CN117396471A - 新的哌啶衍生物和包含其的用于抑制自分泌运动因子的药物组合物 - Google Patents
新的哌啶衍生物和包含其的用于抑制自分泌运动因子的药物组合物 Download PDFInfo
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- CN117396471A CN117396471A CN202280038523.8A CN202280038523A CN117396471A CN 117396471 A CN117396471 A CN 117396471A CN 202280038523 A CN202280038523 A CN 202280038523A CN 117396471 A CN117396471 A CN 117396471A
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- China
- Prior art keywords
- dihydro
- piperidin
- amine
- inden
- triazol
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- 229940035436 maltitol Drugs 0.000 description 1
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- 235000010355 mannitol Nutrition 0.000 description 1
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- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
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- OIRDBPQYVWXNSJ-UHFFFAOYSA-N methyl trifluoromethansulfonate Chemical compound COS(=O)(=O)C(F)(F)F OIRDBPQYVWXNSJ-UHFFFAOYSA-N 0.000 description 1
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- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- FTMVNUGLWHCBJK-UHFFFAOYSA-N piperidin-1-ium;2,2,2-trifluoroacetate Chemical compound C1CCNCC1.OC(=O)C(F)(F)F FTMVNUGLWHCBJK-UHFFFAOYSA-N 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
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- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
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- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- FZLWEUTZHQZRRT-UHFFFAOYSA-N tert-butyl 2-pyrazol-1-ylpiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCCC1N1N=CC=C1 FZLWEUTZHQZRRT-UHFFFAOYSA-N 0.000 description 1
- ADFSCQGCEAKLOE-UHFFFAOYSA-N tert-butyl 4-(2-methoxy-2-oxoethyl)piperidine-1-carboxylate Chemical compound COC(=O)CC1CCN(C(=O)OC(C)(C)C)CC1 ADFSCQGCEAKLOE-UHFFFAOYSA-N 0.000 description 1
- HNVBBNZWMSTMAZ-UHFFFAOYSA-N tert-butyl 4-acetylpiperidine-1-carboxylate Chemical compound CC(=O)C1CCN(C(=O)OC(C)(C)C)CC1 HNVBBNZWMSTMAZ-UHFFFAOYSA-N 0.000 description 1
- CJVRIMIDHYKFLD-UHFFFAOYSA-N tert-butyl 4-ethynyl-2-methylpiperidine-1-carboxylate Chemical compound CC1CC(CCN1C(=O)OC(C)(C)C)C#C CJVRIMIDHYKFLD-UHFFFAOYSA-N 0.000 description 1
- DVGWDBGQOAGBTF-UHFFFAOYSA-N tert-butyl 4-ethynyl-4-fluoropiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(F)(C#C)CC1 DVGWDBGQOAGBTF-UHFFFAOYSA-N 0.000 description 1
- WOEQSXAIPTXOPY-UHFFFAOYSA-N tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1 WOEQSXAIPTXOPY-UHFFFAOYSA-N 0.000 description 1
- DKACXUFSLUYRFU-UHFFFAOYSA-N tert-butyl n-aminocarbamate Chemical compound CC(C)(C)OC(=O)NN DKACXUFSLUYRFU-UHFFFAOYSA-N 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- ZWZVWGITAAIFPS-UHFFFAOYSA-N thiophosgene Chemical compound ClC(Cl)=S ZWZVWGITAAIFPS-UHFFFAOYSA-N 0.000 description 1
- 230000017423 tissue regeneration Effects 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
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- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
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- 230000006459 vascular development Effects 0.000 description 1
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- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
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- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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Abstract
本发明提供:新的哌啶衍生物化合物、其水合物、其溶剂合物或其可药用盐;以及用于预防或治疗与自分泌运动因子活性相关的疾病的药物组合物,所述药物组合物包含作为活性成分的新的哌啶衍生物化合物、其水合物、其溶剂合物或其可药用盐。本发明的哌啶衍生物化合物针对自分泌运动因子表现出优异的抑制活性,并且因此可有效地用于治疗和预防与自分泌运动因子抑制相关的疾病,例如纤维化疾病、炎性疾病、自身免疫病、呼吸系统疾病、心血管疾病、代谢性疾病、癌症和癌症转移、眼部疾病、淤胆型和其他形式的慢性瘙痒、以及急性或慢性器官移植排斥。
Description
技术领域
本发明涉及新的哌啶衍生物,并且更具体地,涉及新的哌啶衍生物和包含其的用于抑制自分泌运动因子的药物组合物。
背景技术
自分泌运动因子(Autotaxin,ATX),也称为外核苷酸焦磷酸酶/磷酸二酯酶家族成员2(ectonucleotide pyrophosphatase/phosphodiesterase family member 2,ENPP2),是在脂质信号传导分子溶血磷脂酸(lysophosphatidic acid,LPA)的产生中重要的分泌酶。自分泌运动因子表现出溶血磷脂酶D活性,其使溶血磷脂酰胆碱(lysophosphatidylcholine,LPC)转化为LPA。因此,血浆和腹水中的LPA水平与ATX活性相关。
血浆LPA是影响多种细胞类型的迁移、增殖和存活的生物活性脂质。另外,ATX-LPA信号传导涉及多种疾病的生理和病理生理过程,包括神经功能、血管发育、心血管生理、组织再生、免疫系统功能、慢性炎症、肿瘤转移和进展、器官纤维化和肥胖和/或其他代谢性疾病(例如糖尿病)。
因此,提高的ATX活性和提高的LPA水平、改变的LPA受体表达和改变的对LPA的响应可与涉及ATX/LPA信号传导通路的多种病理生理病症的起始、进展和/或结局相关。特别是,已知与癌症、淋巴细胞归巢、慢性炎症、神经性疼痛、纤维化疾病(例如特发性肺纤维化(idiopathic pulmonary fibrosis,IPF))和血栓形成相关。因此,为了治疗这些疾病,有必要降低LPA的水平和/或诱导LPA的ATX的水平。
发明目的
本发明待解决的问题是提供具有新的结构的自分泌运动因子抑制性化合物,其针对自分泌运动因子表现出优异的抑制活性。
此外,本发明待解决的的问题是提供用于抑制自分泌运动因子的药物组合物,其包含具有新的结构的自分泌运动因子抑制性化合物。
此外,本发明待解决的问题是提供用于抑制自分泌运动因子并治疗和预防由其引起的疾病的方法,所述方法使用具有新的结构的自分泌运动因子抑制性化合物。
此外,本发明待解决的问题是提供具有新的结构的自分泌运动因子抑制性化合物用于抑制自分泌运动因子并治疗由其引起的疾病的用途。
本发明待解决的问题不限于上述问题,并且本领域技术人员从下面的描述中可清楚地理解未提及的其他技术问题。
发明内容
为了解决上述问题,根据本发明的一个方面,提供了由下式1表示的哌啶衍生物化合物、其水合物、其溶剂合物或其可药用盐:
<式1>
其中:
X是芳基C1-4烷基;稠合双环,所述稠合双环中芳环或具有1至3个N的杂芳环与非芳族环烷基环稠合;或稠合双环,所述稠合双环中芳环与具有1至3个O的非芳族杂环稠合,其中X被一个或更多个R1取代或未被一个或更多个R1取代,
A是具有1至3个选自N、O和S的杂原子的5至6元杂芳基,
L是C1-6亚烷基;-(CH2)aCO-;-(CH)aCO-;-(CH2)bO(CH2)cCO-;或者具有1至3个选自N和O的杂原子的5元芳族或非芳族杂环,其中所述a、b、c独立地为1至5的整数,
B是COOH;CH2COOH;CONHOH;SO2NH2;具有1至3个选自N和O的杂原子的4至5元非芳族杂环;或具有1至4个选自N和O的杂原子的5元杂芳基,
R1是卤素或C1-4烷基磺酰基,
R2是氢、C1-4烷基、C1-4卤代烷基、羟基、氧代(O)或芳基C1-4烷基,
R3是氢、C1-4烷基、C1-4烷氧基或卤素,
R4是氢、卤素或C1-4烷基,
R5是氢或C1-4烷基。
根据本发明的另一方面,提供了用于预防或治疗与自分泌运动因子活性相关的疾病的药物组合物,其包含作为活性成分的哌啶衍生物化合物、其水合物、其溶剂合物或其可药用盐。
根据本发明的另一方面,提供了用于抑制自分泌运动因子并治疗或预防由其引起的疾病的方法,所述方法使用哌啶衍生物化合物、其水合物、其溶剂合物或其可药用盐。
根据本发明的另一方面,提供了哌啶衍生物化合物、其水合物、其溶剂合物或其可药用盐用于抑制自分泌运动因子并治疗或预防由自分泌运动因子引起的疾病的用途。
根据本发明的另一方面,提供了包含哌啶衍生物化合物、其水合物、其溶剂合物或其可药用盐、以及可药用添加剂的药物组合物。
根据本发明,发现本发明新的结构的哌啶衍生物针对自分泌运动因子表现出优异的抑制活性。
因此,本发明的新的结构的哌啶衍生物可用于治疗和预防与自分泌运动因子抑制相关的疾病,例如纤维化疾病、炎性疾病、自身免疫病、呼吸系统疾病、心血管疾病、代谢性疾病、癌症和癌症转移、眼部疾病、淤胆型和其他形式的慢性瘙痒、以及急性或慢性器官移植排斥。
本发明的作用不限于上述那些,而应理解为包括从本发明的详细说明书或权利要求书中描述的本发明组合物中可推断出的所有作用。
具体实施方式
在本发明的说明书中,自分泌运动因子(ATX)是在溶血磷脂酸(LPA)的产生中重要的分泌酶,并且其也称为外核苷酸焦磷酸酶/磷酸二酯酶家族成员2(ENPP2)。自分泌运动因子表现出溶血磷脂酶D活性,其使溶血磷脂酰胆碱(LPC)转化为LPA。因此,血浆和腹水中的LPA水平与ATX活性相关。
本发明提供了由下式1表示的哌啶衍生物化合物、其水合物、其溶剂合物或其可药用盐:
<式1>
其中:
X是芳基C1-4烷基;稠合双环,所述稠合双环中芳环或具有1至3个N的杂芳环与非芳族环烷基环稠合;或者稠合双环,所述稠合双环中芳环与具有1至3个O的非芳族杂环稠合,X被一个或更多个R1取代或未被一个或更多个R1取代,
A是具有1至3个选自N、O和S的杂原子的5至6元杂芳基,
L是C1-6亚烷基;-(CH2)aCO-;-(CH)aCO-;-(CH2)bO(CH2)cCO-;或者具有1至3个选自N和O的杂原子的5元芳族或非芳族杂环,其中所述a、b、c独立地为1至5的整数,
B是COOH;CH2COOH;CONHOH;SO2NH2;具有1至3个选自N和O的杂原子的4至5元非芳族杂环;或具有1至4个选自N和O的杂原子的5元杂芳基,
R1是卤素或C1-4烷基磺酰基,
R2是氢、C1-4烷基、C1-4卤代烷基、羟基、氧代(O)或芳基C1-4烷基,
R3是氢、C1-4烷基、C1-4烷氧基或卤素,
R4是氢、卤素或C1-4烷基,
R5是氢或C1-4烷基。
在一个实施方案中,X可以是选自苄基、苯乙基、二氢茚基、二氢环戊吡嗪基和苯并间二氧杂环戊烯基中的一者。
在一个实施方案中,A可以是选自吡啶、嘧啶、哒嗪、吡嗪、二唑和噻二唑中的一者。
在一个实施方案中,L可以是选自-(CH2)3-、-(CH2)2CO-、-(CH2)3CO-、-(CH)2CO-、-CH2OCH2CO-、唑、异唑、二氢异唑和二唑中的一者。
在一个实施方案中,B可以是选自羧基、羧甲基、甲酰胺基、磺酰胺、氮杂环丁烷、吗啉、二唑、咪唑、三唑和四唑中的一者。
在一个实施方案中,R1可以是选自F、Cl、Br和甲基磺酰基中的一者。
在一个实施方案中,R2可以是选自氢、甲基、二氟甲基、三氟甲基、羟基、氧代(O)和苄基中的一者。
在一个实施方案中,R3可以是选自氢、甲基、甲氧基和F中的一者。
在一个实施方案中,R4可以是选自氢、Cl和甲基中的一者。
在一个实施方案中,R5可以是氢或烷基。
根据本发明的哌啶衍生物化合物的代表性实例如下:
[1]
5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(2,3-二氢
-1H-茚-2-基)嘧啶-2-胺,
[2]
5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(5-氟-2,3-二氢-1H-茚-2-基)嘧啶-2-胺,
[3]
5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(5-氯-2,3-二氢-1H-茚-2-基)嘧啶-2-胺,
[4]
5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(5-溴-2,3-二氢-1H-茚-2-基)嘧啶-2-胺,
[5]
5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(5,6-二氟
-2,3-二氢-1H-茚-2-基)嘧啶-2-胺,
[6]
5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(5,6-二氯
-2,3-二氢-1H-茚-2-基)嘧啶-2-胺,
[7]
N-(5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)嘧啶-2-基)-6,7-二氢-5H-环戊[b]吡嗪-6-胺,
[8]
6-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(2,3-二氢-1H-茚-2-基)哒嗪-3-胺,
[9]
5-(5-(4-(1H-1,2,4-三唑-1-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(2,3-二氢-1H-茚-2-基)嘧啶-2-胺,
[10]
N-(2,3-二氢-1H-茚-2-基)-5-(5-(4-(3-甲基-1H-1,2,4-三唑-1-基)哌啶-1-基)-1,3,4-二唑-2-基)嘧啶-2-胺,
[11]
N-(5-溴-2,3-二氢-1H-茚-2-基)-5-(5-(2-甲基-4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)嘧啶-2-胺,
[12]
5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(5-溴-2,3-二氢-1H-茚-2-基)吡啶-2-胺,
[13]
5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(5-溴-2,3-二氢-1H-茚-2-基)吡嗪-2-胺,
[14]
5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(5-溴-2,3-二氢-1H-茚-2-基)-4-氯吡啶-2-胺,
[15]
5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(3,5-二氯苄基)嘧啶-2-胺,
[16]
5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(3,5-二氯苯乙基)嘧啶-2-胺,
[17]
1-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-3-(2-((2,3-二氢-1H-茚-2-基)氨基)嘧啶-5-基)丙-1-酮,
[18]
1-(4-(1H-咪唑-5-基)哌啶-1-基)-3-(2-((2,3-二氢-1H-茚-2-基)氨基)嘧啶-5-基)丙-1-酮,
[19]
1-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-4-(5-((2,3-二氢-1H-茚-2-基)氨基)-1,3,4-噻二唑-2-基)丁-1-酮,
[20]
1-(4-(1H-咪唑-5-基)哌啶-1-基)-4-(5-((2,3-二氢-1H-茚-2-基)氨基)-1,3,4-噻二唑-2-基)丁-1-酮,
[21]
1-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-4-(5-((2,3-二氢-1H-茚-2-基)氨基)-1,3,4-二唑-2-基)丁-1-酮,
[22]
1-(4-(1H-咪唑-5-基)哌啶-1-基)-4-(5-((2,3-二氢-1H-茚-2-基)氨基)-1,3,4-二唑-2-基)丁-1-酮,
[23]
1-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-2-((5-((2,3-二氢-1H-茚-2-基)氨基)-1,3,4-噻二唑-2-基)甲氧基)乙-1-酮,
[24]
N-(5,6-二氟-2,3-二氢-1H-茚-2-基)-5-(5-(4-(5-(三氟甲基)-1,3,4-二唑-2-基)哌啶-1-基)-1,3,4-二唑-2-基)嘧啶-2-胺,
[25]
N-(5,6-二氟-2,3-二氢-1H-茚-2-基)-5-(5-(4-(5-(二氟甲基)-1,3,4-二唑-2-基)哌啶-1-基)-1,3,4-二唑-2-基)嘧啶-2-胺,
[26]
5-(5-(4-(1,2,4-二唑-3-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(5,6-二氟-2,3-二氢-1H-茚-2-基)嘧啶-2-胺,
[27]
5-(5-(4-(1,3,4-二唑-2-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(5,6-二氟-2,3-二氢-1H-茚-2-基)嘧啶-2-胺,
[28]
5-(5-(4-(1H-四唑-1-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(5,6-二氟-2,3-二氢-1H-茚-2-基)嘧啶-2-胺,
[29]
N-(5,6-二氟-2,3-二氢-1H-茚-2-基)-5-(5-(4-(4-甲基-1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)嘧啶-2-胺,
[30]
(E)-1-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-3-(2-((5,6-二氟-2,3-二氢-1H-茚-2-基)氨基)嘧啶-5-基)丙-2-烯-1-酮,
[31]
5-(5-(4-(1-苄基-1H-1,2,3-三唑-5-基)哌啶-1-基)唑-2-基)-N-(2,3-二氢-1H-茚-2-基)嘧啶-2-胺,
[32]
5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(5,6-二氟-2,3-二氢-1H-茚-2-基)-N-甲基嘧啶-2-胺,
[33]
N-(5,6-二氟-2,3-二氢-1H-茚-2-基)-5-(5-(4-(1-甲基-1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)嘧啶-2-胺,
[34]
N-(5,6-二氟-2,3-二氢-1H-茚-2-基)-5-(5-(4-(1-甲基-1H-1,2,3-三唑-4-基)哌啶-1-基)-1,3,4-二唑-2-基)嘧啶-2-胺,
[35]
N-茚满-2-基-5-[3-[4-(1H-三唑-5-基)-1-哌啶基]-4,5-二氢异唑-5-基]嘧啶-2-胺,
[36]
5-(3-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)异唑-5-基)-N-(2,3-二氢-1H-茚-2-基)嘧啶-2-胺,
[37]
N-(5,6-二氟茚满-2-基)-5-[3-[4-(1H-三唑-5-基)-1-哌啶基]-4,5-二氢异唑-5-基]嘧啶-2-胺,
[38]
5-(3-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)异唑-5-基)-N-(5,6-二氟-2,3-二氢-1H-茚-2-基)嘧啶-2-胺,
[39]
5-(3-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-4,5-二氢异唑-5-基)-N-(5-氟-2,3-二氢-1H-茚-2-基)嘧啶-2-胺,
[40]
5-(3-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)异唑-5-基)-N-(5-氟-2,3-二氢-1H-茚-2-基)嘧啶-2-胺,
[41]
N-[(3,5-二氟苯基)甲基]-5-[3-[4-(1H-三唑-5-基)-1-哌啶基]-4,5-二氢异唑-5-基]嘧啶-2-胺,
[42]
N-苄基-5-[3-[4-(1H-三唑-5-基)-1-哌啶基]-4,5-二氢异唑-5-基]嘧啶-2-胺,
[43]
N-[(3,4-二氟苯基)甲基]-5-[3-[4-(1H-三唑-5-基)-1-哌啶基]-4,5-二氢异唑-5-基]嘧啶-2-胺,
[44]
5-(3-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-4,5-二氢异唑-5-基)-N-(3,5-二氯苄基)嘧啶-2-胺,
[45]
5-(3-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-4,5-二氢异唑-5-基)-N-(苯并[d][1,3]间二氧杂环戊烯-5-基甲基)嘧啶-2-胺,
[46]
N-(1,3-苯并间二氧杂环戊烯-5-基甲基)-5-[3-[4-(1H-三唑-5-基)-1-哌啶基]异唑-5-基]嘧啶-2-胺,
[47]
5-(3-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-4,5-二氢异唑-5-基)-N-(3,5-二氯苯乙基)嘧啶-2-胺,
[48]
5-(3-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-4,5-二氢异唑-5-基)-N-(3-(甲基磺酰基)苄基)嘧啶-2-胺,
[49]
5-(3-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-4,5-二氢异唑-5-基)-N-(4-(甲基磺酰基)苄基)嘧啶-2-胺,
[50]
5-(3-(4-(1H-四唑-5-基)哌啶-1-基)-4,5-二氢异唑-5-基)-N-(2,3-二氢-1H-茚-2-基)嘧啶-2-胺,
[51]
5-(3-(4-(5-(二氟甲基)-1,3,4-二唑-2-基)哌啶-1-基)-4,5-二氢异唑-5-基)-N-(2,3-二氢-1H-茚-2-基)嘧啶-2-胺,
[52]
5-(3-(4-(1H-四唑-5-基)哌啶-1-基)-4,5-二氢异唑-5-基)-N-(5,6-二氟-2,3-二氢-1H-茚-2-基)嘧啶-2-胺,
[53]
N-(5-氟-2,3-二氢-1H-茚-2-基)-5-(3-(4-(5-(三氟甲基)-1,3,4-二唑-2-基)哌啶-1-基)-4,5-二氢异唑-5-基)嘧啶-2-胺,
[54]
N-(5,6-二氟-2,3-二氢-1H-茚-2-基)-5-(5-(2-甲基-4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)嘧啶-2-胺,
[55]
5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(苯并[d][1,3]间二氧杂环戊烯-5-基甲基)嘧啶-2-胺,
[56]
5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(3,4-二氯苄基)嘧啶-2-胺,
[57]
5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(3,5-二氟苄基)嘧啶-2-胺,
[58]
5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(3,4-二氟苄基)嘧啶-2-胺,
[59]
5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(3,5-二溴苄基)嘧啶-2-胺,
[60]
5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(5-溴-2,3-二氢-1H-茚-2-基)-4-甲基嘧啶-2-胺,
[61]
5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(5,6-二溴-2,3-二氢-1H-茚-2-基)-4-甲基嘧啶-2-胺,
[62]
5-(3-(4-(1H-1,2,3-三唑-4-基)哌啶-1-基)丙基)-N-(2,3-二氢-1H-茚-2-基)嘧啶-2-胺,
[63]
N-(5,6-二氟-2,3-二氢-1H-茚-2-基)-5-(5-(4-吗啉代哌啶-1-基)-1,3,4-二唑-2-基)嘧啶-2-胺,
[64]
1-(1-(5-(2-((5,6-二氟-2,3-二氢-1H-茚-2-基)氨基)嘧啶-5-基)-1,3,4-二唑-2-基)哌啶-4-基)氮杂环丁烷-3-醇,
[65]
1-(5-(2-((5,6-二氟-2,3-二氢-1H-茚-2-基)氨基)嘧啶-5-基)-1,3,4-二唑-2-基)哌啶-4-磺酰胺,
[66]
5-(1-(5-(2-((5,6-二氟-2,3-二氢-1H-茚-2-基)氨基)嘧啶-5-基)-1,3,4-二唑-2-基)哌啶-4-基)-1,3,4-二唑-2(3H)-酮,
[67]
1-(5-(2-((5,6-二氟-2,3-二氢-1H-茚-2-基)氨基)嘧啶-5-基)-1,3,4-二唑-2-基)哌啶-4-羧酸,
[68]
2-(1-(5-(2-((5,6-二氟-2,3-二氢-1H-茚-2-基)氨基)嘧啶-5-基)-1,3,4-二唑-2-基)哌啶-4-基)乙酸,
[69]
1-(5-(2-((5,6-二氟-2,3-二氢-1H-茚-2-基)氨基)嘧啶-5-基)-1,3,4-二唑-2-基)-N-羟基哌啶-4-甲酰胺,
[70]
N-(5,6-二氟-2,3-二氢-1H-茚-2-基)-5-(5-(4-甲氧基-4-(1H-1,2,3-三唑-4-基)哌啶-1-基)-1,3,4-二唑-2-基)嘧啶-2-胺,和
[71]
N-(5,6-二氟-2,3-二氢-1H-茚-2-基)-5-(5-(4-氟-4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)嘧啶-2-胺。
除非特别定义,否则本说明书在限定式1的化合物时使用以下定义。
术语“烷基”是指直链或支链烃基,优选C1-C10烷基。烷基的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、正己基、3-甲基己基、2,2-二甲基戊基、2,3-二甲基戊基、正庚基、正辛基、正壬基和正癸基。
术语“亚烷基”是指来源于烷基的二价官能团,并且优选地包含1至10个碳原子,但不限于此。亚烷基的实例包括但不限于-CH2-、-CH2CH2-、-CH2CH2CH2-、-CH2CH2CH2CH2-和-CH2CH2CH2CH2CH2-。
术语“环烷基”是指部分或完全饱和的单环或稠环烃,优选C3-C10环烷基。环烷基的实例包括但不限于环丙基、环丁基、环戊基、环己基和环己烯基。
术语“羟基”定义为-OH,并且除非另有定义,否则术语“烷氧基”意指烷基氧基,其中羟基的氢原子被1至10个烷基取代的基团。
术语“卤素”或“卤代”是指氟(F)、氯(Cl)、溴(Br)或碘(I)。
术语“卤代烷基”和“卤代烷氧基”意指经一个或更多个卤素原子取代的烷基或烷氧基。
术语“杂原子”意指N、O或S。
术语“芳基”意指芳族烃,包括其中碳环芳族环或杂芳环与一个或更多个其他环稠合的多环芳族环系统,优选C5-C12芳基,更优选C5-C10芳基。例如,芳基包括但不限于苯基、萘基、四氢萘基等。
另外,芳基包括与环烷基或非芳族杂环稠合的杂芳环,例如二氢环戊吡嗪基。
术语“杂芳基”或“芳族杂环”意指形成包含一个或更多个选自N、O和S的杂原子作为环原子的单环或稠环的3至12元,更优选5至10元芳族烃,并且其可与苯并或C3-C8环烷基稠合。例如,杂芳基包括但不限于吡咯基、咪唑基、吡唑基、三唑基、吡啶基、吡嗪基、嘧啶基、哒嗪基、三嗪基、二唑基、异二唑基、四唑基、吲哚基、吲唑基、异唑基、唑基、噻唑基、异噻唑基、呋喃基、苯并呋喃基、噻吩基、苯并噻唑基、苯并唑基、苯并咪唑基、喹啉基、异喹啉基等。
芳基烷基、烷基芳基和杂芳基烷基是指通过组合如上所定义的芳基和烷基或杂芳基和烷基而形成的基团,并且包括例如苄基、苯乙基等,但不限于此。
根据本发明的由式1表示的化合物可以以前药、水合物、溶剂合物和可药用盐的形式制备和使用以增强体内吸收或提高溶解度,因此前药、水合物、溶剂合物和可药用盐也在本发明的范围内。另外,由式1表示的化合物具有手性碳,使得存在其立体异构体,并且这些立体异构体也包括在本发明的范围内。
术语“前药”是指在体内转化成母体药物的物质。经常使用前药,因为在一些情况下,它们比母体药物更容易施用。例如,它们通过经口施用可以是可生物利用的,而母体药物可能不是。前药在药物组合物中也可具有比母体药物提高的溶解度。例如,前药可以是根据本发明的化合物的体内可水解酯及其可药用盐。前药的另一实例可以是短肽(聚氨基酸),其中肽与酸性基团偶联,其经代谢转化以显示活性位点。
术语“水合物”是指这样的本发明的化合物或其盐,所述化合物或其盐包含通过非共价分子间力结合的化学计量或非化学计量的量的水。
术语“溶剂合物”是指这样的本发明的化合物或其盐,所述化合物或其盐包含通过非共价分子间力结合的化学计量量或非化学计量量的溶剂。因此优选的溶剂包括挥发性、无毒和/或适合于施用于人的溶剂。
术语“异构体”是指具有相同化学式或分子式但结构或空间上不同的本发明化合物或其盐。这样的异构体包括结构异构体和立体异构体二者,所述结构异构体例如互变异构体,以及所述立体异构体例如具有不对称碳中心的R或S异构体和几何异构体(反式,顺式)。所有这些异构体及其混合物也包括在本发明的范围内。
术语“可药用盐”是指不对施用化合物的生物体造成严重刺激并且不损害所述化合物的生物活性和物理特性的化合物的盐形式。药用盐包括由包含可药用阴离子并形成无毒的酸加成盐的酸形成的酸加成盐,例如,无机酸例如盐酸、硫酸、硝酸、磷酸、氢溴酸、碘化氢等,有机碳酸例如酒石酸、甲酸、柠檬酸、乙酸、三氯乙酸、三氟乙酸、葡糖酸、苯甲酸、乳酸、富马酸、苹果酸、水杨酸等,磺酸例如甲磺酸、乙磺酸、苯磺酸、对甲苯磺酸等。例如,可药用羧酸盐包括由锂、钠、钾、钙、镁等形成的金属盐或碱土金属盐,氨基酸盐例如赖氨酸、精氨酸、胍等,有机盐例如二环己基胺、N-甲基-D-葡糖胺、三(羟甲基)甲胺、二乙醇胺、胆碱和三乙胺等。根据本发明的式1化合物也可通过常规方法转化成其盐。
另外,本发明提供了用于合成由式1表示的化合物的方法。
示出了方案1至26为用于合成本发明的式1化合物的方法,并且以下用于合成的方法不旨在限于制备根据本发明的式1化合物的方法。显然以下方案1至26中用于合成的方法仅是示例性的,并且可由本领域技术人员根据特定的取代基容易地进行改进。
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本发明还提供了用于预防或治疗与自分泌运动因子活性相关的疾病的药物组合物,所述药物组合物包含作为活性成分的哌啶衍生物化合物、其水合物、其溶剂合物或其可药用盐。
本发明还提供了用于抑制自分泌运动因子并治疗或预防由其引起的疾病的方法,所述方法包括向有此需要的对象施用哌啶衍生物化合物、其水合物、其溶剂合物或其可药用盐。
本发明还提供了哌啶衍生物化合物、其水合物、其溶剂合物或其可药用盐,用于抑制自分泌运动因子并治疗或预防由自分泌运动因子引起的疾病。
测量了本发明的哌啶衍生物化合物针对自分泌运动因子蛋白(Autotaxin)的抑制活性,并且发现它们甚至在非常低的化合物浓度(nM水平)下也表现出优异的自分泌运动因子抑制活性,并且因此可用于治疗和预防与自分泌运动因子活性相关的疾病。
在一个实施方案中,与自分泌运动因子活性相关的疾病可以选自纤维化疾病、炎性疾病、自身免疫病、呼吸系统疾病、心血管疾病、代谢性疾病、癌症和癌症转移、眼部疾病、淤胆型和其他形式的慢性瘙痒、以及急性或慢性器官移植排斥。
纤维化疾病包括但不限于特发性肺纤维化(IPF)、间质性肺疾病、肝纤维化、肝硬化、非酒精性脂肪性肝炎、辐射诱发的纤维化、心肌和血管纤维化、肾纤维化、皮肤纤维化、肾小球硬化、心肌纤维化和血管纤维化。
炎性疾病包括但不限于类风湿性关节炎、骨关节炎、特应性皮炎、炎性肠病、炎性气道疾病、慢性阻塞性肺疾病(chronic obstructive pulmonarydisease,COPD)和哮喘。
自身免疫病包括但不限于多发性硬化和硬皮病。
呼吸系统疾病包括但不限于石棉诱发的肺纤维化和急性呼吸窘迫综合征(acuterespiratory distress syndrome,ARDS)。
心血管疾病包括但不限于动脉硬化、心肌梗死、动脉和肺动脉高压、心律不齐、卒中和其他血管损伤。
代谢性疾病包括但不限于肥胖和糖尿病。
癌症和癌症转移包括但不限于乳腺癌、卵巢癌、肺癌、前列腺癌、间皮瘤、胶质瘤、肝癌、胃肠癌、胰腺癌、及其进展和转移侵袭。
眼部疾病包括但不限于增殖性和非增殖性(糖尿病)视网膜病变、干性和湿性年龄相关性黄斑变性(age-related macular degeneration,AMD)、黄斑水肿、中央动脉/静脉阻塞、创伤性损伤和青光眼。
本发明还提供了药物组合物,所述药物组合物包含哌啶衍生物化合物、其水合物、其溶剂合物或其可药用盐、以及可药用添加剂。
添加剂可包含可药用载体或稀释剂,其各自可根据常规方法配制成经口制剂的形式,例如散剂、颗粒剂、片剂、胶囊剂、混悬剂、乳剂、糖浆剂、气雾剂;外用品;栓剂;和无菌注射溶液剂。
可药用载体包括乳糖、右旋糖、蔗糖、山梨醇、甘露醇、木糖醇、赤藓糖醇、麦芽糖醇、淀粉、阿拉伯胶、藻酸盐、明胶、磷酸钙、硅酸钙、纤维素、甲基纤维素、微晶纤维素、聚乙烯吡咯烷酮、水、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石、硬脂酸镁和矿物油等。可药用载体还包括稀释剂或赋形剂例如填料、填充剂、黏合剂、润湿剂、崩解剂和表面活性剂。经口固体剂型包括片剂、丸剂、散剂、颗粒剂、胶囊剂等,其可包含至少一种赋形剂,例如淀粉、碳酸钙、蔗糖、乳糖、明胶等,并且可包含润滑剂例如硬脂酸镁和滑石。经口液体制剂可包括混悬剂、经口溶液剂、乳剂、糖浆剂等,并且可包含稀释剂(例如水和液体石蜡)、润湿剂、甜味剂、调味剂、防腐剂等。肠胃外制剂包括无菌水溶液剂、非水溶剂、混悬剂、乳剂、乳膏剂、冻干制剂和栓剂;非水溶剂和混悬剂包括丙二醇、聚乙二醇、植物油(例如橄榄油)和可注射酯例如油酸乙酯。用于栓剂的基质可以是witepsol、聚乙二醇、吐温61、可可胶、月桂胶、甘油明胶等。
本发明药物组合物中活性成分的剂量取决于患者的病症和体重、疾病的程度、活性成分的制剂、施用途径和持续时间,并且可根据患者进行适当调整。例如,活性成分可以以每日0.0001至1000mg/kg,优选0.01至100mg/kg的剂量施用,并且该剂量可每日一次或以数次分开的剂量来施用。此外,基于组合物的总重量,本发明的药物组合物可包含0.001重量%至90重量%的活性成分。
本发明的药物组合物可通过多种途径,例如经口、经皮肤、腹膜内、经直肠或静脉内、肌内、皮下、经子宫内膜或脑室内注射施用于哺乳动物例如大鼠、小鼠、牲畜和人。
在下文中,用制备例、实施例和测试例更详细地描述本公开内容。然而,以下制备例、实施例和测试例旨在说明本发明,并且本发明的范围不限于此。
<制备例1>4-(1H-1,2,3-三唑-5-基)哌啶·HCl(3)的合成
步骤1:4-(1H-1,2,3-三唑-5-基)哌啶-1-羧酸叔丁酯(2)的合成:在氩气下将4-乙炔基哌啶-1-羧酸叔丁酯(1,1.05g,5.00mmol)、三甲基甲硅烷基叠氮化物(5.5mmol)和碘化铜(I)(0.25mmol)添加至N,N-二甲基甲酰胺/甲醇(9∶1,2mL)的混合物中。在氩气下将反应混合物在100℃下加热12小时。将溶剂蒸发至干,用乙酸乙酯萃取并用盐水洗涤。将有机层用无水硫酸钠干燥并浓缩。将产物通过柱色谱(二氯甲烷/甲醇)进行纯化以得到作为白色固体的主题化合物(1.03g,产率81.3%)。
1H NMR(400MHz,CDCl3)δ12.73(br s,1H),7.52(s,1H),4.32-4.01(m,2H),3.00-2.86(m,3H),2.04-1.97(m,2H),1.73-1.60(m,2H),1.48(s,9H).
步骤2:4-(1H-1,2,3-三唑-5-基)哌啶·HCl(3)的合成:向从上述步骤获得的4-(1H-1,2,3-三唑-5-基)哌啶-1-羧酸叔丁酯(3.60mmol)在二氧六环(10mL)中的溶液添加在二氧六环(2mL)中的4.0M盐酸溶液。将反应混合物在室温下搅拌过夜。将溶剂蒸发至干以得到作为白色固体状的主题化合物(定量)。
1H NMR(400MHz,MeOD)δ8.37(s,1H),3.56-3.47(m,2H),3.44-3.35(m,1H),3.27-3.18(m,2H),2.37-2.30(m,2H),2.12-1.98(m,2H).
<制备例2>4-(1H-1,2,4-三唑-1-基)哌啶·HCl(Im15-2a)和4-(3-甲基-1H-1,2,4-三唑-1-基)哌啶·HCl(Im15-2b)的合成
步骤1:4-(1H-1,2,4-三唑-1-基)哌啶-1-羧酸叔丁酯(Im15-1a)和4-(3-甲基-1H-1,2,4-三唑-1-基)哌啶-1-羧酸叔丁酯(Im15-1b)的合成
将1,2,4-三唑或3-甲基-1,2,4-三唑(1mmo1)和氢化钠(1.3mmol)溶解在5mL DMF中并在0℃下搅拌1小时。在氩气下将4-[(甲基磺酰基)氧基]哌啶-1-羧酸叔丁酯(1.1mmol)添加至反应混合物。将反应混合物在90℃下加热5小时。将溶剂蒸发至干,用乙酸乙酯萃取并用盐水洗涤。将有机层用无水硫酸钠干燥并浓缩。将产物通过柱色谱(EA/Hex)进行纯化以得到作为白色固体的主题化合物。
4-(1H-1,2,4-三唑-1-基)哌啶-1-羧酸叔丁酯(Im15-1a)产率:43.5%;
1H NMR(400MHz,氯仿-d)δ8.10(s,1H),7.95(s,1H),4.34(tt,J=11.5,4.1Hz,2H),4.26(s,1H),2.91(s,1H),2.21-2.11(m,2H),1.95(qd,J=12.2,4.5Hz,2H),1.48(s,9H);C12H21N4O2[M+H]+的MS(ESI,m/z)计算值253.15,实测值253.15.
4-(3-甲基-1H-1,2,4-三唑-1-基)哌啶-1-羧酸叔丁酯(Im15-1b)产率38.5%;
1H NMR(400MHz,氯仿-d)δ7.95(s,1H),7.79(s,1H),4.25(dd,J=11.5,4.0Hz,2H),4.13-4.07(m,1H),2.44(d,J=34.8Hz,3H),2.17-2.06(m,3H),2.00-1.82(m,3H),1.48(d,J=2.5Hz,9H);C13H23N4O2[M+H]+的MS(ESI,m/z)计算值267.15,实测值267.15.
步骤2:4-(1H-1,2,4-三唑-1-基)哌啶·HCl(Im15-2a)和4-(3-甲基-1H-1,2,4-三唑-1-基)哌啶·HCl(Im15-2b)的合成
将从上述步骤获得的4-(1H-1,2,4-三唑-1-基)哌啶-1-羧酸叔丁酯(Im15-1a)或4-(3-甲基-1H-1,2,4-三唑-1-基)哌啶-1-羧酸叔丁酯(Iml5-1b)(3.60mmol)溶解于在二氧六环(5mL)中的4M HCl。将反应混合物在室温下搅拌过夜。将溶剂蒸发至干以得到作为白色固体的主题化合物(定量)。
4-(1H-1,2,4-三唑-1-基)哌啶·HCl(Im15-2a)产率:97.8%;C7H13N4[M+H]+的MS(ESI,m/z)计算值153.11,实测值153.10。
4-(3-甲基-1H-1,2,4-三唑-1-基)哌啶·HCl(Im15-2b)。产率:95.7%;C8H15N4[M+H]+的MS(ESI,m/z)计算值167.12,实测值167.15。
<制备例3>5,6-二氟-2,3二氢-1H-茚-2-胺(4e)的合成
步骤1:5,6-二氟-2,3-二氢-1H-茚-1-酮(E3b)的合成
将3,4-二氟苯基丙酸(925.8mg,4.97mmol)溶解在DCM(20mL)中。将草酰氯(9.94mmol)和1滴DMF添加至反应混合物。将所得溶液搅拌3至5小时。在反应完成之后,在真空下除去溶剂。然后,将3-(3,4-二氟苯基)丙酰氯溶解在DCM中并在0℃下缓慢添加至在DCM中的AlCl3(17.4mmol)。将反应混合物在0℃下搅拌15分钟,回流4小时。在冷却至室温之后,将反应混合物倒入冰中,用DCM(2×30mL)萃取。将有机层用MgSO4干燥并过滤。在真空下浓缩溶剂并将剩余物通过硅胶柱色谱(EA/Hex)进行纯化以得到主题化合物(产率:78.0%)。
1H NMR(400MHz,氯仿-d)δ7.53(dd,J=8.7,7.5Hz,1H),7.29-7.23(m,1H),3.16-3.08(m,2H),2.79-2.70(m,2H).
步骤2:(Z)-5,6-二氟-2-(羟基亚氨基)-2,3-二氢-1H-茚-1-酮(E3c)的合成
在40℃下向5,6-二氟-2,3-二氢-1H-茚-1-酮(E3b,3mmol)在MeOH中的溶液添加亚硝酸异戊酯(3.6mmol)随后是浓HCl(1mL)。将反应混合物在40℃下搅拌2至5小时,冷却至室温并添加水(50mL)。通过过滤收集沉淀物并干燥以得到主题化合物(产率:54.0%)。
1H NMR(400MHz,DMSO-d6)δ12.77(s,1H),7.82(dd,J=9.3,7.7Hz,1H),7.75(dd,J=10.3,7.0Hz,1H),3.76(s,2H).
步骤3:5,6-二氟-2,3-二氢-1H-茚-2-胺(4e)的合成
将从上述步骤获得的5,6-二氟-2-(羟基亚氨基)-2,3-二氢-1H-茚-1-酮(E3c,1mmol)溶解在乙酸(37.5mL)和硫酸(1.5mL)中。添加10%钯碳(10重量%)。将反应混合物氢化过夜。在通过硅藻土的垫过滤之后,添加4N NaOH至pH约12并用EA(3×100mL)萃取。将有机层用Na2SO4干燥并过滤。在真空下浓缩溶剂并将剩余物通过氨基硅胶柱色谱(DCM/MeOH)进行纯化以得到主题化合物(产率:12.1%)。
1H NMR(400MHz,CDCl3)δ6.98(t,J=8.9Hz,2H),3.87(tt,J=6.7,4.9Hz,1H),3.12(dd,J=15.8,6.7Hz,2H),2.62(dd,J=15.7,4.9Hz,2H),1.40(s,2H);C9H10F2N[M+H]+的MS(ESI,m/z)计算值170.07,实测值170.01.
<制备例4>5,6-二氯-2,3-二氢-1H-茚-2-胺(4f)的合成
步骤1:5,6-二氯-2,3-二氢-1H-茚-1-酮(F4b)的合成
向3-(3,4-二氯苯基)丙酸(4.56mmol)在DCM中的溶液添加催化量的DMF并在冰浴下逐滴添加过量的草酰氯。将反应混合物在室温下搅拌30分钟,并随后除去溶剂。将DCM添加至粗酰氯混合物并在冰浴下将氯化铝(16mmol)添加至溶液。将反应混合物回流1.5小时并在室温下冷却。将粗制混合物用冰水猝灭并用乙酸乙酯萃取。将合并的有机层蒸发并通过硅胶快速色谱(己烷/乙酸乙酯)进行纯化以得到主题化合物(产率:75.4%)。
1H NMR(400MHz,氯仿-d)δ7.87-7.75(m,1H),7.61(s,1H),3.18-3.06(m,2H),2.76-2.64(m,2H).
步骤2:5,6-二氯-2,3-二氢-1H-茚-1-醇(F4c)的合成
向5,6-二氯-2,3-二氢-1H-茚-1-酮(F4b,2.16mmol)在无水EtOH中的溶液添加硼氢化钠(4.5mmol)并在室温下搅拌过夜。将粗制混合物倒入DCM中,用H2O(40ml)洗涤,并用MgSO4干燥。将粗制混合物通过硅胶快速色谱(己烷/乙酸乙酯)进行纯化以得到主题化合物(产率:88.8%)。
1H NMR(400MHz,氯仿-d)δ7.49-7.41(m,1H),7.31(s,1H),5.18(q,J=6.3Hz,1H),2.99(ddd,J=16.3,8.6,4.5Hz,1H),2.83-2.69(m,1H),2.50(dddd,J=12.8,8.2,6.9,4.5Hz,1H),2.06(d,J=6.4Hz,1H),1.95(dddd,J=13.2,8.6,7.0,5.7Hz,1H);13C NMR(100MHz,氯仿-d)δ145.26,143.36,132.22,130.68,126.81,126.22,75.72,36.39,29.41.
步骤3:5,6-二氯-1H-茚(F4d)的合成
向5,6-二氯-2,3-二氢-1H-茚-1-醇(F4c,1.92mmol)在甲苯中的溶液添加对甲苯磺酸(0.1当量)并使用Dean-Stark分离器回流2小时。将所得混合物在室温下冷却并在真空下除去溶剂。将粗制混合物通过硅胶快速色谱(己烷/乙酸乙酯)进行纯化以得到主题化合物(产率:65.5%)。
1H NMR(400MHz,氯仿-d)δ7.55-7.48(m,1H),7.45(s,1H),6.79(dtd,J=5.5,1.9,0.7Hz,1H),6.61(dt,J=5.5,2.0Hz,1H),3.38(td,J=2.0,0.8Hz,2H);13C NMR(100MHz,氯仿-d)δ144.96,143.44,136.36,130.95,130.43,128.56,125.64,122.50,38.90.
步骤4:3,4-二氯-1a,6a-二氢-6H-茚并[1,2-b]环氧乙烯(F4e)的合成
向5,6-二氯-1H-茚(F4d,1.2mmol)在DCM中的溶液添加m-CPBA(1.8mmol)和NaHCO3(1.8mmol)并在室温下搅拌过夜。将反应混合物用水猝灭并用DCM萃取。将合并的有机层蒸发并通过硅胶快速色谱(己烷/乙酸乙酯)进行纯化以得到主题化合物(产率:84.9%)。
1H NMR(400MHz,氯仿-d)δ7.56(s,1H),7.31(s,1H),4.25-4.18(m,1H),4.14(t,J=2.8Hz,1H),3.18(d,J=18.2Hz,1H),2.99-2.89(m,1H);13C NMR(100MHz,氯仿-d)δ143.62,141.21,132.60,130.30,128.14,127.15,58.20,58.03,34.26.
步骤5:5,6-二氯-2,3-二氢-1H-茚-2-醇(F4f)的合成
在0℃下向3,4-二氯-1a,6a-二氢-6H-茚并[1,2-b]环氧乙烯(F4e,0.98mmol)在THF中的溶液中缓慢添加THF(1.1mmol)中的2.5M氢化铝锂。将反应混合物在室温下搅拌30分钟并用冰水猝灭。将溶液用乙酸乙酯萃取并通过硅胶快速色谱(己烷/乙酸乙酯)进行纯化以得到主题化合物(产率:86.3%)。
1H NMR(400MHz,氯仿-d)δ7.31(s,2H),4.72(ddq,J=8.7,5.8,3.0Hz,1H),3.22-3.10(m,2H),2.87(dd,J=16.7,2.9Hz,2H),1.70(d,J=5.0Hz,1H);13C NMR(100MHz,氯仿-d)δ141.29,130.54,126.87,73.32,42.30.
步骤6:5,6-二氯-2,3-二氢-1H-茚-2-胺(4f)的合成
在0℃下向5,6-二氯-2,3-二氢-1H-茚-2-醇(F4f,0.84mmol)在THF中的溶液添加邻苯二甲酰亚胺(1.7mmol)、三苯基膦(1.7mmol)和偶氮二羧酸二异丙酯(1.3mmol)。将反应混合物在室温下搅拌3小时并在真空下除去溶剂。将水和EtOH倒入粗制混合物中并将一水合肼(1.7mmol)添加至溶液。将反应混合物在室温下搅拌过夜。将所得混合物倒入DCM(40ml)中,用H2O(40ml)洗涤,并用MgSO4干燥。将粗制混合物通过硅胶快速色谱(二氯甲烷/甲醇)进行纯化以得到主题化合物(产率:20.2%)。
1H NMR(400MHz,甲醇-d4)δ7.36(s,2H),3.87(s,1H),3.21(dd,J=15.8,7.1Hz,2H),2.77(dd,J=16.7,5.2Hz,2H);13C NMR(100MHz,甲醇-d4)δ143.28,131.29,127.62,41.35,20.36;C9H10Cl2N[M+H]+的MS(ESI,m/z)计算值202.02实测值202.05.
<制备例5>2-(哌啶-4-基)-5-(三氟甲基)-1,3,4-二唑三氟乙酸盐(im19)的合成
将4-(5-(二氟甲基)-1,3,4-二唑-2-基)哌啶-1-羧酸叔丁酯(23.5mg,0.103mmol)溶解在2ml DCM中之后,添加600μL三氟乙酸并在室温下搅拌1小时(DCM∶TFA=3∶1)。在通过LCMS和TLC确认反应完成之后,将其浓缩以除去TFA并在真空下干燥。在没有纯化的情况下获得呈盐形式的化合物(im19)(17.8mg,产率:54%)。
LCMS m/z 222[M+H]+
<制备例6>2-(二氟甲基)-5-(哌啶-4-基)-1,3,4-二唑(im20)的合成
步骤1:4-(5-(二氟甲基)-1,3,4-二唑-2-基)哌啶-1-羧酸叔丁酯(im20-1)的合成
将4-(1H-四唑-5-基)哌啶-1-羧酸叔丁酯(100mg,0.395mmol)和二氟乙酸酐(64μL,0.592mmol)溶解在DCM(3.9mL)中之后,将所得溶液在室温下搅拌1小时。将反应混合物用水猝灭,用DCM萃取,用盐水洗涤,用Na2SO4干燥,过滤并浓缩。将产物通过柱色谱(DCM∶MeOH)进行纯化以得到作为无色油状物的主题化合物(im20-1)(77mg,产率:64.7%)。
1H NMR(400MHz,CDCl3)δ6.83(t,J=51.8Hz,2H),4.12(d,J=7.7Hz,2H),3.19-3.11(m,1H),2.96(t,J=13.2Hz,2H),2.09(d,J=12.9Hz,3H),1.84(ddd,J=24.6,11.3,4.1Hz,3H),1.47(s,9H).
步骤2:2-(二氟甲基)-5-(哌啶-4-基)-1,3,4-二唑(im20)的合成
在0℃下向im20-1(76mg,0.251mmol)在DCM(2.5mL)中的溶液添加TFA(833μL)。将反应混合物在室温下搅拌2小时。添加1N NaOH至pH 8至10,并用DCM萃取。将有机层用Na2SO4干燥并过滤。在真空下浓缩溶剂。获得作为黄色油状物的主题化合物(im20)并将主题化合物在没有纯化的情况下用于以下反应(32mg,产率:63%)。
<制备例7>4-(4-甲基-1H-1,2,3-三唑-5-基)哌啶三氟乙酸盐(im21)的合成
步骤1:4-(丙-1-炔-1-基)哌啶-1-羧酸叔丁酯(im21-1)的合成
在氮气气氛下将4-乙炔基哌啶-1-羧酸叔丁酯(1.0g,4.8mmol)溶解在四氢呋喃(14mL)中并维持在-78℃。添加2.5M正丁基锂(1.92mL,4.8mmol)并搅拌30分钟。将温度升至室温,然后添加碘甲烷(450μL,7.2mmol)并将反应搅拌12小时。在反应之后,添加乙酸乙酯和H2O并萃取,并且将有机层用Na2SO4干燥并浓缩。将获得的剩余物通过硅胶柱色谱(在DCM中的0至5%MeOH)进行纯化以获得作为棕色液体的主题化合物(im21-1)(1.09g,产率:100%)。
1H NMR(400MHz,CDCl3)δ3.69(d,J=11.7Hz,2H),3.18-3.06(m,2H),2.49(d,J=2.1Hz,1H),1.79(d,J=2.3Hz,3H),1.77-1.67(m,2H),1.57-1.48(m,2H),1.45(s,9H).
步骤2:4-(4-甲基-1H-1,2,3-三唑-5-基)哌啶-1-羧酸叔丁酯(im21-2)的合成
使im21-1(170mg,0.75mmol)和三甲基甲硅烷基叠氮化物(150μL,1.16mmol)在微波反应器中在200℃下反应2小时。将反应溶液通过硅胶柱色谱(在DCM中的0至5%MeOH)进行纯化以获得作为黄色液体的主题化合物(im21-2)(30mg,产率:15%)。
1H NMR(400MHz,CDCl3)δ4.18(m,2H),2.91-2.75(m,3H),2.30(s,3H),1.89-1.66(m,4H),1.46(s,9H).
步骤3:4-(4-甲基-1H-1,2,3-三唑-5-基)哌啶三氟乙酸盐(im21)的合成
将4-(4-甲基-1H-1,2,3-三唑-5-基)哌啶-1-羧酸叔丁酯(30mg,0.11mmol)溶解在DCM(1.5mL)中,然后在0℃下添加三氟乙酸(350μL)。在将温度升至室温并反应12小时之后,将反应溶液浓缩以得到主题化合物(im21),其在没有进一步纯化的情况下用于以下反应中(产率:100%)。
LCMS m/z 167[M+H]+
<制备例8>4-(1H-四唑-5-基)哌啶三氟乙酸盐(im25)的合成
将4-(1H-四唑-5-基)哌啶-1-羧酸叔丁酯(0.3g,1.1844mmol)和3.9mLTFA溶解在30mL DCM中,并将反应混合物在室温下搅拌。在通过TLC确认反应完成之后,将其浓缩并在没有进一步纯化的情况下用于以下反应中(产率:100%)。
[实施例1]5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(2,3-二氢-1H-茚-2-基)嘧啶-2-胺(8a)的合成
步骤1:2-((2,3-二氢-1H-茚-2-基)氨基)嘧啶-5-羧酸乙酯(5a)的合成
将2,3-二氢-1H-茚-2-胺(4a,1.68mmol)、2-氯嘧啶-5-羧酸乙酯(1.4mmol)和三乙胺(3mmol)在二氧六环(5mL)中的混合物在100℃下搅拌3小时。在冷却之后,蒸发溶剂并且用乙酸乙酯萃取粗制产物,并随后用盐水洗涤。将有机层用无水硫酸钠干燥并浓缩。将产物通过柱色谱(己烷/乙酸乙酯)进行纯化以得到作为白色固体的主题化合物(产率:89.2%)。
1H NMR(400MHz,CDCl3)δ8.90(s,1H),8.75(s,1H),7.25-7.15(m,4H),6.00(d,J=7.8Hz,1H),4.97-4.79(m,1H),4.35(q,J=7.1Hz,2H),3.41(dd,J=16.0,7.0Hz,2H),2.90(dd,J=16.0,4.9Hz,2H),1.37(t,J=7.1Hz,3H);C16H18N3O2[M+H]+的MS(ESI,m/z)计算值284.14,实测值284.05.
步骤2:2-((2,3-二氢-1H-茚-2-基)氨基)嘧啶-5-碳酰肼(6a)的合成
将化合物5a(5mmol)和一水合肼(50mmol)溶解在EtOH中并回流6小时。在反应完成之后,在真空下蒸发反应混合物以获得主题化合物(产率:93.4%)。
1H NMR(400MHz,DMSO-d6)δ9.59(s,1H),8.72(s,1H),8.68(s,1H),8.08(d,J=6.9Hz,1H),7.27-7.08(m,4H),4.66(h,J=7.2Hz,1H),4.42(s,2H),3.26(dd,J=15.8,7.6Hz,2H),2.91(dd,J=15.8,6.9Hz,2H);C14H16N5O[M+H]+的MS(ESI,m/z)计算值270.13,实测值270.05.
步骤3:5-(2-((2,3-二氢-1H-茚-2-基)氨基)嘧啶-5-基)-1,3,4-二唑-2(3H)-酮(7a)的合成
在0℃下将化合物6a(0.1mmol)、TEA(0.5mmol)在THF(5mL)中的混合物缓慢添加至三光气(0.04mmol)在THF(5mL)中的溶液。将反应混合物在室温下搅拌3小时。将溶剂蒸发至干。将产物用乙酸乙酯萃取并用盐水洗涤。将有机层用无水硫酸钠干燥并浓缩。将剩余物通过柱色谱(EA/Hex)进行纯化以得到主题化合物(产率:27.4%)。
1H NMR(400MHz,氯仿-d)δ8.75(s,1H),8.67(s,1H),7.26-7.17(m,4H),5.79(d,J=7.9Hz,1H),4.92-4.83(m,1H),3.42(dd,J=16.0,6.9Hz,2H),2.92(dd,J=16.0,4.9Hz,2H);C15H14N5O2[M+H]+的MS(ESI,m/z)计算值296.11,实测值296.05.
步骤4:5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(2,3-二氢-1H-茚-2-基)嘧啶-2-胺(8a)的合成
将从制备例1制备的5-(2-((2,3-二氢-1H-茚-2-基)氨基)嘧啶-5-基)-1,3,4-二唑-2(3H)-酮(7a,1mmol)、4-(1H-1,2,3-三唑-5-基)哌啶·HCl(3,1.2mmol)、DIEA(3mmol)和BOP试剂(1.2mmol)溶解在DMF(5mL)中。将反应混合物在室温下搅拌过夜。将溶剂蒸发至干。将粗制产物用乙酸乙酯萃取并用盐水洗涤。将有机层用无水硫酸钠干燥并浓缩。将产物通过柱色谱(DCM/MeOH)进行分离以得到作为白色固体的主题化合物(产率:46.1%)。
1H NMR(400MHz,CDCl3)δ12.55(s,1H),8.79(s,2H),7.54(s,1H),7.26-7.22(m,2H),7.21-7.16(m,2H),5.88(d,J=7.7Hz,1H),4.93-4.83(m,1H),4.21-4.09(m,2H),3.42(dd,J=16.0,7.0Hz,2H),3.33-3.22(m,2H),3.11-3.02(m,1H),2.92(dd,J=16.0,5.0Hz,2H),2.21-2.11(m,2H),1.97-1.83(m,2H);C22H24N9O[M+H]+的HRMS(ESI,m/z)计算值430.2098,实测值430.2103.
[实施例2]5-(5-(4-(1H-1,2,3-三唑.5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(5-氟-2,3-二氢-1H-茚-2-基)嘧啶-2-胺(8b)的合成
根据与实施例1中相同的步骤合成主题化合物(产率:83.0%),不同之处在于使用5-氟-2,3-二氢-1H-茚-2-胺(4b)代替2,3-二氢-1H-茚-2-胺(4a)。
1H NMR(400MHz,氯仿-d)δ12.69(s,1H),8.79(s,2H),7.54(s,1H),7.16(dd,J=8.3,5.2Hz,1H),7.01-6.79(m,2H),5.97(d,J=7.6Hz,1H),4.96-4.82(m,1H),4.21-4.09(m,2H),3.38(td,J=15.1,14.7,7.0Hz,2H),3.28(ddd,J=13.1,11.7,2.9Hz,2H),3.07(tt,J=11.5,3.7Hz,1H),2.88(td,J=16.0,5.2Hz,2H),2.16(dd,J=13.6,3.5Hz,2H),1.97-1.82(m,2H);C22H23FN9O[M+H]+的HRMS(ESI,m/z)计算值448.2004,实测值448.2003.
[实施例3]5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(5-氯-2,3-二氢-1H-茚-2-基)嘧啶-2-胺(8c)的合成
根据与实施例1中相同的步骤合成主题化合物(产率:62.5%),不同之处在于使用5-氯-2,3-二氢-1H-茚-2-胺(4c)代替2,3-二氢-1H-茚-2-胺(4a)。
1H NMR(400MHz,氯仿-d)δ12.37(s,1H),8.79(s,2H),7.54(s,1H),7.22(q,J=1.2Hz,1H),7.16(d,J=1.3Hz,2H),5.84(d,J=7.6Hz,1H),4.88(qt,J=7.2,5.1Hz,1H),4.15(dt,J=13.3,4.0Hz,2H),3.45-3.33(m,2H),3.27(ddd,J=13.2,11.9,2.9Hz,2H),3.07(tt,J=11.4,3.7Hz,1H),2.95-2.83(m,2H),2.21-2.11(m,2H),1.96-1.80(m,2H);C22H23CIN9O[M+H]+的MS(ESI,m/z)计算值464.1709,实测值464.1709.
[实施例4]5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(5-溴-2,3-二氢-1H-茚-2-基)嘧啶-2-胺(8d)的合成
根据与实施例1中相同的步骤合成主题化合物(产率:38.0%),不同之处在于使用5-溴-2,3-二氢-1H-茚-2-胺(4d)代替2,3-二氢-1H-茚-2-胺(4a)。
1H NMR(400MHz,CDCl3)δ8.79(s,2H),7.55(s,1H),7.38(s,1H),7.31(dd,J=8.0,1.9Hz,1H),7.11(d,J=8.0Hz,1H),5.70(d,J=7.6Hz,1H),4.95-4.79(m,1H),4.20-4.10(m,2H),3.45-3.21(m,4H),3.06(tt,J=11.5,3.8Hz,1H),2.88(ddd,J=20.9,16.2,5.1Hz,2H),2.21-2.10(m,2H),1.98-1.81(m,2H);C22H23BrN9O[M+H]+的MS(ESI,m/z)计算值508.1203,实测值508.1202.
[实施例5]5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(5,6-二氟-2,3-二氢-1H-茚-2-基)嘧啶-2-胺(8e)的合成
根据与实施例1中相同的步骤合成主题化合物(产率:63.8%),不同之处在于使用5,6-二氟-2,3-二氢-1H-茚-2-胺(4e)代替2,3-二氢-1H-茚-2-胺(4a)。
1H NMR(400MHz,氯仿-d)δ13.08(s,1H),8.79(s,2H),7.54(s,1H),7.02(t,J=8.8Hz,2H),6.03(d,J=7.6Hz,1H),4.89(qt,J=7.2,5.2Hz,1H),4.14(dt,J=13.4,3.8Hz,2H),3.42-3.19(m,4H),3.07(tt,J=11.4,3.7Hz,1H),2.97-2.82(m,2H),2.16(dd,J=13.7,3.7Hz,2H),1.99-1.82(m,2H);C22H22F2N9O[M+H]+的HRMS(ESI,m/z)计算值466.1910,实测值466.1913.
[实施例6]5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(5,6-二氯-2,3-二氢-1H-茚-2-基)嘧啶-2-胺(8f)的合成
根据与实施例1中相同的步骤合成主题化合物(产率:54.3%),不同之处在于使用5,6-二氯-2,3-二氢-1H-茚-2-胺(4f)代替2,3-二氢-1H-茚-2-胺(4a)。
1H NMR(400MHz,氯仿-d)δ12.17(s,1H),8.80(s,2H),7.54(s,1H),7.32(s,2H),5.79(d,J=7.5Hz,1H),4.88(qt,J=7.2,5.2Hz,1H),4.15(dt,J=12.6,3.8Hz,2H),3.38(dd,J=16.0,7.3Hz,2H),3.28(td,J=13.2,2.9Hz,2H),3.06(ddt,J=11.4,7.4,3.7Hz,1H),2.88(dd,J=16.3,5.2Hz,2H),2.22-2.12(m,2H),1.98-1.82(m,2H);C22H22Cl2N9O[M+H]+的MS(ESI,m/z)计算值498.13,实测值498.15.
[实施例7]N-(5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)嘧啶-2-基)-6,7-二氢-5H-环戊[d]吡嗪-6-胺(13)的合成
根据与实施例1中相同的步骤合成主题化合物(产率:53.0%),不同之处在于使用6,7-二氢-5H-环戊[b]吡嗪-6-胺(9)代替2,3-二氢-1H-茚-2-胺(4a)。
1H NMR(400MHz,甲醇-d4)δ8.79(s,2H),8.34(s,2H),7.75-7.62(m,1H),4.94(tt,J=7.8,5.7Hz,IH),4.11(dt,J=13.3,3.7Hz,2H),3.54(dd,J=17.5,7.9Hz,2H),3.35(s,2H),3.19-3.04(m,3H),2.19-2.08(m,2H),1.86(qd,J=12.2,4.3Hz,2H);C20H22N11O[M+H]+的MS(ESI,m/z)计算值432.20,实测值432.20.
[实施例8]6-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(2,3-二氢-1H-茚-2-基)哒嗪-3-胺(14)的合成
根据与实施例1中相同的步骤合成主题化合物(产率:42.0%),不同之处在于使用6-氯哒嗪-3-羧酸乙酯代替2-氯嘧啶-5-羧酸乙酯。
1H NMR(400MHz,DMSO-d6)δ14.78(s,1H),7.80(d,J=9.4Hz,1H),7.76(d,J=6.4Hz,1H),7.72(s,1H),7.30-7.24(m,2H),7.19-7.15(m,2H),6.94(d,J=9.4Hz,1H),4.77(h,J=6.7,6.1Hz,1H),4.04-3.96(m,2H),3.30(d,J=2.5Hz,4H),3.08-2.99(m,1H),2.90(dd,J=16.0,5.4Hz,2H),2.09-2.02(m,2H),1.80-1.67(m,2H).C22H24N9O(M+H)+的HRMS(ESI)m/z计算值=430.21;实测值430.2107.
[实施例9]5-(5-(4-(1H-1,2,4-三唑-1-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(2,3-二氢-1H-茚-2-基)嘧啶-2-胺(15a)的合成
根据与实施例1中相同的步骤合成主题化合物(产率:65.2%),不同之处在于使用从制备例2获得的4-(1H-1,2,4-三唑-1-基)哌啶HCl(Im15-2a)代替4-(1H-1,2,3-三唑-5-基)哌啶HCl(3)。
1H NMR(400MHz,CDCl3)δ8.76(s,2H),8.14(s,1H),7.97(s,1H),7.28-7.20(m,2H),7.21-7.14(m,2H),6.02(d,J=7.7Hz,1H),4.87(qt,J=7.2,5.0Hz,1H),4.47(tt,J=11.1,4.1Hz,1H),4.29-4.17(m,2H),3.52-3.35(m,3H),3.30(ddd,J=13.4,11.7,3.0Hz,2H),2.91(dd,J=16.0,5.0Hz,2H),2.37-2.27(m,2H),2.27-2.13(m,2H);C22H24N9O[M+H]+的HRMS(ESI,m/z)计算值430.2098,实测值430.2098.
[实施例10]N-(2,3-二氢-1H-茚-2-基)-5-(5-(4-(3-甲基-1H-1,2,4-三唑-1-基)哌啶-1-基)-1,3,4-二唑-2-基)嘧啶-2-胺(15b)的合成
根据与实施例1中相同的步骤合成主题化合物(产率:57.4%),不同之处在于使用从制备例2获得的4-(3-甲基-1H-1,2,4-三唑-1-基)哌啶·HCl(Im15-2b)代替4-(1H-1,2,3-三唑-5-基)哌啶HCl(3)。
1H NMR(400MHz,氯仿-d)δ8.77(s,2H),7.90(d,J=77.3Hz,1H),7.28-7.20(m,3H),7.23-7.15(m,2H),5.82(d,J=7.7Hz,1H),4.88(dtd,J=12.3,7.3,5.0Hz,1H),4.42-4.16(m,3H),3.42(dd,J=16.0,7.0Hz,2H),3.34-3.22(m,2H),2.91(dd,J=16.0,5.0Hz,2H),2.46(d,J=45.0Hz,3H),2.38-2.24(m,2H),2.26-2.13(m,1H),2.09-1.99(m,1H);C23H26N9O[M+H]+的HRMS(ESI,mz)计算值444.2255,实测值444.2255.
[实施例11]N-(5-溴-2,3-二氢-1H-茚-2-基)-5-(5-(2-甲基-4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)嘧啶-2-胺(16)的合成
步骤1-1:2-甲基-4-(1H-1,2,3-三唑-5-基)哌啶-1-羧酸叔丁酯(M2)的合成
根据与制备例1的步骤1中相同的步骤合成主题化合物(产率:47.0%),不同之处在于使用4-乙炔基-2-甲基哌啶-1-羧酸叔丁酯代替4-乙炔基哌啶-1-羧酸叔丁酯。
1H NMR(400MHz,甲醇-d4)δ7.64(s,1H),4.51(t,J=6.4Hz,1H),4.04(ddd,J=13.8,4.6,2.3Hz,1H),3.28-3.16(m,1H),3.06(s,1H),2.03-1.85(m,2H),1.79(dt,J=13.0,6.5Hz,1H),1.62-1.49(m,1H),1.47(s,9H),1.26(d,J=7.0Hz,3H);C13H23N4O2[M+H]+的MS(ESI,m/z)计算值267.18,实测值267.20.
步骤1-2:2-甲基-4-(1H-1,2,3-三唑-5-基)哌啶·HCl(M3)的合成
使用从上述步骤获得的M2,根据与制备例1步骤2相同的步骤合成主题化合物(定量)。
C8H14N4[M+H]+的MS(ESI,m/z)计算值166.12,实测值166.10。
步骤2:N-(5-溴-2,3-二氢-1H-茚-2-基)-5-(5-(2-甲基-4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)嘧啶-2-胺(16)的合成
根据与实施例4中相同的步骤合成主题化合物(产率:11.2%),不同之处在于使用从上述步骤获得的2-甲基-4-(1H-1,2,3-三唑-5-基)哌啶·HCl(M3)代替4-(1H-1,2,3-三唑-5-基)哌啶·HCl(3)。
1H NMR(400MHz,甲醇-d4)δ8.77(s,2H),7.67(s,1H),7.39(s,1H),7.33-7.26(m,1H),7.14(d,J=8.0Hz,1H),5.36-5.32(m,1H),4.58(s,1H),4.50(dd,J=7.1,3.3Hz,1H),4.05-3.95(m,1H),2.93(ddd,J=21.7,16.1,6.3Hz,2H),2.14(d,J=12.4Hz,1H),2.04-2.02(m,2H),1.80(qd,J=13.0,4.7Hz,1H),1.62-1.56(m,2H),1.42(d,J=6.9Hz,3H);C23H25BrN9O[M+H]+的MS(ESI,m/z)计算值522.13,实测值522.15.
[实施例12]5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(5-溴-2,3-二氢-1H-茚-2-基)吡啶-2-胺(17a)的合成
步骤1:6-氯烟酸乙酯(A4a)的合成
在室温下在Ar气下将6-氯烟酸(3.2mmol)和1,1’-羰基二咪唑(3.5mmol)添加至THF。将反应混合物在相同温度下搅拌3小时。向混合物缓慢添加过量的EtOH并搅拌过夜。在真空下除去THF溶剂并将所得混合物通过硅胶快速色谱(己烷/乙酸乙酯)进行纯化以得到主题化合物(产率:62.8%)。
1H NMR(400MHz,氯仿-d)δ9.00(dd,J=2.4,0.6Hz,1H),8.25(dd,J=8.3,2.4Hz,1H),7.42(dd,J=8.3,0.7Hz,1H),4.42(q,J=7.1Hz,2H),1.41(t,J=7.1Hz,3H);C8H9ClNO2[M+H]+的MS(ESI,m/z)计算值186.03实测值186.05.
步骤2:6-((5-溴-2,3-二氢-1H-茚-2-基)氨基)烟酸乙酯(A5a)的合成根据与实施例1的步骤1中相同的步骤合成主题化合物(产率:12.4%),不同之处在于使用5-溴-2,3-二氢-1H-茚-2-胺代替2,3-二氢-1H-茚-2-胺并且使用6-氯烟酸乙酯(A4a)代替2-氯嘧啶-5-羧酸乙酯。
1H NMR(400MHz,氯仿-d)δ8.75(d,J=1.8Hz,1H),7.99(dd,J=8.8,2.2Hz,1H),7.35(s,1H),7.30(d,J=8.1Hz,1H),7.09(d,J=8.0Hz,1H),6.36(d,J=8.8Hz,1H),5.30(d,J=8.1Hz,1H),4.78-4.59(m,1H),4.33(q,J=7.1Hz,2H),3.42-3.25(m,2H),2.93-2.74(m,2H),1.36(t,J=7.1Hz,3H);C17H18BrN2O2[M+H]+的MS(ESI,m/z)计算值361.05实测值361.00.
步骤3:6-((5-溴-2,3-二氢-1H-茚-2-基)氨基)烟酰肼(A6a)的合成
根据与实施例1的步骤2中相同的步骤合成主题化合物(产率:84.1%),不同之处在于使用化合物A5a代替化合物5a。
1H NMR(400MHz,DMSO-d6)δ9.43(s,1H),8.49(d,J=2.0Hz,1H),7.84-7.74(m,3H),7.44(s,1H),7.39-7.30(m,2H),7.25-7.17(m,1H),6.53-6.40(m,1H),4.63(q,J=5.7Hz,1H),3.28-3.18(m,2H),2.89-2.73(m,2H);;C15H16BrN4O[M+H]+的MS(ESI,m/z)计算值347.05实测值347.05.
步骤4:5-(6-((5-溴-2,3-二氢-1H-茚-2-基)氨基)吡啶-3-基)-1,3,4-二唑-2(3H)-酮(A7a)的合成
在室温下向化合物A6a(0.2mmol)在DMF中的溶液添加1,1’-羰基二咪唑(0.22mmol)和TEA(0.2mmol)并搅拌3小时。在真空下除去DMF溶剂并将粗制混合物通过硅胶快速色谱(己烷/乙酸乙酯)进行纯化以得到主题化合物(产率:84.0%)。
1H NMR(400MHz,DMSO-d6)δ10.94-10.85(m,1H),10.21(dd,J=8.9,2.4Hz,1H),10.13-10.07(m,1H),9.95(s,1H),9.87-9.82(m,1H),9.71(d,J=8.0Hz,1H),9.12-9.05(m,1H),7.17(q,J=5.8Hz,1H),5.81-5.71(m,2H),5.38-526(m,2H);C16H14BrN4O2[M+H]+的MS(ESI,m/z)计算值373.03实测值373.00.
步骤5:5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(5-溴-2,3-二氢-1H-茚-2-基)吡啶-2-胺(17a)的合成
根据与实施例1的步骤4中相同的步骤合成主题化合物(产率:57.2%),不同之处在于使用化合物A7a代替化合物7a。
1H NMR(400MHz,氯仿-d)δ8.60(dd,J=2.4,0.7Hz,1H),7.98(dd,J=8.8,2.4Hz,1H),7.54(s,1H),7.38(s,1H),7.31(dd,J=7.8,1.9Hz,1H),7.11(d,J=7.9Hz,1H),6.46(dd,J=8.9,0.8Hz,1H),5.24(d,J=7.5Hz,1H),4.74-4.62(m,1H),4.19-4.09(m,2H),3.45-3.20(m,4H),3.06(tt,J=11.4,3.7Hz,1H),2.95-2.80(m,2H),2.15(dd,J=13.8,3.8Hz,2H),1.97-1.83(m,2H);C23H24BrN8O[M+H]+的MS(ESI,rm/z)计算值507.13,实测值507.15.
[实施例13]5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(5-溴-2,3-二氢-1H-茚-2-基)吡嗪-2-胺(17b)的合成
根据与实施例12中相同的操作合成主题化合物(产率:48.5%),不同之处在于使用5-氯吡嗪-2-羧酸代替6-氯烟酸。
1H NMR(400MHz,甲醇-d4)δ8.60(d,J=1.3Hz,1H),7.93(d,J=1.5Hz,1H),7.68(s,1H),7.40(s,1H),7.30(dd,J=8.1,1.9Hz,1H),7.15(d,J=8.0Hz,1H),4.77(tt,J=7.2,3.6Hz,2H),4.13(dt,J=13.3,3.5Hz,2H),3.44-3.32(m,4H),3.10(ddt,J=11.6,7.4,3.7Hz,1H),2.90(ddd,J=19.0,16.1,5.4Hz,2H),2.18-2.08(m,2H),1.93-1.76(m,2H);C22H23BrN9O[M+H]+的MS(ESI,m/z)计算值508.12,实测值508.15.
[实施例14]5-(5c(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(5-溴-2,3-二氢-1H-茚-2-基)-4-氯吡啶-2-胺(18)的合成
步骤1:6-((5-溴-2,3-二氢-1H-茚-2-基)氨基)-4-氯烟酸乙酯(A5c)的合成
使用4,6-二氯烟酸乙酯根据与化合物A5a相同的步骤合成主题化合物(产率:64.2%)。
1H NMR(400MHz,氯仿-d)δ8.68(s,1H),8.40(d,J=6.3Hz,1H),7.39(s,1H),7.33(dd,J=8.0,1.8Hz,1H),7.11(d,J=8.0Hz,1H),6.62(s,1H),4.40-4.26(m,3H),3.40(td,J=16.6,7.0Hz,2H),2.92(ddd,J=20.7,16.3,4.8Hz,2H),1.36(t,J=7.1Hz,3H);C17H17BrClN2O2[M+H]+的MS(ESI,m/z)计算值395.02实测值395.05.
步骤2:6-((5-溴-2,3-二氢-1H-茚-2-基)氨基)-4-氯烟酸(A6c)的合成
在室温下向化合物A5c(0.50mmol)在EtOH和水中的溶液添加氢氧化锂(1.5mmol)并搅拌过夜。将所得混合物倒入DCM中,用H2O(40ml)洗涤,并用MgSO4干燥。将粗制混合物通过硅胶快速色谱(己烷/乙酸乙酯)进行纯化以得到主题化合物(产率:64.2%)。
1H NMR(400MHz,DMSO-d6)δ8.61(d,J=6.1Hz,1H),8.51(s,1H),7.47(s,1H),7.35(dd,J=8.0,1.9Hz,1H),7.23(d,J=8.0Hz,1H),6.90(s,1H),4.49(h,J=6.8Hz,1H),3.38(ddd,J=20.2,16.4,7.0Hz,2H),2.84(ddd,J=21.3,16.3,4.7Hz,2H);
C15H13BrClN2O2[M+H]+的MS(ESI,m/z)计算值366.98实测值366.95.
步骤3:5-(6-((5-溴-2,3-二氢-1H-茚-2-基)氨基)-4-氯吡啶-3-基)-1,3,4-二唑-2(3H)-基(A7c)的合成
在室温下在Ar气下向化合物A6c(0.25mmol)在THF中的溶液添加1,1’-羰基二咪唑(0.27mmol)并搅拌3小时。向该溶液添加一水合肼(2.5mmol)并搅拌过夜。在真空下蒸发所得混合物。将1,1’-羰基二咪唑(0.27mmol)和三乙胺(0.25mmol)添加至粗制混合物在DMF中的溶液。将反应混合物搅拌3小时并将粗制混合物通过硅胶快速色谱(己烷/乙酸乙酯)进行纯化以得到主题化合物(产率:59.6%)。
1H NMR(400MHz,DMSO-d6)δ12.74(s,1H),8.30(s,1H),7.48(s,1H),7.43-7.33(m,2H),7.24(d,J=8.0Hz,1H),7.04(s,1H),4.65-4.53(m,1H),3.49-3.36(m,2H),2.91-2.76(m,2H);C16H13BrClN4O2[M+H]+的MS(ESI,m/z)计算值406.99,实测值407.00.
步骤4:5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(5-溴-2,3-二氢-1H-茚-2-基)-4-氯吡啶-2-胺(18)的合成
使用化合物A7c根据与实施例1的步骤4中相同的步骤合成主题化合物(产率:67.8%)。
1H NMR(400MHz,DMSO-d6)δ14.73(s,1H),8.49(s,1H),8.12(d,J=6.9Hz,1H),7.69(s,1H),7.50(d,J=1.9Hz,1H),7.37(dd,J=8.0.2.0Hz,1H),7.26(d,J=8.0Hz,1H),7.02(s,1H),4.60(tt,J=6.9,2.8Hz,1H),4.05-3.96(m,2H),3.42(ddd,了=19.8,16.3,6.8Hz,2H),3.25(td,J=12.5,2.7Hz,2H),3.01(tt,J=11.5,3.7Hz,1H),2.87(ddd,J=20.8,16.4,4.1Hz,2H),2.06-1.96(m,2H),1.70(qd,J=12.6,4.2Hz,2H);C23H23BrClN8O[M+H]+的MS(ESI,m/z)计算值541.09,实测值541.10.
[实施例15]5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(3,5-二氯苄基)嘧啶-2-胺(19a)的合成
根据与实施例1中相同的步骤合成主题化合物(产率:48.7%),不同之处在于使用(3,5-二氯苯基)甲胺代替2,3-二氢-1H-茚-2-胺。
1H NMR(400MHz,DMSO-d6)δ8.84-8.67(m,2H),8.46(t,J=6.4Hz,1H),7.69(s,1H),7.48(t,J=2.0Hz,1H),7.36(d,J=1.9Hz,2H),4.57(d,J=6.3Hz,2H),3.99(dt,J=13.1,3.5Hz,2H),3.27-3.16(m,2H),3.05-2.95(m,1H),2.07-1.98(m,2H),1.77-1.62(m,2H);C20H20Cl2N9O[M+H]+的MS(ESI,m/z)计算值472.12,实测值472.10.
[实施例16]5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(3,5-二氯苯乙基)嘧啶-2-胺(19b)的合成
根据与实施例1中相同的步骤合成主题化合物(产率:54.6%),不同之处在于使用二异丙基乙胺代替2,3-二氢-1H-茚-2-胺。
1H NMR(400MHz,DMSO-d6)δ8.73(d,J=8.1Hz,2H),7.97(t,J=5.8Hz,1H),7.70(s,1H),7.42(t,J=1.9Hz,1H),7.32(d,J=1.9Hz,2H),3.99(dt,J=13.1,3.6Hz,2H),3.59(q,J=6.7Hz,2H),3.23(td,J=12.7,2.8Hz,2H),3.01(tt,J=11.6,3.7Hz,1H),2.89(t,J=6.9Hz,2H),2.03(dd,J=13.5,3.4Hz,2H),1.79-1.61(m,2H);C21H22Cl2N9O[M+H]+的MS(ESI,m/z)计算值486.13,实测值486.15.
[实施例17]1-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-3-(2-((2,3-二氢-1H-茚-2-基)氨基)嘧啶-5-基)丙-1-酮(20a)的合成
步骤1:(E)-3-(2-氯嘧啶-5-基)丙烯酸乙酯(imL14-1)的合成:将5-溴-2-氯嘧啶(0.19g,1.00mmol)、丙烯酸乙酯(0.42mL,4.00mmol)、二乙酸钯(II)(8.98mg,0.04mmol)和三(邻甲苯基)膦(30.43mg,0.10mmol)在二甲基甲酰胺(2mL)和二异丙基乙胺(1mL)中的混合物在回流下加热4小时,然后冷却至室温。将溶剂蒸发至干并用乙酸乙酯萃取。将萃取物用盐水洗涤并用硫酸钠干燥,然后浓缩。将剩余物通过柱色谱(乙酸乙酯/己烷)进行分离以得到作为浅黄色固体的主题化合物(0.15g,71.2%)。
1H NMR(400MHz,CDCl3)δ8.76(d,J=0.6Hz,2H),7.59(d,J=16.2Hz,1H),6.58(d,J=16.2Hz,1H),4.30(q,J=7.2Hz,2H),1.35(t,J=7.1Hz,3H).
步骤2:(E)-3-(2-((2,3-二氢-1H-茚-2-基)氨基)嘧啶-5-基)丙烯酸乙酯(imL14-2)的合成
使用imL14-1(0.11g,0.50mmol)代替2-氯嘧啶-5-羧酸乙酯并使用2-氨基茚满(0.80g,6.00mmol)和三乙胺(1.01g,10mmol)根据与实施例1的步骤1中相同的步骤合成作为白色固体的主题化合物(0.11g,71.5%)。
1H NMR(400MHz,CDCl3)δ8.38(br s,2H),7.48(d,J=16.1Hz,1H),7.26-7.14(m,4H),6.29(d,J=16.1Hz,1H),6.01(s,1H),4.96-4.78(m,1H),4.26(q,J=7.1Hz,2H),3.41(dd,J=16.0,7.0Hz,2H),2.90(dd,J=16.0,4.8Hz,2H),1.34(t,J=7.1Hz,3H).
步骤3:3-(2-((2,3-二氢-1H-茚-2-基)氨基)嘧啶-5-基)丙酸乙酯(imL14-3)的合成
在包含在乙酸乙酯/甲醇/四氢呋喃(1∶2∶1)(20mL)中的imL14-2(92.81mg,0.30mmol)的圆底烧瓶中,在室温下将氢氧化钯碳(50mg)缓慢添加至混合物。将反应混合物在氢气下在室温下搅拌6小时。将混合物通过celite过滤并浓缩滤液。将剩余物通过柱色谱(乙酸乙酯/己烷)进行纯化以得到作为白色固体的主题化合物(78.56mg,84.1%)。
1H NMR(400MHz,CDCl3)δ8.10(s,2H),7.25-7.13(m,4H),5.65(d,J=7.8Hz,1H),4.84-4.68(m,1H),4.13(q,J=7.2Hz,2H),3.38(dd,J=16.0,7.0Hz,2H),2.86(dd,J=15.9,5.0Hz,2H),2.74(t,J=7.5Hz,2H),2.54(t,J=7.3Hz,2H),1.25(t,J=7.1Hz,3H).
步骤4:3-(2-((2,3-二氢-1H-茚-2-基)氨基)嘧啶-5-基)丙酸(L14)的合成
将氢氧化锂(5.00mmol)在水(2mL)中的溶液添加至imL14-3(1.00mmo|)在四氢呋喃/甲醇的混合物(18ml∶2ml)中的溶液。将反应混合物在室温下搅拌6小时。然后蒸发溶剂并再次溶解在水中并通过1M盐酸酸化。将混合物用乙酸乙酯萃取并用水洗涤。将有机层用无水硫酸钠干燥并浓缩。将产物通过柱色谱(乙酸乙酯/己烷)进行纯化以得到作为白色固体的主题化合物(60.33mg,84.4%)。
步骤5:1-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-3-(2-((2,3-二氢-1H-茚-2-基)氨基)嘧啶-5-基)丙-1-酮(20a)的合成
向包含2ml的N,N’-二甲基甲酰胺的10mL小瓶添加L14(0.10mmol)、4-(1H-1,2,3-三唑-5-基)哌啶·HCl(22.64mg,0.12mmol)和N,N-二异丙基乙胺(38.77mg,0.30mmol)。然后将N,N,N’,N’-四甲基-O-(1H-苯并三唑-1-基)脲六氟磷酸盐(HBTU)(45.51mg,0.12mmol)添加至搅拌的混合物。将反应混合物在室温下继续搅拌过夜。将溶剂蒸发至干并将粗制产物通过柱色谱(二氯甲烷/甲醇)进行分离以得到作为白色固体的主题化合物(36.95mg,88.5%)。
1H NMR(400MHz,CDCl2)δ13.71(s,1H),8.19(s,2H),7.47(s,1H),7.23-7.18(m,2H),7.18-7.13(m,2H),5.77(d,J=7.6Hz,1H),4.83-4.70(m,1H),4.71-4.57(m,1H),3.94-3.81(m,1H),3.37(dd,J=16.0,7.1Hz,2H),3.21-3.09(m,1H),3.07-2.94(m,1H),2.91-2.73(m,5H),2.60(t,J=7.2Hz,2H),2.08-1.98(m,2H),1.71-1.49(m,2H);C23H28N7O(M+H)+的HRMS(ESI)m/z计算值=418.24;实测值418.2354.
[实施例18]1-(4-(1H-咪唑-5-基)哌啶-1-基)-3-(2-((2,3-二氢-1H-茚-2-基)氨基)嘧啶-5-基)丙-1-酮(20b)的合成
根据与实施例17中相同的步骤合成主题化合物,不同之处在于使用(1H-咪唑-5-基)哌啶(18.14mg,0.12mmol)代替步骤5中的4-(1H-1,2,3)-三唑-5-基)哌啶·HCl(27.49mg,68.0%)。
1H NMR(400MHz,CDCl3)δ9.97(s,1H),8.17(s,2H),7.55(d,J=1.2Hz,1H),7.25-7.19(m,2H),7.19-7.13(m,2H),6.74(s,1H),5.40(d,J=7.8Hz,1H),4.80-4.71(m,1H),4.69-4.61(m,1H),3.90-3.80(m,1H),3.37(dd,J=15.9,7.0Hz,2H),3.16-3.07(m,1H),2.89-2.77(m,5H),2.76-2.68(m,1H),2.58(t,J=7.4Hz,2H),2.09-1.98(m,2H),1.60-1.44(m,2H);C24H29N6O(M+H)+的HRMS(ESI)m/z计算值=417.24,实测值417.2400.
[实施例19]1-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-4-(5-((2,3-二氢-1H-茚-2-基)氨基)-1,3,4-噻二唑-2-基)丁-1-酮(21a)的合成
步骤1:2-异氰硫基-2,3-二氢-1H-茚(imL15-1)的合成
在0℃下向2-氨基茚满(0.13g,1.00mmol)和N,N-二异丙基乙胺(38.77mg,0.30mmol)在二氯甲烷(5mL)中的冷却混合物逐滴添加硫光气(115.00μL,0.15mmol)。将反应混合物在室温下搅拌3小时,然后将溶剂蒸发至干。将剩余物溶解在乙酸乙酯中并用盐水洗涤。将有机层用无水硫酸钠干燥并浓缩。将产物通过柱色谱(己烷)进行纯化以得到作为浅褐色固体的主题化合物(0.173g,98.8%)。
1H NMR(400MHz,CDCl3)δ7.26-7.19(m,4H),4.53(tt,J=6.9,5.2Hz,1H),3.32(dd,J=15.9,7.0Hz,2H),3.16(dd,J=15.8,5.2Hz,2H).
步骤2:N-(2,3-二氢-1H-茚-2-基)肼硫代酰胺(imL15-2)的合成
将水合肼(200μL)添加至imL15-1(0.14g,0.08mmol)在乙醇(5mL)中的溶液。将反应混合物在室温下搅拌过夜。将溶剂蒸发至干并用乙酸乙酯萃取并用盐水洗涤。将有机层用无水硫酸钠干燥并浓缩。将产物通过柱色谱(乙酸乙酯/己烷)进行纯化以得到作为浅黄色固体的主题化合物(0.156g,94.3%)。
1H NMR(400MHz,CDCl3)δ7.59(s,1H),7.28-7.14(m,4H),5.24-5.13(m,1H),3.68(s,1H),3.43(dd,J=16.2,7.2Hz,2H),2.93(dd,J=16.2,4.7Hz,2H),1.37-1.16(m,2H).
步骤3:4-(5-((2,3-二氢-1H-茚-2-基)氨基)-1,3,4-噻二唑-2-基)丁酸乙酯(imL15-3)的合成
将4-氰基丁酸乙酯(70.59mg,0.50mmol)和imL15-2(0.10g,0.50mmol)的溶液在80℃下在三氟乙酸(3mL)中搅拌过夜。将混合物冷却至O℃并用饱和碳酸氢钠溶液猝灭,然后用乙酸乙酯萃取。将有机层用无水硫酸钠干燥并浓缩。将产物通过柱色谱(二氯甲烷/甲醇)进行纯化以得到作为白色固体的主题化合物(0.10g,62.5%)。
1H NMR(400MHz,CDCl3)δ7.26-7.13(m,4H),6.01(s,1H),4.42(p,J=5.7Hz,1H),4.13(q,J=7.1Hz,2H),3.38(dd,J=16.1,6.9Hz,2H),3.11-2.86(m,4H),2.41(t,J=7.4Hz,2H),2.05(p,J=7.4Hz,2H),1.26(t,J=7.1Hz,3H).
步骤4:4-(5-((2,3-二氢-1H-茚-2-基)氨基)-1,3,4-噻二唑-2-基)丁酸(L15)的合成
使用imL15-3(0.10g,0.30mmol)根据与实施例17的步骤4中相同的步骤合成作为白色固体的主题化合物(68.90mg,75.7%)。
步骤5:1-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-4-(5-((2,3-二氢-1H-茚-2-基)氨基)-1,3,4-噻二唑-2-基)丁-1-酮(21a)的合成
向包含2ml的N,N’-二甲基甲酰胺的10mL小瓶添加L15(0.10mmol)、4-(1H-1,2,3-三唑-5-基)哌啶·HCl(0.12mmol)和N,N-二异丙基乙胺(0.30mmol)。然后将N,N,N’,N’-四甲基-O-(1H-苯并三唑-1-基)脲六氟磷酸盐(HBTU)(0.12mmol)添加至搅拌的混合物。将反应混合物在室温下继续搅拌过夜。将溶剂蒸发至干并将粗制产物通过柱色谱(二氯甲烷/甲醇)进行分离以得到作为白色固体的主题化合物(19.34mg,44.2%)。
1H NMR(400MHz,CDCl3)δ7.47(s,1H),7.24-7.16(m,4H),6.33-5.57(m,1H),4.66-4.56(m,1H),4.50-4.40(m,1H),3.94-3.85(m,1H),3.43-3.33(m,2H),3.19-3.09(m,1H),3.06-2.92(m,5H),2.77-2.68(m,1H),2.53-2.39(m,2H),2.19-2.04(m,2H),2.04-1.92(m,2H),1.80-1.61(m,2H);C22H28N7OS(M+H)+的HRMS(ESI)m/z计算值=438.21;实测值438.2076.
[实施例20]1-(4-(1H-咪唑-5-基)哌啶-1-基)-4-(5-((2,3-二氢-1H-茚-2-基)氨基)-1,3,4-噻二唑-2-基)丁-1-酮(21b)的合成:根据与实施例19的步骤5中相同的步骤合成作为白色固体的主题化合物(38.24mg,68.0%),不同之处在于使用4-(1H-咪唑-5-基)哌啶(18.14mg,0.12mmol)代替4-(1H-1,2,3-三唑-5-基)哌啶·HCl(0.12mmol)。
1H NMR(400MHz,CDCl3)δ7.52(s,1H),7.22-7.12(m,4H),6.73(s,1H),6.62-6.51(m,1H),4.60-4.53(m,1H),4.49-4.39(m,1H),3.87-3.78(m,1H),3.40-3.28(m,2H),3.12-3.03(m,1H),3.01-2.90(m,4H),2.88-2.78(m,1H),2.70-2.59(m,1H),2.48-2.34(m,2H),2.11-1.89(m,4H),1.68-1.49(m,2H);C23H29N6OS(M+H)+的HRMS(ESI)m/z计算值=437.21;实测值437.2126.
[实施例21]1-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-4-(5-((2,3-二氢-1H-茚-2-基)氨基)-1,3,4-二唑-2-基)丁-1-酮(22a)的合成
步骤1:2-(5-甲氧基-5-氧代戊酰基)肼羧酸叔丁酯(imL17-1)的合成
向包含二氯甲烷(2mL)中的戊二酸单甲酯(5.00mmol)、肼基甲酸叔丁酯(6.00mmol)和4-二甲基氨基吡啶(0.025mmol)的混合物添加N-(3-二甲基氨基丙基)-N’-乙基碳二亚胺盐酸盐(6.00mmol)。将反应混合物在室温下持续搅拌过夜。将混合物用二氯甲烷萃取并用水洗涤。将有机层用无水硫酸钠干燥并浓缩。将粗制产物通过柱色谱(乙酸乙酯/己烷)进行分离以得到作为白色固体的主题化合物(1.14g,87.6%)。
步骤2:5-肼基-5-氧代戊酸甲酯盐酸盐(imL17-2)的合成
使用imL17-1(0.52g,2.00mmol)根据与制备例1的步骤2中相同的步骤合成作为白色固体的主题化合物(定量)。
1H NMR(400MHz,MeOD)δ3.66(s,3H),2.41(t,J=7.3Hz,2H),2.36(t,J=7.4
Hz,2H),1.94(p,J=7.4Hz,2H).
步骤3:4-(5-氧代-4,5-二氢-1,3,4-二唑-2-基)丁酸甲酯(imL17-3)的合成
向im17-2(0.52g,2.00mmol)在二氧六环(10mL)中的溶液添加在二氧六环中的4.0M盐酸(2mL)溶液。将反应混合物在室温下搅拌过夜。将溶剂蒸发至干以得到作为白色固体的主题化合物(定量)。
1H NMR(400MHz,MeOD)δ3.66(s,3H),2.41(t,J=7.3Hz,2H),2.36(t,J=7.4Hz,2H),1.94(p,J=7.4Hz,2H).
步骤4:4-(5-((2,3-二氢-1H-茚-2-基)氨基)-1,3,4-二唑-2-基)丁酸甲酯(imL17-4)的合成
使用imL17-3(0.149mg,0.80mmol)和2-氨基茚满(0.13g,0.96mmol)根据与实施例1的步骤4中相同的步骤合成作为白色固体的主题化合物(0.12g,50.2%)。
1H NMR(400MHz,CDCl3)δ7.27-7.15(m,4H),5.34(s,1H),4.51(qt,J=6.9,4.6Hz,1H),3.67(s,3H),3.36(dd,J=16.1,6.9Hz,2H),2.97(dd,J=16.1,4.6Hz,2H),2.74(t,J=7.3Hz,2H),2.43(t,J=7.3Hz,2H),2.03(p,J=7.3Hz,2H).
步骤5:4-(5-((2,3-二氢-1H-茚-2-基)氨基)-1,3,4-二唑-2-基)丁酸(L17)的合成
根据与实施例17的步骤4中相同的步骤合成作为白色固体的主题化合物(0.11g,96.8%),不同之处在于使用imL17-4(0.12g,0.40mmol)代替imL14-3。
1H NMR(400MHz,CDCl3)δ8.42(br s,1H),7.25-7.14(m,4H),6.09(br s,1H),4.47(tt,J=7.0,5.2Hz,1H),3.35(dd,J=16.0,7.0Hz,2H),2.95(dd,J=16.0,5.2Hz,2H),2.77(t,J=7.3Hz,2H),2.43(t,J=7.1Hz,2H),2.02(p,J=7.2Hz,2H).
步骤6:1-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-4-(5-((2,3-二氢-1H-茚-2-基)氨基)-1,3,4-二唑-2-基)丁-1-酮(22a)的合成
使用L17(28.73mg,0.10mm0l)和4-(1H-1,2,3-三唑-5-基)哌啶·HCl(22.64mg,0.12mmol),根据与实施例19的步骤5中相同的步骤合成作为白色固体的主题化合物(28.37mg,67.3%)。
1H NMR(400MHz,CDCl3)δ13.51(s,1H),7.46(s,1H),7.25-7.14(m,4H),5.54-5.41(m,1H),4.63-4.55(m,1H),4.55-4.48(m,1H),3.95-3.87(m,1H),3.41-3.32(m,2H),3.19-3.10(m,1H),3.06-2.92(m,3H),2.83-2.70(m,3H),2.54-2.41(m,2H),2.17-1.93(m,4H),1.78-1.58(m,2H);C22H28N7O2(M+H)+的HRMS(ESI)m/z计算值=422.2299;实测值422.2300.
[实施例22]1-(4-(1H-咪唑-5-基)哌啶-1-基)-4-(5-((2,3-二氢-1H-茚-2-基)氨基)-1,3,4-二唑-2-基)丁-1-酮(22b)的合成
根据与实施例21中相同的步骤合成主题化合物(产率:69.4%),不同之处在于使用4-(1H-咪唑-5-基)哌啶(18.14mg,0.12mmol)代替步骤6中的4-(1H-1,2,3-三唑-5-基)哌啶·HCl。
1H NMR(400MHz,CDCl3)δ7.50(d,J=1.2Hz,1H),7.23-7.14(m,4H),6.73(s,1H),6.00-5.92(m,1H),4.62-4.55(m,1H),4.53-4.44(m,1H),3.93-3.81(m,1H),3.38-3.30(m,2H),3.13-3.05(m,1H),3.02-2.92(m,2H),2.89-2.80(m,1H),2.79-2.70(m,2H),2.70-2.61(m,1H),2.48-2.36(m,2H),2.10-1.91(m,4H),1.70-1.52(m,2H);C23H29N6O2的HRMS(EsI)m/z(M+H)+计算值=421.2347;实测值421.2348.
[实施例23]1-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-2-((5-((2,3-二氢-1H-茚-2-基)氨基)-1,3,4-噻二唑-2-基)甲氧基)乙酮(23)的合成
步骤1:2-(氰基甲氧基)乙酸甲酯(imL18-1)的合成
在室温下向乙醇酸甲酯(0.45g,5.00mmol)在无水四氢呋喃(10mL)中的溶液缓慢添加氢化钠60%(0.24g,6.00mmol)。将反应混合物在室温下持续搅拌1小时直到停止产生气泡。将溴乙腈(0.72g,6.00mmol)添加至混合物并将反应混合物在室温下继续搅拌过夜。将混合物用乙醚萃取并用水洗涤。将有机层用无水硫酸钠干燥并浓缩。将产物通过柱色谱(乙酸乙酯/己烷)进行纯化以得到作为无色油状物的主题化合物(0.395g,61.2%)。
1H NMR(400MHz,CDCl3)δ4.46(s,2H),4.25(s,2H),3.80(s,3H).
步骤2:2-((5-((2,3-二氢-1H-茚-2-基)氨基)-1,3,4-噻二唑-2-基)甲氧基)乙酸甲酯(imL18-2)的合成
将imL15-2(0.41g,2.00mmol)和imL18-1(0.26g,2.00mmol)的混合物在三氟乙酸(3mL)中在80℃下加热过夜。将混合物冷却至0℃并用饱和碳酸氢钠溶液猝灭,并随后用乙酸乙酯萃取。将有机层用无水硫酸钠干燥并浓缩。将产物通过柱色谱(二氯甲烷/甲醇)进行纯化以得到作为白色固体的主题化合物(0.29g,62.5%)。
1H NMR(400MHz,CDCl3)δ7.26-7.16(m,4H),6.04(s,1H),4.84(s,2H),4.52-4.38(m,1H),4.17(s,2H),3.77(s,3H),3.40(dd,J=16.1,6.8Hz,2H),2.99(dd,J=16.1,4.7Hz,2H).
步骤3:2-((5-((2,3-二氢-1H-茚-2-基)氨基)-1,3,4-噻二唑-2-基)甲氧基)乙酸(L18)的合成
使用imL18-2(0.32g,1.00mmol)根据与实施例17的步骤4中相同的步骤合成主题化合物(产率:91.3%)。
1H NMR(400MHz,DMSO-d6)δ8.09(d,J=6.2Hz,1H),7.30-7.11(m,4H),4.70(s,2H),4.52-4.39(m,1H),3.91(s,2H),3.29(dd,J=16.1,7.1Hz,2H),2.89(dd,J=16.1,5.1Hz,2H).
步骤4:1-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-2-((5-((2,3-二氢-1H-茚-2-基)氨基)-1,3,4-噻二唑-2-基)甲氧基)乙酮(23)的合成
使用L18(30.53mg,0.10mmol)和4-(1H-1,2,3-三唑-5-基)哌啶·HCl(22.64mg,0.12mmol)根据与实施例17的步骤5中相同的步骤合成作为白色固体的主题化合物(产率:60.2%)。
1H NMR(400MHz,CDCl3)δ7.46(s,1H),7.24-7.12(m,4H),6.49(br s,1H),4.86-4.73(m,2H),4.60-4.49(m,1H),4.48-4.41(m,1H),4.33-4.18(m,2H),3.80-3.70(m,1H),3.42-3.33(m,2H),3.17-3.07(m,1H),3.06-2.93(m,3H),2.83-2.73(m,1H),2.06-1.95(m,2H),1.79-1.58(m,2H);C21H25N7O2S的HRMS(ESI)m/z(M+H)+计算值=462.1863;实测值462.1686.
[实施例24]N-(5,6-二氟-2,3-二氢-1H-茚-2-基)-5-(5-(4-(5-(三氟甲基)-1,3,4-二唑-2-基)哌啶-1-基)-1,3,4-二唑-2-基)嘧啶-2-胺的合成
根据与实施例1中相同的步骤合成主题化合物(14.7mg产率:30%),不同之处在于使用5,6-二氟-2,3-二氢-1H-茚-2-胺(4e)代替2,3-二氢-1H-茚-2-胺(4a),并且使用2-(哌啶-4-基)-5-(三氟甲基)-1,3,4-二唑三氟乙酸盐(im19)代替4-(1H-1,2,3-三唑-5-基)哌啶·HCl(3)。
1H NMR(400MHz,CDCl3):δ8.79(s,2H),7.03(t,J=8.7Hz,2H),5.71(d,J=7.6Hz,1H),4.94-4.84(m,1H),4.14(d,J=13.6Hz,2H),3.49(d,J=4.7Hz,1H),3.43-3.25(m,5H),2.86(dd,J=16.0,5.2Hz,2H),2.30(dd,J=13.7,3.0Hz,2H),2.17-2.02(m,2H);LCMSm/z535[M+H]+。
[实施例25]N-(5,6-二氟-2,3-二氢-1H-茚-2-基)-5-(5-(4-(5-(二氟甲基)-1,3,4-二唑-2-基)哌啶-1-基)-1,3,4-二唑-2-基)嘧啶-2-胺的合成
根据与实施例1中相同的步骤合成主题化合物(32.5mg,产率:62.4%),不同之处在于使用5,6-二氟-2,3-二氢-1H-茚-2-胺(4e)代替2,3-二氢-1H-茚-2-胺(4a),并且使用2-(二氟甲基)-5-(哌啶-4-基)-1,3,4-二唑(im20)代替4-(1H-1,2,3-三唑-5-基)哌啶·HCl(3)。
1H NMR(400MHz,CDCl3):δ8.78(s,2H),7.03(t,J=8.8Hz,2H),6.72-6.98(t,J=52Hz,1H),5.77(d,J=7.4Hz,7H),4.89(m,1H),4.13(d,J=13.5Hz,2H),3.43-3.23(m,4H),2.86(dd,J=16.0,5.2Hz,2H),2.29(dd,J=10.6,3.2Hz,2H),2.18-2.01(m,2H),1.51(dd,J=12.0,6.8Hz,1H);LCMS m/z 517[M+H]+。
[实施例26]5-(5-(4-(1,2,4-二唑-3-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(5,6-二氟-2,3-二氢-1H-茚-2-基)嘧啶-2-胺的合成
根据与实施例1中相同的步骤合成主题化合物(12.6mg,产率:29.8%),不同之处在于使用5,6-二氟-2,3-二氢-1H-茚-2-胺(4e)代替2,3-二氢-1H-茚-2-胺(4a),并且使用3-(哌啶-4-基)-1,2,4-二唑代替4-(1H-1,2,3-三唑-5-基)哌啶·HCl(3)。
1H NMR(400MHz,DMSO-d6):δ9.53(s,1H),8.75(s,2H),8.25(d,J=6.7Hz,1H),7.27(t,J=9.3Hz,2H),4.69(dd,J=13.8,7.2Hz,1H),3.96(d,J=13.1Hz,2H),3.24(dd,J=16.1,7.6Hz,4H),3.17(dd,J=9.0,6.4Hz,1H),2.88(dd,J=16.1,6.5Hz,2H),2.06(d,J=11.1Hz,2H),1.83-1.70(m,2H);LCMS m/z 467[M+H]+。
[实施例27]5-(5-(4-(1,3,4-二唑-2-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(5,6-二氟-2,3-二氢-1H-茚-2-基)嘧啶-2-胺的合成
根据与实施例1中相同的步骤合成主题化合物(7.6mg,产率:6.7%),不同之处在于使用5,6-二氟-2,3-二氢-1H-茚-2-胺(4e)代替2,3-二氢-1H-茚-2-胺(4a),并且使用2-(哌啶-4-基)-1,3,4-二唑代替4-(1H-1,2,3-三唑-5-基)哌啶·HCl(3)。
1H NMR(400MHz,DMSO-d6):δ9.17(s,1H),8.76(d,J=11.8Hz,2H),8.26(d,J=8.0Hz,1H),7.28(t,J=9.1Hz,2H),4.69(dd,J=15.0,7.9Hz,1H),3.95(d,J=12.5Hz,2H),3.24(dd,J=18.0,9.2Hz,5H),2.88(dd,J=16.3,6.2Hz,2H),2.12(d,J=13.3Hz,2H),1.81(dd,J=22.6,9.9Hz,2H);LCMS m/z 467[M+H]+。
[实施例28]5-(5-(4-(1H-四唑-1-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(5,6-二氟-2,3-二氢-1H-茚-2-基)嘧啶-2-胺的合成
根据与实施例1中相同的步骤合成主题化合物(20.9mg,产率:54.4%),不同之处在于使用5,6-二氟-2,3-二氢-1H-茚-2-胺(4e)代替2,3-二氢-1H-茚-2-胺(4a),并且使用4-(1H-四唑-1-基)哌啶代替4-(1H-1,2,3-三唑-5-基)哌啶·HCl(3)。
1H NMR(400MHz,DMSO-d6):(DMSO-d6)δ9.00(s,1H),8.77(d,J=10.6Hz,2H),8.27(d,J=6.7Hz,1H),7.28(t,J=9.4Hz,2H),5.21(dd,J=14.3,8.5Hz,1H),4.68(dd,J=14.1,6.9Hz,1H),4.02(d,J=13.5Hz,2H),3.39(t,J=11.3Hz,2H),3.24(dd,J=16.2,7.6Hz,2H),2.88(dd,J=16.0,6.3Hz,2H),2.31(d,J=9.8Hz,2H),2.20-2.06(m,2H);LCMSm/z 467[M+H]+。
[实施例29]N-(5,6-二氟-2,3-二氢-1H-茚-2-基)-5-(5-(4-(4-甲基-1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)嘧啶-2-胺的合成
根据与实施例1中相同的步骤合成主题化合物(3.7mg,产率:20%),不同之处在于使用5,6-二氟-2,3-二氢-1H-茚-2-胺(4e)代替2,3-二氢-1H-茚-2-胺(4a),并且使用4-(4-甲基-1H-1,2,3-三唑-5-基)哌啶(im21)代替4-(1H-1,2,3-三唑-5-基)哌啶·HCl(3)。
1H NMR(400MHz,CDCl3):δ8.79(s,2H),7.02(t,J=8.8Hz,2H),5.90(d,J=7.7Hz,1H),4.88(dd,J=12.6,5.4Hz,1H),4.16(d,J=12.9Hz,2H),3.36(dd,J=16.0,7.0Hz,2H),3.30-3.20(m,2H),2.88(d,J=5.1Hz,1H),2.84(d,J=5.0Hz,1H),2.33(s,3H),2.06-1.90(m,2H),1.52-1.39(m,2H);LCMS m/z 480[M+H]+。
[实施例30](E)-1-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-3-(2-((5,6-二氟-2,3-二氢-1H-茚-2-基)氨基)嘧啶-5-基)丙-2-烯-1-酮的合成
步骤1:(E)-3-(2-((5,6-二氟-2,3-二氢-1H-茚-2-基)氨基)嘧啶-5-基)丙烯酸乙酯(imL22-1)的合成
将imL14-1(0.249g,1.17mmol)、5,6-二氟-2,3-二氢-1H-茚-2-胺(0.160g,0.585mmol)、二异丙基乙胺(1.5g,11.7mmol)和n-BuOH(1.2mL)的混合物在微波反应器中在150℃下搅拌2小时。将反应混合物在真空下浓缩,并随后通过柱色谱(己烷/乙酸乙酯)进行纯化以得到作为褐色固体的主题化合物(0.132g,65.3%)。
1H NMR(400MHz,DMSO-d6)δ8.67(s,2H),8.09(d,J=6.8Hz,1H),7.48(d,J=16.1Hz,1H),7.26(t,J=9.3Hz,2H),6.51(d,J=16.1Hz,1H),4.66(dd,J=13.8,6.8Hz,1H),4.15(dd,J=14.1,7.0Hz,2H),3.22(dd,J=16.1,7.7Hz,2H),2.86(dd,J=15.8,6.3Hz,2H),1.22(t,J=7.1Hz,3H);LCMSm/z 346[M+HJ+。
步骤2:(E)-3-(2-((5,6-二氟-2,3-二氢-1H-茚-2-基)氨基)嘧啶-5-基)丙烯酸(L22)的合成
根据与实施例17的步骤4中相同的步骤合成作为浅黄色固体的主题化合物(0.90g,97.0%),不同之处在于使用imL22-1代替imL14-3。
1H NMR(400MHz,DMSO-d6)δ12.17(bs,1H),8.64(s,2H),8.05(d,J=7.2Hz,1H),7.41(d,J=16.0Hz,1H),7.26(t,J=9.3Hz,2H),6.41(d,J=16.2Hz,1H),4.66(dd,J=14.0,6.8Hz,1H),3.26-3.19(m,2H),2.86(dd,J=16.1,6.6Hz,2H);LCMSm/z 318[M+H]+。
步骤3:(E)-1-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-3-(2-((5,6-二氟-2,3-二氢-1H-茚-2-基)氨基)嘧啶-5-基)丙-2-烯-1-酮(30)的合成
根据与实施例17的步骤5中相同的步骤合成作为黄色固体的主题化合物(0.019g,29.3%),不同之处在于使用L22代替L14。
1H NMR(400MHz,DMSO-d6):δ8.71(s,2H),8.06(s,1H),7.67(s,1H),7.35(d,J=15.3Hz,1H),7.26(t,J=9.2Hz,2H),7.21(d,J=15.5Hz,1H),4.69-4.63(m,1H),4.39(dd,J=62.1,11.5Hz,4H),3.23(dd,J=16.0,7.5Hz,2H),3.00(dd,J=18.4,7.4Hz,1H),2.86(dd,J=16.2,6.6Hz,2H),1.95(s,2H),1.51(s,2H);LCMS m/z452[M+H]+。
[实施例31]5-(5-(4-(1-苄基-1H-1,2,3-三唑-5-基)哌啶-1-基)唑-2-基)-N-(2,3-二氢-1H-茚-2-基)嘧啶-2-胺(31)的合成
步骤1-1:4-乙炔基哌啶盐酸盐(imL23-1)的合成
将4-乙炔基哌啶-1-羧酸叔丁酯(12.0g,57.4mmol)溶解在Et2O(100mL)中,并冷却至0℃。添加Et2O中的HCl(4M,100mL)并将混合物搅拌20小时。蒸发Et2O并添加PE。然后将该固体过滤并用PE和Et2O洗涤以得到作为白色固体的主题化合物(imL23-1)(8.3g,产率:99.4%)。
LCMS m/z 110[M+H]+
步骤1-2:(2-(4-乙炔基哌啶-1-基)-2-氧代乙基)氨基甲酸叔丁酯(imL23-2)的合成
在0℃下向2-((叔丁氧基羰基)氨基)乙酸(10.0g,57.1mmol)在DMF(50mL)中的溶液添加EDCI(13.1g,68.5mmol)和HOBt(9.2g,68.5mmol),然后在室温下搅拌0.5小时。添加imL23-1(8.3g,57.1mmol,HCl盐)和TEA(17.3g,171.3mmol)并在室温下搅拌过夜。将反应混合物用EA萃取,用水和NaCl洗涤,用Na2SO4干燥,过滤并浓缩。获得作为黄色油状物的主题化合物(imL23-2)(15.1g,产率:99.7%)。
LCMS m/z 267[M+H]+
步骤1-3:2-氨基-1-(4-乙炔基哌啶-1-基)乙酮盐酸盐(imL23-3)的合成
将imL23-2(15.1g,57.1mmol)溶解在Et2O(100mL)中并冷却至0℃。添加Et2O中的HCl(4M,70mL)并将混合物搅拌20小时。蒸发Et2O并添加PE。然后将该固体过滤并用PE和Et2O洗涤以得到作为白色固体的主题化合物(imL23-3)(17.7g,产率:100%)。
LCMS m/z 167[M+H]+
步骤2-1:2-氯嘧啶-5-碳酰氯(imL23-4)的合成
在0℃下向2-氯嘧啶-5-羧酸(30.0g,189mmol)在DCM(200mL)中的溶液中缓慢添加草酰二氯(48.0g,378mmol)和6滴DMF。将反应混合物在室温下搅拌20小时。将反应混合物蒸发至干以得到作为白色固体的主题化合物(imL23-4)(33g,产率:99.8%),其在没有纯化的情况下用于以下反应。
步骤2-2:2-氯-N-(2-(4-乙炔基哌啶-1-基)-2-氧代乙基)嘧啶-5-甲酰胺(imL23-5)的合成
向imL23-3(17.7g,87.0mmol)在DCM(400mL)中的溶液添加TEA(52.7g,522mmol)和DMAP(600mg)。将反应混合物在室温下搅拌1小时,并冷却至0℃。添加imL23-4(16.9g,95.7mmol)并在室温下搅拌过夜。将反应混合物用DCM萃取,用水和NaCl洗涤,用Na2SO4干燥,过滤并浓缩。将产物通过柱色谱(DCM∶MeOH=100∶1至20∶1)进行纯化以得到作为黄色固体的主题化合物(imL23-5)(15.8g,产率:59.4%)。
LCMS m/z 307[M+H]+
步骤2-3:2-(2-氯嘧啶-5-基)-5-(4-乙炔基哌啶-1-基)唑(imL23-6)的合成
在Ar气下冷却至0℃之后,向PPh3(51.0g,193.9mmol)在DCM(400mL)中的溶液添加全氯乙烷(46.5g,193.9mmol)。将混合物在0至20℃下搅拌0.5小时。在再次冷却至0℃之后,添加imL23-5(15.0g,48.9mmol)并将反应混合物在室温下搅拌1小时。将Na2CO3(aq)添加至混合物至pH 9至10并在室温下搅拌过夜。将反应混合物用DCM萃取,用水和NaCl、随后是饱和Na2CO3洗涤,并随后用Na2SO4干燥,过滤并浓缩。用Et2O稀释以除去P(O)Ph3固体,浓缩滤液并用Al2O3柱(PE∶EA=20∶1至10∶1至DCM∶EA=100∶0至20∶1)进行纯化以得到7.3g的黄色固体(粗制物,88%纯度)。将其用Al2O3柱(0.1%TEA)(PE∶EA=50∶1至1∶1)再次进行纯化以得到5.3g的黄色固体,将所述黄色固体用PE纯化以得到作为黄色固体的主题化合物(imL23-6)(5.2g,产率:36.9%)。
1H NMR(400MHz,CDCl3):δ9.04(s,2H),6.21(s,1H),3.44-3.50(m,2H),3.10-3.16(m,2H),2.68-2.70(m,1H),2.15(brs,1H),1.95-2.01(m,2H),2.12-2.06(m,2H),1.80-1.87(m,2H);LCMS m/z 289[M+H]+。
步骤2-4:N-(2,3-二氢-1H-茚-2-基)-5-(5-(4-乙炔基哌啶-1-基)唑-2-基)嘧啶-2-胺(L23)的合成
将2-氨基茚满(0.703g,4.16mmol)、imL23-6(1g,3.46mmol)、三乙胺(1.2mL,8.30mmol)和二氧六环(35mL)的混合物在100℃下搅拌1小时。在冷却之后,蒸发溶剂并将产物通过柱色谱(己烷/乙酸乙酯)进行纯化以得到作为褐色固体的主题化合物(0.190g,14.2%)。
步骤2-5:5-(5-(4-(1-苄基-1H-1,2,3-三唑-5-基)哌啶-1-基)唑-2-基)-N-(2,3-二氢-1H-茚-2-基)嘧啶-2-胺(31)的合成
向L23(0.145g,0.376mmol)在DMF/MeOH(3.4mL/0.38mL)中的溶液添加(在DCM中的)0.5M苄基叠氮溶液(502μL,0.564mmol)、CuI(0.115g,0.602mmol)和DIPEA(128μL,0.564mmol),在40℃下搅拌1小时。将反应混合物用EA萃取,将有机层用盐水洗涤,用MgSO4干燥,过滤并浓缩。将获得的剩余物通过柱色谱(DCM/MeOH)进行纯化以得到作为褐色固体的主题化合物(1.3mg,6.7%)。
1H NMR(400MHz,DMSO-d6):δ8.71(s,2H),8.01(d,J=6.8Hz,1H),7.99(s,1H),7.37-7.26(m,5H),7.16(d,J=21.5Hz,4H),6.23(s,1H),5.53(s,2H),3.57(d,J=12.6Hz,1H),3.24(dd,J=15.1,7.8Hz,4H),2.91(d,J=7.8Hz,2H),2.87(t,J=7.0Hz,3H),2.00(d,J=12.8Hz,2H),1.69(dd,J=13.4,4.6Hz,2H);LCMS m/z519[M+H]+。
[实施例32]5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(5,6-二氟-2,3-二氢-1H-茚-2-基)-N-甲基嘧啶-2-胺的合成
步骤1:5-(2-((5,6-二氟-2,3-二氢-1H-茚-2-基)(甲基)氨基)嘧啶-5-基)-1,3,4-二唑-2(3H)-酮(L26)的合成
在0℃下向7e(20mg,0.060mmol)在DMF(0.6mL)中的溶液添加NaH(60%)(7.2mg,0.181mmol)并在0℃下搅拌30分钟。添加CH3I(11μL,0.181mmol)并在室温下搅拌过夜。将反应混合物用EA萃取,将有机层用盐水洗涤,用Na2SO4干燥,过滤并浓缩。将获得的剩余物通过柱色谱(DCM/MeOH)进行纯化以得到作为白色固体的主题化合物(L26)(9.9mg,产率:47.5%)。
LCMS m/z 346[M+H]+
步骤2:5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(5,6-二氟-2,3-二氢-1H-茚-2-基)-N-甲基嘧啶-2-胺(32)的合成
将L26(8.1mg,0.024mmol)、4-(1H-1,2,3-三唑-5-基)哌啶三氟乙酸盐(3-1)(7.0mg,0.028mmo1)、BOP试剂(12.4mg,0.028mmol)和DIPEA(12μL,0.070mmol)溶解在DMF(0.1mL)中并在室温下搅拌6小时。将反应混合物用EA萃取,将有机层用盐水洗涤,用Na2SO4干燥,过滤并浓缩。将获得的剩余物通过柱色谱(DCM/MeOH)进行纯化以得到作为白色固体的主题化合物(32)(1.5mg,产率:13.3%)。
1H NMR(400MHz,DMSO-d6):δ8.81(s,2H),7.69(s,1H),7.31(t,J=9.2Hz,2H),5.75(dt,J=15.4,7.9Hz,1H),3.97(d,J=13.2Hz,2H),3.27-3.10(m,5H),3.05(d,J=6.9Hz,2H),3.01(s,3H),2.02(d,J=11.9Hz,2H),1.69(dd,J=22.4,11.0Hz,2H);LCMS m/z480[M+H]+。
[实施例33]N-(5,6-二氟-2,3-二氢-1H-茚-2-基)-5-(5-(4-(1-甲基-1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)嘧啶-2-胺的合成
步骤1-1:新戊酸叠氮基甲酯(im27-1)的合成
向新戊酸氯甲酯(1g,6.64mmol)在H2O(1.7mL)中的溶液添加NaN3(0.648g,9.96mmol)并在90℃下搅拌过夜。将反应混合物用水稀释,用EA萃取,用Na2SO4干燥,过滤并浓缩。获得作为无色液体的主题化合物(im27-1)(1g,产率:96%)并在没有纯化的情况下用于以下反应。
步骤1-2:4-(1-((新戊酰氧基)甲基)-1H-1,2,3-三唑-4-基)哌啶-1-羧酸叔丁酯(im27-2)的合成
向im27-1(1g,6.36mmol)和4-乙炔基-1-哌啶羧酸叔丁酯(1.3g,6.36mmol)在THF/H2O(12.7mL)中的溶液添加CuOAc(78.0mg,0.636mmol)和NaOAc(1.7g,19.1mmol)并在室温下搅拌4小时。将反应混合物用EA萃取,并将有机层用Na2SO4干燥,过滤并浓缩。将获得的剩余物通过柱色谱(DCM/MeOH)进行纯化以得到作为浅绿色油状物的主题化合物(im27-2)(1.18g,产率:51%)。
1H NMR(400MHz,CDCl3):δ7.53(s,1H),6.20(s,2H),4.15(s,2H),2.88(dd,J=26.4,13.4Hz,2H),2.02(d,J=13.1Hz,2H),1.65-1.56(m,3H),1.46(s,9H),1.18(s,9H).
步骤1-3:(4-(哌啶-4-基)-1H-1,2,3-三唑-1-基)新戊酸甲酯三氟乙酸盐(im27)的合成
在0℃下向im27-2(0.658g,1.80mmol)在DCM(17.9mL)中的溶液添加TFA(6.0mL)并在室温下搅拌过夜。将反应混合物在减压下浓缩以得到作为白色固体的主题化合物(im27)(0.493g,产率:74.9%),其在没有纯化的情况下用于以下反应。
步骤2-1:(4-(1-(5-(2-((5,6-二氟-2,3-二氢-1H-茚-2-基)氨基)嘧啶-5-基)-1,3,4-二唑-2-基)哌啶-4-基)-1H-1,2,3-三唑-1-基)新戊酸甲酯(L27)的合成
向7e(0.374mg,1.13mmol)在DMF(5.6mL)中的溶液添加im27(0.494g,1.35mmol),然后冷却至0℃并添加DIPEA(576μL,3.39mmol)。将混合物在0℃下搅拌30分钟,然后添加BOP试剂(0.599g,1.35mmol)并在室温下搅拌过夜。将反应混合物用EA萃取,将有机层用盐水洗涤,用Na2SO4干燥,过滤并浓缩。将获得的剩余物通过柱色谱(DCM/MeOH)进行纯化以得到作为黄色固体的主题化合物(L27)(0.344g,产率:52.61%)。
LC/MS m/z 580[M+H]+
步骤2-2:N-(5,6-二氟-2,3-二氢-1H-茚-2-基)-5-(5-(4-(1-甲基-1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)嘧啶-2-胺(33)的合成
将L27(0.25g,0.431mmol)和MeOTf(57μL,0.518mmol)溶解在DCM(500μL)中并在室温下搅拌过夜。将反应混合物溶解在MeOH(2.2mL)中,添加K2CO3(0.119g,1.24mmol),并将混合物在室温下搅拌4小时。将反应混合物过滤,用DCM洗涤,并将滤液浓缩。将获得的剩余物通过柱色谱(DCM/MeOH)进行纯化以得到作为黄色固体的主题化合物(33)(17.7mg,产率:6.9%)。
1H NMR(400MHz,DMSO-d6):δ8.76(s,2H),8.25(d,J=6.8Hz,1H),7.57(s,1H),7.27(t,J=9.4Hz,2H),4.69(dd,J=12.8,5.5Hz,1H),4.03(d,J=12.5Hz,1H),3.99(s,3H),3.24(dd,J=16.1,8.0Hz,4H),3.06(t,J=11.8Hz,2H),2.91-2.85(m,2H),1.95(d,J=13.7Hz,2H),1.64(dd,J=23.9,11.1Hz,2H);LCMS m/z 480[M+H]+。
[实施例34]N-(5,6-二氟-2,3-二氢-1H-茚-2-基)-5-(5-(4-(1-甲基-1H-1,2,3-三唑-4-基)哌啶-1-基)-1,3,4-二唑-2-基)嘧啶-2-胺的合成
步骤1:N-(5,6-二氟-2,3-二氢-1H-茚-2-基)-5-(5-(4-乙炔基哌啶-1-基)-1,3,4-二唑-2-基)嘧啶-2-胺(L28)的合成
向7e(0.2g,0.603mmol)在DMF(3.1mL)中的溶液添加4-乙炔基哌啶三氟乙酸盐(0.150g,0.724mmol),冷却至0℃并添加DIPEA(308μL,1.81mmol)。将混合物在0℃下搅拌30分钟,然后添加BOP试剂(0.320g,0.724mmol)并在室温下搅拌3小时。将反应混合物用EA萃取,并将有机层用盐水洗涤,用Na2SO4干燥,过滤并浓缩。将获得的剩余物通过柱色谱(DCM/MeOH)进行纯化以得到作为白色固体的主题化合物(L28)(0.101g,产率:39.6%)。
LCMS m/z 423[M+H]+
步骤2:N-(5,6-二氟-2,3-二氢-1H-茚-2-基)-5-(5-(4-(1-甲基-1H-1,2,3-三唑-4-基)哌啶-1-基)-1,3,4-二唑-2-基)嘧啶-2-胺(34)的合成
将MeI(33mg,0.232mmo|)和NaN3(15.1mg,0.697mmo|)溶解在THF/H2O(v/v=1∶1,2.3mL)中并在室温下搅拌过夜。将L28(98mg,0.232mmol)、CuOAc(2.9mg,0.023mmol)和NaOAc(57.2mg,0.697mmol)添加至反应混合物并在室温下搅拌过夜。将反应混合物用EA萃取,并将有机层用Na2SO4干燥,过滤并浓缩。将获得的剩余物通过柱色谱(DCM/MeOH)进行纯化以得到作为黄色固体的主题化合物(34)(1.6mg,产率:1.4%)。
1H NMR(400MHz,DMSO-d6):δ8.75(s,2H),8.24(d,J=6.8Hz,1H),7.87(s,1H),7.27(t,J=9.4Hz,2H),4.68(dd,J=13.8,6.9Hz,1H),3.97(s,5H),3.24(dd,J=15.9,7.3Hz,4H),2.96(d,J=11.0Hz,1H),2.88(dd,J=16.2,6.5Hz,2H),2.00(d,J=11.5Hz,2H),1.66(dd,J=20.0,11.1Hz,2H);LCMSm/z 480[M+H]+。
[实施例35]N-茚满-2-基-5-[3-[4-(1H-三唑-5-基)-1-哌啶基]+4,5-二氢异唑-5-基]嘧啶-2-胺(35)的合成
步骤1:N-(2,3-二氢-1H-茚-2-基)-5-乙烯基嘧啶-2-胺(imL24-1)的合成
将2-氨基茚满(1g,7.508mmol)、2-氯-5-乙烯基嘧啶(0.704g,5.005mmol)和DIPEA(17mL,100.1mmol)溶解在10mL n-BuOH中,然后在微波反应器中反应2小时。在通过TLC确认反应完成之后,浓缩反应混合物。然后将获得的剩余物吸附到硅胶上并通过硅胶柱色谱(己烷中的15%EA)进行纯化以得到作为白色固体的主题化合物(imL24-1)(0.837g,产率:47%)。
LCMS m/z 238[M+H]+
步骤2:5-(3-溴-4,5-二氢异唑-5-基)-N-(2,3-二氢-1H-茚-2-基)嘧啶-2-胺(L24)的合成
在将1,1-二溴甲醛肟(0.960g,6.742mmol)溶解在DMF(7mL)中并冷却至-10℃之后,将imL24-1(0.8g,3.371mmo|)和KHCO3(0.843g,8.428mmol)在H2O(7mL)中的溶液缓慢逐滴添加至反应混合物并在室温下搅拌1小时。在通过TLC确认反应完成之后,将反应混合物用EtOAc萃取(3次),并且将有机层用盐水洗涤并用MgSO4干燥。在过滤并浓缩之后,将获得的剩余物吸附到硅胶上并通过硅胶柱色谱(己烷中的25%EA)进行纯化以得到作为黄色固体的主题化合物(L24)(0.905g,产率:74.8%)。
1H NMR(400MHz,CDCl3):δ8.28(s,2H),7.25-7.16(m,4H),5.56-5.51(m,1H),4.84-4.77(m,1H),3.60-3.52(m,1H),3.44-3.34(m,2H),3.21(dd,J=17.3,9.4Hz,1H),2.92-2.83(m,2H);LCMS m/z 360[M+H]+。
步骤3:N-茚满-2-基-5-[3-[4-(1H-三唑-5-基)-1-哌啶基]-4,5-二氢异唑-5-基]嘧啶-2-胺(35)的合成
将5-(3-溴-4,5-二氢异唑-5-基)-N-(2,3-二氢-1H-茚-2-基)嘧啶-2-胺(L24)(20mg,0.0557mmol)、4-(1H-1,2,3-三唑-5-基)哌啶·HCl(3)(12.6mg,0.0668mmol)和Na2CO3(14.8mg,0.139mmol)溶解在1mL t-BuOH中,然后在微波反应器中反应1小时。在通过TLC确认反应完成之后,将其过滤并用10%MeOH在DCM中的溶液洗涤。将通过浓缩滤液获得的剩余物吸附到硅胶上并通过硅胶柱色谱(DCM中的5%MeOH)进行纯化以得到作为黄色固体的主题化合物(35)(10.8mg,产率:45.1%)。
1H NMR(400MHz,CDCl3):δ8.31(s,2H),7.65(s,1H),7.58(d,J=7.0Hz,1H),7.15(td,J=8.3,3.2Hz,4H),5.25(t,J=9.4Hz,1H),4.62-4.55(m,1H),3.59(d,J=14.2Hz,2H),3.25-3.10(m,4H),2.99-2.81(m,5H),1.91(d,J=14.6Hz,2H),1.62(d,J=9.0Hz,2H);LCMSm/z 431[M+H]+。
[实施例36]5-(3-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)异唑-5-基)-N-(2,3-二氢-1H-茚-2-基)嘧啶-2-胺的合成
将N-茚满-2-基-5-[3-[4-(1H-三唑-5-基)-1-哌啶基]-4,5-二氢异唑-5-基]嘧啶-2-胺(35)(29.8mg,0.0692mmol)、I2(26.3mg,0.104mmol)和咪唑(14.1mg,0.208mmol)溶解在甲苯(3mL)中并在110℃下搅拌2小时。在冷却至室温之后,将其用EA稀释,添加10%Na2S2O4,并搅拌10分钟。将1N NaOH添加至反应混合物以调节pH至8至10,并将反应混合物用EA萃取。将有机层用盐水洗涤,用MgSO4干燥,过滤并浓缩。将获得的剩余物吸附到硅胶上并通过硅胶柱色谱(DCM中的2%MeOH)进行纯化以得到作为白色固体的主题化合物(36)(12.8mg,产率:44.3%)。
1H NMR(400MHz,DMSO-d6):δ8.68(s,2H),8.12(d,J=6.3Hz,1H),7.22-7.10(m,4H),6.73(s,1H),4.66(d,J=6.8Hz,1H),3.71(d,J=13.0Hz,2H),3.25(dd,J=15.9,7.6Hz,3H),3.00(d,J=12.1Hz,2H),2.90(dd,J=15.8,7.0Hz,2H),1.95(s,2H),1.67(d,J=9.8Hz,2H);LCMS m/z 429[M+H]+。
[实施例37]N-(5,6-二氟茚满-2-基)-5-[3-[4-(1H-三唑-5-基)-1-哌啶基]+4,5-二氢异唑-5-基]嘧啶-2-胺的合成
根据与实施例35中相同的操作合成主题化合物(7.3mg,产率:30.9%),不同之处在于使用5,6-二氟-2,3-二氢-1H-茚-2-胺(4e)代替2-氨基茚满。
1H NMR(400MHz,DMSO-d6):δ8.31(s,1H),7.66-7.60(m,2H),7.25(t,J=9.2Hz,2H),5.26(t,J=9.2Hz,1H),4.61(dd,J=14.0,7.3Hz,1H),3.59(d,J=13.2Hz,2H),3.20(dd,J=15.9,7.3Hz,2H),3.17-3.09(m,2H),2.98-2.88(m,3H),2.83(dd,J=15.9,6.8Hz,2H),1.91(d,J=11.7Hz,2H),1.62(d,J=13.4Hz,2H);LCMS m/z467[M+H]+。
[实施例38]5-(3-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)异唑-5-基)-N-(5,6-二氟-2,3-二氢-1H-茚-2-基)嘧啶-2-胺的合成
根据与实施例36中相同的步骤合成主题化合物(9.2mg,产率71.6%),不同之处在于使用N-(5,6-二氟茚满-2-基)-5-[3-[4-(1H-三唑-5-基)-1-哌啶基]-4,5-二氢异唑-5-基]嘧啶-2-胺(实施例37)代替N-茚满-2-基-5-[3-[4-(1H-三唑-5-基)-1-哌啶基]-4,5-二氢异唑-5-基]嘧啶-2-胺(35)。
1H NMR(400MHz,DMSO-d6):δ8.67(s,1H),8.13(d,J=6.7Hz,1H),7.64(d,J=23.5Hz,1H),7.27(t,J=9.2Hz,2H),6.73(s,1H),4.68(dd,J=13.8,6.9Hz,1H),3.71(d,J=12.9Hz,2H),3.24(dd,J=16.2,7.5Hz,2H),3.02-2.94(m,2H),2.87(dd,J=16.2,6.5Hz,2H),1.97(d,J=12.5Hz,3H),1.72-1.60(m,2H);LCMS m/z465[M+H]+。
[实施例39]5-(3-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-4,5-二氢异唑-5-基)-N-(5-氟-2,3-二氢-1H-茚-2-基)嘧啶-2-胺的合成
根据与实施例35中相同的步骤合成主题化合物(3.1mg,产率:17.5%),不同之处在于使用5-氟-2,3-二氢-1H-茚-2-胺(4b)代替2-氨基茚满。
1H NMR(400MHz,CDCl3):δ8.35(s,2H),7.53(s,1H),7.11-7.19(m,1H),6.82-6.97(m,2H),5.49(d,J=6.8Hz,1H),5.40(t,J=8.9Hz,1H),4.87-4.77(m,1H),3.73(dd,J=13.2,3.1Hz,2H),3.36(m,3H),3.11-2.93(m,4H),2.84(td,J=15.6,5.1Hz,2H),2.02-2.08(m,2H),1.75-1.85(m,2H);LCMS m/z 449[M+H]+。
[实施例40]5-(3-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)异唑-5-基)-N-(5-氟-2,3-二氢-1H-茚-2-基)嘧啶-2-胺的合成
根据与实施例36中相同的步骤合成主题化合物(20.3mg,产率:58%),不同之处在于使用5-(3-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-4,5-二氢异唑-5-基)-N-(5-氟-2,3-二氢-1H-茚-2-基)嘧啶-2-胺(实施例39)代替N-茚满-2-基-5-[3-[4-(1H-三唑-5-基)-1-哌啶基]-4,5-二氢异唑-5-基]嘧啶-2-胺(35)。
1H NMR(400MHz,DMSO-d6):δ8.65(s,2H),8.02(d,J=6.7Hz,1H),7.57(s,1H),7.16-7.23(m,1H),6.97(d,J=8.3Hz,1H),6.89(t,J=8.7Hz,1H),6.60(s,1H),4.81-4.66(m,1H),3.78(d,J=12.8Hz,2H),3.42-3.21(m,3H),2.96(m,2H),2.02(d,J=10.9Hz,2H),1.75(m,2H);LCMS m/z 447[M+H]+。
[实施例41]N-[(3,5-二氟苯基)甲基]-5-[3-[4-(1H-三唑-5-基)-1-哌啶基]-4,5-二氢异唑-5-基]嘧啶-2-胺的合成
根据与实施例35中相同的步骤合成主题化合物(8.3mg,产率:18.2%),不同之处在于使用(3,5-二氟苯基)甲胺代替2-氨基茚满。
1H NMR(400MHz,DMSO-d6):δ8.30(s,2H),7.89(t,J=6.5Hz,1H),7.65(bs,1H),7.04(t,J=9.6Hz,1H),6.97(d,J=6.7Hz,2H),5.24(t,J=9.1Hz,1H),4.49(d,J=6.2Hz,2H),3.57(d,J=12.8Hz,2H),3.13(dd,J=15.9,9.3Hz,2H),2.96-2.87(m,3H),1.90(d,J=12.6Hz,2H),1.61(dd,J=23.3,14.4Hz,2H);LCMS m/z 441[M+H]+。
[实施例42]N-苄基-5-[3-[4-(1H-三唑-5-基)-1-哌啶基]-4,5-二氢异唑-5-基]嘧啶-2-胺的合成
根据与实施例35中相同的步骤合成主题化合物(6.2mg,产率:12.8%),不同之处在于使用苯基甲胺代替2-氨基茚满。
1H NMR(400MHz,DMSO-d6):δ8.28(s,2H),7.82(t,J=6.4Hz,1H),7.64(bs,1H),7.27(d,J=4.3Hz,4H),7.19(dd,J=8.5,4.2Hz,1H),5.23(t,J=9.4Hz,1H),4.48(d,J=6.4Hz,2H),3.57(d,J=12.9Hz,2H),3.12(dd,J=15.9,9.2Hz,2H),2.97-2.86(m,3H),1.90(d,J=11.6Hz,2H),1.61(dd,J=21.2,11.8Hz,2H);LCMS m/z 405[M+H]+。
[实施例43]N-[(3,4-二氟苯基)甲基]-5-[3-[4-(1H-三唑-5-基)-1-哌啶基]-4,5-二氢异唑-5-基]嘧啶-2-胺的合成
根据与实施例35中相同的步骤合成主题化合物(9.7mg,产率:20.3%),不同之处在于使用(3,4-二氟苯基)甲胺代替2-氨基茚满。
1H NMR(400MHz,DMSO-d6):δ8.29(s,2H),7.85(t,J=6.3Hz,1H),7.64(s,1H),7.32(dt,J=17.3,7.3Hz,2H),7.12(s,1H),5.24(t,J=9.2Hz,1H),4.45(d,J=6.1Hz,2H),3.57(d,J=12.7Hz,2H),3.12(dd,J=15.6,9.4Hz,2H),2.91(dd,J=24.4,11.8Hz,3H),1.90(d,J=12.0Hz,2H),1.61(dd,J=20.6,10.6Hz,2H);LCMSm/z 441[M+H]+。
[实施例44]5-(3-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-4,5-二氢异唑-5-基)-N-(3,5-二氯苄基)嘧啶-2-胺的合成
根据与实施例35中相同的步骤合成主题化合物(4.8mg,产率:10.2%),不同之处在于使用(3,5-二氯苯基)甲胺代替2-氨基茚满。
1H NMR(400MHz,DMSO-d6):δ8.30(s,2H),7.90(t,J=6.4Hz,1H),7.62(bs,1H),7.43(s,1H),7.32(s,2H),5.24(t,J=9.2Hz,1H),4.48(d,J=6.4Hz,2H),4.09(dd,J=10.5,5.2Hz,1H),3.57(d,J=12.8Hz,2H),3.15(d,J=5.3Hz,2H),2.96-2.88(m,2H),1.90(d,J=10.3Hz,2H),1.66-1.56(m,2H);LCMS m/z 474[M+H]+。
[实施例45]5-(3-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-4,5-二氢异唑-5-基)-N-(苯并[d][1,3]间二氧杂环戊烯-5-基甲基)嘧啶-2-胺的合成
根据与实施例35中相同的操作合成主题化合物(5.1mg,产率:10.7%),不同之处在于使用苯并[d][1,3]间二氧杂环戊烯-5-基甲胺代替2-氨基茚满。
1H NMR(400MHz,DMSO-d6):δ8.28(s,2H),7.76(t,J=6.2Hz,1H),7.62(bs,1H),6.85-6.78(m,2H),6.75(d,J=7.7Hz,1H),5.94(s,2H),5.23(t,J=9.0Hz,1H),4.37(d,J=6.1Hz,2H),3.57(d,J=12.8Hz,2H),3.12(dd,J=15.9,9.3Hz,2H),2.96-2.88(m,3H),1.90(d,J=12.8Hz,2H),1.61(dd,J=19.9,10.1Hz,2H);LCMS m/z 449[M+H]+。
[实施例46]N-(1,3-苯并间二氧杂环戊烯-5-基甲基)-5-[3-[4-(1H-三唑-5-基)-1-哌啶基]异唑-5-基]嘧啶-2-胺的合成
根据与实施例36中相同的步骤合成主题化合物(3.4mg,产率:21%),不同之处在于使用5-(3-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-4,5-二氢异唑-5-基)-N-(苯并[d][1,3]间二氧杂环戊烯-5-基甲基)嘧啶-2-胺(实施例45)代替N-茚满-2-基-5-[3-[4-(1H-三唑-5-基)-1-哌啶基]-4,5-二氢异唑-5-基]嘧啶-2-胺(35)。
1H NMR(400MHz,DMSO-d6):δ8.64(s,2H),8.25(t,J=5.9Hz,1H),6.87-6.80(m,2H),6.77(d,J=8.3Hz,1H),6.71(s,1H),5.95(s,2H),4.43(d,J=6.5Hz,2H),3.70(d,J=12.5Hz,2H),3.48(s,1H),3.02-2.93(m,3H),1.96(d,J=9.8Hz,2H),1.66(dd,J=20.8,12.7Hz,2H);LCMS m/z 447[M+H]+。
[实施例47]5-(3-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-4,5-二氢异唑-5-基)-N-(3,5-二氯苯乙基)嘧啶-2-胺的合成
根据与实施例35中相同的步骤合成主题化合物(5.8mg,产率:12.4%),不同之处在于使用2-(3,5-二氯苯基)乙-1-胺代替2-氨基茚满。
1H NMR(400MHz,DMSO-d6):δ8.28(s,2H),7.99(s,1H),7.40(s,1H),7.35(s,1H),7.29(s,2H),5.24(t,J=9.4Hz,1H),3.49(dd,J=12.0,6.3Hz,4H),3.17-3.11(m,2H),2.95(d,J=12.9Hz,2H),2.83(t,J=6.6Hz,2H),1.91(d,J=17.4Hz,3H),1.62(d,J=10.8Hz,2H);LCMS m/z 487[M+H]+。
[实施例48]5-(3-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-4,5-二氢异唑-5-基)-N-(3-(甲基磺酰基)苄基)嘧啶-2-胺的合成
根据与实施例35中相同的步骤合成主题化合物(15.3mg,产率:32.6%),不同之处在于使用(3-(甲基磺酰基)苯基)甲胺代替2-氨基茚满。
1H NMR(400MHz,DMSO-d6):δ8.30(s,2H),7.96(t,J=6.5Hz,1H),7.85(s,1H),7.76(d,J=7.5Hz,1H),7.63(d,J=8.1Hz,2H),7.57(d,J=7.6Hz,1H),5.24(t,J=9.2Hz,1H),4.58(d,J=6.1Hz,2H),3.57(d,J=12.8Hz,2H),3.31(dd,J=15.6,9.1Hz,1H),3.17(s,3H),2.91(dd,J=22.5,10.5Hz,4H),1.90(d,J=11.3Hz,2H),1.61(dd,J=23.4,13.5Hz,2H);LCMS m/z 483[M+H]+。
[实施例49]5-(3-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-4,5-二氢异唑-5-基)-N-(4-(甲基磺酰基)苄基)嘧啶-2-胺的合成
根据与实施例35中相同的步骤合成主题化合物(13.2mg,产率:28.1%),不同之处在于使用(4-(甲基磺酰基)苯基)甲胺代替2-氨基茚满。
1H NMR(400MHz,DMSO-d6):δ8.29(s,2H),7.97(dd,J=9.6,3.2Hz,1H),7.83(d,J=8.3Hz,2H),7.63(bs,1H),7.52(d,J=8.2Hz,2H),5.23(t,J=9.2Hz,1H),4.61-4.54(m,2H),3.57(d,J=12.8Hz,2H),3.31(dd,J=15.9,9.3Hz,2H),3.15(d,J=2.1Hz,3H),3.13-3.08(m,1H),2.96-2.88(m,2H),1.90(d,J=12.3Hz,2H),1.61(dd,J=21.0,12.2Hz,2H);LCMS m/z 483[M+H]+。
[实施例50]5-(3-(4-(1H-四唑-5-基)哌啶-1-基)-4,5-二氢异唑-5-基)-N-(2,3-二氢-1H-茚-2-基)嘧啶-2-胺的合成
根据与实施例35中相同的步骤合成主题化合物(15.7mg,产率:65.4%),不同之处在于使用4-(1H-四唑-5-基)哌啶三氟乙酸盐(im25)代替4-(1H-1,2,3-三唑-5-基)哌啶·HCl(3)。
1H NMR(400MHz,DMSO-d6):δ8.31(s,2H),7.59(d,J=6.5Hz,1H),7.15(d,J=20.3Hz,4H),5.26(t,J=9.6Hz,1H),4.62-4.57(m,1H),4.08(s,1H),3.59(d,J=12.9Hz,1H),3.20(dd,J=14.3,6.8Hz,3H),3.15(s,2H),3.02-2.93(m,2H),2.89-2.82(m,2H),1.95(t,J=11.6Hz,2H),1.74(d,J=13.6Hz,2H);LCMS m/z 432[M+H]+。
[实施例51]5-(3-(4-(5-(二氟甲基)-1,3,4-二唑-2-基)哌啶-1-基)-4,5-二氢异唑-5-基)-N-(2,3-二氢-1H-茚-2-基)嘧啶-2-胺的合成
根据与实施例35中相同的步骤合成主题化合物(3.7mg,产率:13.8%),不同之处在于使用2-(二氟甲基)-5-(哌啶-4-基)-1,3,4-二唑(im20)代替4-(1H-1,2,3-三唑-5-基)哌啶·HCl(3)。
1H NMR(400MHz,DMSO-d6):δ8.31(s,1H),7.59(t J=134.0Hz,1H),7.59(J=6.6Hz,1H),7.20-7.10(m,4H),5.26(t,J=9.4Hz,1H),4.59(d,J=7.1Hz,1H),3.58(d,J=13.1Hz,2H),3.26-3.11(m,5H),3.05-2.95(m,2H),2.86(dd,J=15.7,6.6Hz,2H),2.01(dd,J=25.3,16.9Hz,3H),1.77(d,J=9.4Hz,1H);LCMS m/z 482[M+H]+。
[实施例52]5-(3-(4-(1H-四唑-5-基)哌啶-1-基)-4,5-二氢异唑-5-基)-N-(5,6-二氟-2,3-二氢-1H-茚-2-基)嘧啶-2-胺的合成
根据与实施例35中相同的步骤合成主题化合物(18.7mg,产率:79%),不同之处在于使用5,6-二氟-2,3-二氢-1H-茚-2-胺(4e)代替步骤1中的2-氨基茚满,并且使用4-(1H-四唑-5-基)哌啶三氟乙酸盐(im25)代替步骤3中的4-(1H-1,2,3-三唑-5-基)哌啶·HCl(3)。
1H NMR(400MHz,DMSO-d6):δ8.32(s,2H),7.62(d,J=6.5Hz,1H),7.25(t,J=9.5Hz,2H),5.26(t,J=9.4Hz,1H),4.61(d,J=6.9Hz,1H),3.59(d,J=12.8Hz,2H),3.20(dd,J=16.2,7.8Hz,5H),3.01-2.93(m,2H),2.83(dd,J=15.8,7.0Hz,2H),1.98-1.91(m,2H),1.73(dd,J=22.3,13.3Hz,2H);LCMS m/z 468[M+H]+。
[实施例53]N-(5-氟-2,3-二氢-1H-茚-2-基)-5-(3-(4-(5-(三氟甲基)-1,3,4-二唑-2-基)哌啶-1-基)-4,5-二氢异唑-5-基)嘧啶-2-胺的合成
步骤1:5-(3-(4-(1H-四唑-5-基)哌啶-1-基)-4,5-二氢异唑-5-基)-N-(5-氟-2,3-二氢-1H-茚-2-基)嘧啶-2-胺的合成
根据与实施例35中相同的步骤合成主题化合物(15.4mg,产率:46%),不同之处在于使用5-氟-2,3-二氢-1H-茚-2-胺(4b)代替步骤1中的2-氨基茚满,并且使用4-(1H-四唑-5-基)哌啶三氟乙酸盐(im25)代替步骤3中的4-(1H-1,2,3-三唑-5-基)哌啶·HCl(3)。
LCMS m/z 450[M+H]+
步骤2:N-(5-氟-2,3-二氢-1H-茚-2-基)-5-(3-(4-(5-(三氟甲基)-1,3,4-二唑-2-基)哌啶-1-基)-4,5-二氢异唑-5-基)嘧啶-2-胺的合成
将5-(3-(4-(1H-四唑-5-基)哌啶-1-基)-4,5-二氢异唑-5-基)-N-(5-氟-2,3-二氢-1H-茚-2-基)嘧啶-2-胺(9.3mg,0.021mmol)溶解在DCM中,然后在0℃下逐滴添加三氟乙酸酐(6.5mg,0.031mmol)。将温度升至室温,并将混合物搅拌过夜。添加三氟乙酸酐(0.1ml),并将混合物搅拌另外的2小时,然后将反应混合物用DCM萃取,并将有机层用饱和NaHCO3水溶液、水和盐水洗涤。用MgSO4干燥、过滤并浓缩之后,将获得的剩余物通过Prep-TLC(DCM中的5%MeOH)进行纯化以得到主题化合物(0.5mg,产率:4.7%)。
1H NMR(400MHz,CDCl3):δ8.33(s,2H),7.15(m,1H),6.97-6.81(m,2H),5.42(m,2H),4.81(m,1H),3.73(d,J=13.6Hz,2H),3.35(s,J=6Hz,2H),3.22(m,1H),3.13-2.94(m,4H),2.84(td,J=16.2,5.5Hz,2H),2.27-2.14(m,2H),2.08-1.92(m,2H);LCMS m/z 518[M+H]+。
[实施例54]N-(5,6-二氟-2,3-二氢-1H-茚-2-基)-5-(5-(2-甲基-4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)嘧啶-2-胺的合成
根据与实施例11中相同的步骤合成主题化合物(产率:8%),不同之处在于使用7e代替7d。
1H NMR(400MHz,氯仿-d)δ8.79(s,2H),7.54(s,1H),7.51(s,1H),7.03(t,J=8.8Hz,2H),5.68(d,J=7.6Hz,1H),4.94-4.84(m,1H),4.60-4.47(m,1H),4.04(dd,J=13.4,3.1Hz,1H),3.41-3.34(m,3H),3.31-3.24(m,1H),2.86(dd,J=16.0,5.3Hz,2H),2.03(d,J=4.4Hz,2H),1.81(dd,J=12.9,4.8Hz,1H),1.40(d,J=6.9Hz,3H);C23H24F2N9O[M+H]+的MS(ESI,m/z)计算值480.21,实测值480.15.
[实施例55]5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(苯并[d][1,3]间二氧杂环戊烯-5-基甲基)嘧啶-2-胺的合成
根据与实施例1中相同的步骤合成主题化合物(产率:46%),不同之处在于使用苯并[d][1,3]间二氧杂环戊烯-5-基甲胺代替2,3-二氢-1H-茚-2-胺。
1H NMR(400MHz,CDCl3)δ12.36(s,1H),8.79(s,2H),7.54(s,1H),6.86-6.75(m,3H),5.95(s,2H),4.60(d,J=5.9Hz,2H),4.14(dt,J=13.6,3.7Hz,2H),3.27(ddd,J=13.2,11.8,2.9Hz,2H),3.06(tt,J=11.4,3.7Hz,1H),2.19-2.13(m,2H),1.95-1.84(m,2H);13C NMR(100MHz,CDCl3)δ163.93,162.18,156.08,155.79,150.40,147.95,147.03,132.12,130.02,120.89,109.48,108.36,108.25,101.10,46.34,45.42,32.56,30.65;C21H22N9O3[M+H]+的HRMS(ESI,m/z)计算值448.1840,实测值448.1841.
[实施例56]5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(3,4-二氯苄基)嘧啶-2-胺的合成
根据与实施例1中相同的步骤合成主题化合物(产率:36%),不同之处在于使用(3,4-二氯苯基)甲胺代替2,3-二氢-1H-茚-2-胺。
1H NMR(400MHz,CDCl3)δ8.80(s,2H),7.54(s,1H),7.47-7.38(m,2H),7.21-7.17(m,1H),5.88(t,J=6.2Hz,1H),4.67(d,J=6.3Hz,2H),4.20-4.11(m,2H),3.33-3.20(m,2H),3.12-3.00(m,1H),2.20-2.13(m,2H),1.94-1.84(m,2H);C20H20Cl2N9O[M+H]+的HRMS(ESI,m/z)计算值472.1162,实测值472.1162.
[实施例57]5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(3,5-二氟苄基)嘧啶-2-胺的合成
根据与实施例1中相同的步骤合成主题化合物(产率:40%),不同之处在于使用(3,4-二氟苯基)甲胺代替2,3-二氢-1H-茚-2-胺。
1H NMR(400MHz,CD3OD)δ8.78(s,2H),7.52(s,1H),6.92-6.87(m,2H),6.71(tt,J=8.9,2.3Hz,1H),4.67(s,2H),4.14-4.09(m,2H),3.29(ddd,J=13.2,11.9,2.9Hz,2H),3.07(tt,J=11.5,3.6Hz,1H),2.20-2.14(m,2H),1.92-1.82(m,2H);13C NMR(100MHz,CD3OD)δ163.99,163.39(q,J=12.8Hz),162.41,156.13,156.05,149.06,143.21,128.77-127.05(m),110.17(dd,J=11.9,7.0Hz),102.74(t,J=25.4Hz),46.45,44.57(d,J=2.3Hz),32.49,30.86;C20H20F2N9O[M+H]+的HRMS(ESI,m/z)计算值440.1753,实测值440.1755.
[实施例58]5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(3,4-二氟苄基)嘧啶-2-胺的合成
根据与实施例1中相同的步骤合成主题化合物(产率:43.4%),不同之处在于使用(3,4-二氟苯基)甲胺代替2,3-二氢-1H-茚-2-胺。
1H NMR(400MHz,CD3OD)δ8.77(s,2H),7.51(s,1H),7.22-7.07(m,3H),4.64(s,2H),4.12(dLJ=13.3,3.5Hz,2H),3.32-3.25(m,2H),3.07(ddt,J=11.5,7.8,3.7Hz,1H),2.20-2.14(m,2H),1.87(td,J=12.0,7.8Hz,2H);13C NMR(100MHz,CD3OD)δ163.96,162.32,156.11,156.00,151.38(dd,J=74.0,12.7Hz),149.02,148.91(dd,J=60.1,12.7Hz),135.93(dd,J=5.2,3.7Hz),127.67,123.55(dd,J=6.3,3.6Hz),117.00(dd,J=90.3,17.4Hz),109.33,46.43,44.37(d,J=1.5Hz),32.47,30.83;C20H20F2N9O+[M+H]+的HRMS(ESI,m/z)计算值440.1753,实测值440.1754.
[实施例59]5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(3,5-二溴苄基)嘧啶-2-胺的合成
根据与实施例1中相同的步骤合成主题化合物(产率:31.7%),不同之处在于使用(3,5-二溴苯基)甲胺代替2,3-二氢-1H-茚-2-胺。
1H NMR(400MHz,CD3OD)δ8.78(s,2H),7.57(t,J=1.8Hz,1H),7.52(s,1H),7.45(d,J=1.7Hz,2H),4.64(s,2H),4.15-4.07(m,2H),3.32-3.22(m,2H),3.12-3.01(m,1H),2.20-2.13(m,2H),1.92-1.82(m,2H).;13C NMR(100MHz,CD3OD)δ163.99,162.31,156.12,156.05,149.16,143.10,133.05,129.37,127.61,123.22,109.49,46.45,44.25,32.48,30.85;C20H20Br2N9O+[M+H]+的HRMS(ESI,m/z)
计算值560.0152,实测值560.0132.
[实施例60]5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(5-溴-2,3-二氢-1H-茚-2-基)-4-甲基嘧啶-2-胺的合成
根据与实施例1中相同的步骤合成主题化合物(产率:52%),不同之处在于使用5-溴-2,3-二氢-1H-茚-2-胺(4d)代替2,3-二氢-1H-茚-2-胺,并且使用2-氯-4-甲基嘧啶-5-羧酸乙酯代替2-氯嘧啶-5-羧酸酯。
1H NMR(400MHz,CD3OD)δ8.61(s,1H),7.53(s,1H),7.37(d,J=1.8Hz,1H),7.30(dd,J=8.0,1.9Hz,1H),7.12(d,J=8.0Hz,1H),4.15-4.08(m,4H),3.43-3.38(m,1H),3.34-3.32(m,1H),3.30-3.26(m,1H),3.08(tt,J=11.5,3.7Hz,1H),2.95-2.84(m,2H),2.68(s,3H),2.20-2.13(m,2H),1.94-1.83(m,2H);13C NMR(100MHz,CD3OD)δ167.27,163.85,161.29,157.08,143.75,140.30,129.94,128.07,126.46.120.51,108.11,52.82,46.46,39.90,39.52,32.52,30.89,24.59;C23H25BrN9O[M+H]+的HRMS(ESI,m/z)计算值522.1360,实测值522.1359.
[实施例61]5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(5,6-二溴-2,3-二氢-1H-茚-2-基)-4-甲基嘧啶-2-胺的合成
根据与实施例1中相同的步骤合成主题化合物(产率:50%),不同之处在于使用5,6-二溴-2,3-二氢-1H-茚-2-胺代替2,3-二氢-1H-茚-2-胺,并且使用2-氯-4-甲基嘧啶-5-羧酸乙酯代替2-氯嘧啶-5-羧酸酯。
1H NMR(400MHz,CDCl3)δ11.96(s,1H),8.63(s,1H),7.54(s,1H),7.49(s,2H),5.65(d,J=7.5Hz,1H),4.89(d,J=6.6Hz,1H),4.16-4.11(m,2H),3.38-3.24(m,4H),3.07(ddt,J=11.5,7.8,3.7Hz,1H),2.85(dd,J=16.3,5.4Hz,2H),2.71(s,3H),2.19-2.13(m,2H),1.95-1.85(m,2H);C23H24BrN9O[M+H]+的MS(ESI,m/z)计算值600.04,实测值600.05.
[实施例62]5-(3-(4-(1H-1,2,3-三唑-4-基)哌啶-1-基)丙基)-N-(2,3-二氢1H-茚-2-基)嘧啶-2-胺的合成
将1-(4-(1H-1,2,3-三唑-4-基)哌啶-1-基)-3-(2-((2,3-二氢-1H-茚-2-基)氨基)嘧啶-5-基)丙-1-酮(实施例17,0.47mmol)溶解在DMF中并冷却至0℃,然后缓慢逐滴添加ACN中的氢化铝锂(LiAl4,0.10mmol)。将反应混合物在室温下搅拌2小时之后,将反应用1N HCl猝灭反应。用Na2CO3水溶液将pH调节至7至8,并将混合物用乙醚萃取。将有机层用Na2SO4干燥,过滤并浓缩。将获得的剩余物通过硅胶柱色谱(乙酸乙酯/己烷)进行纯化以得到主题化合物(产率:45%)。
1H NMR(400MHz,CD3OD):δ8.17(s,2H),7.55(s,1H),7.25-7.20(m,2H),7.18-7.13(m,2H),4.75-4.72(m,1H),3.41-3.35(m,2H),3.14-3.08(m,2H),2.94-2.84(m,3H),2.58-2.50(m,4H),2.33(t,J=11.7Hz,2H),2.12-2.06(m,2H),1.90-1.78(m,4H);13C NMR(100MHz,CD3OD)δ161.24,158.39,148.90,141.74,127.35,127.10,125.17,123.42,58.21,53.74,53.12,40.38,32.70,31.52,28.14,27.70;C23H30N7 +[M+H]+的MS(ESI,m/z)计算值404.26,实测值404.30.
[实施例63]N-(5,6-二氟-2,3-二氢-1H-茚-2-基)-5-(5-(4-吗啉代哌啶-1-基)-1,3,4-二唑-2-基)嘧啶-2-胺的合成
根据与实施例1中相同的步骤合成作为白色固体的主题化合物(14.8mg,产率:33.8%),不同之处在于使用4-(哌啶-4-基)吗啉代替4-(1H-1,2,3-三唑-5-基)哌啶·HCl(3)。
1H NMR(400MHz,DMSO-d6):δ8.73(s,2H),8.24(d,J=6.5Hz,1H),7.27(t,J=9.3Hz,2H),4.68(dd,J=13.7,7.0Hz,1H),3.93(d,J=13.0Hz,2H),3.59-3.48(m,4H),3.24(dd,J=16.1,7.6Hz,2H),3.06(t,J=11.4Hz,2H),2.87(dd,J=16.1,6.5Hz,2H),2.46-2.35(m,4H),1.84(d,J=11.0Hz,2H),1.46(ddd,J=16.3,12.8,4.8Hz,2H),1.19-1.11(m,1H);LCMS m/z 484[M+H]+。
[实施例64]1-(1-(5-(2-((5,6-二氟-2,3-二氢-1H-茚-2-基)氨基)嘧啶-5-基)-1,3,4-二唑-2-基)哌啶-4-基)氮杂环丁烷-3-醇的合成
根据与实施例1中相同的步骤合成作为灰白色固体的主题化合物(25.1mg,产率:59%),不同之处在于使用1-(哌啶-4-基)氮杂环丁烷-3-醇(1-(哌啶-4-基)氮杂环丁烷-3-醇)代替4-(1H-1,2,3-三唑-5-基)哌啶·HCl(3)。
1H NMR(400MHz,DMSO-d6):δ8.73(s,2H),8.23(d,J=6.8Hz,1H),7.27(t,J=9.3Hz,2H),5.31(d,J=3.2Hz,1H),4.68(dd,J=14.0,7.2Hz,1H),4.23-3.99(m,2H),3.74(dd,J=7.7,5.4Hz,2H),3.52(t,J=6.2Hz,2H),3.30(s,2H),3.23(dd,J=16.1,7.5Hz,2H),3.19-3.12(m,2H),2.87(dd,J=15.9,6.5Hz,2H),2.74(s,1H),2.25(s,1H),1.71(d,J=10.5Hz,2H),1.23(d,J=12.6Hz,2H);LCMS m/z470[M+H]+。
[实施例65]1-(5-(2-((5,6-二氟-2,3-二氢-1H-茚-2-基)氨基)嘧啶-5-基)-1,3,4-二唑-2-基)哌啶-4-磺酰胺的合成
根据与实施例1中相同的步骤合成作为白色固体的主题化合物(20.7mg,产率:47.9%),不同之处在于使用哌啶-4-磺酰胺代替4-(1H-1,2,3-三唑-5-基)哌啶·HCl(3)。
1H NMR(400MHz,DMSO-d6):δ8.76(d,J=12.8Hz,2H),8.26(d,J=6.9Hz,1H),7.27(t,J=9.4Hz,2H),6.82(s,2H),4.68(dd,J=14.1,7.0Hz,1H),4.04(d,J=12.9Hz,2H),3.24(dd,J=16.1,7.5Hz,2H),3.13(t,J=11.4Hz,3H),2.87(dd,J=16.0,6.5Hz,2H),2.08(d,J=12.4Hz,2H),1.64(qd,J=12.6,4.5Hz,2H);LCMSm/z 478[M+H]+。
[实施例66]5-(1-(5-(2-((5,6-二氟-2,3-二氢-1H-茚-2-基)氨基)嘧啶-5-基)-1,3,4-二唑-2-基)哌啶-4-基)-1,3,4-二唑-2(3H)-酮的合成
根据与实施例1中相同的步骤合成作为白色固体的主题化合物(10.9mg,产率:24.9%),不同之处在于使用5-(哌啶-4-基)-1,3,4-二唑-2(3H)-酮代替4-(1H-1,2,3-三唑-5-基)哌啶·HCl(3)。
1H NMR(400MHz,DMSO-d6):δ12.14(s,1H),8.75(d,J=9.9Hz,2H),8.26(d,J
=4.1Hz,1H),7.28(t,J=8.8Hz,2H),4.68(d,J=4.9Hz,1H),3.92(d,J=13.0Hz,2H),3.21(t,J=12.3Hz,4H),2.83(dd,J=34.8,13.5Hz,3H),1.99(d,J=11.4Hz,2H),1.68(dd,J=23.7,12.3Hz,2H);LCMSm/z 483[M+H]+。
[实施例67]1-(5-(2-((5,6-二氟-2,3-二氢-1H-茚-2-基)氨基)嘧啶-5-基)-1,3,4-二唑-2-基)哌啶-4-羧酸的合成
步骤1:哌啶-4-羧酸甲酯三氟乙酸盐(im29)的合成
在0℃下向1-(叔丁氧基羰基)-4-哌啶羧酸甲酯(0.2g,0.822mmol)在DCM(8.2mL)中的溶液添加TFA(2.7mL)并在室温下搅拌1小时。将反应混合物在减压下浓缩以得到作为白色固体的主题化合物(im29)(0.181g,产率:91.5%),其在没有纯化的情况下用于以下反应。
1H NMR(400MHz,DMSO-d6):δ8.43(bs,1H),3.61(s,3H),3.23(d,J=12.9Hz,2H),2.91(td,J=12.6,3.0Hz,2H),2.66(dd,J=12.9,9.0Hz,1H),1.96(d,J=14.5Hz,2H),1.67(td,J=15.0,4.0Hz,2H)。
步骤2:1-(5-(2-((5,6-二氟-2,3-二氢-1H-茚-2-基)氨基)嘧啶-5-基)-1,3,4-二唑-2-基)哌啶-4-羧酸甲酯(L29)的合成
向7e(60mg,0.181mmol)在DMF(0.9mL)中的溶液添加im29(52.2mg,0.217mmol)并冷却至0℃。将DIPEA(52μL,0.543mmol)添加至反应混合物并在相同温度下搅拌另外30分钟,然后添加BOP试剂(96.1mg,0.217mmol)并在室温下搅拌过夜。将反应混合物用EA萃取,将有机层用盐水洗涤,用Na2SO4干燥,过滤并浓缩。将获得的剩余物通过柱色谱(DCM/MeOH)进行纯化以得到作为浅黄色固体的主题化合物(L29)(60.6mg,73.3%)。
1H NMR(400MHz,DMSO-d6):δ8.74(s,2H),8.24(d,J=6.5Hz,1H),7.27(t,J=9.3Hz,2H),4.68(dd,J=14.0,6.8Hz,1H),3.87(d,J=13.0Hz,2H),3.61(s,3H),3.24(dd,J=16.1,7.4Hz,2H),3.15(t,J=11.0Hz,2H),2.87(dd,J=15.9,6.5Hz,2H),2.79(d,J=10.7Hz,1H),1.92(d,J=10.6Hz,2H),1.62(dd,J=20.8,11.1Hz,2H);LCMS m/z 457[M+H]+。
步骤3:1-(5-(2-((5,6-二氟-2,3-二氢-1H-茚-2-基)氨基)嘧啶-5-基)-1,3,4-二唑-2-基)哌啶-4-羧酸(67)的合成
向L29(10mg,0.022mmo|)在THF(0.1mL)中的溶液添加1N NaOH(55μL,0.055mmol)并在室温下搅拌过夜。将3N HCl添加至反应混合物以调节pH至2至4,并将反应混合物用EA萃取。收集有机层,用盐水洗涤,用Na2SO4干燥,过滤并浓缩。获得作为白色固体的主题化合物(8.6mg,88.7%)。
1H NMR(400MHz,DMSO-d6)δ12.30(bs,1H),8.74(s,2H),8.24(d,J=6.8Hz,1H),7.27(t,J=9.3Hz,2H),4.68(dd,J=13.7,6.9Hz,1H),3.86(d,J=12.9Hz,2H),3.24(dd,J=16.1,7.6Hz,2H),3.14(t,J=11.0Hz,2H),2.87(dd,J=15.9,6.4Hz,2H),1.91(d,J=13.5Hz,2H),1.59(d,J=9.4Hz,2H),1.18(d,J=24.2Hz,1H);LCMSm/z 443[M+H]+。
[实施例68]2-(1-(5-(2-((5,6-二氟-2,3-二氢-1H-茚-2-基)氨基)嘧啶-5-基)-1,3,4-二唑-2-基)哌啶-4-基)乙酸的合成
根据与实施例67中相同的步骤合成作为灰白色固体的主题化合物(5.6mg,38.5%),不同之处在于使用4-(2-甲氧基-2-氧代乙基)哌啶-1-羧酸叔丁酯代替1-(叔丁氧基羰基)-4-哌啶羧酸甲酯。
[实施例69]1-(5-(2-((5,6.二氟-2,3-二氢-1H-茚.2-基)氨基)嘧啶-5-基)-1,3,4-二唑-2-基)-N-羟基哌啶-4-甲酰胺的合成
向1-(5-(2-((5,6-二氟-2,3-二氢-1H-茚-2-基)氨基)嘧啶-5-基)-1,3,4-二唑-2-基)哌啶-4-羧酸(实施例67)(68mg,0.154mmol)在THF(0.5mL)中的溶液添加CDI(37.4mg,0.231mmol),在室温下搅拌1小时并随后添加NH2OH-HCl(21.4mg,0.307mmol)并搅拌过夜。将反应混合物用EA萃取,收集有机层,用盐水洗涤,用MgSO4干燥,过滤并浓缩。将获得的剩余物通过柱色谱(DCM/MeOH)进行纯化以得到作为白色固体的主题化合物(2.5mg,3.6%)。
1H NMR(400MHz,DMSO-d6):δ10.49(s,1H),8.74(s,2H),8.24(d,J=7.1Hz,1H),7.27(t,J=9.5Hz,2H),4.68(d,J=7.1Hz,1H),3.94(d,J=13.1Hz,2H),3.26-3.21(m,2H),3.12-3.01(m,2H),2.88(dd,J=15.1,8.0Hz,2H),2.19-2.13(m,1H),1·68-1.61(m,2H),0.83(t,J=6·4Hz,2H);LCMSm/z 458[M+H]+。
[实施例70]N-(5,6-二氟-2,3-二氢-1H-茚-2-基)-5-(5-(4-甲氧基-4-(1H-1,2,3-三唑-4-基)哌啶-1-基)-1,3,4-二唑-2-基)嘧啶-2-胺的合成
根据与实施例33的步骤1-1至步骤2-1中相同的步骤合成(4-(1-(5-(2-((5,6-二氟-2,3-二氢-1H-茚-2-基)氨基)嘧啶-5-基)-1,3,4-二唑-2-基)-4-氟哌啶-4-基)-1H-1,2,3-三唑-1-基)新戊酸甲酯(L30)(90mg,产率:65%),不同之处在于使用4-乙炔基-4-氟哌啶-1-羧酸叔丁酯代替4-乙炔基哌啶-1-羧酸叔丁酯。
1H NMR(400MHz,DMSO-d6)δ8.76(s,2H),8.25(d,J=6.7Hz,1H),7.27(t,J=9.3Hz,2H),6.31(s,2H),4.69(dd,J=14.0,7.1Hz,1H),3.78(m,2H),3.51(m,2H),3.24(dd,J=16.1,7.5Hz,2H),2.93-2.82(m,4H),2.32(m,2H),1.11(s,9H);LCMSm/z 598[M+H]+。
向L30(80mg,0.13mmol)在MeOH(1mL)中的溶液添加K2CO3(37mg,0.27mmol)并在室温下搅拌过夜。将通过浓缩反应混合物获得的剩余物通过柱色谱(DCM/MeOH)进行纯化以得到作为白色固体的主题化合物(70)(20mg,产率:31%)。
1H NMR(400MHz,DMSO-d6)δ8.74(s,2H),8.24(d,J=6.7Hz,1H),7.27(t,J=9.3Hz,2H),4.68(dd,J=13.8,6.8Hz,1H),3.60(s,2H),3.49(m,2H),3.24(dd,J=15.9,7.5Hz,2H),2.95(s,3H),2.88(dd,J=15.9,6.6Hz,2H),2.16(m,2H),2.06(m,2H);LCMSm/z496[M+H]+。
[实施例71]N-(5,6-二氟-2,3-二氢-1H-茚-2-基)-5-(5-(4-氟-4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)嘧啶-2-胺的合成
根据与实施例34的步骤1中相同的步骤合成N-(5,6-二氟-2,3-二氢-1H-茚-2-基)-5-(5-(4-乙炔基-4-氟哌啶-1-基)-1,3,4-二唑-2-基)嘧啶-2-胺(L31)(55mg,产率:83%),不同之处在于使用4-乙炔基-4-氟哌啶三氟乙酸盐代替4-乙炔基哌啶三氟乙酸盐。
1H NMR(400MHz,DMSO-d6)δ8.74(s,2H),8.26(d,J=6.7Hz,1H),7.27(t,J=9.3Hz,2H),4.68(m,1H),4.02(d,J=5.2Hz,1H),3.68-3.48(m,4H),3.29-3.17(m,2H),2.94-2.81(m,2H),2.15-2.00(m,4H);LCMS m/z 441[M+H]+。
将L31(50mg,0.11mmol)、三甲基甲硅烷基叠氮化物(18μL,0.14mmol)和碘化铜(I)(2.4mg,0.013mmol)添加至N,N-二甲基甲酰胺/甲醇(9∶1,2mL)混合物的溶液并在100℃下加热2小时。将反应混合物浓缩并用乙酸乙酯萃取。将有机层用无水硫酸钠干燥并浓缩,并随后将获得的剩余物通过柱色谱(二氯甲烷/甲醇)进行纯化以得到作为白色固体的主题化合物(71)(12mg,产率:23%)。
1H NMR(400MHz,DMSO-d6)δ8.75(s,2H),8.26(d,J=6.8Hz,1H),7.27(t,J=9.4Hz,2H),4.74-4.62(m,1H),3.78(m,2H),3.51(m,2H),3.26-3.22(m,2H),2.92-2.84(m,2H),2.32-2.24(m,4H);LCMS m/z 484[M+H]+。
测试例.针对人自分泌运动因子蛋白的抑制活性的评价
(1)方法
将各自合成的化合物的溶液(80μM,100%二甲基亚砜)顺序用二甲基亚砜稀释5倍以制备6种浓度。将每种浓度的化合物用1×测试缓冲液(50mM Tris-Cl(pH 8.0),5mM KCl,1mM CaCl2,1mM MgCl2,140mM NaCl,去离子水,1mg/mL BSA)稀释两倍,并将1μL(1.25%二甲基亚砜)的该稀释混合物分配到96孔透明圆底板的每个孔中。将9μL的1×测试缓冲液添加至每个孔,随后添加20μL的240nM人自分泌运动因子蛋白(缓冲液:50mM Tris-HCl,pH 8.0,含150mM氯化钠和20%甘油)。将10μL的声处理的360μM 18:1LysoPC(用1×测试缓冲液稀释)添加至每个孔。反应在37℃下的振荡培养箱中进行2小时,并制备第二反应混合物(胆碱测定试剂盒,KA1662)(65μL 1×测试缓冲液:1μL的胆碱氧化酶:1μL的染料探针)。将60μL的第二反应混合物添加至反应板并在摇床上反应30分钟。使用SpectraMax iD3微板读取器,在570nm波长下测量吸光度。抑制活性的百分比(%抑制)通过下式计算:(1-吸光度测试组/吸光度对照组)×100。
(2)结果
计算实施例1至71的化合物针对自分泌运动因子蛋白的抑制活性百分比,在下表1中示出。
【表1】
实施例1至实施例71的所有合成的化合物均显示出针对人自分泌运动因子蛋白的优异抑制活性。
本发明的前述描述仅出于举例说明性目的,并且在不脱离本发明的精神或本发明的基本特征的情况下可对本文中公开的本发明进行多种替换和修改对本发明所属领域的技术人员将是显而易见的。因此应该理解,上述实施方案仅出于举例说明本发明的目的,并不旨在以任何方式限制本发明的范围。例如,描述为单一形式的各组件也可以以分布的方式实现,并且类似地,描述为分布的组件也可以以组合的形式实现。
本发明的范围由所附专利权利要求书指示。专利权利要求书的含义和范围以及来源于其等同方案的所有修改或变化均被认为落入本发明的范围内。
权利要求书(按照条约第19条的修改)
1.由下式1表示的哌啶衍生物化合物、其水合物、其溶剂合物或其可药用盐:
<式1>
其中,
X是芳基C1-4烷基;稠合双环,所述稠合双环中芳环与非芳族环烷基环稠合;稠合双环,所述稠合双环中具有1至3个N的杂芳环与非芳族环烷基环稠合;或稠合双环,所述稠合双环中芳环与具有1至3个O的非芳族杂环稠合,其中X被一个或更多个R1取代或未被一个或更多个R1取代,
A是具有1至3个选自N、O和S的杂原子的5至6元杂芳基,
L是-(CH2)3-;-(CH2)aCO-;-(CH)aCO-;-(CH2)bO(CH2)cCO-;或者具有1至3个选自N和O的杂原子的5元芳族或非芳族杂环,其中所述a、b、c独立地为1至5的整数,
B是COOH;CH2COOH;CONHOH;SO2NH2;具有1至3个选自N和O的杂原子的4至5元非芳族杂环;或具有1至4个选自N和O的杂原子的5元杂芳基,
R1是卤素或C1-4烷基磺酰基,
R2是氢、C1-4烷基、C1-4卤代烷基、羟基、氧代(O)或芳基C1-4烷基,
R3是氢、C1-4烷基、C1-4烷氧基或卤素,
R4是氢、卤素或C1-4烷基,
R5是氢或C1-4烷基。
2.权利要求1所述的哌啶衍生物化合物、其水合物、其溶剂合物或其可药用盐,特征在于X是选自苄基、苯乙基、二氢茚基、二氢环戊吡嗪基和苯并间二氧杂环戊烯基中的一者。
3.权利要求1所述的哌啶衍生物化合物、其水合物、其溶剂合物或其可药用盐,特征在于A是选自吡啶、嘧啶、哒嗪、吡嗪、二唑和噻二唑中的一者。
4.权利要求1所述的哌啶衍生物化合物、其水合物、其溶剂合物或其可药用盐,特征在于L是选自-(CH2)3-、-(CH2)2CO-、-(CH2)3CO-、-(CH)2CO-、-CH2OCH2CO-、唑、异唑、二氢异唑和二唑中的一者。
5.权利要求1所述的哌啶衍生物化合物、其水合物、其溶剂合物或其可药用盐,特征在于B是选自羧基、羧甲基、甲酰胺基、磺酰胺、氮杂环丁烷、吗啉、二唑、咪唑、三唑和四唑中的一者。
6.权利要求1所述的哌啶衍生物化合物、其水合物、其溶剂合物或其可药用盐,特征在于R1是选自F、Cl、Br和甲基磺酰基中的一者。
7.权利要求1所述的哌啶衍生物化合物、其水合物、其溶剂合物或其可药用盐,特征在于R2是选自氢、甲基、二氟甲基、三氟甲基、羟基、氧代(O)和苄基中的一者。
8.权利要求1所述的哌啶衍生物化合物、其水合物、其溶剂合物或其可药用盐,特征在于R3是选自氢、甲基、甲氧基和F中的一者。
9.权利要求1所述的哌啶衍生物化合物、其水合物、其溶剂合物或其可药用盐,特征在于R4是选自氢、Cl和甲基中的一者。
10.权利要求1所述的哌啶衍生物化合物、其水合物、其溶剂合物或其可药用盐,特征在于R5是氢或烷基。
11.权利要求1所述的哌啶衍生物化合物、其水合物、其溶剂合物或其可药用盐,特征在于选自:
[1]5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(2,3-二氢-1H-茚-2-基)嘧啶-2-胺,
[2]5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(5-氟-2,3-二氢-1H-茚-2-基)嘧啶-2-胺,
[3]5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(5-氯-2,3-二氢-1H-茚-2-基)嘧啶-2-胺,
[4]5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(5-溴-2,3-二氢-1H-茚-2-基)嘧啶-2-胺,
[5]5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(5,6-二氟-2,3-二氢-1H-茚-2-基)嘧啶-2-胺,
[6]5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(5,6-二氯-2,3-二氢-1H-茚-2-基)嘧啶-2-胺,
[7]N-(5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)嘧啶-2-基)-6,7-二氢-5H-环戊[b]吡嗪-6-胺,
[8]6-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(2,3-二氢-1H-茚-2-基)哒嗪-3-胺,
[9]5-(5-(4-(1H-1,2,4-三唑-1-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(2,3-二氢-1H-茚-2-基)嘧啶-2-胺,
[10]N-(2,3-二氢-1H-茚-2-基)-5-(5-(4-(3-甲基-1H-1,2,4-三唑-1-基)哌啶-1-基)-1,3,4-二唑-2-基)嘧啶-2-胺,
[11]N-(5-溴-2,3-二氢-1H-茚-2-基)-5-(5-(2-甲基-4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)嘧啶-2-胺,
[12]5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(5-溴-2,3-二氢-1H-茚-2-基)吡啶-2-胺,
[13]5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(5-溴-2,3-二氢-1H-茚-2-基)吡嗪-2-胺,
[14]5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(5-溴-2,3-二氢-1H-茚-2-基)-4-氯吡啶-2-胺,
[15]5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(3,5-二氯苄基)嘧啶-2-胺,
[16]5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(3,5-二氯苯乙基)嘧啶-2-胺,
[17]1-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-3-(2-((2,3-二氢-1H-茚-2-基)氨基)嘧啶-5-基)丙-1-酮,
[18]1-(4-(1H-咪唑-5-基)哌啶-1-基)-3-(2-((2,3-二氢-1H-茚-2-基)氨基)嘧啶-5-基)丙-1-酮,
[19]1-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-4-(5-((2,3-二氢-1H-茚-2-基)氨基)-1,3,4-噻二唑-2-基)丁-1-酮,
[20]1-(4-(1H-咪唑-5-基)哌啶-1-基)-4-(5-((2,3-二氢-1H-茚-2-基)氨基)-1,3,4-噻二唑-2-基)丁-1-酮,
[21]1-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-4-(5-((2,3-二氢-1H-茚-2-基)氨基)-1,3,4-二唑-2-基)丁-1-酮,
[22]1-(4-(1H-咪唑-5-基)哌啶-1-基)-4-(5-((2,3-二氢-1H-茚-2-基)氨基)-1,3,4-二唑-2-基)丁-1-酮,
[23]1-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-2-((5-((2,3-二氢-1H-茚-2-基)氨基)-1,3,4-噻二唑-2-基)甲氧基)乙-1-酮,
[24]N-(5,6-二氟-2,3-二氢-1H-茚-2-基)-5-(5-(4-(5-(三氟甲基)-1,3,4-二唑-2-基)哌啶-1-基)-1,3,4-二唑-2-基)嘧啶-2-胺,
[25]N-(5,6-二氟-2,3-二氢-1H-茚-2-基)-5-(5-(4-(5-(二氟甲基)-1,3,4-二唑-2-基)哌啶-1-基)-1,3,4-二唑-2-基)嘧啶-2-胺,
[26]5-(5-(4-(1,2,4-二唑-3-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(5,6-二氟-2,3-二氢-1H-茚-2-基)嘧啶-2-胺,
[27]5-(5-(4-(1,3,4-二唑-2-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(5,6-二氟-2,3-二氢-1H-茚-2-基)嘧啶-2-胺,
[28]5-(5-(4-(1H-四唑-1-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(5,6-二氟-2,3-二氢-1H-茚-2-基)嘧啶-2-胺,
[29]N-(5,6-二氟-2,3-二氢-1H-茚-2-基)-5-(5-(4-(4-甲基-1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)嘧啶-2-胺,
[30](E)-1-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-3-(2-((5,6-二氟-2,3-二氢-1H-茚-2-基)氨基)嘧啶-5-基)丙-2-烯-1-酮,
[31]5-(5-(4-(1-苄基-1H-1,2,3-三唑-5-基)哌啶-1-基)唑-2-基)-N-(2,3-二氢-1H-茚-2-基)嘧啶-2-胺,
[32]5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(5,6-二氟-2,3-二氢-1H-茚-2-基)-N-甲基嘧啶-2-胺,
[33]N-(5,6-二氟-2,3-二氢-1H-茚-2-基)-5-(5-(4-(1-甲基-1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)嘧啶-2-胺,
[34]N-(5,6-二氟-2,3-二氢-1H-茚-2-基)-5-(5-(4-(1-甲基-1H-1,2,3-三唑-4-基)哌啶-1-基)-1,3,4-二唑-2-基)嘧啶-2-胺,
[35]N-茚满-2-基-5-[3-[4-(1H-三唑-5-基)-1-哌啶基]-4,5-二氢异唑-5-基]嘧啶-2-胺,
[36]5-(3-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)异唑-5-基)-N-(2,3-二氢-1H-茚-2-基)嘧啶-2-胺,
[37]N-(5,6-二氟茚满-2-基)-5-[3-[4-(1H-三唑-5-基)-1-哌啶基]-4,5-二氢异唑-5-基]嘧啶-2-胺,
[38]5-(3-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)异唑-5-基)-N-(5,6-二氟-2,3-二氢-1H-茚-2-基)嘧啶-2-胺,
[39]5-(3-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-4,5-二氢异唑-5-基)-N-(5-氟-2,3-二氢-1H-茚-2-基)嘧啶-2-胺,
[40]5-(3-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)异唑-5-基)-N-(5-氟-2,3-二氢-1H-茚-2-基)嘧啶-2-胺,
[41]N-[(3,5-二氟苯基)甲基]-5-[3-[4-(1H-三唑-5-基)-1-哌啶基]-4,5-二氢异唑-5-基]嘧啶-2-胺,
[42]N-苄基-5-[3-[4-(1H-三唑-5-基)-1-哌啶基]-4,5-二氢异唑-5-基]嘧啶-2-胺,
[43]N-[(3,4-二氟苯基)甲基]-5-[3-[4-(1H-三唑-5-基)-1-哌啶基]-4,5-二氢异唑-5-基]嘧啶-2-胺,
[44]5-(3-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-4,5-二氢异唑-5-基)-N-(3,5-二氯苄基)嘧啶-2-胺,
[45]5-(3-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-4,5-二氢异唑-5-基)-N-(苯并[d][1,3]间二氧杂环戊烯-5-基甲基)嘧啶-2-胺,
[46]N-(1,3-苯并间二氧杂环戊烯-5-基甲基)-5-[3-[4-(1H-三唑-5-基)-1-哌啶基]异唑-5-基]嘧啶-2-胺,
[47]5-(3-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-4,5-二氢异唑-5-基)-N-(3,5-二氯苯乙基)嘧啶-2-胺,
[48]5-(3-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-4,5-二氢异唑-5-基)-N-(3-(甲基磺酰基)苄基)嘧啶-2-胺,
[49]5-(3-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-4,5-二氢异唑-5-基)-N-(4-(甲基磺酰基)苄基)嘧啶-2-胺,
[50]5-(3-(4-(1H-四唑-5-基)哌啶-1-基)-4,5-二氢异唑-5-基)-N-(2,3-二氢-1H-茚-2-基)嘧啶-2-胺,
[51]5-(3-(4-(5-(二氟甲基)-1,3,4-二唑-2-基)哌啶-1-基)-4,5-二氢异唑-5-基)-N-(2,3-二氢-1H-茚-2-基)嘧啶-2-胺,
[52]5-(3-(4-(1H-四唑-5-基)哌啶-1-基)-4,5-二氢异唑-5-基)-N-(5,6-二氟-2,3-二氢-1H-茚-2-基)嘧啶-2-胺,
[53]N-(5-氟-2,3-二氢-1H-茚-2-基)-5-(3-(4-(5-(三氟甲基)-1,3,4-二唑-2-基)哌啶-1-基)-4,5-二氢异唑-5-基)嘧啶-2-胺,
[54]N-(5,6-二氟-2,3-二氢-1H-茚-2-基)-5-(5-(2-甲基-4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)嘧啶-2-胺,
[55]5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(苯并[d][1,3]间二氧杂环戊烯-5-基甲基)嘧啶-2-胺,
[56]5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(3,4-二氯苄基)嘧啶-2-胺,
[57]5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(3,5-二氟苄基)嘧啶-2-胺,
[58]5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(3,4-二氟苄基)嘧啶-2-胺,
[59]5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(3,5-二溴苄基)嘧啶-2-胺,
[60]5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(5-溴-2,3-二氢-1H-茚-2-基)-4-甲基嘧啶-2-胺,
[61]5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(5,6-二溴-2,3-二氢-1H-茚-2-基)-4-甲基嘧啶-2-胺,
[62]5-(3-(4-(1H-1,2,3-三唑-4-基)哌啶-1-基)丙基)-N-(2,3-二氢-1H-茚-2-基)嘧啶-2-胺,
[63]N-(5,6-二氟-2,3-二氢-1H-茚-2-基)-5-(5-(4-吗啉代哌啶-1-基)-1,3,4-二唑-2-基)嘧啶-2-胺,
[64]1-(1-(5-(2-((5,6-二氟-2,3-二氢-1H-茚-2-基)氨基)嘧啶-5-基)-1,3,4-二唑-2-基)哌啶-4-基)氮杂环丁烷-3-醇,
[65]1-(5-(2-((5,6-二氟-2,3-二氢-1H-茚-2-基)氨基)嘧啶-5-基)-1,3,4-二唑-2-基)哌啶-4-磺酰胺,
[66]5-(1-(5-(2-((5,6-二氟-2,3-二氢-1H-茚-2-基)氨基)嘧啶-5-基)-1,3,4-二唑-2-基)哌啶-4-基)-1,3,4-二唑-2(3H)-酮,
[67]1-(5-(2-((5,6-二氟-2,3-二氢-1H-茚-2-基)氨基)嘧啶-5-基)-1,3,4-二唑-2-基)哌啶-4-羧酸,
[68]2-(1-(5-(2-((5,6-二氟-2,3-二氢-1H-茚-2-基)氨基)嘧啶-5-基)-1,3,4-二唑-2-基)哌啶-4-基)乙酸,
[69]1-(5-(2-((5,6-二氟-2,3-二氢-1H-茚-2-基)氨基)嘧啶-5-基)-1,3,4-二唑-2-基)-N-羟基哌啶-4-甲酰胺,
[70]N-(5,6-二氟-2,3-二氢-1H-茚-2-基)-5-(5-(4-甲氧基-4-(1H-1,2,3-三唑-4-基)哌啶-1-基)-1,3,4-二唑-2-基)嘧啶-2-胺,和
[71]N-(5,6-二氟-2,3-二氢-1H-茚-2-基)-5-(5-(4-氟-4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)嘧啶-2-胺。
12.用于预防或治疗与自分泌运动因子活性相关的疾病的药物组合物,所述药物组合物包含作为活性成分的权利要求1至11中任一项所述的哌啶衍生物化合物、其水合物、其溶剂合物或其可药用盐。
13.权利要求12所述的药物组合物,特征在于所述与自分泌运动因子活性相关的疾病选自纤维化疾病、炎性疾病、自身免疫病、呼吸系统疾病、心血管疾病、代谢性疾病、癌症和癌症转移、眼部疾病、淤胆型和其他形式的慢性瘙痒、以及急性或慢性器官移植排斥。
14.包含权利要求1至11中任一项所述的哌啶衍生物化合物、其水合物、其溶剂合物或其可药用盐的药物组合物,所述药物组合物的特征在于为选自以下:选自特发性肺纤维化(IPF)、间质性肺疾病、肝纤维化、肝硬化、非酒精性脂肪性肝炎、心肌和血管纤维化、肾纤维化、皮肤纤维化、肾小球硬化、心肌纤维化和血管纤维化的纤维化疾病;选自类风湿性关节炎、骨关节炎、特应性皮炎、炎性肠病、炎性气道疾病、慢性阻塞性肺疾病(COPD)和哮喘的炎性疾病;选自多发性硬化和硬皮病的自身免疫病;选自石棉诱发的肺纤维化和急性呼吸窘迫综合征(ARDS)的呼吸系统疾病;选自动脉硬化、心肌梗死、动脉和肺动脉高压、心律不齐、卒中和其他血管损伤的心血管疾病;选自肥胖和糖尿病的代谢性疾病;选自乳腺癌、卵巢癌、肺癌、前列腺癌、间皮瘤、胶质瘤、肝癌、胃肠道癌、胰腺癌、及其进展和转移侵袭的癌症和癌症转移;选自增殖性和非增殖性(糖尿病)视网膜病变、干性和湿性年龄相关性黄斑变性(AMD)、黄斑水肿、中央动脉/静脉阻塞、创伤性损伤和青光眼的眼部疾病;淤胆型和其他形式的慢性瘙痒;以及急性或慢性器官移植排斥。
15.用于预防或治疗辐射诱发的纤维化的药物组合物,所述药物组合物包含权利要求1至11中任一项所述的哌啶衍生物化合物、其水合物、其溶剂合物或其可药用盐。
16.药物组合物,所述药物组合物包含权利要求1至11中任一项所述的哌啶衍生物化合物、其水合物、其溶剂合物或其可药用盐、以及可药用添加剂。
Claims (16)
1.由下式1表示的哌啶衍生物化合物、其水合物、其溶剂合物或其可药用盐:
<式1>
其中,
X是芳基C1-4烷基;稠合双环,所述稠合双环中芳环或具有1至3个N的杂芳环与非芳族环烷基环稠合;或稠合双环,所述稠合双环中芳环与具有1至3个O的非芳族杂环稠合,其中X被一个或更多个R1取代或未被一个或更多个R1取代,
A是具有1至3个选自N、O和S的杂原子的5至6元杂芳基,
L是C1-6亚烷基;-(CH2)aCO-;-(CH)aCO-;-(CH2)bO(CH2)cCO-;或者具有1至3个选自N和O的杂原子的5元芳族或非芳族杂环,其中所述a、b、c独立地为1至5的整数,
B是COOH;CH2COOH;CONHOH;SO2NH2;具有1至3个选自N和O的杂原子的4至5元非芳族杂环;或具有1至4个选自N和O的杂原子的5元杂芳基,
R1是卤素或C1-4烷基磺酰基,
R2是氢、C1-4烷基、C1-4卤代烷基、羟基、氧代(O)或芳基C1-4烷基,
R3是氢、C1-4烷基、C1-4烷氧基或卤素,
R4是氢、卤素或C1-4烷基,
R5是氢或C1-4烷基。
2.权利要求1所述的哌啶衍生物化合物、其水合物、其溶剂合物或其可药用盐,特征在于X是选自苄基、苯乙基、二氢茚基、二氢环戊吡嗪基和苯并间二氧杂环戊烯基中的一者。
3.权利要求1所述的哌啶衍生物化合物、其水合物、其溶剂合物或其可药用盐,特征在于A是选自吡啶、嘧啶、哒嗪、吡嗪、二唑和噻二唑中的一者。
4.权利要求1所述的哌啶衍生物化合物、其水合物、其溶剂合物或其可药用盐,特征在于L是选自-(CH2)3-、-(CH2)2CO-、-(CH2)3CO-、-(CH)2CO-、-CH2OCH2CO-、唑、异唑、二氢异唑和二唑中的一者。
5.权利要求1所述的哌啶衍生物化合物、其水合物、其溶剂合物或其可药用盐,特征在于B是选自羧基、羧甲基、甲酰胺基、磺酰胺、氮杂环丁烷、吗啉、二唑、咪唑、三唑和四唑中的一者。
6.权利要求1所述的哌啶衍生物化合物、其水合物、其溶剂合物或其可药用盐,特征在于R1是选自F、Cl、Br和甲基磺酰基中的一者。
7.权利要求1所述的哌啶衍生物化合物、其水合物、其溶剂合物或其可药用盐,特征在于R2是选自氢、甲基、二氟甲基、三氟甲基、羟基、氧代(O)和苄基中的一者。
8.权利要求1所述的哌啶衍生物化合物、其水合物、其溶剂合物或其可药用盐,特征在于R3是选自氢、甲基、甲氧基和F中的一者。
9.权利要求1所述的哌啶衍生物化合物、其水合物、其溶剂合物或其可药用盐,特征在于R4是选自氢、Cl和甲基中的一者。
10.权利要求1所述的哌啶衍生物化合物、其水合物、其溶剂合物或其可药用盐,特征在于R5是氢或烷基。
11.权利要求1所述的哌啶衍生物化合物、其水合物、其溶剂合物或其可药用盐,特征在于选自:
[1]5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(2,3-二氢-1H-茚-2-基)嘧啶-2-胺,
[2]5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(5-氟-2,3-二氢-1H-茚-2-基)嘧啶-2-胺,
[3]5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(5-氯-2,3-二氢-1H-茚-2-基)嘧啶-2-胺,
[4]5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(5-溴-2,3-二氢-1H-茚-2-基)嘧啶-2-胺,
[5]5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(5,6-二氟-2,3-二氢-1H-茚-2-基)嘧啶-2-胺,
[6]5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(5,6-二氯-2,3-二氢-1H-茚-2-基)嘧啶-2-胺,
[7]N-(5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)嘧啶-2-基)-6,7-二氢-5H-环戊[b]吡嗪-6-胺,
[8]6-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(2,3-二氢-1H-茚-2-基)哒嗪-3-胺,
[9]5-(5-(4-(1H-1,2,4-三唑-1-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(2,3-二氢-1H-茚-2-基)嘧啶-2-胺,
[10]N-(2,3-二氢-1H-茚-2-基)-5-(5-(4-(3-甲基-1H-1,2,4-三唑-1-基)哌啶-1-基)-1,3,4-二唑-2-基)嘧啶-2-胺,
[11]N-(5-溴-2,3-二氢-1H-茚-2-基)-5-(5-(2-甲基-4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)嘧啶-2-胺,
[12]5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(5-溴-2,3-二氢-1H-茚-2-基)吡啶-2-胺,
[13]5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(5-溴-2,3-二氢-1H-茚-2-基)吡嗪-2-胺,
[14]5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(5-溴-2,3-二氢-1H-茚-2-基)-4-氯吡啶-2-胺,
[15]5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(3,5-二氯苄基)嘧啶-2-胺,
[16]5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(3,5-二氯苯乙基)嘧啶-2-胺,
[17]1-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-3-(2-((2,3-二氢-1H-茚-2-基)氨基)嘧啶-5-基)丙-1-酮,
[18]1-(4-(1H-咪唑-5-基)哌啶-1-基)-3-(2-((2,3-二氢-1H-茚-2-基)氨基)嘧啶-5-基)丙-1-酮,
[19]1-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-4-(5-((2,3-二氢-1H-茚-2-基)氨基)-1,3,4-噻二唑-2-基)丁-1-酮,
[20]1-(4-(1H-咪唑-5-基)哌啶-1-基)-4-(5-((2,3-二氢-1H-茚-2-基)氨基)-1,3,4-噻二唑-2-基)丁-1-酮,
[21]1-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-4-(5-((2,3-二氢-1H-茚-2-基)氨基)-1,3,4-二唑-2-基)丁-1-酮,
[22]1-(4-(1H-咪唑-5-基)哌啶-1-基)-4-(5-((2,3-二氢-1H-茚-2-基)氨基)-1,3,4-二唑-2-基)丁-1-酮,
[23]1-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-2-((5-((2,3-二氢-1H-茚-2-基)氨基)-1,3,4-噻二唑-2-基)甲氧基)乙-1-酮,
[24]N-(5,6-二氟-2,3-二氢-1H-茚-2-基)-5-(5-(4-(5-(三氟甲基)-1,3,4-二唑-2-基)哌啶-1-基)-1,3,4-二唑-2-基)嘧啶-2-胺,
[25]N-(5,6-二氟-2,3-二氢-1H-茚-2-基)-5-(5-(4-(5-(二氟甲基)-1,3,4-二唑-2-基)哌啶-1-基)-1,3,4-二唑-2-基)嘧啶-2-胺,
[26]5-(5-(4-(1,2,4-二唑-3-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(5,6-二氟-2,3-二氢-1H-茚-2-基)嘧啶-2-胺,
[27]5-(5-(4-(1,3,4-二唑-2-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(5,6-二氟-2,3-二氢-1H-茚-2-基)嘧啶-2-胺,
[28]5-(5-(4-(1H-四唑-1-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(5,6-二氟-2,3-二氢-1H-茚-2-基)嘧啶-2-胺,
[29]N-(5,6-二氟-2,3-二氢-1H-茚-2-基)-5-(5-(4-(4-甲基-1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)嘧啶-2-胺,
[30](E)-1-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-3-(2-((5,6-二氟-2,3-二氢-1H-茚-2-基)氨基)嘧啶-5-基)丙-2-烯-1-酮,
[31]5-(5-(4-(1-苄基-1H-1,2,3-三唑-5-基)哌啶-1-基)唑-2-基)-N-(2,3-二氢-1H-茚-2-基)嘧啶-2-胺,
[32]5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(5,6-二氟-2,3-二氢-1H-茚-2-基)-N-甲基嘧啶-2-胺,
[33]N-(5,6-二氟-2,3-二氢-1H-茚-2-基)-5-(5-(4-(1-甲基-1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)嘧啶-2-胺,
[34]N-(5,6-二氟-2,3-二氢-1H-茚-2-基)-5-(5-(4-(1-甲基-1H-1,2,3-三唑-4-基)哌啶-1-基)-1,3,4-二唑-2-基)嘧啶-2-胺,
[35]N-茚满-2-基-5-[3-[4-(1H-三唑-5-基)-1-哌啶基]-4,5-二氢异唑-5-基]嘧啶-2-胺,
[36]5-(3-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)异唑-5-基)-N-(2,3-二氢-1H-茚-2-基)嘧啶-2-胺,
[37]N-(5,6-二氟茚满-2-基)-5-[3-[4-(1H-三唑-5-基)-1-哌啶基]-4,5-二氢异唑-5-基]嘧啶-2-胺,
[38]5-(3-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)异唑-5-基)-N-(5,6-二氟-2,3-二氢-1H-茚-2-基)嘧啶-2-胺,
[39]5-(3-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-4,5-二氢异唑-5-基)-N-(5-氟-2,3-二氢-1H-茚-2-基)嘧啶-2-胺,
[40]5-(3-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)异唑-5-基)-N-(5-氟-2,3-二氢-1H-茚-2-基)嘧啶-2-胺,
[41]N-[(3,5-二氟苯基)甲基]-5-[3-[4-(1H-三唑-5-基)-1-哌啶基]-4,5-二氢异唑-5-基]嘧啶-2-胺,
[42]N-苄基-5-[3-[4-(1H-三唑-5-基)-1-哌啶基]-4,5-二氢异唑-5-基]嘧啶-2-胺,
[43]N-[(3,4-二氟苯基)甲基]-5-[3-[4-(1H-三唑-5-基)-1-哌啶基]-4,5-二氢异唑-5-基]嘧啶-2-胺,
[44]5-(3-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-4,5-二氢异唑-5-基)-N-(3,5-二氯苄基)嘧啶-2-胺,
[45]5-(3-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-4,5-二氢异唑-5-基)-N-(苯并[d][1,3]间二氧杂环戊烯-5-基甲基)嘧啶-2-胺,
[46]N-(1,3-苯并间二氧杂环戊烯-5-基甲基)-5-[3-[4-(1H-三唑-5-基)-1-哌啶基]异唑-5-基]嘧啶-2-胺,
[47]5-(3-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-4,5-二氢异唑-5-基)-N-(3,5-二氯苯乙基)嘧啶-2-胺,
[48]5-(3-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-4,5-二氢异唑-5-基)-N-(3-(甲基磺酰基)苄基)嘧啶-2-胺,
[49]5-(3-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-4,5-二氢异唑-5-基)-N-(4-(甲基磺酰基)苄基)嘧啶-2-胺,
[50]5-(3-(4-(1H-四唑-5-基)哌啶-1-基)-4,5-二氢异唑-5-基)-N-(2,3-二氢-1H-茚-2-基)嘧啶-2-胺,
[51]5-(3-(4-(5-(二氟甲基)-1,3,4-二唑-2-基)哌啶-1-基)-4,5-二氢异唑-5-基)-N-(2,3-二氢-1H-茚-2-基)嘧啶-2-胺,
[52]5-(3-(4-(1H-四唑-5-基)哌啶-1-基)-4,5-二氢异唑-5-基)-N-(5,6-二氟-2,3-二氢-1H-茚-2-基)嘧啶-2-胺,
[53]N-(5-氟-2,3-二氢-1H-茚-2-基)-5-(3-(4-(5-(三氟甲基)-1,3,4-二唑-2-基)哌啶-1-基)-4,5-二氢异唑-5-基)嘧啶-2-胺,
[54]N-(5,6-二氟-2,3-二氢-1H-茚-2-基)-5-(5-(2-甲基-4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)嘧啶-2-胺,
[55]5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(苯并[d][1,3]间二氧杂环戊烯-5-基甲基)嘧啶-2-胺,
[56]5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(3,4-二氯苄基)嘧啶-2-胺,
[57]5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(3,5-二氟苄基)嘧啶-2-胺,
[58]5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(3,4-二氟苄基)嘧啶-2-胺,
[59]5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(3,5-二溴苄基)嘧啶-2-胺,
[60]5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(5-溴-2,3-二氢-1H-茚-2-基)-4-甲基嘧啶-2-胺,
[61]5-(5-(4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)-N-(5,6-二溴-2,3-二氢-1H-茚-2-基)-4-甲基嘧啶-2-胺,
[62]5-(3-(4-(1H-1,2,3-三唑-4-基)哌啶-1-基)丙基)-N-(2,3-二氢-1H-茚-2-基)嘧啶-2-胺,
[63]N-(5,6-二氟-2,3-二氢-1H-茚-2-基)-5-(5-(4-吗啉代哌啶-1-基)-1,3,4-二唑-2-基)嘧啶-2-胺,
[64]1-(1-(5-(2-((5,6-二氟-2,3-二氢-1H-茚-2-基)氨基)嘧啶-5-基)-1,3,4-二唑-2-基)哌啶-4-基)氮杂环丁烷-3-醇,
[65]1-(5-(2-((5,6-二氟-2,3-二氢-1H-茚-2-基)氨基)嘧啶-5-基)-1,3,4-二唑-2-基)哌啶-4-磺酰胺,
[66]5-(1-(5-(2-((5,6-二氟-2,3-二氢-1H-茚-2-基)氨基)嘧啶-5-基)-1,3,4-二唑-2-基)哌啶-4-基)-1,3,4-二唑-2(3H)-酮,
[67]1-(5-(2-((5,6-二氟-2,3-二氢-1H-茚-2-基)氨基)嘧啶-5-基)-1,3,4-二唑-2-基)哌啶-4-羧酸,
[68]2-(1-(5-(2-((5,6-二氟-2,3-二氢-1H-茚-2-基)氨基)嘧啶-5-基)-1,3,4-二唑-2-基)哌啶-4-基)乙酸,
[69]1-(5-(2-((5,6-二氟-2,3-二氢-1H-茚-2-基)氨基)嘧啶-5-基)-1,3,4-二唑-2-基)-N-羟基哌啶-4-甲酰胺,
[70]N-(5,6-二氟-2,3-二氢-1H-茚-2-基)-5-(5-(4-甲氧基-4-(1H-1,2,3-三唑-4-基)哌啶-1-基)-1,3,4-二唑-2-基)嘧啶-2-胺,和
[71]N-(5,6-二氟-2,3-二氢-1H-茚-2-基)-5-(5-(4-氟-4-(1H-1,2,3-三唑-5-基)哌啶-1-基)-1,3,4-二唑-2-基)嘧啶-2-胺。
12.用于预防或治疗与自分泌运动因子活性相关的疾病的药物组合物,所述药物组合物包含作为活性成分的权利要求1至11中任一项所述的哌啶衍生物化合物、其水合物、其溶剂合物或其可药用盐。
13.权利要求12所述的药物组合物,特征在于所述与自分泌运动因子活性相关的疾病选自纤维化疾病、炎性疾病、自身免疫病、呼吸系统疾病、心血管疾病、代谢性疾病、癌症和癌症转移、眼部疾病、淤胆型和其他形式的慢性瘙痒、以及急性或慢性器官移植排斥。
14.包含权利要求1至11中任一项所述的哌啶衍生物化合物、其水合物、其溶剂合物或其可药用盐的药物组合物,所述药物组合物的特征在于为选自以下:选自特发性肺纤维化(IPF)、间质性肺疾病、肝纤维化、肝硬化、非酒精性脂肪性肝炎、心肌和血管纤维化、肾纤维化、皮肤纤维化、肾小球硬化、心肌纤维化和血管纤维化的纤维化疾病;选自类风湿性关节炎、骨关节炎、特应性皮炎、炎性肠病、炎性气道疾病、慢性阻塞性肺疾病(COPD)和哮喘的炎性疾病;选自多发性硬化和硬皮病的自身免疫病;选自石棉诱发的肺纤维化和急性呼吸窘迫综合征(ARDS)的呼吸系统疾病;选自动脉硬化、心肌梗死、动脉和肺动脉高压、心律不齐、卒中和其他血管损伤的心血管疾病;选自肥胖和糖尿病的代谢性疾病;选自乳腺癌、卵巢癌、肺癌、前列腺癌、间皮瘤、胶质瘤、肝癌、胃肠道癌、胰腺癌、及其进展和转移侵袭的癌症和癌症转移;选自增殖性和非增殖性(糖尿病)视网膜病变、干性和湿性年龄相关性黄斑变性(AMD)、黄斑水肿、中央动脉/静脉阻塞、创伤性损伤和青光眼的眼部疾病;淤胆型和其他形式的慢性瘙痒;以及急性或慢性器官移植排斥。
15.用于预防或治疗辐射诱发的纤维化的药物组合物,所述药物组合物包含权利要求1至11中任一项所述的哌啶衍生物化合物、其水合物、其溶剂合物或其可药用盐。
16.药物组合物,所述药物组合物包含权利要求1至11中任一项所述的哌啶衍生物化合物、其水合物、其溶剂合物或其可药用盐、以及可药用添加剂。
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