实例86
6-[(3S,4S)-4-甲基-1-(喹啉-4-基甲基)吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-
1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
遵循6-{(3S,4S)-4-甲基-1-[(2-甲基嘧啶-5-基)甲基]吡咯烷-3-基}-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用喹啉-4-甲醛替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ10.68(brs,1H),8.83(d,J=4.1Hz,1H),8.25-8.22(m,1H),8.12-8.08(m,1H),7.98(s,1H),7.75-7.72(m,1H),7.54(d,J=3.3Hz,1H),7.36(d,J=3.3Hz,1H),5.21(m,1H),4.77(m,1H),4.13-4.06(m,3H),3.59-3.52(m,2H),3.32(d,J=8.7Hz,1H),3.03(d,J=9.9Hz,1H),2.88-2.86(m,1H),2.72-2.69(m,1H),2.36-2.28(m,3H),2.04-2.00(m,1H),1.89-1.84(m,2H),1.20(d,J=7.1Hz,3H)。MS:(M+H m/z 445.1)。
实例87
6-[(3S,4S)-4-甲基-1-(吡啶-2-基甲基)吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-
1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
向6-[(3S,4S)-4-甲基吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮盐酸盐(3.98g)在二甲基甲酰胺(60mL)中的溶液中先后添加2-吡啶基甲醛(1.63g)、乙酸(1.34mL)和三乙酰氧硼氢化钠(4.99g)。将反应混合物在环境温度下搅拌20分钟,用24mL的1N NaoH溶液猝灭。将反应混合物用饱和碳酸氢钠溶液调节至pH9,用乙酸乙酯萃取3次,用硫酸镁干燥,过滤并浓缩,从而得到3.6g标题化合物。将游离碱溶于乙酸乙酯中,然后添加25mL的HCl/乙酸乙酯并搅拌。滤出白色固体,将其干燥从而得到5.10g二盐酸盐形式的标题化合物。400MHz 1H NMR(CDCl3)δ8.64-8.63(m,1H),8.03(s,1H),7.72-7.67(m,1H),7.43(d,J=7.9Hz,1H),7.21-7.18(m,1H),4.85-4.75(m,1H),4.14-4.05(m,3H),3.80-3.76(m,1H),3.63-3.54(m,2H),3.47-3.42(m,1H),3.10(m,1H),2.87(m,1H),2.66(m,1H),2.46-2.28(m,3H),2.14(m,1H),1.93-1.84(m,2H),1.20(d,J=7.1Hz,3H)。MS:(M+H m/z 495.2)。
实例88
(a)5-氨基-3-甲基-1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-甲腈
遵循5-氨基-1-(2-甲氧基苯基)-1H-吡唑-4-甲腈的制备方法,但用1-(四氢-2H-吡喃-4-基)肼和2-(1-甲氧基亚乙基)丙二腈替换,从而得到标题化合物。400MHz 1H NMR(CD3OD)δ4.20(m,1H),4.05(m,2H),3.50(m,2H),2.18(s,3H),2.09(m,2H),1.77(m,2H)。MS:(M+H m/z 207.0)。
(b)5-氨基-3-甲基-1-(四氢-2H-吡喃-4-基)-1H-吡唑-4甲酰胺
遵循5-氨基-1-(2-甲氧基苯基)-1H-吡唑-4-甲酰胺的制备方法,但用5-氨基-3-甲基-1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-甲腈替换,从而得到标题化合物。400MHz 1H NMR(CD3OD)δ4.20(m,1H),4.05(m,2H),3.50(m,2H),2.18(s,3H),2.09(m,2H),1.77(m,2H)。MS:(M+H m/z 225.0)。
(c)6-[(3S,4S)-1-苄基-4-甲基吡咯烷-3-基]-3-甲基-1-(四氢-2H-吡喃-4-基)- 1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
遵循6-[(3,4-反式)-1-苄基-4-甲基吡咯烷-3-基]-1-(2-甲氧基苯基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用5-氨基-3-甲基-1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-甲酰胺和(3S,4S)-1-苄基-4-甲基吡咯烷-3-羧酸甲酯替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ8.51-7.30(m,5H),4.75-4.68(m,1H),4.13-4.08(m,2H),3.84-3.73(m,1H),3.63-3.48(m,2H),3.40(m,1H),3.10-2.78(m,2H),2.55(s,3H),2.50-2.24(m,3H),1.87-1.80(m,2H),.61-1.41(m,3H),1.19(d,J=6.6Hz,3H)。MS:(M+H m/z=408.1)。
实例89
6-[(3S,4S)-1-(3-氟苄基)-4-甲基吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1,5-二
氢-4H-吡唑并[3,4-d]嘧啶-4-酮
遵循6-{(3S,4S)-4-甲基-1-[(2-甲基嘧啶-5-基)甲基]吡咯烷-3-基}-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用氰基硼氢化钠和3-氟苯甲醛替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ8.02(s,1H),7.35-7.30(m,1H),7.21-7.20(m,1H),7.05(d,J=9.5Hz,1H),6.98-6.93(m,1H),4.83-4.77(m,1H),4.14-4.08(m,2H),3.80-3.77(m,1H),3.64-3.54(m,3H),3.36(t,J=8.8Hz,1H),3.01(d,J=9.9Hz,1H),2.84-2.83(m,1H),2.57(m,1H),2.44-2.27(m,3H),1.95-1.83(m,3H),1.20(d,J=7.1Hz,3H)。MS:(M+H m/z 412.4)。
实例90
6-[(3S,4S)-1-(3,5-二氟苄基)-4-甲基吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1,5-
二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
遵循6-{(3S,4S)-4-甲基-1-[(2-甲基嘧啶-5-基)甲基]吡咯烷-3-基}-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用氰基硼氢化钠和3,5-二氟苯甲醛替换,从而得到标题化合物。400MHz 1HNMR(CDCl3)δ8.03(s,1H),6.93-6.90(m,2H),6.73-6.69(m,1H),4.81-4.80(m,1H),4.14-4.10(m,2H),3.79-3.67(m,2H),3.62-3.55(m,2H),3.30-3.26(m,1H),3.10-3.07(m,1H),2.95-2.92(m,1H),2.83-2.79(m,1H),2.26-2.53(m,1H),2.38-2.32(m,2H),2.18-2.14(m,1H),1.91-1.85(m,2H),1.18(d,J=7.1Hz,3H)。MS:(M+H m/z 430.4)。
实例91
6-{(3S,4S)-4-甲基-1-[4-(三氟甲基)苄基]吡咯烷-3-基}-1-(四氢-2H-吡喃-4-
基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
遵循6-{(3S,4S)-4-甲基-1-[(2-甲基嘧啶-5-基)甲基]吡咯烷-3-基}-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用4-(三氟甲基)苯甲醛替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ8.03(s,1H),7.62-7.59(m,2H),7.51-7.49(m,2H),4.83-4.76(m,1H),4.14-4.08(m,2H),3.87-3.84(m,1H),3.70-3.67(m,1H),3.61-3.54(m,2H),3.34(t,J=8.3Hz,1H),3.01(d,J=9.9Hz,1H),2.88-2.86(m,1H),2.67-2.62(m,1H),2.48-2.46(m,1H),2.38-2.30(m,2H),2.05-2.00(m,1H),1.81-1.82(m,2H),1.19(d,J=7.1Hz,3H)。MS:(M+H m/z 462.4)。
实例92
3-甲基-6-[(3S,4S)-4-甲基-1-(吡啶-3-基甲基)吡咯烷-3-基]-1-(四氢-2H-吡喃-
4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
遵循6-{(3S,4S)-4-甲基-1-[(2-甲基嘧啶-5-基)甲基]吡咯烷-3-基}-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用3-甲基-6-[(3S,4S)-4-甲基吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮和烟醛替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ8.53(m,2H),7.83(d,J=7.9Hz,1H),7.36-7.33(m,1H),4.74-4.68(m,1H),4.12-4.07(m,2H),3.79-3.76(m,1H),3.68-3.65(m,1H),3.59-3.52(m,2H),3.47(s,1H),3.34(t,J=8.7Hz,1H),2.99(d,J=9.9Hz,1H),2.82-2.80(m,1H),2.61-2.57(m,1H),2.54(s,3H),2.42-2.28(m,2H),1.95(t,J=8.7Hz,1H),1.87-1.78(m,2H),1.19(d,J=7.1Hz,3H)。MS:(M+H m/z 409.2)。
实例93
(a)3-甲基-6-[(3S,4S)-4-甲基吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1H-吡唑 并[3,4-d]嘧啶-4(5H)-酮
遵循6-[(3S,4S)-4-甲基吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮的制备方法,但用6-[(3S,4S)-1-苄基-4-甲基吡咯烷-3-基]-3-甲基-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ4.85-4.81(m,1H),4.08-4.04(m,2H),3.61-3.55(m,2H),3.31-3.28(m,3H),2.84-2.82(m,1H),2.60-2.53(m,2H),2.49(s,3H),2.29-2.25(m,2H),1.85-1.81(m,2H),1.12(d,J=6.2Hz,3H)。MS:(M+H m/z=249.1)。
(b)3-甲基-6-{(3S,4S)-4-甲基-1-[(2-甲基嘧啶-5-基)甲基]吡咯烷-3-基}-1-(四 氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
遵循6-{(3S,4S)-4-甲基-1-[(2-甲基嘧啶-5-基)甲基]吡咯烷-3-基}-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用3-甲基-6-[(3S,4S)-4-甲基吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ8.63(s,2H),4.74-4.68(m,1H),4.11-4.08(m,2H),3.74-3.63(m,2H),3.60-3.52(m,2H),3.28(t,J=8.3Hz,1H),3.03(d,J=9.5Hz,1H),2.85-2.83(m,1H),2.71(s,3H),2.65-2.61(m,1H),2.53(s,3H),2.48-2.29(m,2H),1.98(t,J=8.7Hz,1H),1.87-1.80(m,3H),1.19(d,J=7.1Hz,3H)。MS:(M+H m/z 424.2)。
实例94
6-{(3S,4S)-1-[(6-甲氧基吡啶-3-基)甲基]-4-甲基吡咯烷-3-基}-3-甲基-1-(四
氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
遵循6-{(3S,4S)-4-甲基-1-[(2-甲基嘧啶-5-基)甲基]吡咯烷-3-基}-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用3-甲基-6-[(3S,4S)-4-甲基吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮和6-甲氧基烟醛替换,从而得到标题化合物。400MHz 1HNMR(CDCl3)δ8.03(d,J=2.1Hz,1H),7.69(dd,J=8.7,2.1Hz,1H),6.78(d,J=9.1Hz,1H),4.74-4.68(m,1H),4.13-4.07(m,2H),3.89(s,3H),3.70-3.67(m,1H),3.59-3.51(m,2H),3.32(t,J=8.7Hz,1H),2.97(d,J=9.9Hz,1H),2.79-2.77(m,1H),2.54(s,3H),2.53-2.50(m,1H),2.41-2.29(m,2H),1.92-1.78(m,3H),1.30-1.18(m,2H),10.86(t,J=76.6Hz,3H)。MS:(M+H m/z439.2)。
实例95
6-{(3S,4S)-4-甲基-1-[(6-甲基吡啶-2-基)甲基]吡咯烷-3-基}-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
遵循6-{(3S,4S)-4-甲基-1-[(2-甲基嘧啶-5-基)甲基]吡咯烷-3-基}-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用氰基硼氢化钠和6-甲基比考啉醛替换,从而得到标题化合物。400MHz 1HNMR(CDCl3)δ8.02(s,1H),7.57(t,J=7.7Hz,1H),7.20(d,J=7.9Hz,1H),7.03(d,J=7.5Hz,1H),4.83-4.77(m,1H),4.13-4.08(m,2H),3.99-3.95(m,1H),3.72-3.69(m,1H),3.62-3.54(m,2H),3.42(t,J=8.3Hz,1H),3.06(d,J=9.9Hz,1H),2.85-2.83(m,1H),2.64-2.57(m,1H),2.55(s,3H),2.44-2.29(m,3H),2.08-2.03(m,1H),1.91-1.82(m,2H),1.20(t,J=7.1Hz,3H)。MS:(M+Hm/z 409.1)。
实例96
6-[(3S,4S)-1-(4-氟苄基)-4-甲基吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1,5-二
氢-4H-吡唑并[3,4-d]嘧啶-4-酮
遵循6-{(3S,4S)-4-甲基-1-[(2-甲基嘧啶-5-基)甲基]吡咯烷-3-基}-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用氰基硼氢化钠和4-氟苯甲醛替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ8.02(s,1H),7.36-7.33(m,2H),7.05-7.01(m,2H),4.82-4.77(m,1H),4.14-4.09(m,2H),3.79-3.76(m,1H),3.62-3.54(m,3H),3.34(t,J=8.3Hz,1H),2.99(d,J=9.9Hz,1H),2.85-2.83(m,1H),2.60-2.55(m,1H),2.45-2.30(m,3H),1.99-1.82(m,3H),1.20(d,J=7.1Hz,3H)。MS:(M+H m/z412.1)。
实例97
(a)6-[(3,4-反式)-1-苄基-4-乙基吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1,5-二 氢-4H-吡唑并[3,4-d]嘧啶-4-酮
遵循6-[(3,4-反式)-1-苄基-4-甲基吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用(3,4-反式)-1-苄基-4-甲基吡咯烷-3-羧酸乙酯替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ8.02(s,1H),7.40-7.26(m,5H),4.78(m,1H),4.12-4.09(m,2H),3.82-3.804(m,1H),3.65-3.54(m,3H),3.35(t,J=8.3Hz,1H),2.98(d,J=9.9Hz,1H),2.89-2.86(m,1H),2.48-2.32(m,3H),2.20(m,1H),1.95-1.87(m,2H),1.63-1.58(m,2H),1.50-1.49(m,1H),0.93(t,J=7.1Hz,3H)。MS:(M+Hm/z 408.1)。
(b)6-[(3S,4S)-1-苄基-4-乙基吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1,5-二氢- 4H-吡唑并[3,4-d]嘧啶-4-酮
在Chiralcel OJ-H手性HPLC柱上分离6-[(3,4-反式)-1-苄基-4-乙基吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮外消旋物,移动相80/20 CO2/MeOH,TR=3.27,从而得到对映异构体。分析:AD柱,移动相85/15庚烷/EtOH,TR=12.896。400MHz 1H NMR(CDCl3)δ8.02(s,1H),7.40-7.26(m,5H),4.78(m,1H),4.12-4.09(m,2H),3.82-3.804(m,1H),3.65-3.54(m,3H),3.35(t,J=8.3Hz,1H),2.98(d,J=9.9Hz,1H),2.89-2.86(m,1H),2.48-2.32(m,3H),2.20(m,1H),1.95-1.87(m,2H),1.63-1.58(m,2H),1.50-1.49(m,1H),0.93(t,J=7.1Hz,3H)。MS:(M+H m/z 408.1)。
实例98
6-[(3S,4S)-1-(2-氟苄基)-4-甲基吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1,5-二
氢-4H-吡唑并[3,4-d]嘧啶-4-酮
遵循6-{(3S,4S)-4-甲基-1-[(2-甲基嘧啶-5-基)甲基]吡咯烷-3-基}-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用氰基硼氢化钠和2-氟苯甲醛替换,从而得到标题化合物。400MHz 1H NMR(CD3OD)δ7.98(s,1H),7.47-7.42(m,1H),7.33-7.26(m,2H),7.18-7.07(m,1H),4.08-4.04(m,2H),3.85(s,2H),3.69-3.56(m,3H),3.20-2.93(m,4H),2.69-2.62(m,1H),2.40-2.19(m,3H),1.88-1.85(m,2H),1.14(d,J=6.6Hz,3H)。MS:(M+H m/z 412.1)。
实例99
6-{(3S,4S)-4-甲基-1-[2-(三氟甲基)苄基]吡咯烷-3-基}-1-(四氢-2H-吡喃-4-
基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
遵循6-{(3S,4S)-4-甲基-1-[(2-甲基嘧啶-5-基)甲基]吡咯烷-3-基}-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用氰基硼氢化钠和2-(三氟甲基)苯甲醛替换,从而得到标题化合物。400MHz1H NMR(CDCl3)δ10.58(brs,1H),8.01(s,1H),7.79-7.76(m,1H),7.64-7.58(m,2H),7.37-7.34(m,1H),4.83-4.76(m,1H),4.14-4.08(m,2H),3.88(m,2H),3.62-3.54(m,2H),3.39(t,J=8.3Hz,1H),3.02-2.97(m,1H),2.85(m,1H),2.66(m,1H),2.44-2.27(m,3H),2.06-2.03(m,1H),1.91-1.83(m,2H),1.21(d,J=7.1Hz,3H)。MS:(M+H m/z 462.1)。
实例100
6-[(3S,4S)-1-(2,4-二氟苄基)-4-甲基吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1,5-
二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
遵循6-{(3S,4S)-4-甲基-1-[(2-甲基嘧啶-5-基)甲基]吡咯烷-3-基}-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用氰基硼氢化钠和2,4-二氟苯甲醛替换,从而得到标题化合物。400MHz 1HNMR(CDCl3)δ8.01(s,1H),7.40-7.38(m,2H),6.90-6.79(m,2H),4.81-4.77(m,2H),4.14-4.08(m,2H),3.88(m,2H),3.62-3.54(m,2H),3.32(t,J=8.7Hz,1H),3.02(d,J=9.5Hz,1H),2.86-2.83(m,1H),2.65(m,1H),2.43-2.20(m,3H),2.00-1.83(m,2H),1.21(d,J=6.6Hz,3H)。MS:(M+H m/z430.2)。
实例101
6-[(3S,4S)-1-(4-甲氧基苄基)-4-甲基吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
遵循6-{(3S,4S)-4-甲基-1-[(2-甲基嘧啶-5-基)甲基]吡咯烷-3-基}-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用氰基硼氢化钠和4-甲氧基苯甲醛替换,从而得到标题化合物。400MHz 1HNMR(CDCl3)δ8.01(s,1H),7.29(d,J=8.3Hz,2H),6.87(d,J=8.7Hz,2H),4.82-4.08(m,1H),4.13-4.08(m,2H),3.84-3.75(m,4H),3.61-3.51(m,3H),3.35(t,J=8.7Hz,1H),2.97(d,J=9.9Hz,1H),2.82-2.80(m,1H),2.53-2.49(m,1H),2.42-2.30(m,3H),1.95-1.82(m,3H),1.18(d,J=7.1Hz,3H)。
实例102
(a)5-氨基-1-(四氢-2H-噻喃-4-基)-1H-吡唑-4-甲腈
遵循5-氨基-1-(2-甲氧基苯基)-1H-吡唑-4-甲腈的制备方法,但用1-(四氢-2H-噻喃-4-基)肼替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ7.44(s,1H),4.71(s,2H),3.84-3.76(m,1H),2.80-2.63(m,4H),2.24-2.10(m,4H)。MS:(M+H m/z 209.1)。
(b)5-氨基-1-(四氢-2H-噻喃-4-基)-1H-吡唑-4-甲酰胺
遵循5-氨基-1-(2-甲氧基苯基)-1H-吡唑-4-甲酰胺的制备方法,但用5-氨基-1-(四氢-2H-噻喃-4-基)-1H-吡唑-4-甲腈替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ7.67(s,1H),4.09-3.97(m,1H),2.89-2.82(m,2H),2.72-2.68(m,2H),2.15-2.10(m,4H)。MS:(M+H m/z 227.1)。
(c)6-[(3S,4S)-1-苄基-4-甲基吡咯烷-3-基]-1-(四氢-2H-噻喃-4-基)-1,5-二氢- 4H-吡唑并[3,4-d]嘧啶-4-酮
遵循6-[(3,4-反式)-1-苄基-4-甲基吡咯烷-3-基]-1-(2-甲氧基苯基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用5-氨基-1-(四氢-2H-噻喃-4-基)-1H-吡唑-4-甲酰胺和(3S,4S)-1-苄基-4-甲基吡咯烷-3-羧酸甲酯替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ8.02(s,1H),7.41-7.26(m,5H),4.60-4.53(m,1H),3.86-3.83(m,1H),3.65(m,1H),3.41-3.37(m,1H),3.02(m,1H),2.94-2.75(m,4H),2.60-2.31(m,3H),2.25-2.16(m,2H),1.99-1.94(m,1H),1.62(m,2H),1.20(t,J=7.1Hz,3H)。MS:(M+H m/z410.2)。
实例103
6-[(3S,4S)-1-(2-甲氧基苄基)-4-甲基吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1,5-
二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
遵循6-{(3S,4S)-4-甲基-1-[(2-甲基嘧啶-5-基)甲基]吡咯烷-3-基}-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用氰基硼氢化钠和2-甲氧基苯甲醛替换,从而得到标题化合物。400MHz 1HNMR(CDCl3)δ8.00(s,1H),7.29-7.22(m,2H),6.92-6.88(m,2H),4.83-4.75(m,1H),4.14-4.08(m,2H),3.93(s,3H),3.76-3.69(m,2H),3.62-3.54(m,2H),3.34(t,J=8.7Hz,1H),3.01(d,J=9.5Hz,1H),2.78(m,1H),2.56(m,1H),2.41-2.27(m,3H),1.92-1.82(m,3H),1.18(d,J=7.1Hz,3H)。MS:(M+H m/z 424.1)。
实例104
6-[(3S,4S)-1-(3-甲氧基苄基)-4-甲基吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1,5-
二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
遵循6-{(3S,4S)-4-甲基-1-[(2-甲基嘧啶-5-基)甲基]吡咯烷-3-基}-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用氰基硼氢化钠和3-甲氧基苯甲醛替换,从而得到标题化合物。400MHz 1HNMR(CDCl3)δ8.02(s,1H),7.27-7.21(m,1H),6.96-6.92(m,2H),6.81(d,J=7.1Hz,1H),4.82-4.76(m,1H),4.14-4.08(m,2H),3.85(s,3H),3.79(s,1H),3.62-3.54(m,3H),3.39(t,J=8.7Hz,1H),3.00(d,J=10.3Hz,1H),2.81(m,1H),2.53(m,1H),2.42-2.28(m,3H),1.94-1.82(m,3H),1.20(d,J=7.1Hz,3H)。MS:(M+H m/z 424.1)。
实例105
6-{(3S,4S)-4-甲基-1-[3-(三氟甲基)苄基]吡咯烷-3-基}-1-(四氢-2H-吡喃-4-
基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
遵循6-{(3S,4S)-4-甲基-1-[(2-甲基嘧啶-5-基)甲基]吡咯烷-3-基}-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用氰基硼氢化钠和3-(三氟甲基)苯甲醛替换,从而得到标题化合物。400MHz1H NMR(CDCl3)δ8.02(s,1H),7.68-7.63(m,1H),7.55-7.51(m,3H),4.84-4.76(m,1H),4.14-4.08(m,2H),3.87-3.84(m,1H),3.71-3.69(m,1H),3.62-3.54(m,2H),3.36(t,J=8.3Hz,1H),3.01(m,1H),2.86(m,1H),2.63-2.60(m,1H),2.50-2.27(m,3H),1.98-1.83(m,3H),1.21(d,J=6.6Hz,3H)。MS:(M+H m/z 462.1)。
实例106
6-[(3S,4S)-1-(26-二氟苄基)-4-甲基吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1,5-
二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
遵循6-{(3S,4S)-4-甲基-1-[(2-甲基嘧啶-5-基)甲基]吡咯烷-3-基}-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用氰基硼氢化钠和2,6-二氟苯甲醛替换,从而得到标题化合物。400MHz 1HNMR(CDCl3)δ8.00(s,1H),7.30-7.22(m,1H),6.96-6.89(m,2H),4.83-4.75(m,1H),4.13-4.08(m,2H),3.91(s,2H),3.62-3.54(m,2H),3.34(t,J=8.3Hz,1H),3.06(d,J=9.5Hz,1H),2.80(m,1H),2.66(m,1H),2.40-2.27(m,3H),1.99(m,1H),1.91-1.83(m,2H),1.16(d,J=7.1Hz,3H)。MS:(M+H m/z 430.1)。
实例107
(a)6-[(3S,4S)-4-乙基吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4- d]嘧啶-4(5H)-酮
遵循6-[(3S,4S)-4-甲基吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮的制备方法,但用6-[(3S,4S)-1-苄基-4-乙基吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮替换,从而得到标题化合物。400MHz 1H NMR(CD3OD)δ8.02(s,1H),4.97(m,1H),4.09-4.06(m,2H),3.78-3.58(m,4H),3.34-3.34(m,1H),3.16-3.11(m,1H),2.68(d,J=8.7Hz,1H),2.63(m,1H),2.32-2.27(m,2H),1.90-1.87(m,2H),1.69(m,1H),1.57(m,1H),0.97(t,J=7.5Hz,3H)。MS:(M+H m/z318.2)。
(b)6-{(3S,4S)-4-乙基-1-[(5-甲基吡嗪-2-基)甲基]吡咯烷-3-基}-1-(四氢-2H- 吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
向6-[(3S,4S)-4-乙基吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮(4.4g)在二甲基甲酰胺(62mL)中的溶液中添加乙酸(2.4mL)、5-甲基-吡嗪-2-甲醛(2g)和三乙酰氧基硼氢化钠(5.27g)。将反应混合物在环境温度下搅拌2小时,并用饱和的碳酸氢钠溶液小心猝灭,用二氯甲烷萃取3次,在硫酸镁上干燥,过滤并浓缩。用1-4%甲醇/二氯甲烷/0.5%饱和氢氧化铵洗脱通过Biotage MPLC色谱纯化得到标题化合物(3.9g)。400MHz 1H NMR(CDCl3)δ8.52-8.48(m,1H),8.38(s,1H),8.02(s,1H),4.81-4.75(m,1H),4.11-4.01(m,3H),3.79-3.75(m,1H),3.60-3.53(m,2H),3.40-3.32(m,1H),3.10-3.08(m,1H),2.94(m,1H),2.63-2.57(m,1H),2.53(d,J=7.5Hz,1H),2.37-2.18(m,4H),1.90-1.83(m,2H),1.67-1.60(m,1H),1.54-1.47(m,1H),0.95-0.92(m,3H)。MS:(M+H m/z 424.2)。
实例108
6-{(3S,4S)-4-乙基-1-[(6-甲氧基吡啶-3-基)甲基]吡咯烷-3-基}-1-(四氢-2H-吡
喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
遵循6-{(3S,4S)-4-甲基-1-[(2-甲基嘧啶-5-基)甲基]吡咯烷-3-基}-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用6-[(3S,4S)-4-乙基吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮盐酸盐、氰基硼氢化钠和6-甲氧基烟醛替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ8.04(d,J=2.1Hz,1H),8.02(s,1H),7.73-7.71(m,1H),6.78(d,J=8.7Hz,1H),4.80-4.75(m,1H),4.12-4.10(m,2H),3.92-3.90(m,3H),3.72-3.70(m,1H),3.61-3.54(m,3H),3.32(t,J=8.3Hz,1H),2.99(m,1H),2.91(m,1H),2.41(m,1H),2.40-2.28(m,2H),2.21(m,1H),1.95(m,1H),1.91-1.83(m,2H),1.65-1.45(m,2H),0.92(t,J=7.5Hz,3H)。MS:(M+H m/z 439.2)。
实例109
6-[(S,4S)-4-乙基-1-(吡啶-2-基甲基)吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-
1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
向6-[(3S,4S)-4-乙基吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮盐酸盐(51mg)在乙腈(1mL)中的溶液中添加碳酸钾(88mg)和2-(溴甲基)吡啶溴化氢(40mg),然后将反应混合物在密封试管中在回流下加热72小时。将反应混合物在硅石上浓缩,通过CombiFlash快速色谱纯化,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ11.50(brs,1H),8.63(dd,J=1.7,0.83,Hz,1H),8.02(s,1H),7.70-7.67(m,1H),7.40(d,J=7.9Hz,1H),7.20-7.16(m,1H),4.79-4.77(m,1H),4.12-4.02(m,3H),3.75-3.72(m,1H),3.61-3.53(m,2H),3.39(t,J=7.9Hz,1H),3.07(d,J=9.9Hz,1H),2.92-2.90(m,1H),2.37-2.12(m,4H),1.91-1.83(m,2H),1.65-1.60(m,1H),1.54-1.49(m,1H),0.94(t,J=7.1Hz,3H)。MS:(M+H m/z409.1)。
实例110
6-[(3S,4S)-4-乙基-1-(喹喔啉-2-基羰基)吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-
1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
0℃下,向6-[(3S,4S)-4-乙基吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮盐酸盐(73mg)在二氯甲烷(2mL)中的溶液中添加三乙胺(62mg)和2-喹喔啉基氯化物(40mg)。将反应混合物温热至环境温度并搅拌18小时。将反应混合物用饱和碳酸氢钠猝灭,用二氯甲烷萃取,在硫酸镁上干燥,过滤并浓缩。用2-4%MeOH/二氯甲烷洗脱通过CombiFlash快速色谱纯化,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ12.78-12.62(m,1H),9.41(d,J=7.5,Hz,1H),8.18-8.00(m,3H),7.87-7.73(m,2H),4.84-4.81(m,1H),4.55-3.86(m,6H),3.61-3.53(m,2H),3.38-3.31(m,1H),2.75(m,1H),2.39-2.34(m,2H),1.93-1.89(m,2H),1.58-1.56(m,1H),1.63-1.50(m,1H),1.01-0.88(m,3H)。MS:(M+H m/z474.2)。
实例111
6-[(3S,4S)-4-甲基-1-(嘧啶-2-基甲基)吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-
1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
向6-[(3S,4S)-4-甲基吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮盐酸盐(7.75g)(参见实例73的步骤(a)中的制法)在二甲基甲酰胺(115mL)中的溶液中添加三氟磺酸铁(900mg)、2-(氯甲基)嘧啶盐酸盐(4.5g)和碳酸铯(22.2g),然后将反应混合物在60℃下加热24小时。将反应混合物在硅胶上浓缩,通过快速色谱(采用0-15%甲醇/乙酸乙酯/1%饱和氢氧化铵洗脱)纯化,从而得到标题化合物(6g)。400MHz 1HNMR(CDCl3)δ12.30(brs,1H),8.63(d,J=5.0,Hz,2H),8.03(s,1H),7.20(d,J=5.0,Hz,1H),4.84-4.79(m,1H),4.30-4.27(m,1H),4.14-4.08(m,2H),3.87-3.82(m,1H),3.63-3.55(m,2H),3.47(t,J=7.9Hz,1H),3.29(d,J=9.9Hz,1H),2.88-2.86(m,1H),2.60-2.56(m,1H),2.46-2.24(m,4H),1.93-1.84(m,2H),1.24(t,J=7.1Hz,3H)。MS:(M+H m/z 396.2)。
实例112
2-({(3S,4S)-3-乙基-4-[4-氧代-1-(四氢-2H-吡喃-4-基)-45-二氢-1H-吡唑并
[3,4-d]嘧啶-6-基]吡咯烷-1-基}甲基)苯甲腈
遵循6-{(3S,4S)-4-甲基-1-[(2-甲基嘧啶-5-基)甲基]吡咯烷-3-基}-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用6-[(3S,4S)-4-乙基吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮盐酸盐、氰基硼氢化钠和2-甲酸苯甲腈替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ11.68(brs,1H),8.01(s,1H),7.68-7.58(m,3H),7.40-7.36(m,1H),4.91(s,1H),4.82-4.76(m,1H),4.12-4.10(m,2H),3.94(m,1H),3.61-6.55(m,2H),3.37(m,1H),3.03-2.94(m,2H),2.66(m,1H),2.41-2.23(m,3H),2.09(m,1H),1.91-1.84(m,2H),1.66-1.49(m,2H),0.93(t,J=7.5Hz,3H)。MS:(M+H m/z 433.2)。
实例113
3-({(3S,4S)-3-乙基-4-[4-氧代-1-(四氢-2H-吡喃-4-基)-4,5-二氢-1H-吡唑并
[3,4-d]嘧啶-6-基]吡咯烷-1-基}甲基)苯甲腈
遵循6-{(3S,4S)-4-甲基-1-[(2-甲基嘧啶-5-基)甲基]吡咯烷-3-基}-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用6-[(3S,4S)-4-乙基吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮盐酸盐、氰基硼氢化钠和3-甲酰基苯甲腈替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ8.01(s,1H),7.73-7.41(m,4H),4.79(m,1H),4.72(s,1H),4.12-4.09(m,2H),3.82-3.70(m,2H),3.61-3.54(m,2H),3.27(t,J=8.3Hz,1H),3.02-2.97(m,2H),2.71-2.70(m,1H),2.37-2.30(m,2H),2.20-2.14(m,1H),1.90-1.87(m,2H),1.61-1.60(m,1H),1.51-1.49(m,1H),0.91(t,J=7.5Hz,3H)。MS:(M+H m/z 433.2)。
实例114
4-({(3S,4S)-3-乙基-4-[4-氧代-1-(四氢-2H-吡喃-4-基)-45-二氢-1H-吡唑并
[3,4-d]嘧啶-6-基]吡咯烷-1-基}甲基)苯甲腈
遵循6-{(3S,4S)-4-甲基-1-[(2-甲基嘧啶-5-基)甲基]吡咯烷-3-基}-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮的制备方法,但用6-[(3S,4S)-4-乙基吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮盐酸盐、氰基硼氢化钠和4-甲酰基苯甲腈替换,从而得到标题化合物。400MHz 1H NMR(CDCl3)δ11.82(brs,1H),8.01(s,1H),7.75(t,J=7.9Hz,1H),7.59-7.44(m,3H),4.78-4.75(m,1H),4.74(s,1H),4.13-4.08(m,2H),3.77(m,1H),3.70(m,1H),3.61-3.53(m,2H),3.31-3.29(m,1H),3.01-2.90(m,2H),2.58(m,1H),2.37-2.31(m,2H),2.25(m,1H),2.00(m,1H),1.91-1.83(m,2H),1.64-1.63(m,1H),1.61-1.59(m,1H),0.93(t,J=7.5Hz,3H。MS:(M+H m/z 433.2)。
生物试验方案
式(I)化合物或其药学上可接受盐在治疗或预防哺乳动物(例如人类)中的疾病中的用途可以通过其在本领域普通技术人员已知的常规试验(包括以下试验)中的活性展示。这些试验还提供了一个可以对式(I)化合物的活性与其他已知化合物的活性进行比较的手段。
磷酸二酯酶9(PDE9)抑制活性
使用磷酸二酯酶邻近闪烁分析(SPA)(GE Healthcare LifeSciences)进行PDE9试验。该试验在96孔透明底微滴定板(Costar 3632,Corning Inc)中实施。人重组PDE9酶在SF-9细胞中生成,该细胞小球在缓冲液(20mM TRIS、2mM苄脒、1mM EDTA、250mM蔗糖、100μMPMSF,pH 7.5,采用HCl)中超声,在40,000xg下4℃下离心20分钟。将上层清液在-80℃下储存。在试验缓冲液(50mM Tris-HCl,pH7.5,含有1.3mM MgCl2)中稀释[8-3H]鸟苷3′,5′-环状磷酸酯(TRK 392,GEHealthcare Life Sciences),使得最终孔浓度为50nM。为了得到2%DMSO的最终浓度,将待测化合物溶于DMSO中,在DI H2O中稀释,然后在20%DMSO/80%H2O中连续稀释。对于该试验,用试验缓冲液稀释PDE9,使得20%或更少的底物水解成5′GMP。每个试验孔包含10μl的待测化合物或溶剂、40μl的[3H]cGMP和50μl的酶,通过高浓度PDE抑制剂测定背景。该试验通过添加酶开始,并在室温下实施30分钟。该试验通过添加10μl的PDE9抑制剂(其足以完全抑制酶活性)终止,接着立即每孔添加50μl SPA小球。将板密封、旋转、静置>300min,然后在Wallac TriLux MicroBeta LSC中计数。
实例号 | G5678A(U):IC50 | 实例号 | G5678A(U):IC50 | 实例号 | G5678A(U):IC50 |
3 | 9.46nM | 43 | 36.4nM | 80 | 3.72nM |
4 | 624nM | 44 | 10.9nM | 81 | 2.92nM |
5 | 558nM | 45 | 38.7nM | 82 | 5.18nM |
6 | 57.1nM | 46 | 8.53nM | 83 | 24.5nM |
7 | 11.6nM | 47 | 5.53nM | 84 | 1.87nM |
8 | 11.2nM | 48 | 40.7nM | 85 | 0.903nM |
9 | 2.84nM | 49 | 4.55nM | 86 | 1.44nM |
10 | 4.98nM | 50 | 125nM | 87 | 5.72nM |
11 | 18.9nM | 51 | 8.19nM | 88 | 17.9nM |
12 | 7.23nM | 52 | 26.0nM | 89 | 1.70nM |
13 | 6.61nM | 53 | 7.30nM | 90 | 1.41nM |
14 | 26.0nM | 54 | 14.7nM | 91 | 6.69nM |
17 | 16.2nM | 55 | 6.55nM | 92 | 23.3nM |
18 | 8.26nM | 56 | 4.81nM | 93 | 24.3nM |
19 | 2.68nM | 57 | 122nM | 94 | 14.2nM |
20 | 7.06nM | 58 | 334nM | 95 | 3.92nM |
21 | 34.5nM | 59 | 7.37nM | 96 | 7.13nM |
22 | 43.6nM | 60 | 44.8nM | 97(a) | 7.20nM |
23 | 1.32nM | 61 | 7.35nM | 97(b) | 5.56nM |
24 | 119nM | 62 | 520nM | 98 | 7.93nM |
25 | 9.07nM | 63 | 123nM | 99 | 12.8nM |
26 | 11.4nM | 64 | 873nM | 100 | 22.7nM |
27 | 7.45nM | 65 | 17.1nM | 101 | 7.94nM |
28 | 6.86nM | 66 | 18.1nM | 102 | 19.7nM |
29 | 2.17nM | 67 | 9.74nM | 103 | 15.2nM |
31 | 23.2nM | 68 | 36.7nM | 104 | 3.98nM |
32 | 5.19nM | 69 | 30.7nM | 105 | 3.29nM |
33 | 6.29nM | 70 | 10.2nM | 106 | 8.06nM |
34 | 4.33nM | 71 | 16.1nM | 107 | 4.33nM |
35 | 53.8nM | 72 | 40.1nM | 108 | 3.11nM |
36 | 5.08nM | 73 | 6.01nM | 109 | 4.21nM |
37 | 3.23nM | 74 | 6.14nM | 110 | 2.59nM |
38 | 5.75nM | 75 | 5.46nM | 111 | 12.5nM |
39 | 58.1nM | 76 | 3.50nM | 112 | 1.37nM |
40 | 44.5nM | 77 | 1.24nM | 113 | <1.00nM |
41 | 63.8nM | 78 | 4.35nM | 114 | 2.31nM |
42 | 268nM | 79 | 3.72nM |
另外根据以上阐述的方法制备如下附加化合物:
尽管本文中已经描述了本发明的某些优选实施方式,但是本发明普通技术人员显然知晓可以对所述实施方式进行变形和修正,而并未脱离本发明的精神和范围。因此,本发明仅仅被限定为所附权利要求和适用法律条款所要求的范围。
Claims (15)
1.一种式(I)化合物
或其药学上可接受盐,其中:
R选自由(C1-C6)烷基、(C2-C6)烯基、(C2-C6)炔基、(C3-C8)环烷基、杂环烷基、芳基和杂芳基组成的组,各个基团可选被1至3个取代基取代,所述取代基独立地选自由(C1-C4)烷基、(C1-C4)烷氧基、卤素和(C1-C4)卤代烷基组成的组;
R1选自由氢、(C1-C4)烷基、(C2-C4)烯基、(C2-C4)炔基、(C1-C4)卤代烷基和环丙基组成的组;
R2选自由(C1-C6)烷基、(C2-C6)烯基、(C2-C6)炔基、(C1-C6)卤代烷基、杂芳基和ER5组成的组,所述杂芳基选自由吡啶基、哒嗪基、嘧啶基和吡嗪基组成的组,其中所述杂芳基可选被1至3个取代基取代,所述取代基独立地选自由(C1-C4)烷基和(C1-C4)卤代烷基组成的组;
R3选自由氢、(C1-C4)烷基、(C2-C4)烯基、(C2-C4)炔基、(C3-C6)环烷基和(C1-C4)卤代烷基组成的组;
E选自由-CH2-、-CH2CH2-、-CH2CH2CH2-和-C(O)-组成的组;
R5选自由(C3-C8)环烷基、杂环烷基、芳基、芳氧基和杂芳基组成的组,这些基团中的任意一个可选被1至3个取代基取代,所述取代基独立地选自由(C1-C4)烷基、(C2-C4)烯基、(C2-C4)炔基、(C1-C4)羟烷基、(C1-C4)卤代烷基、(C1-C4)烷氧基、(C1-C4)卤代烷氧基、(C3-C8)环烷基、卤素、氰基、苯基、吗啉基、(C1-C4)烷氨基、吡唑基、三唑基和咪唑基组成的组。
2.如权利要求1所述的化合物或其药学上可接受盐,其中:
R选自由乙基、异丙基、三氟乙基、环丁基、环戊基、二氟环己基、甲氧基苯基、四氢-2H-噻喃-4-基和四氢-2H-吡喃-4-基组成的组;
R1是氢或甲基;
R2是甲基、三氟乙基、三氟丁基、嘧啶基、三氟甲基嘧啶基或ER5;
R3是甲基、乙基、异丙基、三氟甲基、三氟乙基或环丙基;
E是-CH2-或-C(O)-;
R5选自由被取代的或未被取代的环戊基、吗啉基、苯基、萘基、苄氧基、嘧啶基、吡啶基、喹啉基、喹喔啉基、吡嗪基、吡唑基、苯并咪唑基、噌啉基、萘啶基、吡啶并[2,3-b]吡嗪基、咪唑并[4,5-c]吡啶基、苯并噻二唑基、四氢吡唑并[1,5-a]吡啶基、二氢苯并二噁英基、咪唑基、二氢苯并呋喃基、三唑基、噁唑基、异噁唑基、苯并二噁英基、噻唑基、咪唑并[1,2-a]吡啶基、四氢苯并噻唑基、二氢苯并噁嗪基、四氢吡喃基、四氢吡唑并[1,5-a]氮杂卓基和二氢吡咯并[1,2-b]吡唑基组成的组。
3.如权利要求2所述的化合物或其药学上可接受盐,其中;
R选自由异丙基、环丁基、环戊基和四氢-2H-吡喃基组成的组;
R1是氢;
R2是ER5;
R3是甲基或乙基;
E是-CH2-;且
R5选自由苯基、嘧啶-2-基、吡啶-2-基、吡嗪-2-基和5-甲基吡嗪-2-基组成的组。
4.如权利要求1所述的化合物,所述化合物选自由如下物质组成的组:
6-[(3S,4S)1-苄基-4-甲基吡咯烷-3-基]-1-环戊基-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3S,4S)-4-甲基-1-(喹喔啉-6-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-{(3S,4S)-4-甲基-1-[(5-甲基吡嗪-2-基)甲基]吡咯烷-3-基}-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-{(3S,4S)-1-[(1,3-二甲基-1H-吡唑-5-基)甲基]-4-甲基吡咯烷-3-基}-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-[(3S,4S)-4-甲基-1-(4,5,6,7-四氢吡唑并[1,5-a]吡啶-3-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-{(3S,4S)-4-甲基-1-[(1-甲基-1H-苯并咪唑-2-基)甲基]吡咯烷-3-基}-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-[(3S,4S)-1-(噌啉-3-基甲基)-4-甲基吡咯烷-3-基]-1-环戊基-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-环戊基-6-{(3S,4S)-4-甲基-1-[(2-甲基嘧啶-4-基)甲基]吡咯烷-3-基}-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;和
1-环戊基-6-[(3S,4S)-1-{[2-(二甲基氨基)嘧啶-4-基]甲基}-4-甲基吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
或其药学上可接受盐。
5.如权利要求1所述的化合物,其选自由如下物质组成的组:
6-[(3S,4S)-1-苄基-4-乙基吡咯烷-3-基]-1-异丙基-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-[(3S,4S)-1-苄基-4-甲基吡咯烷-3-基]-1-异丙基-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-异丙基-6-[(3S,4S)-4-甲基-1-(喹喔啉-6-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-异丙基-6-[(3S,4S)-4-甲基-1-(喹啉-3-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-异丙基-6-[(3S,4S)-4-甲基-1-(喹喔啉-6-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-异丙基-6-[(3S,4S)-4-甲基-1-(喹啉-3-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-异丙基-6-{(3S,4S)-4-甲基-1-[(2-甲基嘧啶-5-基)甲基]吡咯烷-3-基}-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-异丙基-6-{(3S,4S)-1-[(6-甲氧基吡啶-3-基)甲基]-4-甲基吡咯烷-3-基}-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-异丙基-6-{(3S,4S)-4-甲基-1-[(5-甲基吡嗪-2-基)甲基]吡咯烷-3-基}-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-异丙基-6-[(3S,4S)-4-甲基-1-(1,5-萘啶-4-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-异丙基-6-[(3S,4S)-4-甲基-1-(1,8-萘啶-4-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
1-异丙基-6-[3S,4S)-4-甲基-1-(喹啉-4-基甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;和
1-异丙基-6-[(3S,4S)-4-甲基-1-(吡啶并[2,3-b]吡嗪-8-基-甲基)吡咯烷-3-基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
或其药学上可接受盐。
6.如权利要求1所述的化合物,其选自由如下物质组成的组:
6-[(3S,4S)-1-苄基-4-甲基吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-{(3S,4S)-4-甲基-1-[(2-甲基嘧啶-5-基)甲基]吡咯烷-3-基}-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-{(3S,4S)-4-甲基-1-[(5-甲基吡嗪-2-基)甲基]吡咯烷-3-基}-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-{(3S,4S)-1-[(6-甲氧基吡啶-3-基)甲基]-4-甲基吡咯烷-3-基}-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-[(3S,4S)-4-甲基-1-(喹啉-3-基-甲基)吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-{(3S,4S)-4-甲基-1-[(2-甲基嘧啶-4-基)甲基]吡咯烷-3-基}-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-{(3S,4S)-4-甲基-1-[(6-甲基吡啶-3-基)甲基]吡咯烷-3-基}-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-[(3S,4S)-4-甲基-1-{[6-(三氟甲基)吡啶-3-基]甲基}吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-{(3S,4S)-4-甲基-1-[(1-甲基-1H-咪唑并[4,5-c]吡啶-2-基)甲基]吡咯烷-3-基}-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-{(3S,4S)-1-[(1,3-二甲基-1H-吡唑-5-基)甲基]-4-甲基吡咯烷-3-基}-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-[(3S,4S)-1-(2,1,3-苯并噻二唑-5-基甲基)-4-甲基吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-[(3S,4S)-4-甲基-1-(喹喔啉-2-基甲基)吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-[(3S,4S)-4-甲基-1-(喹啉-4-基甲基)吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-[(3S,4S)-4-甲基-1-(吡啶-2-基甲基)吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-[(3S,4S)-1-苄基-4-甲基吡咯烷-3-基]-3-甲基-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-[(3S,4S)-1-(3-氟苄基)-4-甲基吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-[(3S,4S)-1-(35-二氟苄基)-4-甲基吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-{(3S,4S)-4-甲基-1-[4-(三氟甲基)苄基]吡咯烷-3-基}-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
3-甲基-6-[(3S,4S)-4-甲基-1-(吡啶-3-基甲基)吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
3-甲基-6-{(3S,4S)-4-甲基-1-[(2-甲基嘧啶-5-基)甲基]吡咯烷-3-基}-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-{(3S,4S)-1-[(6-甲氧基吡啶-3-基)甲基]-4-甲基吡咯烷-3-基}-3-甲基-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-{(3S,4S)-4-甲基-1-[(6-甲基吡啶-2-基)甲基]吡咯烷-3-基}-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-[(3S,4S)-1-(4-氟苄基)-4-甲基吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-[(3S,4S)-1-苄基-4-乙基吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-[(3S,4S)-1-(2-氟苄基)-4-甲基吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-{(3S,4S)-4-甲基-1-[2-(三氟甲基)苄基]吡咯烷-3-基}-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-[(3S,4S)-1-(2,4-二氟苄基)-4-甲基吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-[(3S,4S)-1-(4-甲氧基苄基)-4-甲基吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-[(3S,4S)-1-苄基-4-甲基吡咯烷-3-基]-1-(四氢-2H-噻喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-[(3S,4S)-1-(2-甲氧基苄基)-4-甲基吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-[(3S,4S)-1-(3-甲氧基苄基)-4-甲基吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-{(3S,4S)-4-甲基-1-[3-(三氟甲基)苄基]吡咯烷-3-基}-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-[(3S,4S)-1-(26-二氟苄基)-4-甲基吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-{(3S,4S)-4-乙基-1-[(5-甲基吡嗪-2-基)甲基]吡咯烷-3-基}-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-{(3S,4S)-4-乙基-1-[(6-甲氧基吡啶-3-基)甲基]吡咯烷-3-基}-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-[(3S,4S)-4-乙基-1-(吡啶-2-基甲基)吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-[(3S,4S)-4-乙基-1-(喹喔啉-2-基羰基1)吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
6-[(3S,4S)-4-甲基-1-(嘧啶-2-基甲基)吡咯烷-3-基]-1-(四氢-2H-吡喃-4-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮;
2-({(3S,4S)-3-乙基-4-[4-氧代-1-(四氢-2H-吡喃-4-基)-4,5-二氢-1H-吡唑并[3,4-d]嘧啶-6-基]吡咯烷-1-基}甲基)苯甲腈;
3-({(3S,4S)-3-乙基-4-[4-氧代-1-(四氢-2H-吡喃-4-基)-4,5-二氢-1H-吡唑并[3,4-d]嘧啶-6-基]吡咯烷-1-基}甲基)苯甲腈;和
4-({(3S,4S)-3-乙基-4-[4-氧代-1-(四氢-2H-吡喃-4-基)-4,5-二氢-1H-吡唑并[3,4-d]嘧啶-6-基]吡咯烷-1-基}甲基)苯甲腈;
或其药学上可接受盐。
7.一种药物组合物,其包含权利要求1至6中任意一项所述化合物或其药学上可接受盐和药学上可接受载体、载剂或稀释剂。
8.如权利要求7所述的组合物,其进一步包含第二药学试剂。
9.如权利要求8所述的组合物,其中,所述第二药学试剂选自由多萘哌齐、加兰他敏、美金胺、利凡斯的明和他可林组成的组。
10.一种用于抑制哺乳动物中的PDE9的方法,所述哺乳动物需要上述抑制,所述方法包括如下步骤:施予所述哺乳动物PDE9抑制量的权利要求1至6中任意一项所述的化合物或其药学上可接受盐。
11.一种用于治疗哺乳动物中的神经退行疾病的方法,所述哺乳动物需要上述治疗,所述方法包括如下步骤:施予所述哺乳动物治疗有效量的权利要求1至6中任意一项所述的化合物或其药学上可接受盐。
12.如权利要求11所述的方法,其中,所述疾病是阿尔茨海默氏症。
13.一种用于促进哺乳动物中的神经恢复的方法,所述哺乳动物需要上述神经恢复,所述方法包括如下步骤:施予所述哺乳动物治疗有效量的权利要求1至6中任意一项所述的化合物或其药学上可接受盐。
14.一种用于改善哺乳动物中的认知缺陷的方法,所述哺乳动物需要上述改善,所述方法包括如下步骤:施予所述哺乳动物治疗有效量的权利要求1至6中任意一项所述的化合物或其药学上可接受盐。
15.如权利要求10-14中任意一项所述的方法,其中,所述哺乳动物是人类。
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