CN113195055A - 用于hbv治疗的5元杂芳基甲酰胺化合物 - Google Patents
用于hbv治疗的5元杂芳基甲酰胺化合物 Download PDFInfo
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- CN113195055A CN113195055A CN201980082985.8A CN201980082985A CN113195055A CN 113195055 A CN113195055 A CN 113195055A CN 201980082985 A CN201980082985 A CN 201980082985A CN 113195055 A CN113195055 A CN 113195055A
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- Prior art keywords
- alkyl
- methyl
- amino
- chloro
- pyrazole
- Prior art date
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- -1 5-membered heteroaryl carboxamide compounds Chemical class 0.000 title claims abstract description 379
- 238000002560 therapeutic procedure Methods 0.000 title description 6
- 238000000034 method Methods 0.000 claims abstract description 75
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- 208000015181 infectious disease Diseases 0.000 claims abstract description 20
- 208000002672 hepatitis B Diseases 0.000 claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims description 171
- 150000003839 salts Chemical class 0.000 claims description 50
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 49
- 125000000217 alkyl group Chemical group 0.000 claims description 48
- 229910052739 hydrogen Inorganic materials 0.000 claims description 44
- 239000001257 hydrogen Substances 0.000 claims description 43
- 150000002431 hydrogen Chemical class 0.000 claims description 30
- 125000003545 alkoxy group Chemical group 0.000 claims description 22
- 229910052736 halogen Inorganic materials 0.000 claims description 18
- 150000002367 halogens Chemical class 0.000 claims description 18
- 229910052717 sulfur Inorganic materials 0.000 claims description 18
- 229910052799 carbon Inorganic materials 0.000 claims description 17
- 125000002950 monocyclic group Chemical group 0.000 claims description 16
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- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 150000001721 carbon Chemical group 0.000 claims description 7
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 7
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 6
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 6
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- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 4
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- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 3
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 3
- 229910003827 NRaRb Inorganic materials 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- 125000001624 naphthyl group Chemical group 0.000 claims description 3
- 229910052701 rubidium Inorganic materials 0.000 claims description 3
- 125000004469 siloxy group Chemical group [SiH3]O* 0.000 claims description 3
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- 238000004949 mass spectrometry Methods 0.000 description 248
- 239000000203 mixture Substances 0.000 description 245
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- YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Natural products ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 57
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- 238000002953 preparative HPLC Methods 0.000 description 48
- 239000002904 solvent Substances 0.000 description 48
- 239000012044 organic layer Substances 0.000 description 47
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 36
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 36
- 239000011541 reaction mixture Substances 0.000 description 34
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 33
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- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 24
- NXFFJDQHYLNEJK-UHFFFAOYSA-N 2-[4-[(4-chlorophenyl)methyl]-7-fluoro-5-methylsulfonyl-2,3-dihydro-1h-cyclopenta[b]indol-3-yl]acetic acid Chemical compound C1=2C(S(=O)(=O)C)=CC(F)=CC=2C=2CCC(CC(O)=O)C=2N1CC1=CC=C(Cl)C=C1 NXFFJDQHYLNEJK-UHFFFAOYSA-N 0.000 description 24
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- 125000001424 substituent group Chemical group 0.000 description 18
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 16
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 16
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 16
- 238000004440 column chromatography Methods 0.000 description 16
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 16
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 15
- 239000003112 inhibitor Substances 0.000 description 15
- 230000003612 virological effect Effects 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- 239000012065 filter cake Substances 0.000 description 14
- 239000000463 material Substances 0.000 description 14
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- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 13
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 13
- 239000012267 brine Substances 0.000 description 13
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 13
- 239000002253 acid Substances 0.000 description 12
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- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
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- 229920006395 saturated elastomer Polymers 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 10
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 9
- YQTMTTYLZOOAHH-UHFFFAOYSA-N 5-amino-3-bromo-N-(3-chloro-4-fluorophenyl)-1-methylpyrazole-4-carboxamide Chemical compound NC1=C(C(=NN1C)Br)C(=O)NC1=CC(=C(C=C1)F)Cl YQTMTTYLZOOAHH-UHFFFAOYSA-N 0.000 description 9
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Images
Classifications
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- C07D401/00—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
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- C07D401/00—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
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
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- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
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- C—CHEMISTRY; METALLURGY
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- C07D413/08—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing alicyclic rings
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- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
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Abstract
本申请部分提供了可用于破坏HBV核心蛋白组装的5元杂芳基甲酰胺化合物及其药物组合物,和治疗乙肝(HBV)感染的方法。
Description
相关申请
本申请要求在2018年10月22日提交的美国临时申请第62/748,906号,和2019年6月7日提交的美国临时申请第62/858,790号的权益,将其全部内容通过引用并入本文。
技术背景
乙肝(HBV)引起病毒性肝炎,其可进一步导致慢性肝病并增加肝硬化和肝癌(肝细胞癌)的风险。在全世界范围内,大约20亿人已感染了HBV,约3.6亿人是慢性感染的,且每年HBV感染导致超过50万人的死亡。HBV可通过体液传播:母婴传播、性传播和通过血液制品传播。HBV阳性母亲所生的孩子也可能被感染,除非在出生时注射疫苗。
所述肝炎病毒颗粒由布满表面蛋白(HBsAg)的脂质包膜组成,所述表面蛋白围绕该病毒核心。所述核心由120个核心蛋白(Cp)二聚体构成的蛋白质外壳或衣壳所组成,所述核心本身含有该松弛环状DNA(rcDNA)病毒基因组以及病毒和宿主蛋白。在被感染的细胞中,所述基因组被发现为宿主细胞核中的共价闭合环状DNA(cccDNA)。所述cccDNA是病毒RNA的模板并因此是病毒蛋白的模板。在细胞质中,Cp在全长病毒RNA(即所谓的前基因组RNA或pgRNA)和病毒聚合酶(P)的复合体周围组装。组装后,P在该衣壳范围内将所述pgRNA反向转录成rcDNA,从而生成DNA-填充的病毒核心。
目前,慢性HBV主要用核苷(酸)类似物(例如,恩替卡韦)治疗,当患者保持治疗时,所述类似物抑制病毒,但无法消除感染,即使是经过许多年的治疗。一旦患者开始服用核苷(酸)类似物,大多数患者必须持续服用或面临病毒复发的致命性免疫响应的可能性的危险。此外,核苷(酸)疗法可能导致抗病毒药物耐受的出现。
FDA唯一批准的替代核苷(酸)类似物的是用干扰素α或聚乙二醇化干扰素α的治疗。不幸的是,干扰素α的不良事件发生率和概况可能会导致耐受性差,且许多患者不能完成治疗。此外,仅有一小部分的患者被认为适合干扰素疗法,因为仅有一小部分患者可能对干扰素疗法的疗程具有持续的临床响应。因此,基于干扰素的疗法仅用于全部选出进行治疗的确诊患者中的一小部分。
因此,目前HBV治疗的范围从姑息疗法到观察等待(watchful waiting)。核苷酸类似物抑制病毒产生、治疗症状、但保留完整的感染。干扰素α具有严重的副作用且在患者中耐受性差,并且由于有限的治疗策略仅在一小部分的患者中成功。存在对更有效治疗HBV感染的清楚持续的需求。
发明内容
本公开部分提供了可用于破坏HBV核心蛋白组装的5元杂芳基甲酰胺化合物及其药物组合物,和治疗HBV感染的方法。
在一方面,本公开提供了式I化合物:
或其药学上可接受的盐,其中所述变量描述在发明详述中。
在另一个方面,本公开提供了药物组合物,其包含式I化合物或其药学上可接受的盐,和药学上可接受的赋形剂。
在另一个方面,本公开提供了在有需要的受试者中治疗HBV感染的方法,其包括:向所述受试者施用治疗有效量的式I化合物或其药学上可接受的盐。
在另一个方面,本公开提供了在有需要的受试者中治疗HBV感染的方法,其包括:向所述受试者施用药物组合物,所述药物组合物包含治疗有效量的式I化合物或其药学上可接受的盐,和药学上可接受的赋形剂。
附图说明
图1显示了化合物CP-AIA-227-2的ORTEP图。
图2显示了化合物CP-AIA-227-2的相对立体化学图示。
发明详述
本公开的特征和其它细节现将更加具体地描述。在本发公开进一步描述之前,说明书、实施例和所附权利要求中所用的某些术语汇总在此处。这些定义应在本公开其余部分和本领域技术人员所理解的基础上进行阅读。除非另外定义,否则本文所用的所有技术和科学术语具有与本领域技术人员通常所理解的相同的含义。
I.定义
本文使用的术语“烯基”是指具有至少一个碳-碳双键的不饱和直链或支链烃。示例性的烯基包括,但不限于,2-6个碳原子的直链或支链基团,其在本文中被称为C2-6烯基。示例性的烯基包括,但不限于,乙烯基、烯丙基、丁烯基、戊烯基等。
本文使用的术语“烷氧基”是指与氧连接的直链或支链烷基(即,烷基-O-)。示例性的烷氧基包括,但不限于,1-6或1-4个碳原子的烷氧基,其在本文中分别被称作C1-6烷氧基和C1-4烷氧基。示例性的烷氧基包括,但不限于甲氧基、乙氧基、异丙氧基等。
本文使用的术语“烷氧基烷基”是指取代有烷氧基的烷基。实例包括,但不限于,CH3CH2OCH2-、CH3OCH2CH2-和CH3OCH2-。
本文使用的术语“烷基”是指饱和的直链或支链烃。示例性的烷基包括,但不限于,1-6或1-4个碳原子的直链或支链烃,其在本文中分别被称为C1-6烷基和C1-4烷基。示例性的烷基包括,但不限于,甲基、乙基、正丙基、异丙基、2-甲基-1-丁基、3-甲基-2-丁基、2-甲基-1-戊基、3-甲基-1-戊基、4-甲基-1-戊基、2-甲基-2-戊基、3-甲基-2-戊基、4-甲基-2-戊基、2,2-二甲基-1-丁基、3,3-二甲基-1-丁基、2-乙基-1-丁基、正丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、正己基等。本文使用的术语“亚烷基”是指双基烷基。
本文使用的术语“炔基”是指具有至少一个碳-碳叁键的不饱和直链或支链烃。示例性的炔基包括,但不限于,2-6个碳原子的直链或支链基团,其在本文中被称作C2-6炔基。示例性的炔基包括,但不限于,乙炔基、丙炔基、丁炔基、戊炔基、己炔基、甲基丙炔基等。
本文使用的术语“羰基”是指双基-C(O)-。
本文使用的术语“氰基”是指基团-CN。
本文使用的术语“环烷基”是指饱和的单环烃基或双环烃环结构,所述单环烃基例如,含3-6个碳的烃基,其在本文中被称作C3-6单环烷基,所述双环烃环结构例如,含8-12个碳,其在本文中被称作C8-12双环烷基。对于双环环烷基,两个环可以通过相同或不同的碳连接。示例性的单环环烷基包括,但不限于,环己基、环戊基、环戊烯基、环丁基和环丙基。示例性的双环环烷基包括,但不限于,螺[2.5]辛基、螺[3.5]壬基、双环[2.2.2]辛基、双环[4.1.0]庚基、八氢并环戊二烯基、双环[4.2.0]辛基、双环[1.1.1]戊基、双环[2.2.1]庚基和双环[2.2.2]辛基。
本文使用的术语“环烯基”是指部分不饱和的单环烃基或双环烃环结构,所述部分不饱和的单环烃基例如,含有4-6个碳的烃基,其在本文中被称作C4-6单环烯基,所述双环烃环结构例如,含8-12个碳,其在本文中被称作C8-12双环烯基。对于双环烯基:1)一个或两个环可以含有一个或多个双键,和2)两个环可以通过相同或不同的环碳连接。示例性的单环环烯基包括,但不限于,环丙烯基、环丁烯基、环戊烯基、环己烯基和环庚烯基。示例性的双环环烯基包括,但不限于,螺[2.5]辛-5-烯基、螺[2.5]辛-4-烯基、螺[3.5]壬-5-烯基、螺[3.5]壬-6-烯基、双环[4.1.0]庚-3-烯基、双环[4.1.0]庚-2-烯基和双环[2.2.2]辛-2-烯基。
本文使用的术语“碳环基”是指双环环系统,其通过将苯环稠合到C3-6单环烷基或C4-6单环烯基环上形成。碳环基的实例包括,但不限于,2,3-二氢-1H-茚基、1,2,3,4-四氢萘基和1H-茚基。
本文使用的术语“卤素”或“卤代”是指F、Cl、Br或I。
本文使用的术语“卤代烷基”是指取代有一个或多个卤素原子的烷基。例如,卤代C1-6烷基是指取代有一个或多个卤素原子的1-6个碳原子的直链或支链烷基。实例包括,但不限于,CH2F-、CHCl2-、-CHF2、CF3-、CF3CH2-、CH3CF2、CF3CCl2-和CF3CF2-。
本文使用的术语“卤代烷氧基”是指取代有一个或多个卤素原子的烷氧基。实例包括,但不限于CCl3O-、CF3O-、CHF2O-CF3CH2O-和CF3CF2O-。
本文使用的术语“杂芳基”是指5-6元单环芳香环系统或8-12元双环芳香环系统,其含有一至四个独立选择的杂原子,如氮、氧和硫。在可能的情况下,所述杂芳基环可以通过碳或氮与相邻的基团连接。5-6元单环杂芳基的实例包括,但不限于,呋喃基、硫苯基(也被称作噻吩基)、吡咯基、噻唑基、噁唑基、异噻唑基、异噁唑基、咪唑基、吡唑基、1H-1,2,3-三唑基、2H-1,2,3-三唑基、1,2,4-三唑基、吡啶基(吡啶基)(也被称作吡啶基(pyridyl))、哒嗪基、嘧啶基、吡嗪基、1,3,5-三嗪基、1,2,4-三嗪基、1,2,3-三嗪基、1,2,4-噁二唑基、1,3,4-噁二唑基、1,2,5-噁二唑基、1,2,4-噻二唑基、1,3,4-噻二唑基、1,2,5-噻二唑基和四唑基。8-12元双环杂芳基的实例包括,但不限于,苯并呋喃基、异苯并呋喃基、苯并[b]噻吩基、苯并[c]噻吩基、吲哚基、异吲哚基、苯并[d]异噁唑基、苯并[c]异噁唑基、苯并[d]噁唑基、苯并[d]异噻唑基、苯并[c]异噻唑基、苯并[d]噻唑基、吲唑基、苯并[d]咪唑基、苯并[d]咪唑基和苯并[d][1,2,3]三唑基。
术语“杂环烷基”是指饱和的3-6元单环系统或8-12元双环系统,其在本文中被称作C3-6单杂环烷基或C8-12双杂环烷基,其含有一至四个独立选择的杂原子,如氮、氧和硫(包括它的氧化态:S、S(O)和SO2)。在可能的情况下,杂环烷基环可以通过碳或氮与相邻的基团连接。C3-6单杂环烷基的实例包括,但不限于,氮丙啶基、氧杂环丙基、硫杂环丙基1,1-二氧化物、氧杂环丁基、氮杂环丁基、硫杂环丁基1,1-二氧化物、吡咯烷基、四氢呋喃基、哌啶基、四氢-2H-吡喃基、吗啉基、硫吗啉基和哌嗪基。C8-12双杂环烷基的实例包括,但不限于,1,4-二氧杂螺[4.5]葵基和1,5-二氧杂螺[5.5]十一烷基。
术语“杂环烯基”是指部分不饱和的3-6元单环系统或8-12元双环系统,其在本文中被称作C3-6单杂环烯基或C8-12双杂环烯基,其含有一至四个独立选择的杂原子,如氮、氧和硫(包括它的氧化态:S、S(O)和SO2)。在可能的情况下,杂环烯基环可以通过碳或氮与相邻的基团连接。对于双环杂环烯基:1)一个或两个环可以含有一个或多个双键,和2)两个环可以通过相同或不同的环原子连接。C3-6单杂环烯基的实例包括,但不限于,2,3-二氢-1H-吡咯基、2,5-二氢-1H-吡咯基、4,5-二氢-1H-吡唑基、2,3-二氢-1H-吡唑基、4,5-二氢-1H-咪唑基、2,3-二氢-1H-咪唑基、2,3-二氢噻吩基、2,5-二氢噻吩基、4,5-二氢噻唑基、2,3-二氢噻唑基、4,5-二氢异噻唑基、2,3-二氢异噻唑基、2,3-二氢呋喃基、2,5-二氢呋喃基、4,5-二氢噁唑基、2,3-二氢噁唑基、4,5-二氢异噁唑基、2,3-二氢异噁唑基、3,4-二氢吡啶基、2,3-二氢吡啶基、2,3,4,5-四氢吡啶基、1,6-二氢哒嗪基、4,5-二氢哒嗪基、3,4,5,6-四氢哒嗪基、4,5-二氢嘧啶基、1,2,5,6-四氢嘧啶基、1,2-二氢嘧啶基、1,2-二氢吡嗪基、2,3-二氢吡嗪基、1,2,3,6-四氢吡嗪基、4H-1,4-噁嗪基、3,4-二氢-2H-1,4-噁嗪基、4H-1,4-噻嗪基和3,4-二氢-2H-1,4-噻嗪基。C8-12双杂环烯基的实例包括,但不限于,6,7-二氢吲哚基、4,5-二氢吲哚基、7,8-二氢咪唑并[1,2-a]吡啶基、5,6-二氢咪唑并[1,2-a]吡啶基、4,5-二氢苯并[d]咪唑基、6,7-二氢-1H-吲唑基、4,5-二氢-1H-吲唑基、4,5-二氢吡唑并[1,5-a]吡啶基和6,7-二氢吡唑并[1,5-a]吡啶基。
本文使用的术语“杂环基”是指双环环系统,其通过(1)将苯环稠合到3-6元单环杂环烷基或4-7元单环杂环烯基环上形成,或(2)将5-6元单环杂芳基环稠合到C3-6环烷基、C4-7环烯基、3-6元单环杂环烷基或4-6元单环杂环烯基环上形成。在可能的情况下,所述环可以通过碳或氮与相邻的基团连接。杂环基的实例包括,但不限于异色满基、2H-喹啉基、6,7,8,9-四氢-5H-[1,2,4]三唑并[4,3-a]氮杂5,6,8,9-四氢-[1,2,4]三唑并[4,3-d][1,4]氧杂氮杂环庚烷、6,7-二氢-5H,9H-[1,2,4]三唑并[3,4-c][1,4]氧杂氮杂环庚烷、5,6,8,9-四氢-7l2-[1,2,4]三唑并[4,3-d][1,4]二氮杂8,9-二氢-5H-[1,2,4]三唑并[4,3-a]氮杂6,9-二氢-5H-[1,2,4]三唑并[4,3-a]氮杂5,6,7,8-四氢-[1,2,4]三唑并[4,3-a]吡啶、5,6-二氢-8H-[1,2,4]三唑并[3,4-c][1,4]噁嗪、5,6,7,8-四氢咪唑并[1,2-a]吡啶和5H,9H-[1,2,4]三唑并[3,4-c][1,4]氧杂氮杂
本文使用的术语“羟基”是指基团–OH。
本文使用的术语“羟基烷基”是指取代有一个或多个羟基的烷基。实例包括,但不限于HOCH2-、HOCH2CH2-、CH3CH(OH)CH2-和HOCH2CH(OH)CH2-。
本文使用的术语“羟基烷氧基”是指取代有一个或多个羟基的烷氧基。实例包括但不限于HOCH2O-、HOCH2CH2O-、CH3CH(OH)CH2O-和HOCH2CH(OH)CH2O-。
本文使用的术语“RaRbNC1-6烷基-”是指取代有如本文定义的RaRbN-基团的烷基。实例包括但不限于NH2CH2-、NH(CH3)CH2-、N(CH3)2CH2CH2-和CH3CH(NH2)CH2-。
本文使用的术语“RaRbNC1-6烷氧基”是指取代有如本文定义的RaRbN-基团的烷氧基。实例包括但不限于NH2CH2-、NH(CH3)CH2O-、N(CH3)2CH2CH2O-和CH3CH(NH2)CH2O-。
本文使用的术语“氧代”是指基团=O。
术语“个体”、“患者”或“受试者”可以互换使用,并且包括任何动物,所述动物包括哺乳动物,优选地,小鼠、大鼠、其它的啮齿动物、兔、狗、猫、猪、牛、绵羊、马或灵长类动物,并且最优选地是人。本公开的化合物或药物组合物可以施用于哺乳动物(如人),但也可以施用于其它的哺乳动物,如需要兽医治疗的动物,例如家畜(例如,狗、猫等),农场动物(例如,牛、羊、猪、马等)和实验室动物(例如,大鼠、小鼠、豚鼠、狗、灵长类动物等)。在本公开的方法中治疗的哺乳动物期望是哺乳动物,其期望治疗HBV感染。
术语“调节”包括拮抗作用(例如,抑制)、激动作用、部分拮抗作用和/或部分激动作用。
“药学上可接受的”包括分子实体和组合物,当视需要将其施用至动物或人时不产生不良、过敏或其它的不利反应。对于人给药,制剂应满足FDA生物制品标准办公室要求的无菌、致热原性以及一般安全性和纯度标准。
本文使用的术语“药学上可接受的载体”或“药学上可接受的赋形剂”是指与药物施用相容的任意和所有溶剂、分散介质、包衣剂、等渗剂和吸收延迟剂、填料等。针对药学上活性物质使用这些介质和试剂是本领域熟知的。该组合物还可以含有其它的活性化合物,所述其它的活性化合物提供补充的、额外的或增强的治疗功能。
本文使用的术语“药物组合物”是指组合物,其包含与一种或多种药学上可接受的载体一起配制的至少一种本文公开的化合物。
本文使用的术语“药学上可接受的盐”是指酸性基团或碱性基团盐,其可以存在于用在组合物中的化合物里。包含在本发明组合物中的本质上是碱性的化合物能够与各种无机酸和有机酸形成多种盐。可以用于制备这种碱性化合物的药学上可接受的酸加成盐的酸是形成无毒酸加成盐的那些酸,即含有生理学上可接受的阴离子的盐,包括,但不限于,苹果酸盐、草酸盐、氯盐、溴盐、碘盐、硝酸盐、硫酸盐、硫酸氢盐、磷酸盐、酸式磷酸盐、异烟酸盐、乳酸盐、水杨酸盐、柠檬酸盐、酒石酸盐、油酸盐、鞣酸盐、泛酸盐、酒石酸氢盐、抗坏血酸盐、琥珀酸盐、马来酸盐、龙胆酸盐(gentisinate)、富马酸盐、葡糖酸盐、葡萄糖醛酸盐(glucaronate)、糖酸盐、甲酸盐、苯甲酸盐、谷氨酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐和双羟萘酸盐(即1,1’-亚甲基-双-(2-羟基-3-萘甲酸盐))。包含在本发明组合物中的本质上是酸性的化合物能够与各种生理学上可接受的阳离子形成碱式盐。这些盐的实例包括碱金属盐或碱土金属盐,具体是钙盐、镁盐、钠盐、锂盐、锌盐、钾盐和铁盐。包含在本发明组合物中的包含碱性部分或酸性部分的化合物页可以与各种氨基酸形成药学上可接受的盐。本公开的化合物可以含有酸性基团和碱性基团;例如,一个氨基和一个甲酸基团。在这种情况下,所述化合物可以按酸加成盐、两性离子盐或碱盐存在。
本文使用的术语“治疗有效量”或“有效量”是指主题化合物的量,其会引起组织、系统或动物(例如哺乳动物或人)的生物学或医学反应,而这正是研究人员、兽医、医生或其它临床医生所寻找的。将本公开的化合物或药物组合物以治疗有效量施用以治疗疾病。或者,治疗有效量的化合物是指达到所需要的治疗和/或预防效果所需的量。
术语“治疗”包括通过破坏HBV核心蛋白组装而导致疾病改善的任何作用,例如,减轻、减少、调节或消除。“破坏”包括抑制HBV病毒组装和感染。
本公开的化合物可含有一个或多个手性中心,且因此以立体异构体存在。当术语“立体异构体”在本文中使用时,其由所有的对映体或非对映体组成。这些化合物可用符号“(+)”、“(-)”、“R”或“S”指定,其取决于立体碳原子周围的取代基的构型,但是本领域技术人员将理解,一个结构可隐含地表示手性中心。本公开包括这些化合物的各种立体异构体及其混合物。对映体或非对映体的混合物在命名法中可指定为“(±)”,但是本领域技术人员将理解,一个结构可隐含地表示手性中心。
本公开的化合物可以含有一个或多个双键,因此,由于碳-碳双键周围的取代基的排列而以几何异构体存在。符号表示键,其可为本文描述的单键、双键或叁键。碳-碳双键周围的取代基被指定为“Z”或“E”构型,其中术语“Z”和“E”按照IUPAC标准使用。除非另外陈述,否则描绘双键的结构包括“E”和“Z”异构体。碳-碳双键周围的取代基可替代地被称为“顺式”或“反式”,其中“顺式”表示取代基在该双键的同一侧而“反式”表示取代基在该双键的相对侧。
本公开的化合物可含有碳环或杂环,因此,由于该环周围的取代基的排列而以几何异构体存在。碳环或杂环周围取代基的排列被指定为“Z”或“E”构型,其中术语“Z”和“E”按照IUPAC标准使用。除非另外陈述,否则描绘碳环或杂环的结构包括“Z”和“E”异构体。碳环或杂环周围的取代基也可被称为“顺式”或“反式”,其中术语“顺式”表示取代基在该环平面的同一侧而术语“反式”表示取代基在该环平面的相对侧。其中取代基既在该环平面同一侧也在该环平面相对侧排列的化合物的混合物被指定为“顺式/反式”。
本文公开的化合物的单一对映体和非对映体可由含有不对称或立体异构中心的市售可得的起始原料进行合成性制备或通过制备外消旋混合物然后用本领域技术人员熟知的拆分方法来制备。这些拆分方法通过以下举例说明:(1)对映体混合物与手性助剂的连接、通过重结晶或色谱法对获得的非对映体混合物的分离以及光学纯的产物从助剂中的释放,(2)采用光学活性拆分剂形成盐,(3)光学对映体混合物在手性液相色谱柱上的直接分离,或(4)使用立体选择性的化学或酶试剂的动力学拆分。外消旋混合物还可以通过公知方法(如手性液相色谱或将所述化合物在手性溶剂中结晶)被拆分成它们的组分对映体。立体选择性合成是本领域熟知的,即其中单一反应物在形成新的立体中心的过程中或在预先存在的一个立体异构体的转化过程中形成立体异构体的不等混合物的化学或酶反应。立体选择性合成既包括对映选择性转换也包括非对映选择性转换,且可能涉及手性助剂的使用。例如,参见Carreira和Kvaerno,Classics in Stereoselective Synthesis,Wiley-VCH:Weinheim,2009。
本文公开的化合物可以按与药学上可接受的溶剂(如水、乙醇等)形成的溶剂合物形式存在以及按非溶剂合物形式存在,且其预期本公开包括溶剂合物和非溶剂合物形式。在一个实施方案中,所述化合物是无定形的。在一个实施方案中,所述化合物是单一多晶型物。在另一个实施方案中,所述化合物是多晶型物的混合物。在另一个实施方案中,所述化合物为结晶形式。
本公开还包括同位素标记的本公开的化合物,其与本文列举的那些是相同的,除了一个或多个原子被具有不同于自然界中常见的原子质量或质量数的原子质量或质量数的原子所替代。可掺入本公开化合物的同位素的实例包括氢、碳、氮、氧、磷、硫、氟和氯的同位素,分别如2H、3H、13C、14C、15N、18O、17O、31P、32P、35S、18F和36Cl。例如,本公开的化合物可以具有一个或多个被氘替代的H原子。
某些同位素标记的公开的化合物(例如,用3H和14C标记的那些)被用于化合物和/或底物组织分布测定。氚代的(即,3H)和碳-14(即,14C)同位素由于它们易于制备和可检测性,因此是特别优选的。此外,用较重的同位素例如氘(即,2H)取代可以由于较大的代谢稳定性(例如,增加的体内半衰期或降低的剂量需求)而提供某些治疗益处并因此在一些情况下可能是优选的。同位素标记的本公开化合物通常可以通过下面的与本文实施例所公开的那些类似的步骤进行制备,其中用同位素标记的试剂代替非同位素标记的试剂。
术语“前药”是指化合物,其在体内转化以产生本发明的化合物或该化合物的药学上可接受的盐、水合物或溶剂合物。该转化可以在不同位置(如在肠腔中或在肠道、血液或肝脏的运输时),通过各种机制(如通过酯酶、酰胺酶、磷酸酶、氧化性和/或还原性代谢)发生。前药在本领域中是公知的(例如,参见Rautio,Kumpulainen等人,Nature Reviews DrugDiscovery 2008,7,255)。
II.5元杂芳基甲酰胺化合物
在一方面,本公开提供了式I化合物,或其药学上可接受的盐,
其中:
X1是NRx1、O或S;
X2是N或CRx2;
X3是O、NR7、CR4R8、C(O)、S(O)t、C=CR4R0或C=NR4;
X4和X6独立地为O或S;
X5是O、S或NR0;
L是键或C1-6亚烷基;
L1是键、C1-6亚烷基、O、NRc、C(O)、C(O)NRc、S(O)t或S(O)tNRc;
Rx1和Rx2独立地选自氢、C1-6烷基、卤代C1-6烷基和C3-6单环烷基;
Ra、Rb和Rc在每次出现时独立地选自氢、C1-6烷基、卤代C1-6烷基和C3-6单环烷基;
Rd是氢、OH、C1-6烷基或C1-6烷氧基;
R0、R6、R8和R11在每次出现时独立地选自氢、卤素、OH、CN、NO2、氧代、RdN=、肼基、甲酰基、叠氮基、甲硅烷基、甲硅烷氧基、HOC(O)-、RaRbN-、RaRbNS(O)t-、C1-6烷基、C2-6烯基、C2-6炔基、C3-6单环烷基、卤代C1-6烷基、羟基C1-6烷基-、RaRbNC1-6烷基-、HOC(O)C1-6烷基-、RaRbNC1-6烷基NRc-、C1-6烷基NRaC1-6烷基NRc-、C1-6烷氧基、卤代C1-6烷氧基、羟基C1-6烷氧基-、RaRbNC1-6烷氧基-、C1-6烷氧基C1-6烷基-、卤代C1-6烷氧基C1-6烷基-、RaRbNC(O)-、C1-6烷基C(O)-、C1-6烷氧基C(O)-、C1-6烷基C(O)O-、C1-6烷基S(O)q-、C1-6烷基S(O)tNRc-、C1-6烷基S(O)tC1-6烷基-、C1-6烷基S(O)tNRaC1-6烷基-、C3-6环烷基S(O)tC1-6烷基-、C1-6烷基C(O)C1-6烷基-和C1-6烷基C(O)OC1-6烷基-;
R0a在每次出现时独立地选自氢、卤素、OH、CN、NO2、RaRbN-、C1-6烷基和卤代C1-6烷基;
R1是苯基、萘基、C3-6单环烷基、C3-6单杂环烷基或5-6元单环杂芳基,其中:所述苯基、C3-6单环烷基、C3-6单杂环烷基或5-6元单环杂芳基任选地取代有一、二或三个独立选择的R11基团;
R2是氢、卤素、RaRbN、C1-6烷基、卤代C1-6烷基、C3-6单环烷基或C1-6烷氧基;
R3选自:
R4是R5、R6或R5-L1-;
R4a是氢或C1-6烷基;
R4b是R5、R5a、R6或R5-L1-;
R5选自:
R6a是氢或C1-6烷基;
R7是氢、C1-6烷基、C1-6卤代烷基、C1-6烷氧基C1-6烷基-、NRaRbC(O)-、R7aC(O)-、C1-6烷氧基C(O)-、C1-6烷基S(O)q-或C1-6卤代烷基S(O)q-;
R7a是C1-6烷基或C3-6单环烷基;
q、r、t、和w在每次出现时独立地选自0、1和2;且
v在每次出现时独立地选自0、1、2和3。
在一方面,本公开提供了式I化合物,或其药学上可接受的盐,
其中:
X1是NRx1、O或S;
X2是N或CRx2;
X3是O、NR7、CR4R8、C(O)、S(O)t、C=CR4R0或C=NR4;
X4是O或S;
X5是O、S或NR0;
L是键或C1-6亚烷基;
L1是键、C1-6亚烷基、O、NRc、C(O)、C(O)NRc、S(O)t或S(O)tNRc;
Rx1和Rx2独立地选自氢、C1-6烷基、卤代C1-6烷基和C3-6单环烷基;
Ra、Rb和Rc在每次出现时独立地选自氢、C1-6烷基、卤代C1-6烷基和C3-6单环烷基;
Rd是氢、OH、C1-6烷基或C1-6烷氧基;
R0、R6、R8和R11在每次出现时独立地选自氢、卤素、OH、CN、NO2、氧代、RdN=、肼基、甲酰基、叠氮基、甲硅烷基、甲硅烷氧基、HOC(O)-、RaRbN-、RaRbNS(O)t-、C1-6烷基、C2-6烯基、C2-6炔基、C3-6单环烷基、卤代C1-6烷基、羟基C1-6烷基-、RaRbNC1-6烷基-、HOC(O)C1-6烷基-、RaRbNC1-6烷基NRc-、C1-6烷基NRaC1-6烷基NRc-、C1-6烷氧基、卤代C1-6烷氧基、羟基C1-6烷氧基-、RaRbNC1-6烷氧基-、C1-6烷氧基C1-6烷基-、卤代C1-6烷氧基C1-6烷基-、RaRbNC(O)-、C1-6烷基C(O)-、C1-6烷氧基C(O)-、C1-6烷基C(O)O-、C1-6烷基S(O)q-、C1-6烷基S(O)tNRc-、C1-6烷基S(O)tC1-6烷基-、C1-6烷基S(O)tNRaC1-6烷基-、C3-6环烷基S(O)tC1-6烷基-、C1-6烷基C(O)C1-6烷基-、和C1-6烷基C(O)OC1-6烷基-;
R1是苯基、萘基、C3-6单环烷基、C3-6单杂环烷基或5-6元单环杂芳基,其中:所述苯基、C3-6单环烷基、C3-6单杂环烷基或5-6元单环杂芳基任选地取代有一、二或三个独立选择的R11基团;
R2是氢、卤素、RaRbN、C1-6烷基、卤代C1-6烷基、C3-6单环烷基或C1-6烷氧基;
R3选自:
R4是R5、R6或R5-L1-。
R4a是氢或C1-6烷基;
R5选自:
R6a是氢或C1-6烷基;
R7是氢、C1-6烷基、C1-6卤代烷基、C1-6烷氧基C1-6烷基-、NRaRbC(O)-、R7aC(O)-、C1-6烷氧基C(O)-、C1-6烷基S(O)q-或C1-6卤代烷基S(O)q-;
R7a是C1-6烷基或C3-6单环烷基;
q、r、t、和w在每次出现时独立地选自0、1和2;且
v在每次出现时独立地选自0、1、2和3。
下面的实施方案进一步描述式I化合物或其药学上可接受的盐。会理解的是,本文描述的实施方案的所有化学上允许的组合被预想到是本发明的另外的实施方案。
在某些实施方案中,X1是NRx1且X2是N。
在某些实施方案中,X1是NRx1,X2是N且Rx1是甲基的氢。
在某些实施方案中,X1是NRx1,X2是N且Rx1是甲基。
在某些实施方案中,X1是O且X2是N。
在某些实施方案中,X3是CR4R8。
在某些实施方案中,L是键。
在某些实施方案中,X1是NRx1,X2是N、Rx1是甲基且L是键。
在某些实施方案中,L是C1-6亚烷基。
在某些实施方案中,L1是键。
在某些实施方案中,L1是C1-6亚烷基。
在某些实施方案中,R0a是氢。
R11在每次出现时独立地选自卤素、CN、C1-6烷基和卤代C1-6烷基;且
z1是0、1、2或3。
在某些实施方案中,R11在每次出现时独立地选自卤素和CN。
在某些实施方案中,R11在每次出现时独立地选自F、Cl、Br和I。
在某些实施方案中,R1选自:
在某些实施方案中,R1是C3-6单环烷基,其任选地取代有一个、两个或三个独立地选自卤素、CN、C1-6烷基和卤代C1-6烷基的取代基。
R11在每次出现时独立地选自卤素、CN、C1-6烷基且卤代C1-6烷基;且
z1是0、1、2或3。
在某些实施方案中,R1是C3-6单杂环烷基,其任选地取代有一个、两个或三个独立地选自卤素、CN、C1-6烷基和卤代C1-6烷基的取代基。
R11在每次出现时独立地选自氢、卤素、CN、C1-6烷基且卤代C1-6烷基;
R12是氢或C1-6烷基;
X6是O或S;
z1是0、1、2或3;且
z2是0、1或2。
在某些实施方案中,R1是5-6元单环杂芳基,其任选地取代有一个、两个或三个独立地选自卤素、CN、C1-6烷基且卤代C1-6烷基的取代基。
R11在每次出现时独立地选自卤素、CN、C1-6烷基和卤代C1-6烷基;且
z1是0、1、2或3。
在某些实施方案中,R2是RaRbN;
在某些实施方案中,R2是RaRbN且Ra和Rb独立地选自氢和C1-6烷基。
在某些实施方案中,R2是NH2。
在某些实施方案中,R4是R5。
在某些实施方案中,R4是R6。
在某些实施方案中,R4是R5-L1-。
在某些实施方案中,R5选自:
在某些实施方案中,R5选自:
在某些实施方案中,R6是C1-6烷基S(O)tC1-6烷基-或C1-6烷基S(O)tNRaC1-6烷基-。
在某些实施方案中,R6是C1-6烷基S(O)tC1-6烷基-。
在某些实施方案中,R6是C1-6烷基S(O)tC1-6烷基-且t是1或2。
在某些实施方案中,R6是C1-6烷基S(O)tC1-6烷基-且t是2。
在某些实施方案中,R8是氢、OH或C1-6烷氧基。
在某些实施方案中,R8是OH。
R6是C1-6烷基S(O)tC1-6烷基-或C1-6烷基S(O)tNRaC1-6烷基-;且
R8是氢、OH或C1-6烷氧基。
R6是C1-6烷基S(O)tC1-6烷基-;且
R8是氢、OH或C1-6烷氧基。
R6是C1-6烷基S(O)tC1-6烷基-;且
R8是OH。
R6是C1-6烷基S(O)tC1-6烷基-或C1-6烷基S(O)tNRaC1-6烷基-;且
R8是氢,OH或C1-6烷氧基。
R6是C1-6烷基S(O)tC1-6烷基-;且
R8是氢、OH或C1-6烷氧基。
R6是C1-6烷基S(O)tC1-6烷基-;且
R8是OH。
III.药物组合物和试剂盒
在另一个方面,本公开提供了药物组合物,其包含式I化合物或其药学上可接受的盐,和药学上可接受的赋形剂。具体是,本公开提供了药物组合物,其包含与一种或多种药学上可接收的载体配制的本文公开的化合物。这些制剂包括适合于口服、直肠、局部、经颊、胃肠外(例如,皮下、肌内、真皮内或静脉内)、直肠、阴道或气溶胶施用的那些制剂,但在任何给定情况下最适合的施用形式将取决于所治疗病症的程度和严重程度以及所用特定化合物的性质。例如,公开的组合物可以配制成单位剂量,和/或可以配制成用于口服或皮下施用。
在另一个方面,本公开提供了药物组合物,其包含表17的化合物或其药学上可接受的盐和/或立体异构体。
本公开的示例性药物组合物可以以药物制剂的形式使用,例如,以固体,半固体或液体形式使用,其包含一种或多种作为活性成分的本公开的化合物,与适于外部、肠内或胃肠外施用的有机或无机的载体或赋形剂的混合物。所述活性成分可以与,例如通常无毒的药学上可接受的载体混合用于片剂、丸剂、胶囊、栓剂、溶液剂、乳剂、混悬液和任何其它的适于使用的形式。所述活性主题化合物以足以对疾病的过程或状况产生所需效果的量包含在所述药物组合物中。
为了制备固体组合物(如片剂),可以将主要活性成分与药学上的载体,例如常规的片剂成分(如玉米淀粉、乳糖、蔗糖、山梨糖醇、滑石粉、硬脂酸、硬脂酸镁、磷酸二钙或树胶),和其它的药学上的稀释剂(例如,水)混合形成固体预制剂组合物,其包含本公开的化合物或其无毒的药学上可接受的盐的均匀混合物。当将这些预制剂组合物称作均匀的,其意指将所述活性成分均匀地分散在整个组合物中,从而可以容易地将所述组合物细分为同等有效的单位剂型,如片剂、丸剂和胶囊。
在用于口服施用的固体剂型(胶囊、片剂、丸剂、糖衣丸、粉剂、颗粒剂等)中,将主题组合物与一种或多种药学上可接受的载体(如柠檬酸钠或磷酸二钙)和/或下面的任意物质混合:(1)填料或填充剂,如淀粉、乳糖、蔗糖、葡萄糖、甘露醇和/或硅酸;(2)粘合剂,例如羧基甲基纤维素、海藻酸盐、明胶、聚乙烯吡咯烷酮、蔗糖和/或阿拉伯胶;(3)保湿剂,如甘油;(4)崩解剂,如琼脂(agar-agar)、碳酸钙、马铃薯淀粉或木薯淀粉、海藻酸、某些硅酸盐和碳酸钠;(5)缓溶剂,如石蜡;(6)吸收促进剂,如季铵化合物;(7)润湿剂,例如乙酰醇和单硬脂酸甘油酯;(8)吸收剂,如高岭土和膨润土;(9)润滑剂,如滑石粉、硬脂酸钙、硬脂酸镁、固体聚乙二醇、月桂基硫酸钠、和它们的混合物;(10)着色剂。就胶囊、片剂和丸剂而言,所述组合物还可包含缓冲剂。相似类型的固体组合物也可以用作软填充和硬填充明胶胶囊中的填料,其使用如乳糖或奶糖,以及高分子量的聚乙二醇等赋形剂。
片剂可以通过压缩或模制,任选地与一种或多种辅助成分一起制备。压缩的片剂可以通过使用粘合剂(例如,明胶或羟基丙基甲基纤维素)、润滑剂、惰性稀释剂、防腐剂、崩解剂(例如,羟甲基淀粉钠或交联的羧甲基纤维素钠),表面活性剂或分散剂来制备。模制片剂可以通过在适合的机器中将用惰性液体稀释剂润湿的主题组合物的混合物进行模制来制备。片剂和其它的固体剂型,如糖衣丸、胶囊、丸剂和颗粒剂,可以任选地用包衣和衣壳(如肠溶衣和在药物-配制领域公知的其它的包衣)进行刻痕或制备。
用于吸入或吹入的组合物包括溶液或悬浮液和粉剂,所述溶液或悬浮液在在药学上可接受的,水性或有机溶剂,或它们的混合物中。用于口服施用的液体剂型包括药学上可接受的乳剂、微乳剂、溶液、混悬液、糖浆剂和酏剂。除了主题组合物,所述液体剂型可以包含本领域常用的惰性稀释剂,例如水或其它的溶剂、增溶剂和乳化剂,如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苯甲醇、苯甲酸苄基酯、丙二醇、1,3-丁二醇、油(具体是棉籽油、花生油、玉米油、胚芽油、橄榄油、蓖麻油和芝麻油)、甘油、四氢呋喃醇、聚乙二醇和脱水山梨糖醇的脂肪酸酯、环糊精,和它们的混合物。
除了主题组合物,悬浮液可以包含悬浮剂,例如乙氧基化的异硬脂醇,聚氧乙烯山梨糖醇和脱水山梨糖醇酯、微晶纤维素、偏错酸(aluminummetahydroxide)、膨润土,琼脂和黄芪树胶(tragacanth),和它们的混合物。
用于直肠、阴道施用的制剂可呈现为栓剂,所述栓剂可通过将主题组合物与一种或多种适合的无刺激性的赋形剂或载体(包括例如可可脂、聚乙二醇、栓剂蜡或水杨酸酯)混合来制备,并且所述栓剂在室温下为固体,但在体温下为液体并且因此将在体腔中熔化并释放所述活性剂。
用于经皮施用主题组合物的剂型包括粉剂、喷雾剂、软膏剂、糊剂、霜剂、洗剂、凝胶、溶液、贴剂和吸入剂。所述活性组分可以在无菌条件下与药学上可接受的载体以及可能需要的任何防腐剂、缓冲剂或推进剂混合。
除了主题组合物,所述软膏剂、糊剂、霜剂和凝胶还可以包含赋形剂,如动物和植物脂肪、油类、蜡、石蜡、淀粉、黄芪树胶、纤维素衍生物、聚乙二醇、硅酮、膨润土、硅酸、滑石和氧化锌,或它们的混合物。
除了主题组合物,粉剂和喷雾剂还可以包含赋形剂,如乳糖、滑石、硅酸、氢氧化铝、硅酸钙和聚酰胺粉末,或这些物质的混合物。喷雾剂可以额外包含常规推进剂,如氯氟烃和挥发性的未取代的烃(如丁烷或丙烷)。
本公开的组合物和化合物可以替代地通过气溶胶施用。这是通过制备含有所述化合物的水性气溶胶、脂质体制剂或固体颗粒来实现的。可以使用非水性(例如,氟碳化合物推进剂)悬浮液。可以使用声波雾化器,因为它们最小化该药剂在剪切下的暴露,其可能导致主题组合物中包含的化合物降解。一般而言,通过将主题组合物的水性溶液或悬浮液与常规的药学上可接受的载体和稳定剂一起配制来制备水性气溶胶。所述载体和稳定剂随着具体的(particular)主题组合物的要求而变化,但通常包括非离子的表面活性剂(吐温,普朗尼克(Pluronics)或聚乙二醇),无害蛋白质(如血清白蛋白)、脱水山梨糖醇酯、油酸、卵磷脂、氨基酸(如甘氨酸)、缓冲剂、盐、糖或糖醇。气溶胶通常由等渗溶液制备。
适合于胃肠外施用的本公开的药物组合物包含主题化合物与一种或多种药学上可接受的无菌等渗水性溶液或非水溶液、分散剂、混悬液或乳剂,或可在临使用前重构成无菌可注射溶液剂或分散剂的无菌粉剂的组合,所述组合可以含有抗氧化剂、缓冲剂、抑菌剂、使制剂与预期接受者的血液等渗的溶质,或助悬剂或增稠剂。
可用于本公开的药物组合物中的适合的水性和非水性载体的实例包括水、乙醇、多元醇(如甘油、丙二醇、聚乙二醇等)和其适合的混合物、植物油(如橄榄油)和可注射有机酯,如油酸乙酯和环糊精。适当的流动性可以,例如通过使用包衣材料如卵磷脂,在分散剂的情况下通过维持所要求的粒径,以及通过使用表面活性剂来维持。
在另一方面,本公开提供肠内药物制剂,其包括公开的化合物和肠溶材料和其药学上可接受的载体或赋形剂。肠溶材料指的是在胃的酸性环境下实质上不能溶解、而主要在特定pH值的小肠液中可以溶解的聚合物。小肠是胃与大肠之间的胃肠道(消化道)的部分,并且所述小肠包括十二指肠、空肠和回肠。十二指肠的pH值为约5.5,空肠的pH值为约6.5,而回肠末端的pH值为约7.5。因此,肠溶材料是不可溶解的,例如,直到pH值为约5.0、约5.2、约5.4、约5.6、约5.8、约6.0、约6.2、约6.4、约6.6、约6.8、约7.0、约7.2、约7.4、约7.6、约7.8、约8.0、约8.2、约8.4、约8.6、约8.8、约9.0、约9.2、约9.4、约9.6、约9.8或约10.0。示例性肠溶材料包括醋酸邻苯二甲酸纤维素(CAP)、羟丙基甲基纤维素邻苯二甲酸酯(HPMCP)、聚醋酸乙烯邻苯二甲酸酯(PVAP)、醋酸羟丙基甲基纤维素琥珀酸酯(HPMCAS)、醋酸偏苯三酸酯纤维素、羟丙基甲基纤维素琥珀酸酯、醋酸琥珀酸纤维素、醋酸六氢邻苯二甲酸纤维素、丙酸邻苯二甲酸纤维素、醋酸马来酸纤维素、醋酸丁酸纤维素、醋酸丙酸纤维素、甲基甲基丙烯酸和甲基丙烯酸甲酯的共聚物、丙烯酸甲酯、甲基丙烯酸甲酯和甲基丙烯酸的共聚物、甲基乙烯基醚和马来酸酐的共聚物(Gantrez ES系列)、甲基丙烯酸乙基酯-甲基丙烯酸甲酯-乙基丙烯酸氯三甲基铵共聚物、诸如玉蜀黍蛋白、虫胶和柯巴脂(copalcollophorium)的天然树脂,和若干市售的肠溶分散系统(例如,Eudragit L30D55、Eudragit FS30D、Eudragit L100、Eudragit S100、Kollicoat EMM30D、Estacryl 30D、Coateric和Aquateric)。上述材料的每种材料的溶解度是已知或可在体外容易地确定。上文是可行材料的列表,但受益于本公开的本领域的技术人员应认识到,所述列表并不全面并且还存在满足本发明目标的其它肠溶材料。
有利地,本公开还提供,例如,由有需要HBV感染治疗的消费者使用的试剂盒。这些试剂盒包括诸如上文所述那些剂量形式的合适的剂量形式和描述使用这些剂量形式来介导、减少或防止HBV感染的方法的说明书。说明书可以指导消费者或医务人员根据本领域技术人员已知的施用模式来施用剂量形式。这些试剂盒可以有利地以单个试剂盒单元或多个试剂盒单元进行包装并且出售。这种试剂盒的实例为所谓的泡罩包装。泡罩包装在包装工业中是熟知的并且广泛用于包装单位剂量形式药物(片剂、胶囊等)。泡罩包装通常由以优选透明塑性材料薄片覆盖的相对硬质材料薄板构成。在包装过程中,在塑料薄片中会形成凹槽。凹槽具有待包装的片剂或胶囊的尺寸和形状。接着,将片剂或胶囊放置在所述凹槽中,并且相对硬质材料薄板在与形成凹槽的方向相反的薄片一侧封住所述塑料薄片。因此,片剂或胶囊被密封在塑料薄片与薄板之间的凹槽中。优选地,薄片的强度使得可以通过以下方式将片剂或胶囊从泡罩包装中去除:手动施加压力于凹槽处,从而在凹槽位置处的薄片中形成开口。然后可以通过所述开口将片剂或胶囊去除。
在所述试剂盒上提供例如呈片剂或胶囊旁边出现的数字形式的记忆辅助工具可能是合乎需要的,其中数字与应服用指定片剂或胶囊的给药方案的天数对应。这种记忆辅助工具的另一个实例是印刷在卡片上的日历,例如,如下“第一周、周一、周二”等、“第二周、周一、周二”等。记忆辅助工具的其它变化形式是显而易见的。“日剂量”可以是在给定日服用的单个片剂或胶囊或若干丸剂或胶囊。同时,第一化合物的日剂量可以由一个片剂或胶囊组成,而第二化合物的日剂量可以由若干片剂或胶囊组成,反之亦然。记忆辅助应反映这些内容。
IV.方法
在另一方面,提供了在有此需要的患者中治疗乙型肝炎感染的方法,其包括向受试者或患者给药有效量的所公开化合物,和/或给药第一公开化合物和任选地和额外的另一种公开化合物。在另一个实施方案中,提供了在有此需要的患者中治疗乙型肝炎感染的方法,其包括向所述受试者或患者给药治疗上有效量的公开的药物组合物或以下药物组合物,其包含一种所公开的化合物或两种或多种所公开化合物和药学上可接受的赋形剂。
为了符合这方面的使用,预期适当的剂量根据例如,所采用的具体化合物、给药方式和待治疗感染的性质和严重性以及待治疗的具体感染而变化,且在治疗医生的权限范围内。通常,指定的给药剂量可在约0.1至约1000μg/kg体重的范围内。在一些情况下,所述化合物的给药剂量可小于400μg/kg体重。在其他情况下,所述给药剂量可小于200μg/kg体重。还在其他情况下,所述给药剂量可在约0.1至约100μg/kg体重的范围内。所述剂量可以每日一次或以多达,例如每日四次的分开剂量或以持续释放的形式进行方便地施用。
本公开化合物可通过任意常规途径进行给药,具体地:经肠、局部、口服、经鼻,例如以片剂或胶囊的形式,通过栓剂或胃肠外,例如以可注射溶剂或混悬液的形式,用于静脉内、肌内、皮下或腹膜内注射。合适的制剂和药物组合物将包含使用一种或多种生理学可接受的载体或赋形剂以及任意已知和市售可得的和目前临床情况所采用的那些,以常规方式进行配制的那些。因此,所述化合物可被配制用于口服、含服、局部、胃肠外、直肠或经皮给药或被配制成适于吸入或吹入(经口或经鼻)的形式。
对于口服给药,药物组合物可以采取例如,片剂或胶囊的形式,其通过常规方式,用药学上可接受的赋形剂进行制备,所述赋形剂例如粘合剂(例如预胶化玉米淀粉、聚乙烯基吡咯烷酮或羟基丙基甲基纤维素);填充剂(例如乳糖、微晶纤维素或磷酸氢钙);润滑剂(例如硬脂酸镁、滑石或二氧化硅);崩解剂(例如马铃薯淀粉或淀粉羟乙酸钠);或润湿剂(例如月桂基硫酸钠)。片剂可通过本领域熟知的方法进行包衣。用于口服给药的液体制剂可采用,例如,溶液、糖浆或混悬液的形式,或它们可作为干燥产物的形式呈现,使用前用水或其他合适的媒介物进行重构。这种液体制剂可通过常规方式,用药学上可接受的添加剂例如悬浮剂(例如山梨糖醇糖浆、纤维素衍生物或氢化可食用脂肪);乳化剂(例如卵磷脂或阿拉伯胶);非水媒介物(例如杏仁油、油酯、乙醇或分馏植物油);和防腐剂(例如对羟基苯甲酸甲基酯或对羟基苯甲酸丙基酯或山梨酸)进行制备。如果合适,制剂也可含有缓冲盐、调味剂、着色剂和甜味剂。
用于口服给药的制剂也可被适当地配制,以在延长的时间内提供控制释放或持续释放活性化合物。对于含服给药,所述组合物可采用以本领域技术人员已知的常规方式配制的片剂或锭剂形式。
所公开化合物也可被配制用于通过注射进行胃肠外给药,例如推注或连续输注。用于注射的制剂可以单位剂型(例如安瓿或多剂量容器)提供,其添加有防腐剂。所述组合物可采用如在油性或水性媒介物中的混悬液、溶液或乳液的形式且可含有添加剂,例如悬浮剂、稳定剂和/或分散剂。或者,所述化合物可为粉末形式,其用于在使用前与合适的媒介物(例如无菌无热原水)进行重构。化合物还可被配制用于作为栓剂或保留灌肠剂进行直肠给药,例如含有常规栓剂基质例如可可脂或其他甘油酯的栓剂或保留灌肠剂。
本文还考虑了包括第二活性剂或施用第二活性剂的方法和组合物。例如,除了被HBV感染之外,受试者或患者还可以具有与HBV感染相关的合并症,即与HBV感染有关,被其加重或加剧的疾病和其他不良健康状况。本文考虑了公开的化合物与至少一种其他药剂的组合,该其他药剂先前已显示可治疗这些HBV感染相关疾病。
在一些情况下,所公开化合物可作为与一种或多种抗病毒药物联合的组合疗法的一部分进行给药。所述抗病毒药物的实例包括核苷类似物、干扰素α和其他组装效应器,例如杂芳基二氢嘧啶(HAP),例如4-(2-氯-4-氟苯基)-6-甲基-2-(吡啶-2-基)-1,4-二氢嘧啶-5-甲酸甲酯(HAP-1)。例如,本文提供了治疗患有乙型肝炎感染的患者的方法,其包括向患者给药第一量的所公开化合物和第二量的抗病毒药物或其他抗HBV试剂,例如第二量的选自以下的第二化合物:HBV衣壳组装启动子(例如GLS4、BAY 41-4109、AT-130、DVR-23(例如,如下所描绘),
NVR 3-778、NVR1221(通过代码示出);和N890(如下所描绘):
其他衣壳抑制剂,如在以下引入本文作为参考的专利申请中所公开的那些:WO2014037480、WO2014184328、WO2013006394、WO2014089296、WO2014106019、WO2013102655、WO2014184350、WO2014184365、WO2014161888、WO2014131847、WO2014033176、WO2014033167和WO2014033170;干扰病毒聚合酶的核苷(酸)类似物,例如恩替卡韦(博路定)、拉米夫定(Epivir-HBV)、替比夫定(Tyzeka,Sebivo)、阿德福韦酯(贺维力)、替诺福韦(Viread)、替诺福韦艾拉酚胺富马酸盐(TAF,Tenofovir alafenamidefumarate)、替诺福韦的前药(例如AGX-1009)、L-FMAU(克来夫定)、LB80380(Besifovir)和:
病毒进入抑制剂,例如Myrcludex B及相关的脂肽衍生物;HBsAg分泌抑制剂,例如REP 9AC’及相关的基于核酸的两亲聚合物,如下所描绘的HBF-0529(PBHBV-001)、PBHBV-2-15:
以及如下所描绘的BM601:
核衣壳形成或完整性的干扰剂,例如NZ-4/W28F:
cccDNA形成抑制剂:例如BSBI-25、CCC-0346、CCC-0975(如下所描绘):
HBc定向转体(transbody),例如在Wang Y等人,Transbody against hepatitis Bvirus core protein inhibits hepatitis B virus replication in vitro,Int.Immunopharmacol(2014)中所述的那些,位于//dx.doi.org/10.1016/j.intimp.2015.01.028;抗病毒核心蛋白突变体(例如Cp183-V124W及相关的突变体,如在WO/2013/010069、WO2014/074906中所述的那些,其各自引入本文作为参考);HBx-相互作用抑制剂,例如靶向HBV RNA的RNAi、反义和基于核酸的聚合物,例如,RNAi(例如ALN-HBV、ARC-520、TKM-HBV、ddRNAi)、反义基因(ISIS-HBV)或基于核酸的聚合物:(REP2139-Ca);免疫刺激剂,例如干扰素α2a(罗扰素)、Intron A(干扰素α2b)、Pegasys(PEG干扰素α2a)、PEG化IFN 2b、IFNλ1a和PEG IFNλ1a、Wellferon、罗扰素、干复津、淋巴毒素β受体激动剂,例如CBE11和BS1;非干扰素免疫增强剂,例如胸腺素α-1(日达仙)和白细胞介素-7(CYT107);TLR-7/9激动剂如GS-9620、CYT003、瑞喹莫德(Resiquimod);亲环素抑制剂,例如NVP018;OCB-030;SCY-635;Alisporivir;NIM811及相关的环孢菌素类似物;疫苗,例如GS-4774、TG1050、核心抗原疫苗;SMAC模拟物,例如birinapant和其他IAP-拮抗剂;外遗传调节剂(Epigenetic modulator),例如KMT抑制剂(EZH1/2、G9a、SETD7、Suv39抑制剂)、PRMT抑制剂、HDAC抑制剂、SIRT激动剂、HAT抑制剂、WD拮抗剂(例如OICR-9429)、PARP抑制剂、APE抑制剂、DNMT抑制剂、LSD1抑制剂、JMJD HDM抑制剂和溴结构域拮抗剂;激酶抑制剂,例如TKB1拮抗剂、PLK1抑制剂、SRPK抑制剂、CDK2抑制剂、ATM&ATR激酶抑制剂;STING激动剂;利巴韦林;N-乙酰基半胱氨酸;NOV-205(BAM205);硝唑尼特(Alinia)、替唑尼特(Tizoxanide);SB9200小分子核酸杂交物(SMNH);DV-601;阿比朵尔(Arbidol);FXR激动剂(例如GW 4064和Fexaramin);抗体、治疗性蛋白、基因治疗和定向抗病毒成分或与宿主蛋白相互作用的生物制品。
在一些实施方案中,本公开提供了在需要的患者中治疗乙型肝炎感染的方法,其包括给药选自所公开的化合物中的任一个的第一化合物,和一种或者多种其它HBV药剂,所述其它HBV药剂各自选自HBV衣壳组装启动子、HBF病毒聚合酶干扰核苷、病毒进入抑制剂、HBsAg分泌抑制剂、核衣壳形成的破坏剂、cccDNA形成抑制剂、抗病毒核心蛋白突变体、HBc定向转体、靶向HBV RNA的RNAi、免疫刺激剂、TLR-7/9激动剂、亲环素抑制剂、HBV疫苗、SMAC模拟剂、外遗传调节剂、激酶抑制剂,和STING激动剂。在一些实施方案中,本公开提供了在需要的患者中治疗乙型肝炎感染的方法,其包括给药一定量的公开的化合物,并给药另一HBV衣壳组装启动子。
在一些实施方案中,所述第一剂量和第二剂量一起构成药学上有效量。所述第一剂量、第二剂量或这二者可以与作为单一疗法所给药的各化合物的有效量相同、可以比作为单一疗法所给药的各化合物的有效量更多或比作为单一疗法所给药的各化合物的有效量更少。治疗上有效量的所公开化合物和抗病毒药物可共同给药至所述受试者,即,以任意给定顺序且通过相同或不同的给药途径,同时或分开地给药至所述受试者。在一些情况下,在开始给药所述抗病毒药物前例如一天或数天或数周开始首次给药所公开化合物可能是有利的。此外,额外的药物可与上述组合疗法联合给药。
在另一个实施方案中,所公开化合物可与检测部分(例如荧光基团,该基团可例如一旦结合至病毒和/或一旦光子激发,便会再次发射一定的光频率)缀合(例如,直接或通过分子连接物共价连接至所公开化合物的游离碳、氮(例如氨基基团)或氧(例如活性酯))。预期的荧光基团包括[image]488(Invitrogen)和BODIPY FL(Invitrogen),以及荧光素、若丹明、花菁、indocarbocyanine、蒽醌、荧光蛋白、氨基香豆素、甲氧基香豆素、羟基香豆素、Cy2、Cy3等。这种公开的缀合至检测基团的化合物可用于例如检测HBV或HBV感染的生物学途径的方法,例如,体外或体内的方法;和/或评估新的化合物的生物学活性的方法。
实施例
本文描述的化合物可基于本文所含教导和本领域已知的合成性步骤,以各种方式进行制备。在下文所述的合成性方法的描述中,应理解,除非另外提及,所有建议的反应条件,包括溶剂、反应气氛、反应温度、试验的持续时间和后处理步骤的选择,可被选择为用于该反应的标准条件。有机合成领域技术人员应理解,该分子各部分中所存在的官能度应与所建议的试剂和反应相容。与反应条件不相容的取代基对于本领域技术人员将是明显的并因此指明了替代方法。用于实施例的起始原料是市售可得的或通过标准方法从已知的材料容易地制备。
本文中被称为“中间体”的化合物中的至少一些被认为是本公开的化合物。
缩写:
DCM 二氯甲烷
EtOAc 乙酸乙酯
MeOH 甲醇
DMSO 二甲基亚砜
ACN 乙腈
DIAD 偶氮二甲酸二异丙酯
DIEA 二异丙基乙基胺
nBuLi 正丁基锂
iPrOH 异丙醇
AcOH 乙酸
BOC2O 二碳酸二叔丁酯
Et3N 三乙胺
DMF N,N-二甲基甲酰胺
THF 四氢呋喃
TEA 三乙胺
TFA 三氟乙酸
TLC 薄层色谱法
LCMS 液相色谱–质谱分析
HPLC 高效液相色谱法
XPhos 2-二环己基膦-2’,4’,6’-三异丙基联苯
DPPF 1,1’-双(二苯基膦基)二茂铁
NMO N-甲基吗啉-N-氧化物
HATU 氮杂苯并三氮唑四甲基脲六氟磷酸盐
SFC 超临界流体色谱法
NBS N-溴琥珀酰亚胺
可用于合成本发明化合物的方法展示于下面的方案中。在方案I中,甲酸酯或氯化物I-1可与I-2缩合以提供中间体I-3,其随后使用适合的烷基卤化物(I-4)进行处理。可以使用适当取代的酰肼(I-6)处理获得的化合物(I-5)以形成5-胺基吡唑模板。皂化及酰胺键形成可以产生最终化合物I-10。
在方案II中,将5-胺基-吡唑酯II-1溴化并在适当条件下使用Ar2NH2处理以实现酯/酰胺交换反应。在催化(Pd(0)或Pd(II))条件下,获得的中间体II-3可以与II-9偶联以产生倒数第二个中间体II-10。氢化II-10以产生最终化合物II-11。如方案II中所展示,II-11含有2个手性中心,这意味着存在4种可能的非对映异构体构型。可以提供选择性合成单一非对映异构体或从其它的非对映异构体的混合物中选择性分离出单一非对映异构体的方法是公知的(Stereoselective Synthesis of Drugs and Natural Products,由VasylAndrushko及Natalia Andrushko编辑,由John Wiley&Sons,Inc于2013年出版)。
方案III说明本发明的某些化合物的立体选择性合成。根据Org.Biomol.Chem.,2012,10,1764中描述的方法,分别使用手性配体(R)-L-1或(S)-L-2,将芳基或杂-芳基(III-2)对映选择性加成至III-1,提供了S-对映异构体III-3(S)或III-3(R)。中间体III-3(S)及III-3(R)可以各自分别进行到非对映异构体混合物IV(R,S)/IV(S,S)和IV(R,R)/IV(S,R)。可以依据已知的方法分离非对映异构体混合物。
合成本发明化合物的其它的方法说明在方案IV中。选择性修饰二酮IV-1(Tetrahedron,1982,38,63)以产生硼酸酯IV-3,可以使该硼酸酯偶合至溴-吡唑中间体II-3。还原获得的化合物IV-4以产生IV-5。对获得的IV-6的醇基团进行酮还原并活化以提供中间体IV-7,其可以通过使用NucH(IV-8)进行亲核取代以获得IV-9。或者,IV-5的酮基团适于使用IV-10进行还原胺化以产生IV-11。如方案中所示,IV-9和IV-11均可以至少以4种不同的非对映异构体构型存在。基于已知的立体选择性反应原理,可以选择反应条件和途径以相对于其它的非对映异构体,有利于形成一种非对映异构体。另外,使用已知的条件分离IV-9和IV-11的各个非对映异构体。
在方案V中,自IV-5合成的肟V-1可以进行还原以产生胺V-2。所述胺基团可以进一步反应以提供磺酰胺(V-4)或酰胺(V-6)。
另外的合成方法说明在方案VI中。可以使用已知条件将中间体IV-5转化成相应环氧化物VI-1。该中间体可以通过与各种亲核试剂(NucH,VI-2)反应进行转变以形成由VI-3代表的化合物。在VI-3是硫化物的情况下,则可以通过将硫原子氧化成相应砜VI-5来实现进一步修饰。形成VI-5的第二方法涉及使IV-5与磺酰胺VI-4的砜的相应的阴离子进行反应。VI-5和VI-3可以至少4种不同非对映异构体构型存在,如在方案中所说明。基于已知立体选择性反应原理,可以选择反应条件和途径以相对于其它的非对映异构体,有利于形成一种非对映异构体。另外,使用已知的条件分离VI-3和VI-5的各个非对映异构体。
在方案VII中,将Boc保护的VII-I转化成相应的硼酸酯VI-3且根据先前方案中描述的方法偶联至II-3。在偶联反应后,将VII-4氢化以提供VII-5。在去除Boc保护基团后,化合物VII-6可以通过与适当亲电子剂反应进行到VII-8或通过烷基化或还原烷基化进行至VII-11。
方案VIII说明含有亚砜的化合物VIII-6的合成。使用上面描述的方法,合成化合物VIII-5,其可以经氧化以形成VIII-6。
方案I
方案II
方案III
方案IV
方案V
方案VI
方案VII
方案VIII
中间体1
3-苯基环丁烷-1-甲酰氯.将3-苯基环丁烷甲酸(1g,5.68mmol,1当量)在SOCl2(5mL)中的澄清溶液在80℃下搅拌1小时。将该反应物在真空下浓缩以得到粗制浅黄色油状物。将所述油状物用DCM(10mL)稀释。将溶液在真空下浓缩以得到作为浅黄色油状物的3-苯基环丁烷甲酰氯(1.1g,粗制)。
中间体2
2-氰基-3-羟基-3-(3-苯基环丁基)丙烯酸乙酯.在0℃,向2-氰基乙酸乙酯(1.28g,11.30mmol,1.21mL,2当量)在THF(20mL)的溶液中加入60%在矿物油中的NaH(565.04mg,14.13mmol,60%纯度,2.5当量)。将反应搅拌1小时。在0℃,将3-苯基环丁烷甲酰氯(1.1g,5.65mmol,1当量)在THF(10mL)中的溶液逐滴加入。将该反应温热至25℃并搅拌16小时。将该反应用NH4Cl(20mL)水溶液淬灭并用乙酸乙酯(10mLx2)萃取。将有机层合并,用盐水(10mL)洗涤,用Na2SO4干燥,过滤并在真空下浓缩以获得作为棕色油状物的2-氰基-3-羟基-3-(3-苯基环丁基)丙烯酸乙酯(1.8g,粗制)。1H NMR(400MHz,氯仿-d)δppm 1.37-1.43(m,3H)2.51-2.74(m,3H)2.76-2.84(m,1H)3.63-3.73(m,1H)3.74-3.87(m,1H)4.33-4.41(m,2H)7.21-7.40(m,5H)。
中间体3
2-氰基-3-乙氧基-3-(3-苯基环丁基)丙烯酸乙酯.将2-氰基-3-羟基-3-(3-苯基环丁基)丙-2-烯酸乙酯(1.7g,6.27mmol,1当量),Ag2CO3(4.32g,15.66mmol,0.710mL,2.5当量)和EtI(4.89g,31.33mmol,2.51mL,5当量)在DCM(50mL)的悬浮液在25℃搅拌16小时。将反应通过垫过滤,并将滤饼用DCM(10mLx2)洗涤。将滤液在真空下浓缩以获得作为黄色油状物的粗制产物(1.8g)。将残留物使用快速色谱进行纯化(12g硅胶快速柱,0~5%乙酸乙酯/石油醚梯度@20mL/min洗脱)以获得作为无色油状物的2-氰基-3-乙氧基-3-(3-苯基环丁基)丙烯酸乙酯(1.2g)。1H NMR(400MHz,氯仿-d)δppm 1.29-1.37(m,3H)1.45-1.55(m,3H)2.18(d,J=7.03Hz,1H)2.25-2.42(m,1H)2.45-2.70(m,3H)3.39-3.49(m,1H)4.16-4.42(m,2H)4.67-4.84(m,2H)7.18-7.35(m,5H)。
中间体4
5-氨基-1-甲基-3-(3-苯基环丁基)-1H-吡唑-4-甲酸乙酯.2-氰基-3-乙氧基-3-(3-苯基环丁基)丙-2-烯酸乙酯(1.2g,4.01mmol,1当量)、甲基肼-硫酸(577.83mg,4.01mmol,1当量)和TEA(1.42g,14.03mmol,1.95mL,3.5当量)在EtOH(15mL)的黄色混合物在70℃搅拌1小时。LCMS展示出若干新峰,并且检测到25.1%需要的化合物。将该反应用NH4Cl(10mL)水溶液淬灭并用乙酸乙酯(10mLx2)萃取。合并有机层并用盐水(10mL)洗涤,用Na2SO4干燥,过滤,并在真空下浓缩以获得作为棕色油状物的粗制品(1.6g)。将残留物使用快速硅胶色谱进行纯化(4g硅胶快速柱,0~31%乙酸乙酯/石油醚梯度@20mL/min洗脱)以获得作为黄色油状物的5-氨基-1-甲基-3-(3-苯基环丁基)吡唑-4-甲酸乙酯(220mg,0.652mmol,15.3%产率,88.7%纯度)。1H NMR(400MHz,氯仿-d)δppm 1.26-1.42(m,3H)2.36-2.84(m,4H)3.04-3.92(m,2H)4.14-4.33(m,2H)4.92-5.10(m,1H)7.13-7.28(m,2H)7.29-7.36(m,3H);LC-MS:300.2[M+1]+。
中间体5
5-氨基-1-甲基-3-(3-苯基环丁基)-1H-吡唑-4-甲酸.将5-氨基-1-甲基-3-(3-苯基环丁基)吡唑-4-甲酸乙酯(220mg,0.652mmol,1当量)和LiOH-H2O(273.43mg,6.52mmol,10当量)在THF(3mL)、MeOH(3mL)和H2O(3mL)中的混合物在70℃搅拌64小时。将该反应物在真空下浓缩以除去THF和MeOH。将该混合物用1N HCl调整至pH 6并用乙酸乙酯(50mLx2)萃取。将有机层合并,用盐水(40mL)洗涤,用Na2SO4干燥,过滤并在真空下浓缩以获得作为黄色油状物的粗制5-氨基-1-甲基-3-(3-苯基环丁基)-1H-吡唑-4-甲酸(200mg,粗制)。LC-MS:272.1[M+1]+。
中间体6
5-氨基-1-甲基-3-(3-苯基环丁基)-1H-吡唑-4-甲酰氯.将5-氨基-1-甲基-3-(3-苯基环丁基)吡唑-4-甲酸(190mg,0.70mmol)在SOCl2(3mL)的溶液在80℃搅拌1小时。将该反应物在真空下浓缩以获得作为黄色油状物的粗制5-氨基-1-甲基-3-(3-苯基环丁基)-1H-吡唑-4-甲酰氯(200mg),其无需进一步纯化即用于下一步中。
AIA 224A和AIA 224B
5-氨基-N-(3-氯-4-氟苯基)-1-甲基-3-(3-苯基环丁基)-1H-吡唑-4-甲酰胺,非对映异构体1和非对映异构体2.在0℃,于N2中向5-氨基-1-甲基-3-(3-苯基环丁基)吡唑-4-甲酰氯(200mg,0.690mmol)和3-氯-4-氟-苯胺(100.47mg,0.690mmol)在DCM(5mL)的溶液中逐滴加入Et3N(209.53mg,2.07mmol,0.288mL,3当量)。将该反应温热至25℃并搅拌15小时以获得棕色溶液。将该反应用NH4Cl(20mL)水溶液淬灭。分离水相并用DCM(10mL)萃取。合并有机层并用盐水(10mL)洗涤,用Na2SO4干燥,过滤并在真空下浓缩以获得作为棕色油状物的粗制5-氨基-N-(3-氯-4-氟苯基)-1-甲基-3-(3-苯基环丁基)-1H-吡唑-4-甲酰胺(300mg)。将残留物使用快速硅胶色谱进行纯化(4g硅胶快速柱,0~30%乙酸乙酯/石油醚梯度@20mL/min洗脱)以获得5-氨基-N-(3-氯-4-氟-苯基)-1-甲基-3-(3-苯基环丁基)吡唑-4-甲酰胺(100mg,0.225mmol,32.56%产率,89.637%纯度),其为2种非对映异构体的混合物。将该非对映异构体通过制备型HPLC(柱:Xtimate C18150x25mmx5um;流动相:[水(0.05%氢氧化铵v/v)-ACN];B%:52%-92%,12min)分离。5-氨基-N-(3-氯-4-氟苯基)-1-甲基-3-(3-苯基环丁基)-1H-吡唑-4-甲酰胺(AIA-224A);1HNMR(400MHz,DMSO-d6)δppm 2.21-2.33(m,2H)2.62-2.69(m,2H)3.45-3.54(m,4H)3.84-3.98(m,1H)6.10(s,2H)7.11-7.24(m,3H)7.25-7.32(m,2H)7.36(t,J=9.11Hz,1H)7.57(ddd,J=9.05,4.28,2.69Hz,1H)7.95(dd,J=6.91,2.63Hz,1H)8.70(s,1H);LC-MS:399.2[M+1]+。5-氨基-N-(3-氯-4-氟苯基)-1-甲基-3-(3-苯基环丁基)-1H-吡唑-4-甲酰胺(AIA-224B);1H NMR(400MHz,DMSO-d6)δppm 2.21-2.33(m,2H)2.62-2.69(m,2H)3.45-3.54(m,4H)3.84-3.98(m,1H)6.10(s,2H)7.11-7.24(m,3H)7.25-7.32(m,2H)7.36(t,J=9.11Hz,1H)7.57(ddd,J=9.05,4.28,2.69Hz,1H)7.95(dd,J=6.91,2.63Hz,1H)8.70(s,1H);LC-MS:399.2[M+1]+。
中间体7
5-氨基-3-溴-1-甲基-1H-吡唑-4-甲酸乙酯.向5-氨基-1-甲基-吡唑-4-甲酸乙酯(0.206g,1.22mmol,1当量)在EtOH(5mL)的黄色溶液中加入乙酸钠(929.89mg,11.34mmol,9.28当量)在H2O(8mL)的溶液,然后逐滴加入Br2(1.12g,7.04mmol,362.82uL,5.78当量)。将橙色悬浮液在15℃搅拌3小时。将反应混合物倾倒入H2O(15mL)。将该混合物用乙酸乙酯(3x20mL)萃取。合并有机层并用饱和硫代硫酸钠水溶液(2x5mL)洗涤,干燥(Na2SO4),过滤并在减压下浓缩。将固体用甲基叔丁基醚:石油醚(1:10)(10mL)溶液研制5分钟。获得作为黄色固体的5-氨基-3-溴-1-甲基-吡唑-4-甲酸乙酯(0.24g,967.44umol,79.45%产率)。1HNMR(400MHz,氯仿-d)δppm 1.38(t,J=7.15Hz,3H)3.61(s,3H)4.32(q,J=7.13Hz,2H)5.14(br s,2H)。
中间体8
5-氨基-3-溴-N-(3-氯-4-氟苯基)-1-甲基-1H-吡唑-4-甲酰胺在0℃,向3-氯-4-氟-苯胺(281.65mg,1.93mmol,2当量在甲苯(6mL)的无色溶液中加入Me3Al(2M在甲苯中)(2M,1.45mL,3当量)。将浅棕色溶液温热至15℃并搅拌0.5小时。向该溶液加入5-氨基-3-溴-1-甲基-吡唑-4-甲酸乙酯(0.24g,967.44umol,1当量)。将棕色溶液在80℃搅拌16小时。观察到深棕色悬浮液。将该混合物冷却至0℃并用1N HCl(2mL)淬灭。观察到棕色悬浮液。将该混合物过滤。将滤液用水(10mL)稀释,用EtOAc(15mLx3)萃取。将有机层合并,用MgSO4干燥,过滤并在真空下浓缩以获得作为黄色固体的残留物。将该残留物用甲基叔丁基醚(3mL)研制5分钟。获得作为浅黄色固体的5-氨基-3-溴-N-(3-氯-4-氟-苯基)-1-甲基-吡唑-4-甲酰胺(0.1g,275.30umol,28.46%产率,95.732%纯度)。1H NMR(400MHz,氯仿-d)δppm 1.57(s,3H)3.64(s,3H)5.53(br s,2H)7.12(t,J=8.74Hz,1H)7.29-7.41(m,1H)7.80(dd,J=6.54,2.63Hz,1H)8.34(br s,1H)。
中间体9
3-(1-甲基-1H-吡唑-4-基)环戊-2-烯-1-酮.在N2气氛将3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)环戊-2-烯-1-酮(5.0g,24.0mmol),4-溴-1-甲基-1H-吡唑(3.9g,24.0mmol),K3PO4(10.2mg,48.0mmol)和Pd(dppf)Cl2(880mg,1.2mmol)在二噁烷(80mL)和H2O(20mL)中的混合物在80℃搅拌过。真空下除去溶剂并将残留物用硅胶柱色谱进行纯化,其使用1:9石油醚/乙酸乙酯以获得作为黄色固体的3-(1-甲基-1H-吡唑-4-基)环戊-2-烯-1-酮(1.8g,46%产率)。MS理论值:162.1,MS实际值:163.4[M+1]+。
中间体10
3-(1-甲基-1H-吡唑-4-基)环戊酮,对映异构体1和对映异构体2.将3-(1-甲基-1H-吡唑-4-基)环戊-2-烯-1-酮(1.8g,11.1mmol)和Pd/C(900mg,10%纯度)在EtOH(50mL)中的混合物脱气并用H2气氛吹扫5次。在H2(5atm)下,将该混合物在80℃搅拌过夜。将反应通过垫过滤,并将滤饼用EtOH(10mLx3)洗涤。将滤液在真空下浓缩,并将残留物通过硅胶柱色谱进行纯化(其使用1:1石油醚/乙酸乙酯)以获得作为黄色油状物的3-(1-甲基-1H-吡唑-4-基)环戊酮(1.0g,56%产率)。MS理论值:164.1,MS实际值:165.4[M+1]+。将该物质通过SFC分离以获得3-(1-甲基-1H-吡唑-4-基)环戊酮的纯的对映异构体1和对映异构体2。
中间体11
三氟甲磺酸3-(1-甲基-1H-吡唑-4-基)环戊-1-烯基酯,对映异构体1.在-78℃向3-(1-甲基-1H-吡唑-4-基)环戊酮(400mg,2.4mmol)的对映异构体1在THF(10mL)的溶液中加入LiHMDS(3.6mmol,1M,3.6mL,)。将该反应混合物在-78℃搅拌1h并且然后用1,1,1-三氟-N-苯基-N-(三氟甲磺酰基)甲烷磺酰胺(1.3g,3.6mmol)在THF(5mL)的溶液处理。将该反应混合物温热至30℃并搅拌4h。通过在25℃加入NH4Cl(2mL)将该反应混合物淬灭,用H2O(10mL)稀释并用EtOAc(20mLx2)萃取。将合并的有机层用盐水(20mL)洗涤,用Na2SO4干燥,过滤并在减压下浓缩。将残留物通过硅胶柱色谱进行纯化,其使用3:1石油醚/乙酸乙酯以获得作为无色油状物的三氟甲磺酸3-(1-甲基-1H-吡唑-4-基)环戊-1-烯基酯,对映异构体1(450mg,63%产率)。MS理论值:296.0,MS实际值:297.2[M+1]+。
中间体12
1-甲基-4-(3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)环戊-2-烯基)-1H-吡唑,对映异构体1在N2气氛下,三氟甲磺酸3-(1-甲基-1H-吡唑-4-基)环戊-1-烯基酯的将对映异构体1(450mg,1.5mmol),4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1,3,2-二氧杂硼杂环戊烷(580mg,2.3mmol),Pd(dppf)Cl2(55mg,0.075mmol)和乙酸钾(230mg,2.3mmol)在二噁烷(10mL)中的混合物在80℃搅拌4h。将该反应物通过硅藻土垫进行过滤,将滤饼用EtOAc(10mLx3)洗涤。将滤液在真空下浓缩并将残留物用硅胶柱色谱进行纯化,其使用3:1石油醚/乙酸乙酯以获得作为无色油状物的1-甲基-4-(3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)环戊-2-烯基)-1H-吡唑对映异构体1(330mg,79%产率)。MS理论值:274.2,MS实际值:275.4[M+1]+。
中间体13
5-氨基-N-(3-氯-4-氟苯基)-1-甲基-3-(3-(1-甲基-1H-吡唑-4-基)环戊-1-烯基)-1H-吡唑-4-甲酰胺对映异构体1.在N2气氛下,将5-氨基-3-溴-N-(3-氯-4-氟苯基)-1-甲基-1H-吡唑-4-甲酰胺(348mg,1.0mmol),1-甲基-4-(3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)环戊-2-烯基)-1H-吡唑的对映异构体1(330mg,1.2mmol),K3PO4(510mg,2.4mmol)和Pd(dppf)Cl2(44mg,0.06mmol)在二噁烷(10mL)和H2O(2mL)中的混合物于95℃搅拌2h。真空下除去溶剂,并将残留物通过硅胶柱色谱进行纯化(其使用1:9石油醚/乙酸乙酯)以获得作为白色固体的5-氨基-N-(3-氯-4-氟苯基)-1-甲基-3-(3-(1-甲基-1H-吡唑-4-基)环戊-1-烯基)-1H-吡唑-4-甲酰胺对映异构体1(250mg,64%产率)。MS理论值:414.1,MS实际值:415.3[M+1]+。
AIA004-A和AIA-004-B
5-氨基-N-(3-氯-4-氟苯基)-1-甲基-3-(3-(1-甲基-1H-吡唑-4-基)环戊基)-1H-吡唑-4-甲酰胺,非对映异构体1(AIA-004A)和非对映异构体2(AIA-004B).在10atm H2下,将5-氨基-N-(3-氯-4-氟苯基)-1-甲基-3-(3-(1-甲基-1H-吡唑-4-基)环戊-1-烯基)-1H-吡唑-4-甲酰胺的对映异构体1(250mg,0.6mmol)和RhCl(PPh3)3(28mg,0.03mmol)在MeOH(20mL)中的混合物在60℃搅拌过夜。真空下除去溶剂并将残留物用硅胶柱色谱进行纯化,其使用1:9石油醚/乙酸乙酯以获得5-氨基-N-(3-氯-4-氟苯基)-1-甲基-3-(3-(1-甲基-1H-吡唑-4-基)环戊基)-1H-吡唑-4-甲酰胺,其作为非对映异构体的混合物,所述混合物通过SFC分离以获得作为白色固体的非对映异构体1(AIA-004-A)(20mg)和作为白色固体的非对映异构体2(AIA-004-B)(6mg)。AIA-004-A:1H-NMR(DMSO-d6,400MHz):δ8.91(s,1H),7.91(dd,J=6.8,2.4Hz,1H),7.53-7.49(m,1H),7.44(s,1H),7.34(t,J=9.2Hz,1H),7.24(s,1H),6.02(s,2H),3.77-3.74(m,4H),3.51(s,3H),3.02-2.98(m,1H),2.16-2.11(m,1H),2.08-2.00(m,2H),1.94-1.89(m,2H),1.55-1.50(m,1H).AIA-004-B:1H-NMR(DMSO-d6,400MHz):δ8.91(s,1H),7.91(dd,J=6.8,2.4Hz,1H),7.52-7.48(m,1H),7.44(s,1H),7.34(t,J=9.2Hz,1H),7.24(s,1H),6.01(s,2H),3.77-3.74(m,4H),3.51(s,3H),3.02-2.98(m,1H),2.16-2.11(m,1H),2.08-2.00(m,2H),1.94-1.89(m,2H),1.55-1.50(m,1H)。
AIA-004C和AIA-004D
5-氨基-N-(3-氯-4-氟苯基)-1-甲基-3-(3-(1-甲基-1H-吡唑-4-基)环戊基)-1H-吡唑-4-甲酰胺,非对映异构体3(AIA-004C)和非对映异构体4(AIA-004D).由3-(1-甲基-1H-吡唑-4-基)环戊酮的对映异构体2合成标题化合物,其使用描述于5-氨基-N-(3-氯-4-氟苯基)-1-甲基-3-(3-(1-甲基-1H-吡唑-4-基)环戊基)-1H-吡唑-4-甲酰胺,非对映异构体1(AIA-004A)和非对映异构体2(AIA-004B)的相同的方法。AIA-004C:1H-NMR(DMSO-d6,400MHz):δ8.90(s,1H),7.91(dd,J=6.8,2.4Hz,1H),7.53-7.49(m,1H),7.44(s,1H),7.34(t,J=9.2Hz,1H),7.24(s,1H),6.01(s,2H),3.78-3.74(m,4H),3.51(s,3H),3.02-2.98(m,1H),2.16-2.11(m,1H),2.08-2.00(m,2H),1.94-1.89(m,2H),1.55-1.50(m,1H).AIA-004D:1H-NMR(DMSO-d6,400MHz):δ8.94(s,1H),7.93(dd,J=6.8,2.4Hz,1H),7.56-7.52(m,1H),7.45(s,1H),7.35(t,J=9.2Hz,1H),7.23(s,1H),6.00(s,2H),3.74(s,3H),3.67-3.62(m,1H),3.50(s,3H),2.97-2.93(m,1H),2.28-2.23(m,1H),2.01-1.97(m,2H),1.90-1.86(m,1H),1.78-1.69(m,1H),1.56-1.51(m,1H)。
中间体14
(S)-3-(4-甲氧基苯基)环戊酮.在氮气气氛下,将RhCl[(C2H4)2]2(30mg,0.08mmol),(R)-N-肉桂基-2-甲基丙烷-2-亚磺酰胺(R)-L-1(Org.Biomol.Chem.,2012,10,1764)(38mg,0.16mmol)和(4-甲氧基苯基)硼酸(1.2g,8.0mmol)在二噁烷(10mL)的溶液于40℃搅拌0.5h。向该混合物中加入环戊-2-烯-1-酮(330mg,4.0mmol)和K3PO4水溶液(1.6mL,1.5mmol/L,2.5mmol)。在于40℃搅拌1h后,将该混合物在减压下浓缩并将残留物用硅胶柱色谱进行纯化(其使用6:1石油醚/乙酸乙酯)以获得作为无色油状物的的(S)-3-(4-甲氧基苯基)环戊酮(690mg,91%产率和97%ee)。MS理论值:190.1,MS实际值:191.3[M+1]+。
中间体15
三氟甲磺酸(S)-3-(4-甲氧基苯基)环戊-1-烯基酯.在0℃,向(S)-3-(4-甲氧基苯基)环戊酮(690mg,3.6mmol)和Tf2O(1.5g,5.4mmol)在DCM(10mL)的溶液中逐滴加入2,6-二-叔丁基-4-甲基-吡啶(1.5g,7.2mmol)。将该反应温热至40℃并搅拌2h以获得黑色悬浮液。将该反应物在真空下浓缩。将石油醚(5mL)加入到该棕色固体中,将该混合物搅拌2min,过滤,并将滤饼用石油醚(2mL)洗涤。将滤液在真空下浓缩以获得作为棕色油状物的三氟甲磺酸(S)-3-(4-甲氧基苯基)环戊-1-烯基酯(1.1g粗制,92%产率)。MS理论值:322.0,MS实际值:323.0[M+1]+.
中间体16
(S)-2-(3-(4-甲氧基苯基)环戊-1-烯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷.在N2气氛下,将三氟甲磺酸(S)-3-(4-甲氧基苯基)环戊-1-烯基酯(1.1g,3.4mmol),4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1,3,2-二氧杂硼杂环戊烷(1.3g,5.1mmol),Pd(dppf)Cl2(125mg,0.17mmol)和乙酸钾(500mg,5.1mmol)在二噁烷(10mL)中的混合物在80℃搅拌4h。将反应通过垫过滤,并将滤饼用EtOAc(10mLx3)洗涤。将滤液在真空下浓缩,并将残留物通过硅胶柱色谱进行纯化(其使用15:1石油醚/乙酸乙酯)以获得作为黄色油状物的(S)-2-(3-(4-甲氧基苯基)环戊-1-烯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷(700mg,68%产率)。MS理论值:300.2,MS实际值:301.3[M+1]+。
中间体17
(S)-5-氨基-N-(3-氯-4-氟苯基)-3-(3-(4-甲氧基苯基)环戊-1-烯基)-1-甲基-1H-吡唑-4-甲酰胺.在N2气氛下,将5-氨基-3-溴-N-(3-氯-4-氟苯基)-1-甲基-1H-吡唑-4-甲酰胺(348mg,1.0mmol),(S)-2-(3-(4-甲氧基苯基)环戊-1-烯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷(700mg,2.3mmol),K3PO4(424mg,2.0mmol)和Pd(dppf)Cl2(73mg,0.1mmol)在二噁烷(10mL)和H2O(2mL)中的混合物于95℃搅拌2h。真空下除去溶剂,并将残留物通过硅胶柱色谱进行纯化(其使用1:1石油醚/乙酸乙酯)以获得作为黄色固体的(S)-5-氨基-N-(3-氯-4-氟苯基)-3-(3-(4-甲氧基苯基)环戊-1-烯基)-1-甲基-1H-吡唑-4-甲酰胺(300mg,68%产率)。MS理论值:440.1,MS实际值:441.1[M+1]+。
AIA-003A和AIA-003B
5-氨基-N-(3-氯-4-氟苯基)-3-((1R,3S)-3-(4-甲氧基苯基)环戊基)-1-甲基-1H-吡唑-4-甲酰胺(AIA-003A)和5-氨基-N-(3-氯-4-氟苯基)-3-((1S,3S)-3-(4-甲氧基苯基)环戊基)-1-甲基-1H-吡唑-4-甲酰胺(AIA-003B):在10atm H2下,将(S)-5-氨基-N-(3-氯-4-氟苯基)-3-(3-(4-甲氧基苯基)环戊-1-烯基)-1-甲基-1H-吡唑-4-甲酰胺(300mg,0.68mmol)和RhCl(PPh3)3(31mg,0.034mmol)在MeOH(20mL)中的混合物在60℃搅拌过夜。真空下除去溶剂,并将残留物通过硅胶柱色谱进行纯化(其使用1:1石油醚/乙酸乙酯)以获得5-氨基-N-(3-氯-4-氟苯基)-3-3-(4-甲氧基苯基)环戊基)-1-甲基-1H-吡唑-4-甲酰胺(AP-AIA-003A和AIA-003B的混合物),其通过SFC分离以获得作为白色固体的5-氨基-N-(3-氯-4-氟苯基)-3-((1R,3S)-3-(4-甲氧基苯基)环戊基)-1-甲基-1H-吡唑-4-甲酰胺(AIA-003A)(80mg)和作为白色固体的5-氨基-N-(3-氯-4-氟苯基)-3-((1S,3S)-3-(4-甲氧基苯基)环戊基)-1-甲基-1H-吡唑-4-甲酰胺(AIA-003(10mg)。AIA-003-A:1H-NMR(DMSO-d6,400MHz):δ8.97(s,1H),7.93(dd,J=6.8,2.8Hz,1H),7.57-7.53(m,1H),7.35(t,J=9.2Hz,1H),7.17(d,J=8.8Hz,2H),6.83(d,J=8.8Hz,2H),6.00(s,2H),3.72-3.67(m,4H),3.52(s,3H),3.08-3.03(m,1H),2.29-2.03(m,1H),2.07-1.99(m,2H),1.95-1.80(m,2H),1.64-1.58(m,1H).AIA-003-B:1H-NMR(DMSO-d6,400MHz):δ8.96(s,1H),7.91(dd,J=6.8,2.8Hz,1H),7.56-7.52(m,1H),7.34(t,J=9.2Hz,1H),7.16(d,J=8.4Hz,2H),6.81(d,J=8.8Hz,2H),6.03(s,2H),3.85-3.82(m,1H),3.70(s,3H),3.52(s,3H),3.10-3.06(m,1H),2.17-2.05(m,3H),1.99-1.88(m,2H),1.62-1.56(m,1H)。
AIA-003C和AIA-003D
5-氨基-N-(3-氯-4-氟苯基)-3-((1S,3R)-3-(4-甲氧基苯基)环戊基)-1-甲基-1H-吡唑-4-甲酰胺(AIA-003C)和5-氨基-N-(3-氯-4-氟苯基)-3-((1R,3R)-3-(4-甲氧基苯基)环戊基)-1-甲基-1H-吡唑-4-甲酰胺(AIA-003D):根据描述于AIA-003A和AIA-003B的操作合成标题化合物,其使用手性配体(S)-N-肉桂基-2-甲基丙烷-2-亚磺酰胺(S)-L-1(Org.Biomol.Chem.,2012,10,1764)。AIA-003C:1H-NMR(DMSO-d6,400MHz):δ8.96(s,1H),7.91(dd,J=6.8,2.8Hz,1H),7.56-7.52(m,1H),7.34(t,J=9.2Hz,1H),7.16(d,J=8.4Hz,2H),6.81(d,J=8.8Hz,2H),6.03(s,2H),3.86-3.82(m,1H),3.70(s,3H),3.52(s,3H),3.10-3.06(m,1H),2.17-2.05(m,3H),1.99-1.88(m,2H),1.62-1.56(m,1H).AIA-003D:1H-NMR(DMSO-d6,400MHz):δ8.97(s,1H),7.93(dd,J=6.8,2.8Hz,1H),7.57-7.53(m,1H),7.35(t,J=9.2Hz,1H),7.17(d,J=8.8Hz,2H),6.83(d,J=8.8Hz,2H),6.00(s,2H),3.72-3.67(m,4H),3.52(s,3H),3.08-3.03(m,1H),2.29-2.03(m,1H),2.07-1.99(m,2H),1.95-1.80(m,2H),1.64-1.58(m,1H)。
AIA-005A和AIA-005B
5-氨基-N-(3-氯-4-氟苯基)-1-甲基-3-((1R,3S)-3-(4-(1-甲基-1H-吡唑-4-基)苯基)环戊基)-1H-吡唑-4-甲酰胺(AIA-050A)和5-氨基-N-(3-氯-4-氟苯基)-1-甲基-3-((1S,3S)-3-(4-(1-甲基-1H-吡唑-4-基)苯基)环戊基)-1H-吡唑-4-甲酰胺(AIA-050B):根据描述于AIA-003A和AIA-003B的操作合成标题化合物。AIA-050-A:1H-NMR(DMSO-d6,400MHz):δ8.94(s,1H),8.05(s,1H),7.93(dd,J=7.2,2.8Hz,1H),7.79(s,1H),7.56-7.52(m,1H),7.43(d,J=8.4Hz,2H),7.34(t,J=9.2Hz,1H),7.23(d,J=8.0Hz,2H),6.04(s,2H),3.88-3.84(m,4H),3.53(s,3H),3.15-3.09(m,1H),2.20-2.08(m,3H),2.03-1.91(m,2H),1.67-1.62(m,1H).AIA-050-B:1H-NMR(DMSO-d6,400MHz):δ8.98(s,1H),8.06(s,1H),7.94(dd,J=6.8,2.8Hz,1H),7.79(s,1H),7.58-7.54(m,1H),7.45(d,J=8.4Hz,2H),7.36(t,J=9.2Hz,1H),7.23(d,J=8.0Hz,2H),6.01(s,2H),3.85(s,3H),3.73-3.67(m,1H),3.53(s,3H),3.13-3.07(m,1H),2.33-2.26(m,1H),2.09-1.95(m,2H),1.92-1.86(m,2H),1.69-1.63(m,1H).
AIA-124-A和AIA-124-B
5-氨基-N-(3-氯-4-氟苯基)-1-甲基-3-((1R,3S)-3-(4-(1-甲基-1H-咪唑-4-基)苯基)环戊基)-1H-吡唑-4-甲酰胺(CP-AIA-124-B)和5-氨基-N-(3-氯-4-氟苯基)-1-甲基-3-((1S,3S)-3-(4-(1-甲基-1H-咪唑-4-基)苯基)环戊基)-1H-吡唑-4-甲酰胺(CP-AIA-124-A).根据描述于AIA-003A和AIA-003B的操作合成标题化合物。CP-AIA-124-A:1H-NMR(DMSO-d6,400MHz):δ8.94(s,1H),7.92(dd,J=2.4,6.8Hz,1H),7.60(t,J=8.0Hz,3H),7.54-7.51(m,2H),7.33(t,J=9.2Hz,1H),7.21(d,J=8.4Hz,2H),6.05(s,2H),3.86(t,J=8.0Hz,1H),3.67(s,3H),3.53(s,3H),3.12(t,J=8.0Hz,1H),2.20-2.08(m,3H),2.00-1.94(m,2H),1.65(t,J=8.4Hz,1H).CP-AIA-124-B:1H-NMR(DMSO-d6,400MHz):δ8.98(s,1H),7.93(dd,J=2.4,6.8Hz,1H),7.65-7.52(m,5H),7.36(t,J=9.2Hz,1H),7.23(d,J=8.4Hz,2H),6.02(s,2H),3.71(t,J=9.6Hz,1H),3.67(s,3H),3.53(s,3H),2.33-2.27(m,1H),2.10-2.04(m,2H),2.02-1.87(m,2H),1.70-1.64(m,2H)。
中间体18
3-(吡啶-4-基)环戊-2-烯-1-酮.向4-溴吡啶(2g,10.29mmol,1eq,HCl)在二噁烷(30mL)和H2O(6mL)的溶液中加入3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)环戊-2-烯-1-酮(3.21g,15.43mmol,1.5当量),Pd(dppf)Cl2(752.56mg,1.03mmol,0.1当量)和K3PO4(6.55g,30.87mmol,3当量)。将悬浮液脱气并用N2吹扫3次。于N2下,将该混合物在80℃搅拌16小时。将该反应混合物过滤,并将滤液用水(20mL)稀释并用EtOAc(30mLx3)萃取。将合并的有机层用盐水(15mLx2)洗涤,用Na2SO4干燥,过滤并在减压下浓缩以获得残留物,其通过快速硅胶色谱进行纯化(40g硅胶快速柱,0~100%乙酸乙酯/石油醚梯度@40mL/min洗脱)以获得3-(4-吡啶基)环戊-2-烯-1-酮(1.2g,7.54mmol,73.26%产率),其作为黄色固体。1H NMR(400MHz,氯仿-d)δ2.52-2.67(m,2H),3.00(dt,J=4.85,2.21Hz,2H),6.65(d,J=1.76Hz,1H),7.40-7.47(m,2H),8.69(br d,J=4.41Hz,2H)。
中间体19-23.根据描述于中间体18的操作合成中间体19-23。
中间体24
3-(4-(二甲基氨基)苯基)环戊--1-酮.在N2气氛下,向3-[4-(二甲基氨基)苯基]环戊-2-烯-1-酮(1.05g,4.97mmol,1当量)在MeOH(20mL)的溶液中加入Pd/C(200mg,10%纯度)。将悬浮液脱气并用H2吹扫3次。于H2(40psi)下,将该混合物在20℃搅拌16小时。将该混合物过滤,并将滤液在真空下浓缩以获得3-[4-(二甲基氨基)苯基]环戊酮(900mg,2.51mmol,50.6%产率,56.7%纯度),其作为黄色油状物.LCMS:203.9[M+1]+。
中间体25-26.根据描述于中间体24的操作合成中间体25-26。
中间体27
3-(2-氯苯基)环戊--1-酮。将(2-氯苯基)硼酸(1.14g,7.31mmol),环戊-2-烯-1-酮(500mg,6.09mmol,0.510mL)和[Rh(COD)2Cl]2(60.06mg,0.122mmol)在7.7mL 10:1EtOH/H2O的黄色悬浮液在50℃搅拌50小时。然后将黄色悬浮液过滤,并将滤液在真空下浓缩。将获得的残留物通过硅胶色谱进行纯化(0至9.4%EtOAc在石油醚中的梯度洗脱)以获得作为黄色油状物的标题化合物。1H NMR(400MHz,氯仿-d)δppm 1.96-2.07(1H,m),2.26-2.49(4H,m),2.72(1H,dd,J=18.19,7.83Hz),3.81-3.90(1H,m),7.16-7.22(1H,m),7.25-7.28(2H,m),7.39(1H,dt,J=7.77,0.85Hz)。
中间体28-38.根据描述于中间体27的操作合成中间体28-38。
中间体39-55.根据描述于中间体11或15的操作合成中间体39-55。
中间体56-72.根据描述于中间体16的操作合成中间体56-72。
中间体73-89.根据描述于中间体18的操作合成中间体73-89。
AIA-202A、AIA-202B、AIA-202C和CP-202D
5-氨基-N-(3-氯-4-氟苯基)-1-甲基-3-(3-苯基环戊基)-1H-吡唑-4-甲酰胺非对映异构体1(AIA-202A),非对映异构体2(AIA-202B),非对映异构体3(AIA-202C),非对映异构体4(AIA-202D)。于50Psi H2,将5-氨基-N-(3-氯-4-氟-苯基)-1-甲基-3-(3-苯基环戊烯-1-基)吡唑-4-甲酰胺(400mg,0.801mmol,1当量)和RhCl(PPh3)3(37.05mg,0.040mmol,0.05当量)在MeOH(20mL)中的棕色溶液在45℃搅拌16小时。将该反应物在真空下浓缩以获得粗制棕色油状物。将残留物使用快速硅胶色谱进行纯化(4g硅胶快速柱,0~5.5%MeOH/DCM梯度@20mL/min洗脱),然后通过SFC获得5-氨基-N-(3-氯-4-氟-苯基)-1-甲基-3-(3-苯基环戊基)吡唑-4-甲酰胺的4种非对映异构体。AIA-202A:1HNMR(400MHz,DMSO-d6)δppm1.67(dt,J=9.87,4.91Hz,1H)1.86-1.99(m,2H)2.01-2.12(m,2H)2.26-2.35(m,1H)3.07-3.16(m,1H)3.52(s,3H)3.66-3.76(m,1H)6.01(s,2H)7.14-7.22(m,1H)7.24-7.38(m,5H)7.56(ddd,J=9.05,4.34,2.63Hz,1H)7.94(d,J=6.71Hz,1H)8.99(s,1H);LC-MS:413.3[M+1]+;和de:100%。AIA-202B:1H NMR(400MHz,DMSO-d6)δppm 1.60-1.74(m,1H)1.85-2.01(m,2H)2.01-2.13(m,2H)2.31(br dd,J=12.05,6.27Hz,1H)3.05-3.20(m,1H)3.48-3.56(m,3H)3.65-3.79(m,1H)6.01(s,2H)7.05-7.22(m,1H)7.24-7.39(m,5H)7.47-7.74(m,1H)7.94(d,J=6.59Hz,1H)8.98(s,1H);LC-MS:413.3[M+1]+;和de:100%。AIA-202C:1H NMR(400MHz,DMSO-d6)δppm 1.59-1.70(m,1H)1.91-2.04(m,2H)2.07-2.23(m,3H)3.10-3.23(m,1H)3.53(s,3H)3.82-3.90(m,1H)6.04(s,2H)7.12-7.19(m,1H)7.24-7.37(m,5H)7.54(ddd,J=9.02,4.31,2.57Hz,1H)7.91(d,J=6.74Hz,1H)8.94(s,1H);LC-MS:413.3[M+1]+;和de:97.6%。AIA-202D:1H NMR(400MHz,DMSO-d6)δppm 1.12-1.33(m,4H)1.57-1.72(m,1H)1.90-2.02(m,2H)2.04-2.20(m,3H)2.26-2.39(m,1H)3.07-3.21(m,1H)3.53(d,J=1.47Hz,3H)3.71(br s,1H)3.79-3.91(m,1H)5.96-6.09(m,2H)7.13-7.38(m,7H)7.45-7.59(m,1H)7.86-7.96(m,1H)8.91-9.00(m,1H);LC-MS:413.3[M+1]+。
表1.根据描述于CP-AIA-202A-D的操作合成表1中的化合物
中间体90
5-氨基-1-甲基-3-(3-苯基环戊基)-1H-吡唑-4-甲酰氯.将5-氨基-1-甲基-3-(3-苯基环戊基)吡唑-4-甲酸(50mg,0.175mmol,1当量)在SOCl2(2mL)的溶液在80℃搅拌1小时。将该反应物在真空下浓缩以获得5-氨基-1-甲基-3-(3-苯基环戊基)吡唑-4-甲酰氯(50mg,粗制),其作为黄色油状物。该粗制品无需进一步纯化即用于下一步中。
AIA-278
5-氨基-N-(3-溴-4,5-二氟苯基)-1-甲基-3-(3-苯基环戊基)-1H-吡唑-4-甲酰胺.在0℃,向5-氨基-1-甲基-3-(3-苯基环戊基)吡唑-4-甲酰氯(50mg,0.165mmol,1当量)和3-溴-4,5-二氟-苯胺(51.35mg,0.247mmol,0.032mL,1.5当量)在DCM(3mL)的溶液中逐滴加入Et3N(33.31mg,0.329mmol,0.046mL,2.0当量)。将该反应温热至25℃并搅拌2小时。将反应物用DCM(20mL)稀释并用NH4Cl(10mL)水溶液、盐水(10mL)洗涤,用Na2SO4干燥,过滤并在真空下浓缩以获得作为棕色油状物的粗制产物。将粗制产物通过制备型HPLC进行纯化(柱:Gemini 150x25 5u;流动相:[水(0.05%氢氧化铵v/v)-ACN];B%:55%-85%,10min)。将所需要的级分通过冻干以获得5-氨基-N-(3-溴-4,5-二氟-苯基)-1-甲基-3-(3-苯基环戊基)吡唑-4-甲酰胺(7.5mg,0.015mmol,9.30%产率,96.97%纯度),其作为灰色固体。1HNMR(400MHz,DMSO-d6)δppm 1.65-1.78(m,1H)1.95-2.21(m,4H)2.22-2.39(m,1H)3.13-3.24(m,1H)3.56-3.61(m,3H)3.75(br t,J=8.71Hz,1H)6.09-6.16(m,2H)7.17-7.26(m,1H)7.29-7.36(m,4H)7.79-7.89(m,2H)9.08-9.17(m,1H);LC-MS:475.0[M+1]+。
AIA-279
5-氨基-N-(3-氰基-4-氟苯基)-1-甲基-3-(3-苯基环戊基)-1H-吡唑-4-甲酰胺.根据描述于AIA-278的操作合成标题化合物。1H NMR(400MHz,DMSO-d6)δppm 1.63-1.69(m,1H)1.89-2.14(m,4H)2.15-2.32(m,1H)3.07-3.23(m,1H)3.47-3.55(m,3H)3.65-3.77(m,1H)6.02-6.20(m,2H)7.13-7.21(m,1H)7.24-7.31(m,4H)7.44-7.53(m,1H)7.93(tdd,1H)8.08-8.17(m,1H)9.06-9.15(m,1H);LC-MS:404.0[M+1]+。
中间体91
2-溴-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-咪唑.向2-溴-咪唑(10.0g,68.0mmol)在丙酮(100mL)的溶液中加入K2CO3(23.5g,170.0mmol)和SEMCl(13.6g,81.6mmol)。将该反应混合物在室温搅拌过夜。将该混合物通过垫过滤,并浓缩滤液以获得粗制产物,其通过硅胶柱色谱进行纯化(其使用10:1石油醚/乙酸乙酯)以获得作为黄色油状物的2-溴-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-咪唑(12.0g,63.7%)。MS理论值:276.0,MS实际值:277.1[M+1]+。
中间体92
2-(4-溴-3-甲氧基苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷.于N2气氛下,将1-溴-4-碘-2-甲氧基苯(8.0g,25.6mmol),pin2B2(6.8g,26.9mmol),Pd(dppf)Cl2(940.0mg,1.3mmol)和乙酸钾(6.3g,64.0mmol)在二噁烷(100mL)中的混合物在80℃搅拌过夜。将反应通过垫过滤并将滤饼用EtOAc(50mLx3)洗涤。将滤液在真空下浓缩,并将残留物通过硅胶柱色谱进行纯化(其使用15:1石油醚/乙酸乙酯)以获得作为黄色油状物的2-(4-溴-3-甲氧基苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷(6.0g,75.0%)。MS理论值:312.0;1H-NMR(CDCl3,400MHz):δ7.53(d,J=7.6Hz,1H),7.28-7.25(m,2H),3.93(s,3H),1.34(s,12H)。
中间体93
2-(4-溴-3-甲氧基苯基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-咪唑.向2-(4-溴-3-甲氧基苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷(6.0g,19.2mmol)在二噁烷/H2O(60mL,v/v=5:1)的溶液中加入2-溴-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-咪唑(5.9g,21.1mmol),Pd(dppf)Cl2(1.4g,1.9mmol)和Na2CO3(5.1g,48.0mmol)。于N2气氛下,将反应物在90℃搅拌过夜。除去溶剂,并加入水,并将混合物用EtOAc(50mLx3)萃取。将合并的有机层用Na2SO4干燥然后浓缩以获得粗制产物,其通过硅胶柱色谱进行纯化(使用10:1石油醚/乙酸乙酯)以获得作为灰色固体的2-(4-溴-3-甲氧基苯基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-咪唑(1.5g,20.4%)。MS理论值:382.1,MS实际值:383.2[M+1]+。
中间体94
3-(2-甲氧基-4-(1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-咪唑-2-基)苯基)环戊-2-烯酮。向2-(4-溴-3-甲氧基苯基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-咪唑(1.5g,3.9mmol)在二噁烷/H2O(60mL,v/v=5:1)的溶液中加入3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)环戊-2-烯-1-酮(1.0g,4.7mmol),Pd(dppf)Cl2(500.0mg,0.4mmol)和K3PO4(2.1g,9.8mmol)。于N2气氛下,将反应物在90℃搅拌过夜。除去溶剂,加入水,并将混合物用EtOAc(50mLx3)萃取。将合并的有机层用Na2SO4干燥并浓缩以获得粗制产物,其通过硅胶柱色谱进行纯化(使用10:1石油醚/乙酸乙酯)以获得作为灰色固体的3-(2-甲氧基-4-(1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-咪唑-2-基)苯基)环戊-2-烯酮(1.0g,66.7%)。MS理论值:384.2,MS实际值:385.3[M+1]+。
中间体95
5-氨基-N-(3-氯-4-氟苯基)-3-(3-(2-甲氧基-4-(1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-咪唑-2-基)苯基)环戊基)-1-甲基-1H-吡唑-4-甲酰胺.根据上面描述的操作合成标题化合物。MS理论值:638.2,MS实际值:639.3[M+1]+.
AIA-352-1和AIA-352-2
3-(3-(4-(1H-咪唑-2-基)-2-甲氧基苯基)环戊基)-5-氨基-N-(3-氯-4-氟苯基)-1-甲基-1H-吡唑-4-甲酰胺。非对映异构体1(AIA-352-1)和非对映异构体2(AIA-352-2)。将5-氨基-N-(3-氯-4-氟苯基)-3-(3-(2-甲氧基-4-(1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-咪唑-2-基)苯基)环戊基)-1-甲基-1H-吡唑-4-甲酰胺(230.0mg,0.4mmol)和TFA(2mL)在DCM(10mL)中的混合物在室温搅拌过夜。除去溶剂并加入氢氧化铵(2mL)。将获得的混合物在室温搅拌15分钟。除去溶剂以获得粗制产物,其通过制备型HPLC进行纯化以获得AIA-352-1(11mg,5.4%)和AIA-352-2(7mg,3.4%)AIA-352-1:1H-NMR(DMSO-d6,400MHz):δ12.42(s,1H),8.93(s,1H),7.92(dd,J=6.8,2.4Hz,1H),7.49-7.44(m,3H),7.33-7.27(m,2H),7.22(s,1H),6.98(s,1H),6.03(s,2H),3.90-3.86(m,1H),3.84(s,3H),3.53(s,3H),3.45-3.39(m,1H),2.14-1.92(m,5H),1.68-1.63(m,1H).AIA-352-2:1H-NMR(DMSO-d6,400MHz):δ12.43(s,1H),8.94(s,1H),7.94(dd,J=6.8,2.8Hz,1H),7.58-7.54(m,1H),7.51-7.45(m,2H),7.36(t,J=8.8Hz,1H),7.28(d,J=8.0Hz,1H),7.22(s,1H),6.98(s,1H),6.03(s,2H),3.83(s,3H),3.73-3.67(m,1H),3.52(s,3H),3.46-3.38(m,1H),2.27-2.20(m,1H),2.07-1.83(m,4H),1.65-1.60(m,1H)。
表2.根据描述于AIA-352-1和AIA-352-2的操作合成表2中的化合物
中间体96
3-甲氧基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯甲酸甲酯.于N2气氛下,将4-溴-3-甲氧基苯甲酸甲酯(3.0g,12.2mmol),4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1,3,2-二氧杂硼杂环戊烷(4.8g,19mmol),Pd(dppf)Cl2(450mg,0.6mmol)和乙酸钾(1.9g,19.0mmol)在二噁烷(50mL)中的混合物在80℃搅拌4h。将反应通过垫过滤,并将滤饼用EtOAc(10mLx3)洗涤。将滤液在真空下浓缩,并将残留物通过硅胶柱色谱进行纯化(其使用15:1石油醚/乙酸乙酯)以获得作为白色固体的3-甲氧基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯甲酸甲酯(2.5g,70%产率)。MS理论值:292.1,MS实际值:293.4[M+1]+。
中间体97
3-甲氧基-4-(3-氧代环戊-1-烯基)苯甲酸甲酯.于N2气氛下,将3-甲氧基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯甲酸甲酯(2.5g,8.6mmol),3-溴环戊-2-烯-1-酮(1.3g,8.6mmol),Pd(PPh3)4(500mg,0.43mmol)和碳酸钾(1.8g,12.9mmol)在二噁烷(50mL)和水(10mL)中的混合物在100℃搅拌4h。将反应通过垫过滤并将滤饼用EtOAc(10mLx3)洗涤。将滤液在真空下浓缩,并将残留物通过硅胶柱色谱进行纯化(其使用3:1石油醚/乙酸乙酯)以获得作为微黄色固体的3-甲氧基-4-(3-氧代环戊-1-烯基)苯甲酸甲酯(1.8g,86%产率)。MS理论值:246.1,MS实际值:247.4[M+1]+。
中间体98
4-(3-(5-氨基-4-(3-氯-4-氟苯基氨基甲酰基)-1-甲基-1H-吡唑-3-基)环戊基)-3-甲氧基苯甲酸甲酯.根据上描述的步骤,由3-甲氧基-4-(3-氧代环戊-1-烯基)苯甲酸甲酯和5-氨基-3-溴-N-(3-氯-4-氟苯基)-1-甲基-1H-吡唑-4-甲酰胺合成标题化合物。MS理论值:500.2,MS实际值:501.3[M+1]+。
中间体99
4-(3-(5-氨基-4-(3-氯-4-氟苯基氨基甲酰基)-1-甲基-1H-吡唑-3-基)环戊基)-3-甲氧基苯甲酸.将4-(3-(5-氨基-4-(3-氯-4-氟苯基氨基甲酰基)-1-甲基-1H-吡唑-3-基)环戊基)-3-甲氧基苯甲酸甲酯(800mg,1.6mmol)和LiOH-H2O(670mg,16.0mmol)在THF/H2O=1:1(10mL)中的混合物在60℃加热过夜。将该反应用2N HCl中和,并在真空下除去溶剂。将残留物通过硅胶柱色谱进行纯化,其使用乙酸乙酯以获得作为白色固体的4-(3-(5-氨基-4-(3-氯-4-氟苯基氨基甲酰基)-1-甲基-1H-吡唑-3-基)环戊基)-3-甲氧基苯甲酸(700mg,90%产率)。MS理论值:486.1,MS实际值:487.3[M+1]+。
AIA-150-C,AIA-150-D
5-氨基-3-(3-(4-氨基甲酰基-2-甲氧基苯基)环戊基)-N-(3-氯-4-氟苯基)-1-甲基-1H-吡唑-4-甲酰胺.非对映异构体1(AP-AIA-150-C),非对映异构体2(AIA-150-D).将4-(3-(5-氨基-4-(3-氯-4-氟苯基氨基甲酰基)-1-甲基-1H-吡唑-3-基)环戊基)-3-甲氧基苯甲酸(700mg,1.4mmol),HCOONH4(180mg,2.9mmol),HATU(1.1g,2.9mmol)和TEA(300mg,2.9mmol)在DMF(5mL)中的混合物在室温搅拌过夜。将反应用水(20mL)淬灭,然后用EtOAc(20mLx3)萃取。将有机层在减压下浓缩并将获得的残留物通过硅胶柱色谱进行纯化(其使用乙酸乙酯)以获得作为白色固体的AIA-150-1(30mg,4%产率)和作为白色固体的AIA-150-2(300mg,43%产率)。MS理论值:485.2,MS实际值:486.3[M+1]+.通过SFC分离100mgAIA-150-2以获得作为白色固体的AIA-150-C(30mg)和作为白色固体的AIA-150-D(30mg)。AIA-150-C:1H-NMR(DMSO-d6,400MHz):δ8.94(s,1H),7.93(dd,J=6.8,2.4Hz,1H),7.91(brs,1H),7.58-7.54(m,1H),7.44-7.41(m,2H),7.36(t,J=9.2Hz,1H),7.30-7.27(m,2H),6.03(s,2H),3.81(s,3H),3.73-3.69(m,1H),3.52(s,3H),3.46-3.41(m,1H),2.27-2.20(m,1H),2.08-2.00(m,2H),1.99-1.83(m,2H),1.65-1.59(m,1H)。AIA-150-D:1H-NMR(DMSO-d6,400MHz):δ8.94(s,1H),7.93(dd,J=6.8,2.4Hz,1H),7.91(brs,1H),7.58-7.54(m,1H),7.44-7.41(m,2H),7.36(t,J=9.2Hz,1H),7.30-7.27(m,2H),6.03(s,2H),3.81(s,3H),3.73-3.69(m,1H),3.52(s,3H),3.46-3.41(m,1H),2.27-2.20(m,1H),2.08-2.00(m,2H),1.99-1.83(m,2H),1.65-1.59(m,1H)。
AIA-070-2
5-氨基-N-(3-氯-4-氟苯基)-3-(3-(4-氰基-2-甲氧基苯基)环戊基)-1-甲基-1H-吡唑-4-甲酰胺向AIA-150-2(150mg,0.3mmol)在吡啶(5mL)的溶液中加入POCl3(140mg,0.9mmol)并将混合物在-40℃搅拌10分钟。将该反应用水(10mL)淬灭并用EtOAc(10mLx3)萃取。将合并的有机层在真空下浓缩。将获得的残留物通过硅胶柱色谱进行纯化(其使用1:1石油醚/乙酸乙酯)以获得作为白色固体的5-氨基-N-(3-氯-4-氟苯基)-3-(3-(4-氰基-2-甲氧基苯基)环戊基)-1-甲基-1H-吡唑-4-甲酰胺(7mg,5%产率)。MS理论值:467.2,MS实际值:468.2[M+1]+.1H-NMR(DMSO-d6,400MHz):δ8.94(s,1H),7.93(dd,J=6.8,2.4Hz,1H),7.58-7.54(m,1H),7.44(d,J=8.0Hz,1H),7.38-7.33(m,3H),6.03(s,2H),3.83(s,3H),3.74-3.70(m,1H),3.51(s,3H),3.48-3.43(m,1H),2.28-2.22(m,1H),2.08-2.00(m,2H),1.99-1.83(m,2H),1.65-1.59(m,1H)。
表3.根据描述于AIA-150-C和AIA-150-D的操作合成表3中的化合物
AIA-262
5-氨基-N-(3-氯-4-氟苯基)-1-甲基-3-(1-苯基吡咯烷-3-基)-1H-吡唑-4-甲酰胺.于N2下,将5-氨基-N-(3-氯-4-氟-苯基)-1-甲基-3-吡咯烷-3-基-吡唑-4-甲酰胺(100mg,0.296mmol,1当量),溴苯(46.48mg,0.296mmol,0.031mL,1当量),Pd2(dba)3(8.13mg,0.009mmol,0.03当量),XPhos(4.23mg,0.009mmol,0.03当量)和NaOtBu(85.35mg,0.888mmol,3当量)在二噁烷(3mL)中的混合物在105℃搅拌2小时。观察到棕色悬浮液。于N2下,将反应继续在105℃搅拌2小时。向该反应中加入乙酸乙酯(10mL)和水(10mL)。分离水相并用乙酸乙酯(10mL)萃取。合并有机层并用盐水(10mL)洗涤,用Na2SO4干燥,过滤并在真空下浓缩以获得作为棕色油状物的5-氨基-N-(3-氯-4-氟-苯基)-1-甲基-3-(1-苯基吡咯烷-3-基)吡唑-4-甲酰胺(150mg,粗制)。将残留物通过制备型TLC(1:1石油醚/EtOAc)进行纯化以获得作为黄色油状物的5-氨基-N-(3-氯-4-氟-苯基)-1-甲基-3-(1-苯基吡咯烷-3-基)吡唑-4-甲酰胺(5mg,粗制),其通过制备型HPLC进行纯化(柱:Gemini 150x25 5u;流动相:[水(0.05%氢氧化铵v/v)-ACN];B%:50%-80%,10min)以获得5-氨基-N-(3-氯-4-氟-苯基)-1-甲基-3-(1-苯基吡咯烷-3-基)吡唑-4-甲酰胺(1.8mg,0.004mmol,36.00%产率,100%纯度),其作为黄色固体。1H NMR(400MHz,氯仿-d)δppm 2.35-2.57(m,2H)3.13-3.23(m,1H)3.46-3.60(m,4H)3.75-3.82(m,2H)5.47(br s,2H)6.75(br d,J=7.72Hz,2H)6.80-6.98(m,2H)7.11(ddd,J=8.99,4.02,2.65Hz,1H)7.25-7.32(m,2H)7.39-7.48(m,1H)8.66(br s,1H);LC-MS:414.0[M+1]+。
中间体100
三氟甲磺酸5-氧代-1,3a,4,5,6,6a-六氢并环戊二烯-2-基酯.在室温,向1,3,3a,4,6,6a-六氢并环戊二烯-2,5-二酮(40.0g,289.5mmol)和吡啶(24.0g,304.0mmol)在DCM(600ml)的溶液中逐滴加入Tf2O(89.8g,318.5mmol)。将该混合物在室温搅拌3h。加入盐水(300mL)并用DCM(200mLx3)萃取水层。将有机层分离,用Na2SO4干燥并浓缩以获得粗制产物,其通过硅胶柱色谱进行纯化(其使用8:1石油醚/乙酸乙酯)以获得作为黄色油状物的三氟甲磺酸5-氧代-1,3a,4,5,6,6a-六氢并环戊二烯-2-基酯(36.0g,46%产率)。1H NMR(400MHz,氯仿-d)δppm 2.17(ddd,J=19.14,7.34,1.63Hz,1H)2.26-2.34(m,1H)2.40-2.56(m,2H)2.58-2.67(m,1H)3.00-3.14(m,2H)3.50-3.57(m,1H)5.63(q,J=1.92Hz,1H)。
中间体101
5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-3,3a,6,6a-四氢并环戊二烯-2(1H)-酮.于N2气氛下,将三氟甲磺酸5-氧代-1,3a,4,5,6,6a-六氢并环戊二烯-2-基酯(110.0g,407.0mmol),4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1,3,2-二氧杂硼杂环戊烷(108.5g,427.4mmol),Pd(dppf)Cl2(8.9g,12.2mmol)和乙酸钾(119.7g,1221.0mmol)在二噁烷(1000ml)中的混合物在80℃搅拌2h。将该反应混合物通过垫过滤并将滤饼用EtOAc(250mLx3)洗涤。将滤液在真空下浓缩并将残留物用硅胶柱色谱进行纯化,其使用8:1石油醚/乙酸乙酯以获得作为黄色油状物的5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-3,3a,6,6a-四氢并环戊二烯-2(1H)-酮(90.0g,89%产率)。1H NMR(400MHz,氯仿-d)δppm 1.28(s,13H)1.95-2.07(m,1H)2.24-2.55(m,4H)2.79(ddt,J=16.48,7.58,2.64,2.64Hz,1H)2.93-3.05(m,1H)3.41-3.54(m,1H)6.37(q,J=2.08Hz,1H)。
中间体102
5-氨基-N-(3-氯-4-氟苯基)-1-甲基-3-(5-氧代-1,3a,4,5,6,6a-六氢并环戊二烯-2-基)-1H-吡唑-4-甲酰胺.于N2下,将5-氨基-3-溴-N-(3-氯-4-氟苯基)-1-甲基-1H-吡唑-4-甲酰胺(68.6g,197.5mmol),5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-3,3a,6,6a-四氢并环戊二烯-2(1H)-酮(70.0g,282.1mmol),Pd(dppf)Cl2(10.1g,13.8mmol)和Na2CO3(41.9g,395.0mmol)在二噁烷(1200mL)和H2O(150mL)中的混合物在80℃搅拌过夜。该混合物是棕色悬浮液。将溶剂在真空下蒸发。将残留物通过硅胶柱色谱进行纯化(其使用1:2石油醚/乙酸乙酯)以获得作为黄色固体的5-氨基-N-(3-氯-4-氟苯基)-1-甲基-3-(5-氧代-1,3a,4,5,6,6a-六氢并环戊二烯-2-基)-1H-吡唑-4-甲酰胺(55.0g,72%产率)。MS理论值:388.1,MS实际值:389.0[M+1]+。1HNMR(400MHz,氯仿-d)δppm 2.19(dd,J=19.20,5.26Hz,1H)2.33(br d,J=18.83Hz,1H)2.55-2.79(m,3H)3.15-3.28(m,2H)3.63(s,3H)3.66(s,1H)3.68-3.77(m,1H)5.24-5.45(m,2H)6.05(d,J=1.71Hz,1H)6.95-7.20(m,2H)7.47-7.58(m,1H)7.68-7.86(m,2H);LCMS:389.0[M+1]+。
AIA-002
5-氨基-N-(3-氯-4-氟苯基)-1-甲基-3-(5-氧代八氢并环戊二烯-2-基)-1H-吡唑-4-甲酰胺.于H2下,向5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-3,3a,6,6a-四氢并环戊二烯-2(1H)-酮(5.0g,12.9mmol)在EtOAc(500ml)的溶液中加入Pd/C(2.5g,10%w/w Pd)。将该混合物在40℃搅拌2h。将该混合物过滤并在真空下蒸发以获得作为白色固体的目标化合物(4.6g,92%)。该粗制品直接使用而无需进一步纯化。MS理论值:390.1;MS实际值:391.0[M+1]+.1H NMR(400MHz,氯仿-d)δppm 1.85-2.01(m,2H)2.07-2.29(m,2H)2.41-2.67(m,4H)2.83-3.06(m,2H)3.32-3.50(m,1H)3.54-3.61(m,3H)5.15-5.32(m,2H)7.12(t,J=8.74Hz,1H)7.27-7.35(m,2H)7.65-7.83(m,1H);LCMS:391.2[M+1]+。
AIA-290
5-氨基-N-(3-氯-4-氟苯基)-3-(六氢-1H-螺[并环戊二烯-2,2'-[1,3]二氧杂环戊基]-5-基)-1-甲基-1H-吡唑-4-甲酰胺.向5-氨基-N-(3-氯-4-氟-苯基)-1-甲基-3-(5-氧代-2,3,3a,4,6,6a-六氢-1H-并环戊二烯-2-基)吡唑-4-甲酰胺(30mg,0.071mmol,1当量)和乙二醇(4.39mg,0.0708mmol,1当量)在甲苯(3mL)的淡棕色溶液中加入p-TsOH(12.19mg,0.0708mmol,1.0当量)。将该混合物在110℃搅拌16小时。将该混合物用EtOAc(10mL)稀释,用饱和NaHCO3溶液(10mL)洗涤,用Na2SO4干燥,过滤并在真空下浓缩以获得残留物。将残留物通过制备型TLC进行纯化(SiO2,10:1DCM:MeOH)。获得作为无色胶体的化合物5-氨基-N-(3-氯-4-氟-苯基)-1-甲基-3-螺[1,3-二氧杂环戊烷-2,5'-2,3,3a,4,6,6a-六氢-1H-并环戊二烯]-2'-基-吡唑-4-甲酰胺(30mg,0.0659mmol,55.9%产率,95.6%纯度),并且进一步通过制备型HPLC(碱性)进行纯化。1HNMR(400MHz,氯仿-d)δppm 1.74(2H,br dd,J=13.45,4.85Hz),1.81-1.92(2H,m),2.00-2.10(2H,m),2.30-2.42(2H,m),2.60-2.74(2H,m),3.07-3.19(1H,m),3.60(3H,s),3.85-3.95(4H,m),5.28(2H,s),7.11(1H,t,J=8.71Hz),7.27-7.33(2H,m),7.72(1H,dd,J=6.62,2.65Hz);LCMS:435.0[M+1]+。
中间体103
5-氨基-N-(3-氯-4-氟苯基)-3-(六氢-1H-螺[并环戊二烯-2,2'-[1,3]二硫杂环戊基]-5-基)-1-甲基-1H-吡唑-4-甲酰胺.向5-氨基-N-(3-氯-4-氟-苯基)-1-甲基-3-(5-氧代-2,3,3a,4,6,6a-六氢-1H-并环戊二烯-2-基)吡唑-4-甲酰胺(0.2g,0.512mmol,1当量)和乙烷-1,2-二硫醇(77.13mg,0.819mmol,0.069mL,1.6当量)在DCM(5mL)的混合物中加入BF3.Et2O(290.51mg,2.05mmol,0.253mL,4当量)。将该混合物在25℃搅拌3小时。将该混合物用H2O(15mL)洗涤三次,然后用盐水(20mL)洗涤。将有机层用Na2SO4干燥并在真空下蒸发以获得黄色固体。将该黄色固体通过快速硅胶色谱(combi4g硅胶快速柱,0~41.4%乙酸乙酯/石油醚梯度@18mL/min洗脱)进行纯化。获得作为黄色固体的5-氨基-N-(3-氯-4-氟-苯基)-1-甲基-3-螺[1,3-二硫杂环戊烷-2,5'-2,3,3a,4,6,6a-六氢-1H-并环戊二烯]-2'-基-吡唑-4-甲酰胺(190mg,0.397mmol,77.58%产率,97.580%纯度)。LCMS:467.0[M+1]+。
AIA-232
5-氨基-N-(3-氯-4-氟苯基)-1-甲基-3-(八氢并环戊二烯-2-基)-1H-吡唑-4-甲酰胺.向兰尼镍(100mg,1.17mmol)在EtOH(10mL)的溶液中加入5-氨基-N-(3-氯-4-氟-苯基)-1-甲基-3-螺[1,3-二硫杂环戊烷-2,5'-2,3,3a,4,6,6a-六氢-1H-并环戊二烯]-2'-基-吡唑-4-甲酰胺(50mg,0.078mmol,1当量)。将该混合物在80℃搅拌4小时。将该混合物过滤,并将滤液在真空下蒸发以获得黄色胶体。将粗制产物通过制备型HPLC(柱:Gemini150x25 5u;流动相:[水(0.05%氢氧化铵v/v)-ACN];B%:55%-85%,10min)进行纯化,以获得作为白色固体的3-(1,2,3,3a,4,5,6,6a-八氢并环戊二烯-2-基)-5-氨基-N-(3-氯-4-氟-苯基)-1-甲基-吡唑-4-甲酰胺(10mg,0.0265mmol,16.9%产率,100%纯度)。1H NMR(400MHz,DMSO-d6)δppm 1.16-1.29(m,2H)1.36(br s,2H)1.41-1.54(m,4H)2.07-2.18(m,2H)2.43(br s,2H)3.26-3.34(m,1H)3.48(s,3H)5.95(s,2H)7.34(t,J=9.15Hz,1H)7.51(ddd,J=9.04,4.41,2.65Hz,1H)7.91(dd,J=6.84,2.65Hz,1H)8.97(s,1H);LCMS:376.9[M+1]+。
AIA-026
5-氨基-N-(3-氯-4-氟苯基)-3-(5-羟基八氢并环戊二烯-2-基)-1-甲基-1H-吡唑-4-甲酰胺.向AIA-002(39mg,0.1mmol,1当量)在THF/MeOH(1mL/1mL)的悬浮液中逐次加入NaBH4(6mg,0.15mmol,1.5当量)。将反应物在室温搅拌30分钟。观察到黄色溶液。将该反应用水淬灭并用乙酸乙酯(10mLx2)萃取。将有机相在真空下浓缩并将残留物通过制备型HPLC进行纯化以获得作为白色固体的5-氨基-N-(3-氯-4-氟苯基)-3-(5-羟基八氢并环戊二烯-2-基)-1-甲基-1H-吡唑-4-甲酰胺(28mg,71%产率)。MS理论值:392.1;MS实际值:393.0[M+1]+.1H-NMR(DMSO-d6,400MHz):δ8.93(s,1H),7.91(dd,J=6.8,2.8Hz,1H),7.53-7.49(m,1H),7.34(t,J=9.2Hz,1H),5.96(s,2H),4.45(d,J=3.2Hz,1H),4.04-4.02(m,1H),3.49(s,3H),3.45-3.39(m,1H),2.38-2.32(m,2H),2.17-2.11(m,2H),1.92-1.89(m,2H),1.62-1.54(m,2H),1.30-1.24(m,2H)
中间体104
甲磺酸5-(5-氨基-4-((3-氯-4-氟苯基)氨基甲酰基)-1-甲基-1H-吡唑-3-基)八氢并环戊二烯-2-基酯向AIA-026(400mg,1mmol)和TEA(204mg,2mmol)在DCM(20mL)的混合物中加入MsCl(172mg,1.5mmol)并将该混合物在25℃搅拌4h。将反应物在真空下浓缩,并将残留物通过硅胶柱色谱进行纯化(其使用5-10%乙酸乙酯/石油醚)以获得作为浅白色固体的甲磺酸5-(5-氨基-4-((3-氯-4-氟苯基)氨基甲酰基)-1-甲基-1H-吡唑-3-基)八氢并环戊二烯-2-基酯(311mg,65%产率)。MS理论值:470.9;MS实际值:471.7[M+1]+。
AIA-027
5-氨基-N-(3-氯-4-氟苯基)-3-(5-氰基八氢并环戊二烯-2-基)-1-甲基-1H-吡唑-4-甲酰胺向甲磺酸5-(5-氨基-4-((3-氯-4-氟苯基)氨基甲酰基)-1-甲基-1H-吡唑-3-基)八氢并环戊二烯-2-基酯(46.7mg,0.10mmol)在乙腈(5mL)的溶液中加入TMSCN(100mg,1.01mmol)和TBAF(100mg,0.38mmol),并将获得的混合物在70℃搅拌4h。将该混合物在真空下浓缩,并将残留物通过制备型HPLC进行纯化以获得作为白色固体的5-氨基-N-(3-氯-4-氟苯基)-3-(5-氰基八氢并环戊二烯-2-基)-1-甲基-1H-吡唑-4-甲酰胺(6.7mg,16%产率)。MS理论值:401.8;MS实际值:402.7[M+1]+.V1H-NMR(DMSO-d6,400MHz):δ8.96(s,1H),7.91(dd,J=6.8,2.8Hz,1H),7.53-7.49(m,1H),7.34(t,J=9.2Hz,1H),5.97(s,2H),3.48(s,3H),3.31-3.29(m,1H),2.93-2.88(m,1H),2.60-2.57(m,2H),2.17-2.11(m,2H),1.85-1.73(m,4H),1.30-1.22(m,2H)
AIA-028
5-氨基-N-(3-氯-4-氟苯基)-1-甲基-3-(5-(甲基硫基)八氢并环戊二烯-2-基)-1H-吡唑-4-甲酰胺.将甲磺酸5-(5-氨基-4-((3-氯-4-氟苯基)氨基甲酰基)-1-甲基-1H-吡唑-3-基)八氢并环戊二烯-2-基酯(46mg,0.1mmol)和MeSNa(28mg,0.4mmol)在DMF(4mL)的混合物在70℃搅拌4h。向该混合物中加入H2O(10mL)。将溶液用乙酸乙酯(10mLx3)萃取。将合并的有机层用Na2SO4干燥,浓缩然后通过硅胶柱色谱进行纯化(其使用5-30%乙酸乙酯/石油醚)以获得作为浅白色固体的5-氨基-N-(3-氯-4-氟苯基)-1-甲基-3-(5-(甲基硫基)八氢并环戊二烯-2-基)-1H-吡唑-4-甲酰胺(10mg,23%产率)。MS理论值:422.13;MS实际值:423.2[M+1]+.1H-NMR(DMSO-d6,400MHz):δ8.96(s,1H),7.91(d,J=4.8,1H),7.52-7.50(m,1H),7.34(t,J=9.2Hz,1H),5.96(s,2H),3.48(s,3H),3.05-3.02(m,1H),2.45-2.50(m,3H),2.16-2.14(m,2H),2.00(s,3H),1.76-1.72(m,2H),1.50-1.48(m,2H),1.31-1.25(m,2H)
表4.根据描述于5-氨基-N-(3-氯-4-氟苯基)-1-甲基-3-(5-(甲基硫基)八氢并环戊二烯-2-基)-1H-吡唑-4-甲酰胺的操作合成表4中的化合物
AIA-030
5-氨基-N-(3-氯-4-氟苯基)-1-甲基-3-(5-(甲磺酰基)八氢并环戊二烯-2-基)-1H-吡唑-4-甲酰胺.向5-氨基-N-(3-氯-4-氟苯基)-1-甲基-3-(5-(甲基硫基)八氢并环戊二烯-2-基)-1H-吡唑-4-甲酰胺(35mg,0.08mmol)在DCM(5mL)的溶液中加入m-CPBA(14mg,0.08mmol),并将获得的混合物在25℃搅拌1h。真空下除去溶剂并将残留物通过制备型HPLC以获得作为白色固体的5-氨基-N-(3-氯-4-氟苯基)-1-甲基-3-(5-(甲磺酰基)八氢并环戊二烯-2-基)-1H-吡唑-4-甲酰胺(6mg,17%产率)。MS理论值:454.12;MS实际值:455.3[M+1]+.1H-NMR(DMSO-d6,400MHz):δ8.96(s,1H),7.91(dd,J=6.8,2.8Hz,1H),7.53-7.49(m,1H),7.34(t,J=9.2Hz,1H),5.98(s,2H),3.69-3.66(m,1H),3.49(s,3H),3.35-3.34(m,1H),2.92(s,3H),2.67-2.62(m,2H),2.21-2.15(m,2H),1.90-1.83(m,2H),1.78-1.73(m,2H),1.39-1.31(m,2H)。
AIA-074
5-氨基-N-(3-氯-4-氟苯基)-1-甲基-3-(5-(甲基亚磺酰基)八氢并环戊二烯-2-基)-1H-吡唑-4-甲酰胺.向5-氨基-N-(3-氯-4-氟苯基)-1-甲基-3-(5-(甲基硫基)八氢并环戊二烯-2-基)-1H-吡唑-4-甲酰胺(50mg,0.11mmol)在DCM(5mL)的溶液中加入m-CPBA(10mg,0.05mmol),并将获得的混合物在25℃搅拌1h。在真空下除去溶剂,并将残留物通过制备型HPLC进行纯化以获得作为白色固体的5-氨基-N-(3-氯-4-氟苯基)-1-甲基-3-(5-(甲基亚磺酰基)八氢并环戊二烯-2-基)-1H-吡唑-4-甲酰胺(8mg,15%产率)。MS理论值:438.13;MS实际值:439.3[M+1]+.1H-NMR(DMSO-d6,400MHz):δ8.96(s,1H),7.92(dd,J=7.2,2.8Hz,1H),7.54-7.50(m,1H),7.34(t,J=8.8Hz,1H),5.97(s,2H),3.49(s,3H),3.37-3.31(m,1H),3.31-3.12(m,1H),2.60-2.58(m,2H),2.50-2.47(m,3H),2.21-2.17(m,2H),1.93-1.90(m,1H),1.68-1.62(m,3H),1.40-1.32(m,2H)。
表5.根据描述于5-氨基-N-(3-氯-4-氟苯基)-1-甲基-3-(5-(甲磺酰基)八氢并环戊二烯-2-基)-1H-吡唑-4-甲酰胺和5-氨基-N-(3-氯-4-氟苯基)-1-甲基-3-(5-(甲基亚磺酰基)八氢并环戊二烯-2-基)-1H-吡唑-4-甲酰胺的操作合成表5中的化合物。
AIA-285
5-氨基-N-(3-氯-4-氟苯基)-3-(5-甲氧基八氢并环戊二烯-2-基)-1-甲基-1H-吡唑-4-甲酰胺.向5-氨基-N-(3-氯-4-氟-苯基)-3-(5-羟基-1,2,3,3a,4,5,6,6a-八氢并环戊二烯-2-基)-1-甲基吡唑-4-甲酰胺(50mg,0.127mmol,1当量)在DCM(3mL)的溶液中加入三甲基氧鎓-四氟硼酸盐(37.65mg,0.255mmol,2.0当量)和N1,N1,N8,N8-四甲基萘-1,8-二胺(54.55mg,0.255mmol,2.0当量)。在N2下,将该混合物在25℃搅拌16小时。加入额外的三甲基氧鎓-四氟硼酸盐(37.65mg,0.255mmol,2.0当量),并在N2下,持续搅拌48小时。将水(10mL)加入到反应混合物中。将水层用乙酸乙酯(10mLx2)萃取。将合并的有机层用Na2SO4干燥,过滤并浓缩以获得浅白色(pale)的残留物。将残留物通过制备型TLC进行纯化(SiO2,1:1石油醚:乙酸乙酯)以获得粗制产物(25mg)。将粗制产物进一步通过制备型HPLC进行纯化。柱:Gemini150x25 5u;流动相:[水(0.05%氢氧化铵v/v)-ACN];B%:40%-70%,10min。将需要的级份通过冻干干燥以获得作为白色固体的5-氨基-N-(3-氯-4-氟-苯基)-3-(5-甲氧基-1,2,3,3a,4,5,6,6a-八氢并环戊二烯-2-基)-1-甲基-吡唑-4-甲酰胺(10.8mg,0.027mmol,20.9%产率,100%纯度)。1H NMR(400MHz,氯仿-d)δppm 1.60-1.64(m,2H)1.81-1.93(m,2H)2.06(ddd,J=13.40,8.10,5.62Hz,2H)2.33(br d,J=5.95Hz,2H)2.49-2.62(m,2H)3.11(tt,J=11.85,5.79Hz,1H)3.28(s,3H)3.57(s,3H)3.84(quin,J=6.01Hz,1H)5.25(s,2H)7.10(t,J=8.71Hz,1H)7.26-7.30(m,1H)7.30(s,1H)7.70(dd,J=6.50,2.76Hz,1H);LC-MS:406.9[M+1]+。
AIA-009
5-氨基-N-(3-氯-4-氟苯基)-1-甲基-3-(5-(三氟甲氧基)八氢并环戊二烯-2-基)-1H-吡唑-4-甲酰胺.将AIA-026(100mg,0.25mmol),1-(三氟甲基)-1λ3-苯并[d][1,2]碘杂氧杂环戊二烯-3(1H)-酮(157mg,0.5mmol)和双(三氟甲磺酰基)酰亚胺锌(306mg,0.5mmol)在DCM(15mL)中的混合物在室温搅拌8h。加入水并将该混合物用DCM(20mLx3)萃取。将有机层干燥并浓缩。将获得的残留物通过硅胶柱色谱(使用20-60%乙酸乙酯/石油醚)和制备型HPLC进行纯化以获得作为白色固体的5-氨基-N-(3-氯-4-氟苯基)-1-甲基-3-(5-(三氟甲氧基)八氢并环戊二烯-2-基)-1H-吡唑-4-甲酰胺(5mg,4.3%)。MS理论值:460.1;MS实际值:461.3[M+1]+.1H-NMR(DMSO-d6,400MHz):δ8.97(s,1H),7.91(dd,J=6.8,2.4Hz,1H),7.54-7.50(m,1H),7.34(t,J=3.2Hz,1H),5.96(s,2H),4.79(t,J=6.0Hz,1H),3.46(t,J=6.0Hz,4H),2.22-2.09(m,5H),1.65-1.51(m,5H)。
AIA-286
5-氨基-N-(3-氯-4-氟苯基)-3-(5-(二甲基氨基)八氢并环戊二烯-2-基)-1-甲基-1H-吡唑-4-甲酰胺.在25℃,向5-氨基-N-(3-氯-4-氟-苯基)-1-甲基-3-(5-氧代-2,3,3a,4,6,6a-六氢-1H-并环戊二烯-2-基)吡唑-4-甲酰胺(54.21mg,0.128mmol,1当量),N-甲基甲胺-盐酸盐(12.52mg,0.154mmol,1.2当量),TEA(19.42mg,0.192mmol,0.027mL,1.5当量)和MgSO4(76.99mg,0.640mmol,5当量)在DCM(3mL)的混合物中分批加入三乙酰氧基硼氢化钠(54.23mg,0.256mmol,2当量)。向该混合物中加入AcOH(催化量),将其搅拌16小时。将反应物用DCM(10mL)稀释并用NaHCO3水溶液(10mL)洗涤。分离水相并用乙酸乙酯(10mL)萃取。合并有机层并用盐水(10mL)洗涤,用Na2SO4干燥,过滤并浓缩以获得作为黄色油状物的粗制产物。将粗制产物通过制备型HPLC进行纯化(柱:Phenomenex Gemini C18 250x5010u;流动相:[水(0.225%FA)-ACN];B%:28%-58%,11.2min)以获得5-氨基-N-(3-氯-4-氟苯基)-3-(5-(二甲基氨基)八氢并环戊二烯-2-基)-1-甲基-1H-吡唑-4-甲酰胺,(8mg,0.017mmol,13.42%产率,100%纯度,FA盐),其作为白色固体。1H NMR(400MHz,DMSO-d6)δppm 1.18-1.31(m,2H)1.47(td,J=11.86,8.16Hz,2H)2.05-2.24(m,4H)2.32(s,6H)2.37-2.44(m,2H)2.52-2.55(m,1H)2.73-2.89(m,1H)3.50-3.50(m,3H)5.98(br s,2H)7.35(t,J=9.04Hz,1H)7.49-7.54(m,1H)7.90(d,J=6.56Hz,1H)8.27(s,1H)9.00(s,1H);LC-MS:420.0[M+1]+。
表6.根据描述于5-氨基-N-(3-氯-4-氟苯基)-3-(5-(二甲基氨基)八氢并环戊二烯-2-基)-1-甲基-1H-吡唑-4-甲酰胺的操作合成表6中的化合物
AIA-102
5-氨基-N-(3-氯-4-氟苯基)-1-甲基-3-(5-(甲基氨基)八氢并环戊二烯-2-基)-1H-吡唑-4-甲酰胺.向AIA-002(300mg,0.7mmol)在Ti(OiPr)4(5mL)的溶液中加入MeNH2(100mg,1.05mmol)。将该混合物在40℃搅拌1h。将该混合物用MeOH(5mL)稀释,加入NaBH4(100mg,1.4mmol),然后在室温继续搅拌1h。将该混合物用水淬灭,然后过滤并在真空中浓缩。将残留物通过柱色谱进行纯化(其使用10:3H2O/MeCN)以获得作为白色固体的粗制化合物(200mg,64.3%)。将该物质进一步通过制备型-HPLC纯化以获得作为白色固体的5-氨基-N-(3-氯-4-氟苯基)-1-甲基-3-(5-(甲基氨基)八氢并环戊二烯-2-基)-1H-吡唑-4-甲酰胺。1H NMR(DMSO-d6,400MHz):δ8.94(s,1H),7.90(dd,J=2.8,2.4Hz,1H),7.51-7.49(m,1H),7.34(t,J=8.8,9.2Hz,1H),5.95(s,2H),3.52-3.47(m,5H),2.87(s,1H),2.37(s,2H),2.22(s,3H),2.17-2.12(m,2H),2.02(t,J=5.6Hz,2H),1.48-1.46(m,2H),1.03-1.01(m,2H);MS理论值:405.1;MS实际值:406.2[M+1]+。
表7.根据描述于5-氨基-N-(3-氯-4-氟苯基)-1-甲基-3-(5-(甲基氨基)八氢并环戊二烯-2-基)-1H-吡唑-4-甲酰胺的操作合成表7中的化合物
AIA-043
5-氨基-N-(3-氯-4-氟苯基)-1-甲基-3-(5-(N-甲基甲磺酰胺基)八氢并环戊二烯-2-基)-1H-吡唑-4-甲酰胺.向5-氨基-N-(3-氯-4-氟苯基)-1-甲基-3-(5-(甲基氨基)八氢并环戊二烯-2-基)-1H-吡唑-4-甲酰胺(100mg,0.2mmol)在DCM(10mL)的溶液中加入TEA(50mg,0.4mmol)和MsCl(28mg,0.2mmol)。将该混合物在室温搅拌2h。将该混合物用MeOH淬灭并在真空下浓缩。将残留物通过制备型HPLC进行纯化以获得作为白色固体的5-氨基-N-(3-氯-4-氟苯基)-1-甲基-3-(5-(N-甲基甲磺酰胺基)八氢并环戊二烯-2-基)-1H-吡唑-4-甲酰胺(10.5mg,8.8%)。1H NMR(DMSO-d6,400MHz):δ8.96(s,1H),7.90(dd,J=2.4,2.8Hz,1H),7.54-7.50(m,1H),7.34(t,J=2.8,10.0Hz,1H),5.97(s,2H),4.06-4.00(m,1H),3.57-3.52(m,4H),2.83(s,3H),2.67(s,3H),2.42-2.32(m,2H),2.20-2.14(m,2H),1.90-1.84(m,2H),1.55-1.48(m,2H),1.43-1.35(m,2H);MS理论值:483.1;MS实际值:484.2[M+1]+。
AIA-047
5-氨基-N-(3-氯-4-氟苯基)-1-甲基-3-(5-(2-氧代咪唑烷-1-基)八氢并环戊二烯-2-基)-1H-吡唑-4-甲酰胺.将5-氨基-3-(5-((2-氨基乙基)氨基)八氢并环戊二烯-2-基)-N-(3-氯-4-氟苯基)-1-甲基-1H-吡唑-4-甲酰胺(120mg,0.28mmol),CDI(68mg,0.42mmol)和DIPEA(108mg,0.84mmol)在DCM(10mL)的溶液在室温搅拌过夜。将该混合物在真空下浓缩并将残留物通过制备型HPLC进行纯化以获得作为白色固体的5-氨基-N-(3-氯-4-氟苯基)-1-甲基-3-(5-(2-氧代咪唑烷-1-基)八氢并环戊二烯-2-基)-1H-吡唑-4-甲酰胺(20mg,15%)。1H-NMR(DMSO-d6,400MHz):δ8.96(s,1H),7.91(dd,J=6.8,2.4Hz,1H),7.54-7.50(m,1H),7.35(t,J=9.2Hz,1H),6.17(s,1H),5.98(s,2H),4.06-4.00(m,1H),3.57-3.54(m,1H),3.32-3.17(m,7H),2.43-2.37(m,2H),2.21-2.16(m,2H),1.82-1.76(m,2H),1.52-1.44(m,2H),1.37-1.29(m,2H);MS理论值:460.2;MS实际值:461.3[M+1]+。
AIA-046
5-氨基-N-(3-氯-4-氟苯基)-1-甲基-3-(5-(2-氧代噁唑烷-3-基)八氢并环戊二烯-2-基)-1H-吡唑-4-甲酰胺.将5-氨基-N-(3-氯-4-氟苯基)-3-(5-((2-羟基乙基)氨基)八氢并环戊二烯-2-基)-1-甲基-1H-吡唑-4-甲酰胺(110mg,0.25mmol),CDI(62mg,0.38mmol)和DIPEA(97mg,0.75mmol)在DCM(10mL)的溶液在室温搅拌过夜。将该混合物在真空下浓缩并将残留物通过制备型HPLC进行纯化以获得作为白色固体的5-氨基-N-(3-氯-4-氟苯基)-1-甲基-3-(5-(2-氧代噁唑烷-3-基)八氢并环戊二烯-2-基)-1H-吡唑-4-甲酰胺(20mg,17%)。1H-NMR(DMSO-d6,400MHz):δ8.99(s,1H),7.91(dd,J=6.8,2.4Hz,1H),7.54-7.50(m,1H),7.35(t,J=9.2Hz,1H),5.99(s,2H),4.24(t,J=7.6Hz,2H),4.02-3.97(m,1H),3.58-3.48(m,6H),2.44-2.40(m,2H),2.22-2.16(m,2H),1.93-1.87(m,2H),1.54-1.47(m,2H),1.43-1.35(m,2H);MS理论值:461.2;MS实际值:462.3[M+1]+。
AIA-032
5-氨基-N-(3-氯-4-氟苯基)-3-(5-(羟基亚氨基)八氢并环戊二烯-2-基)-1-甲基-1H-吡唑-4-甲酰胺.向AIA-002(800mg,2.1mmol)在混合溶剂(THF:EtOH=10:10mL)的溶液中加入NH2OH-HCl(440mg,6.3mmol)和NaOAc(1.2g,14.7mmol)。将该混合物在室温搅拌过夜,然后过滤并在真空中浓缩。将残留物通过硅胶柱色谱进行纯化,其使用10:1DCM/MeOH以获得作为白色固体的5-氨基-N-(3-氯-4-氟苯基)-3-(5-(羟基亚氨基)八氢并环戊二烯-2-基)-1-甲基-1H-吡唑-4-甲酰胺(800mg,96.0%)。);MS理论值:405.1;MS实际值:406.2[M+1]+。
AIA-073
5-氨基-3-(5-氨基八氢并环戊二烯-2-基)-N-(3-氯-4-氟苯基)-1-甲基-1H-吡唑-4-甲酰胺.向5-氨基-N-(3-氯-4-氟苯基)-3-(5-(羟基亚氨基)八氢并环戊二烯-2-基)-1-甲基-1H-吡唑-4-甲酰胺(300mg,0.4mmol)在MeOH(15mL)的溶液中加入NiCl26H2O(23mg,0.08mmol)。将该混合物在-30℃搅拌0.5h。向其中加入NaBH4(94mg,2mmol)并将混合物搅拌1h,并使其回到室温。将该混合物用水淬灭并用乙酸乙酯萃取。将有机层在真空下浓缩以获得作为浅黄色固体的粗制化合物,其通过制备型HPLC进行纯化以获得作为白色固体的5-氨基-3-(5-氨基八氢并环戊二烯-2-基)-N-(3-氯-4-氟苯基)-1-甲基-1H-吡唑-4-甲酰胺(10mg,10%产率)。1H NMR(DMSO-d6,400MHz):δ8.96(s,1H),7.90(dd,J=2.8,2.4Hz,1H),7.53-7.49(m,1H),7.34(t,J=9.2,9.2Hz,1H),5.97(s,2H),3.49-3.33(m,5H),3.14-3.11(m,1H),2.34(d,J=5.6Hz,2H),2.17-2.12(m,2H),1.99-1.93(m,2H),1.57-1.42(m,2H),1.23(s,1H),1.02-0.95(m,2H);MS理论值:391.1;MS实际值:392.2[M+1]+。
AIA-042
5-氨基-N-(3-氯-4-氟苯基)-1-甲基-3-(5-(甲磺酰胺基)八氢并环戊二烯-2-基)-1H-吡唑-4-甲酰胺.向5-氨基-3-(5-氨基八氢并环戊二烯-2-基)-N-(3-氯-4-氟苯基)-1-甲基-1H-吡唑-4-甲酰胺(200mg,0.2mmol)在DCM(10mL)的溶液中加入TEA(52mg,0.4mmol)和MsCl(39mg,0.2mmol)。将该混合物在室温搅拌2h。除去溶剂,并将残留物通过制备型HPLC进行纯化以获得作为白色固体的5-氨基-N-(3-氯-4-氟苯基)-1-甲基-3-(5-(甲磺酰胺基)八氢并环戊二烯-2-基)-1H-吡唑-4-甲酰胺(19.3mg,16.8%)。1H NMR(DMSO-d6,400MHz):δppm 8.96(s,1H),7.90(dd,J=2.4,4.0Hz,1H),7.53-7.49(m,1H),7.34(t,J=8.8,9.2Hz,1H),7.10(d,J=7.6Hz,1H),5.97(s,2H),3.60-3.50(m,2H),3.47(s,3H),2.87(s,3H),2.34(t,J=8.0Hz,2H),2.20-2.11(m,4H),1.48-1.40(m,2H),1.23-1.16(m,2H);MS理论值:469.1;MS实际值:470.2[M+1]+。
AIA-086
5-氨基-N-(3-氯-4-氟苯基)-1-甲基-3-(5-((三氟甲基)磺酰胺基)八氢并环戊二烯-2-基)-1H-吡唑-4-甲酰胺.根据描述于5-氨基-N-(3-氯-4-氟苯基)-1-甲基-3-(5-(甲磺酰胺基)八氢并环戊二烯-2-基)-1H-吡唑-4-甲酰胺的操作合成标题化合物。1H NMR(DMSO-d6,400MHz):δ9.46(s,1H),8.97(s,1H),7.89(dd,J=2.4,2.4Hz,1H),7.53-7.49(m,1H),7.34(t,J=9.2Hz,1H),5.98(s,2H),3.74(s,1H),3.54-3.33(m,4H),2.39-2.37(m,2H),2.21-2.09(m,4H),1.48-1.40(m,2H),1.32-1.24(m,2H);MS理论值:523.1;MS实际值:524.2[M+1]+。
AIA-087
氨基-N-(3-氯-4-氟苯基)-1-甲基-3-(5-((1-甲基-1H-咪唑)-4-磺酰胺基)八氢并环戊二烯-2-基)-1H-吡唑-4-甲酰胺根据描述于5-氨基-N-(3-氯-4-氟苯基)-1-甲基-3-(5-(甲磺酰胺基)八氢并环戊二烯-2-基)-1H-吡唑-4-甲酰胺的操作合成标题化合物。MS理论值:535.1;MS实际值:536.2[M+1]+.1H NMR(DMSO-d6,400MHz):δ8.95(s,1H),7.88(dd,J=2.4,2.4Hz,1H),7.74(s,1H),7.65(d,J=0.8Hz,1H),7.52-7.47(m,2H),7.33(t,J=9.2,9.2Hz,1H),5.96(s,2H),3.68(s,3H),3.49-3.43(m,5H),2.23(t,J=4.8,8.4Hz,2H),2.14-2.07(m,2H),1.92-1.85(m,2H),1.37(dd,J=12.4,12.0Hz,2H),1.11(t,J=12.0,11.6Hz,2H)。
中间体106
5-氨基-N-(3-氯-4-氟苯基)-3-(5-((3-氯丙基)磺酰胺基)八氢并环戊二烯-2-基)-1-甲基-1H-吡唑-4-甲酰胺:根据描述于5-氨基-N-(3-氯-4-氟苯基)-1-甲基-3-(5-(甲磺酰胺基)八氢并环戊二烯-2-基)-1H-吡唑-4-甲酰胺的操作合成标题化合物。MS理论值:531.1;MS实际值:532.2[M+1]+。
AIA-044
5-氨基-N-(3-氯-4-氟苯基)-3-(5-(1,1-二氧化异噻唑烷-2-基)八氢并环戊二烯-2-基)-1-甲基-1H-吡唑-4-甲酰胺.向5-氨基-N-(3-氯-4-氟苯基)-3-(5-((3-氯丙基)磺酰胺基)八氢并环戊二烯-2-基)-1-甲基-1H-吡唑-4-甲酰胺(100mg,0.2mmol)在DMF(5mL)的溶液中加入NaH(13mg,0.6mmol)。将该混合物在室温搅拌1h,然后用水淬灭并用乙酸乙酯萃取。将有机层在真空下浓缩。将残留物通过制备型HPLC进行纯化以获得作为白色固体的5-氨基-N-(3-氯-4-氟苯基)-3-(5-(1,1-二氧化异噻唑烷-2-基)八氢并环戊二烯-2-基)-1-甲基-1H-吡唑-4-甲酰胺(47.3mg,51%产率)。1H NMR(DMSO-d6,400MHz):δ8.97(s,1H),7.90(dd,J=2.8,2.4Hz,1H),7.53-7.49(m,1H),7.34(t,J=9.2,9.2Hz,1H),5.97(s,2H),3.55-3.49(m,5H),3.17-3.13(m,4H),2.41-2.39(m,2H),2.21-2.14(m,4H),2.06-1.99(m,2H),1.52-1.44(m,2H),1.41-1.33(m,2H);MS理论值:495.1;MS实际值:496.2[M+1]+
AIA-288
3-(5-乙酰氨基八氢并环戊二烯-2-基)-5-氨基-N-(3-氯-4-氟苯基)-1-甲基-1H-吡唑-4-甲酰胺根据描述于5-氨基-N-(3-氯-4-氟苯基)-1-甲基-3-(5-(甲磺酰胺基)八氢并环戊二烯-2-基)-1H-吡唑-4-甲酰胺的操作合成标题化合物。1HNMR(400MHz,氯仿-d)δppm 1.19-1.31(2H,m),1.71-1.83(2H,m),1.95(3H,s),2.28-2.42(4H,m),2.52-2.63(2H,m),3.23(1H,dt,J=11.30,5.71Hz),3.58(3H,s),4.24-4.37(1H,m),5.25(2H,s),5.49-5.58(1H,m),7.11(1H,t,J=8.77Hz),7.22-7.25(2H,m),7.71(1H,dd,J=6.39,2.21Hz);LCMS:434.0[M+1]+。
AIA-033A,AIA-033B
5-氨基-N-(3-氯-4-氟苯基)-1-甲基-3-(3-氧代八氢-1H-环戊二烯并[c]吡啶-6-基)-1H-吡唑-4-甲酰胺。非对映异构体1(AIA-033A)和非对映异构体2(AIA-033B)。将5-氨基-N-(3-氯-4-氟苯基)-3-(5-(羟基亚氨基)八氢并环戊二烯-2-基)-1-甲基-1H-吡唑-4-甲酰胺(90mg,0.22mmol),TsCl(90mg,1.47mmol),Na2CO3(90mg,0.85mmol)在H2O(5mL)/丙酮(5mL)中的混合物在80℃搅拌4h。将该反应混合物在真空下浓缩并将残留物通过手性HPLC纯化,以获得AIA-033A和AIA-03-B。AIA-033-A(20mg,22%产率),作为白色固体。MS理论值:405.14;MS实际值:406.3[M+1]+;1H-NMR(DMSO-d6,400MHz):δ8.95(s,1H),7.91(dd,J=6.8,2.4Hz,1H),7.52-7.45(m,2H),7.32(t,J=9.2Hz,1H),5.95(s,2H),3.47(s,3H),3.38-3.35(m,1H),3.16-3.12(m,1H),2.84-2.81(m,1H),2.42-2.41(m,1H),2.31-2.21(m,2H),2.09-2.04(m,2H),1.96-1.91(m,1H),1.48-1.45(m,1H),1.29-1.27(m,1H).AIA-033-B(20mg,22%产率)作为白色固体。MS理论值:405.14;MS实际值:406.3[M+1]+.1H-NMR(DMSO-d6,400MHz):δ8.95(s,1H),7.91(dd,J=6.8,2.4Hz,1H),7.52-7.45(m,2H),7.32(t,J=9.2Hz,1H),5.95(s,2H),3.47(s,3H),3.38-3.35(m,1H),3.16-3.12(m,1H),2.84-2.81(m,1H),2.42-2.41(m,1H),2.31-2.21(m,2H),2.09-2.04(m,2H),1.96-1.91(m,1H),1.48-1.45(m,1H),1.30-1.27(m,1H)。
中间体107
5-氨基-N-(3-氯-4-氟苯基)-3-(六氢-1'H-螺[环氧乙烷-2,2'-并环戊二烯]-5'-基)-1-甲基-1H-吡唑-4-甲酰胺.向2-甲基丙-2-醇钾(230mg,2.05mmol)在THF(30mL)的溶液中加入三甲基氧锍碘化物(450mg,2.05mmol)。在N2下,将该混合物在室温搅拌1h。然后将AIA-002(200mg,0.53mmol)加入到混合物中,并于N2气氛下在60℃继续搅拌5h。真空下除去溶剂并将产物通过硅胶柱色谱进行纯化(其使用1:1乙酸乙酯/石油醚)以获得作为黄色固体的5-氨基-N-(3-氯-4-氟苯基)-3-(六氢-1'H-螺[环氧乙烷-2,2'-并环戊二烯]-5'-基)-1-甲基-1H-吡唑-4-甲酰胺(200mg,96.6%)。MS理论值:404.1;MS实际值:405.2[M+1]+。
AIA-225
5-氨基-N-(3-氯-4-氟苯基)-3-(5-羟基-5-(甲基硫基甲基)八氢并环戊二烯-2-基)-1-甲基-1H-吡唑-4-甲酰胺.向5-氨基-N-(3-氯-4-氟苯基)-3-(六氢-1'H-螺[环氧乙烷-2,2'-并环戊二烯]-5'-基)-1-甲基-1H-吡唑-4-甲酰胺(200mg,0.495mmol)在THF/H2O(6mL/2mL)的溶液中加入NaSMe(138.6mg,1.98mmol)。将该混合物在室温搅拌过夜。除去溶剂并将粗制产物通过硅胶柱色谱进行纯化(其使用3:1石油醚/乙酸乙酯)以获得作为黄色固体的5-氨基-N-(3-氯-4-氟苯基)-3-(5-羟基-5-(甲基硫基甲基)八氢并环戊二烯-2-基)-1-甲基-1H-吡唑-4-甲酰胺(100mg,44.7%)。MS理论值:452.1;MS实际值:452.2[M+1]+.
表8.根据描述于5-氨基-N-(3-氯-4-氟苯基)-3-(5-羟基-5-(甲基硫基甲基)八氢并环戊二烯-2-基)-1-甲基-1H-吡唑-4-甲酰胺的操作合成表8中的化合物
AIA-227-1,AIA-227-2
5-氨基-N-(3-氯-4-氟苯基)-3-((2r,5r)-5-羟基-5-(甲基磺酰基甲基)八氢并环戊二烯-2-基)-1-甲基-1H-吡唑-4-甲酰胺(AIA-227-1)和5-氨基-N-(3-氯-4-氟苯基)-3-((2s,5s)-5-羟基-5-(甲基磺酰基甲基)八氢并环戊二烯-2-基)-1-甲基-1H-吡唑-4-甲酰胺(AIA-227-2).向5-氨基-N-(3-氯-4-氟苯基)-3-(5-羟基-5-(甲基硫基甲基)八氢并环戊二烯-2-基)-1-甲基-1H-吡唑-4-甲酰胺(100mg,0.22mmol)在DCM(5mL)的溶液中加入m-CPBA(114.8mg,0.66mmol)。将该混合物在室温搅拌过夜。除去溶并将粗制物质通过硅胶柱色谱进行纯化(其使用3:1DCM/MeOH)以获得作为白色固体的AIA-227(40mg,37.3%)。MS理论值:484.1;MS实际值:484.3[M+1]+。通过SFC分离AIA-227以获得作为白色固体的AIA-227-1(4mg)和作为白色固体的AIA-227-2(4mg)。AIA-227-1:1H-NMR(DMSO,400MHz):δ8.95(s,1H),7.91(dd,J=6.8,2.4Hz,1H),7.54-7.50(m,1H),7.35(t,J=9.2Hz,1H),5.97(s,2H),4.79(s,1H),3.59-3.53(m,1H),3.49(s,3H),3.35(s,2H),2.97(s,3H),2.67-2.60(m,2H),2.18-2.12(m,2H),2.07-2.02(m,2H),1.45-1.36(m,4H).AIA-227-2:1H-NMR(DMSO,400MHz):δ8.94(s,1H),7.91(dd,J=2.8,2.4Hz,1H),7.53-7.49(m,1H),7.34(t,J=9.2Hz,1H),5.97(s,2H),4.87(s,1H),3.49(s,3H),3.43-3.35(m,1H),3.25(s,2H),2.97(s,3H),2.49(s,2H),2.15-2.09(m,2H),2.02-1.97(m,2H),1.73-1.60(m,4H)。
表9.根据描述于5-氨基-N-(3-氯-4-氟苯基)-3-((2r,5r)-5-羟基-5-(甲基磺酰基甲基)八氢并环戊二烯-2-基)-1-甲基-1H-吡唑-4-甲酰胺(AIA-227-1)和5-氨基-N-(3-氯-4-氟苯基)-3-((2s,5s)-5-羟基-5-(甲基磺酰基甲基)八氢并环戊二烯-2-基)-1-甲基-1H-吡唑-4-甲酰胺(AIA-227-2)的操作合成表9中的化合物
AIA-227-2
5-氨基-N-(3-氯-4-氟苯基)-3-((2s,5s)-5-羟基-5-(甲基磺酰基甲基)八氢并环戊二烯-2-基)-1-甲基-1H-吡唑-4-甲酰胺的替代合成.在78℃,向二甲基亚砜(77.0g,818.7mmol)在THF(800mL)的溶液中逐滴加入n-BuLi(327.5mL,818.7mmol,2.5M)。将获得的溶液温热至-20℃并搅拌1小时。将反应物冷却至-78℃,并且2小时内加入AIA-002(40.0g,102.3mmol)在无水四氢呋喃(1200mL)中的溶液。将该混合物温热至RT并搅拌额外4小时。将该反应混合物用饱和氯化铵水溶液(200mL)淬灭。除去溶剂,然后通过用水稀释,用乙酸乙酯(3x200mL)萃取,用Na2SO4干燥,过滤,并浓缩以获得粗制产物。将粗制产物通过柱色谱(其使用0-5%在DCM中的甲醇)和碱式制备型HPLC进行纯化以获得作为白色固体的5-氨基-N-(3-氯-4-氟苯基)-3-((2s,5s)-5-羟基-5-(甲基磺酰基甲基)八氢并环戊二烯-2-基)-1-甲基-1H-吡唑-4-甲酰胺(26.0g,52.4%)。MS理论值:484.1,MS实际值:485.2[M+1]+;1H NMR(DMSO-d6,400MHz):δ8.96(s,1H),7.92(dd,J=6.8,2.8Hz,1H),7.54-7.50(m,1H),7.35(t,J=8.8Hz,1H),5.98(s,2H),4.88(s,1H),3.49(s,3H),3.42-3.37(m,1H),3.25(s,2H),2.97(s,3H),2.15-2.10(m,2H),2.03-1.97(m,2H),1.73-1.60(m,4H)。
中间体110
甲磺酸3-(((5-(5-氨基-4-((3-氯-4-氟苯基)氨基甲酰基)-1-甲基-1H-吡唑-3-基)-2-羟基八氢并环戊二烯-2-基)甲基)硫基)丙基酯非对映异构体1。向5-氨基-N-(3-氯-4-氟苯基)-3-(5-羟基-5-(((3-羟基丙基)硫基)甲基)八氢并环戊二烯-2-基)-1-甲基-1H-吡唑-4-甲酰胺非对映异构体1(AIA-295-2A)(198.8mg,0.4mmol)在DCM(15mL)的溶液加入TEA(121.4mg,1.2mmol)和MsCl(91.6mg,0.8mmol)。将该混合物在室温搅拌1h。该反应完成后,将该混合物用H2O淬灭并用DCM萃取。将有机层在减压下除去,并将残留物通过柱色谱进行纯化以获得作为白色固体的甲磺酸3-(((5-(5-氨基-4-((3-氯-4-氟苯基)氨基甲酰基)-1-甲基-1H-吡唑-3-基)-2-羟基八氢并环戊二烯-2-基)甲基)硫基)丙基酯非对映异构体1(200.0mg,86.9%)。MS理论值:574.15;MS实际值:575.2[M+1]+。
中间体111
甲磺酸3-(((5-(5-氨基-4-((3-氯-4-氟苯基)氨基甲酰基)-1-甲基-1H-吡唑-3-基)-2-羟基八氢并环戊二烯-2-基)甲基)硫基)丙基酯非对映异构体2.向5-氨基-N-(3-氯-4-氟苯基)-3-(5-羟基-5-(((3-羟基丙基)硫基)甲基)八氢并环戊二烯-2-基)-1-甲基-1H-吡唑-4-甲酰胺非对映异构体2(AIA-295-2B)(452.3mg,0.91mmol)在DCM(15mL)的溶液加入TEA(276.2mg,2.73mmol)和MsCl(208.5mg,1.82mmol)。将该混合物在室温搅拌1h。该反应完成后,将该混合物用H2O淬灭并用DCM萃取。将有机层在减压下除去,并将残留物通过柱色谱进行纯化以获得作为白色固体的甲磺酸3-(((5-(5-氨基-4-((3-氯-4-氟苯基)氨基甲酰基)-1-甲基-1H-吡唑-3-基)-2-羟基八氢并环戊二烯-2-基)甲基)硫基)丙基酯非对映异构体2(460.0mg,87.9%)。MS理论值:574.15;MS实际值:575.2[M+1]+。
中间体112
5-氨基-3-(5-(((3-溴丙基)硫基)甲基)-5-羟基八氢并环戊二烯-2-基)-N-(3-氯-4-氟苯基)-1-甲基-1H-吡唑-4-甲酰胺.非对映异构体1.将甲磺酸3-(((5-(5-氨基-4-((3-氯-4-氟苯基)氨基甲酰基)-1-甲基-1H-吡唑-3-基)-2-羟基八氢并环戊二烯-2-基)甲基)硫基)丙基酯非对映异构体1(201.3mg,0.35mmol)和LiBr(76.4mg,0.88mmol)在NMP中的混合物在80℃搅拌。该反应完成后,将该混合物通过制备型HPLC进行纯化以获得作为白色固体的5-氨基-3-(5-(((3-溴丙基)硫基)甲基)-5-羟基八氢并环戊二烯-2-基)-N-(3-氯-4-氟苯基)-1-甲基-1H-吡唑-4-甲酰胺,非对映异构体1(120mg,61.2%)。MS理论值:558.09;MS实际值:559.13[M+1]+。
中间体113
5-氨基-3-(5-(((3-溴丙基)硫基)甲基)-5-羟基八氢并环戊二烯-2-基)-N-(3-氯-4-氟苯基)-1-甲基-1H-吡唑-4-甲酰胺.非对映异构体2.将甲磺酸3-(((5-(5-氨基-4-((3-氯-4-氟苯基)氨基甲酰基)-1-甲基-1H-吡唑-3-基)-2-羟基八氢并环戊二烯-2-基)甲基)硫基)丙基酯非对映异构体2(460.1mg,0.8mmol)和LiBr(173.7mg,2.0mmol)在NMP的混合物在80℃搅拌。该反应完成后,将该混合物通过制备型HPLC进行纯化以获得作为白色固体的5-氨基-3-(5-(((3-溴丙基)硫基)甲基)-5-羟基八氢并环戊二烯-2-基)-N-(3-氯-4-氟苯基)-1-甲基-1H-吡唑-4-甲酰胺,非对映异构体2.(200mg,44.6%)。MS理论值:558.09;MS实际值:559.1[M+1]+,561.2[M+2+H]+。
中间体114
5-氨基-3-(5-(((3-溴丙基)磺酰基)甲基)-5-羟基八氢并环戊二烯-2-基)-N-(3-氯-4-氟苯基)-1-甲基-1H-吡唑-4-甲酰胺.非对映异构体1.将5-氨基-3-(5-(((3-溴丙基)硫基)甲基)-5-羟基八氢并环戊二烯-2-基)-N-(3-氯-4-氟苯基)-1-甲基-1H-吡唑-4-甲酰胺,非对映异构体1(117.6mg,0.21mmol)和m-CPBA(108.7mg,0.63mmol)在DCM中的混合物在室温搅拌2h。该反应完成后,将该混合物用NaHCO3淬灭并用DCM萃取。将有机层在减压下除去,并将残留物通过柱色谱进行纯化以获得作为白色固体的5-氨基-3-(5-(((3-溴丙基)磺酰基)甲基)-5-羟基八氢并环戊二烯-2-基)-N-(3-氯-4-氟苯基)-1-甲基-1H-吡唑-4-甲酰胺,非对映异构体1(60mg,48.3%)。MS理论值:590.08;MS实际值:591.13[M+1]+。
中间体115
5-氨基-3-(5-(((3-溴丙基)磺酰基)甲基)-5-羟基八氢并环戊二烯-2-基)-N-(3-氯-4-氟苯基)-1-甲基-1H-吡唑-4-甲酰胺.非对映异构体2.将5-氨基-3-(5-(((3-溴丙基)硫基)甲基)-5-羟基八氢并环戊二烯-2-基)-N-(3-氯-4-氟苯基)-1-甲基-1H-吡唑-4-甲酰胺,非对映异构体1(117.6mg,0.21mmol)和m-CPBA(108.7mg,0.63mmol)在DCM中的混合物在室温搅拌2h。该反应完成后,将该混合物用NaHCO3淬灭并用DCM萃取。将有机层在减压下除去,并将残留物通过柱色谱进行纯化以获得作为白色固体的5-氨基-3-(5-(((3-溴丙基)磺酰基)甲基)-5-羟基八氢并环戊二烯-2-基)-N-(3-氯-4-氟苯基)-1-甲基-1H-吡唑-4-甲酰胺,非对映异构体1(150mg,72.4%)。MS理论值:590.08;MS实际值:591.1[M+1]+,593.2[M+2+H]+。
AIA-295-1
5-氨基-N-(3-氯-4-氟苯基)-3-(5-羟基-5-(((3-吗啉代丙基)磺酰基)甲基)八氢并环戊二烯-2-基)-1-甲基-1H-吡唑-4-甲酰胺.非对映异构体1(AIA-295-1).将5-氨基-3-(5-(((3-溴丙基)磺酰基)甲基)-5-羟基八氢并环戊二烯-2-基)-N-(3-氯-4-氟苯基)-1-甲基-1H-吡唑-4-甲酰胺,非对映异构体1(50.0mg,0.08mmol),吗啉(14.0mg,0.16mmol)和K2CO3(22.1mg,0.16mmol)在ACN中的混合物在80℃搅拌。该反应完成后,将该混合物用H2O淬灭并用DCM萃取。将有机层在减压下除去,并将残留物通过制备型HPLC进行纯化以获得作为白色固体的5-氨基-N-(3-氯-4-氟苯基)-3-(5-羟基-5-(((3-吗啉代丙基)磺酰基)甲基)八氢并环戊二烯-2-基)-1-甲基-1H-吡唑-4-甲酰胺,非对映异构体1(AIA-295-1)(10.0mg,21.3%)。MS理论值:597.22;MS实际值:598.22[M+1]+;AIA-295-1的1H NMR(DMSO-d6,400MHz):δ8.95(S,1H),7.92-7.90(m,1H),7.53-7.51(m,1H),7.38-7.33(t,J=8.6Hz,1H),5.98(S,2H),4.89(S,1H),3.60(S,4H),3.60(S,3H),3.42-3.38(m,1H),3.28-3.10(m,4H),2.64-2.57(m,2H),2.42-2.33(m,6H),2.14-2.11(m,2H),2.03-1.96(m,2H),1.87-1.83(m,2H),1.73-1.58(m,4H)。
AIA-295-B
5-氨基-N-(3-氯-4-氟苯基)-3-(5-羟基-5-(((3-吗啉代丙基)磺酰基)甲基)八氢并环戊二烯-2-基)-1-甲基-1H-吡唑-4-甲酰胺.非对映异构体2(AIA-295-B).将5-氨基-3-(5-(((3-溴丙基)磺酰基)甲基)-5-羟基八氢并环戊二烯-2-基)-N-(3-氯-4-氟苯基)-1-甲基-1H-吡唑-4-甲酰胺,非对映异构体1(2)(50.0mg,0.08mmol),吗啉(14.0mg,0.16mmol)和K2CO3(22.1mg,0.16mmol)在ACN中的混合物在80℃搅拌。该反应完成后,将该混合物用H2O淬灭并用DCM萃取。将有机层在减压下除去,并将残留物通过制备型HPLC进行纯化以获得作为白色固体的5-氨基-N-(3-氯-4-氟苯基)-3-(5-羟基-5-(((3-吗啉代丙基)磺酰基)甲基)八氢并环戊二烯-2-基)-1-甲基-1H-吡唑-4-甲酰胺,非对映异构体1(AIA-295-B)(33mg,55.2%)。MS理论值:597.22;MS实际值:598.2[M+1]+;1H NMR(DMSO-d6,400MHz):δ8.95(s,1H),7.91(dd,J=2.4Hz,6.8Hz,1H),7.54-7.50(m,1H),7.35(t,J=9.2Hz,1H),5.97(s,2H),4.78(s,1H),3.57-3.54(m,5H),3.49(s,3H),3.32(brs,2H),3.16-3.12(m,2H),2.63-2.61(m,2H),2.36-2.33(m,6H),2.18-2.11(m,2H),2.06-2.01(m,2H),1.85-1.81(m,2H),1.47-1.36(m,4H)。
表10.根据描述于5-氨基-N-(3-氯-4-氟苯基)-3-(5-羟基-5-(((3-吗啉代丙基)磺酰基)甲基)八氢并环戊二烯-2-基)-1-甲基-1H-吡唑-4-甲酰胺,非对映异构体1和2的操作合成表10中的化合物
AIA-351-A
5-氨基-N-(3-氯-4-氟苯基)-3-(5-羟基-5-(((3-(2-氧代哌嗪-1-基)丙基)磺酰基)甲基)八氢并环戊二烯-2-基)-1-甲基-1H-吡唑-4-甲酰胺.将4-(3-(((5-(5-氨基-4-((3-氯-4-氟苯基)氨基甲酰基)-1-甲基-1H-吡唑-3-基)-2-羟基八氢并环戊二烯-2-基)甲基)磺酰基)丙基)-3-氧代哌嗪-1-甲酸叔丁酯,非对映异构体1(50.0mg,0.08mmol)在HCl/CH3OH(5mL)的溶液在室温搅拌1h。反应完成后,在减压下除去溶剂,并将获得的残留物通过制备型HPLC进行纯化以获得作为白色固体的5-氨基-N-(3-氯-4-氟苯基)-3-(5-羟基-5-(((3-(2-氧代哌嗪-1-基)丙基)磺酰基)甲基)八氢并环戊二烯-2-基)-1-甲基-1H-吡唑-4-甲酰胺.(10.0mg,47.6%)。MS理论值:610.21;MS实际值:611.1[M+1]+;1H NMR(DMSO-d6,400MHz):δ8.92(s,1H),7.89(dd,J=2.8Hz,7.2Hz,1H),7.51-7.47(m,1H),7.33(t,J=5.2Hz,1H),5.95(s,2H),4.96-4.94(m,1H),4.87(s,1H),3.47(s,3H),3.45-3.36(m,3H),3.33-3.32(m,1H),3.29-3.28(m,1H),3.18-3.12(m,5H),2.83-2.82(m,2H),2.47(brs,2H),2.14-2.09(m,2H),2.02-1.93(m,2H),1.70-1.59(m,4H),1.16(d,J=6.8Hz,3H)。
AIA-259-A,AIA-259-B
5-氨基-N-(3-氯-4-氟苯基)-3-((2r,5r)-5-羟基-5-((2,2,2-三氟乙基亚磺酰基)甲基)八氢并环戊二烯-2-基)-1-甲基-1H-吡唑-4-甲酰胺非对映异构体1(AIA-259-A),非对映异构体2(AIA-259-B).向5-氨基-N-(3-氯-4-氟苯基)-3-(5-羟基-5-(((2,2,2-三氟乙基)硫基)甲基)八氢并环戊二烯-2-基)-1-甲基-1H-吡唑-4-甲酰胺,非对映异构体1(100mg,0.2mmol)在干燥的DCM(10mL)的溶液中加入m-CPBA(99mg,0.6mmol),并将混合物在室温搅拌4小时。在减压下除去溶剂,并将残留物通过制备型HPLC进行纯化以获得AIA-259-1。将其进一步通过手性HPLC纯化以获得AIA-259-A(9mg)和AIA-259-B(12mg)。AIA-259-A:1H NMR(DMSO-d6,400MHz):δ8.95(s,1H),7.91(dd,J=6.8,2.4Hz,1H),7.54-7.51(m,1H),7.35(t,J=9.2Hz,1H),5.98(s,2H),4.91(s,1H)4.06-3.89(m,2H),3.59-3.56(m,1H),3.49(s,3H),3.16(dd,J=28.8,13.6Hz,2H),2.68-2.62(m,2H),2.18-2.14(m,2H),2.08-2.00(m,1H),1.92-1.89(m,1H)1.49-1.37(m,4H).AIA-259-B:1H NMR(DMSO-d6,400MHz):δ8.95(s,1H),7.91(dd,J=6.8,2.4Hz,1H),7.54-7.50(m,1H),7.35(t,J=9.2Hz,1H),5.98(s,2H),4.91(s,1H)4.03-3.89(m,2H),3.58-3.56(m,1H),3.49(s,3H),3.22-3.11(m,2H),2.68-2.62(m,2H),2.18-2.14(m,2H),2.08-2.00(m,2H),1.92-1.89(m,2H),1.49-1.37(m,4H)。
AIA-259-C,AIA-259-D
5-氨基-N-(3-氯-4-氟苯基)-3-((2r,5r)-5-羟基-5-((2,2,2-三氟乙基亚磺酰基)甲基)八氢并环戊二烯-2-基)-1-甲基-1H-吡唑-4-甲酰胺非对映异构体3(AIA-259-C),非对映异构体4(AIA-259-D).向5-氨基-N-(3-氯-4-氟苯基)-3-(5-羟基-5-(((2,2,2-三氟乙基)硫基)甲基)八氢并环戊二烯-2-基)-1-甲基-1H-吡唑-4-甲酰胺,非对映异构体2(200mg,0.4mmol)在干燥的DCM(10mL)的溶液中加入m-CPBA(331mg,1.9mmol),并将该混合物在室温搅拌4小时。在初始物质消耗完全后,在减压下除去溶剂,并将残留物通过制备型HPLC进行纯化以获得AIA-259-2,其通过手性HPLC进一步纯化,以获得AIA-259-C(6mg)和AIA-259-D(6mg)。AIA-259-C:1H NMR(DMSO-d6,400MHz):δ8.96(s,1H),7.92(dd,J=7.2,2.8Hz,1H),7.54-7.50(m,1H),7.35(t,J=9.2Hz,1H),5.98(s,2H),4.99(s,1H)4.05-3.90(m,2H),3.49(s,3H),3.45-3.39(m,1H),3.10(dd,J=16.8,13.2Hz,2H),2.33-2.32(m,2H),2.14-2.12(m,2H),2.07-2.02(m,1H),1.89-1.82(m,1H),1.69-1.56(m,4H).AIA-259-D:1HNMR(DMSO-d6,400MHz):δ8.96(s,1H),7.91(dd,J=6.8,2.4Hz,1H),7.54-7.50(m,1H),7.35(t,J=9.2Hz,1H),5.98(s,2H),4.99(s,1H)4.02-3.90(m,2H),3.49(s,3H),3.44-3.37(m,1H),3.10(dd,J=16.8,13.6Hz,2H),2.44-2.33(m,2H),2.14-2.12(m,2H),2.07-2.02(m,1H),1.88-1.82(m,1H),1.69-1.56(m,4H)。
AIA-339-1,AIA-339-2
5-氨基-N-(3-氯-4-氟苯基)-3-(5-羟基-5-(异丙氧基甲基)八氢并环戊二烯-2-基)-1-甲基-1H-吡唑-4-甲酰胺.非对映异构体1(AIA-339-1),非对映异构体2(AIA-339-2).将5-氨基-N-(3-氯-4-氟苯基)-3-(六氢-1'H-螺[环氧乙烷-2,2'-并环戊二烯]-5'-基)-1-甲基-1H-吡唑-4-甲酰胺(420mg粗制,1.0mmol)和丙-2-醇钠(410mg,5.0mmol)在iPrOH(20mL)中的混合物搅拌回流过夜。将该反应混合物通过制备型HPLC进行纯化以获得作为白色固体的AIA-339-1(9mg,2%)和作为白色固体的化合物AIA-339-2(10mg,2%)。AIA-339-1:MS理论值:464.20;MS实际值:465.3[M+H]+.1H-NMR(d6-DMSO,400MHz):δ8.92(s,1H),7.90(dd,J=6.8,2.4Hz,1H),7.52-7.48(m,1H),7.33(t,J=9.2Hz,1H),5.95(s,2H),4.07(s,1H),3.52-3.45(m,5H),3.20(s,2H),2.63-2.60(m,2H),2.13-2.09(m,2H),1.67-1.61(m,2H),1.39-1.34(m,4H),1.05(d,J=6.0Hz,6H).AIA-339-2:MS理论值:464.20;MS实际值:465.3[M++H]+。1H-NMR(d6-DMSO,400MHz):δ8.90(s,1H),7.89(dd,J=6.8,2.8Hz,1H),7.51-7.46(m,1H),7.32(t,J=9.2Hz,1H),5.95(s,2H),4.13(s,1H),3.51-3.47(m,4H),3.38-3.35(m,1H),3.15(s,2H),2.40-2.39(m,2H),2.13-2.06(m,2H),1.80-1.86(m,2H),1.72-1.66(m,2H),1.34-1.30(m,2H),1.05(d,J=6.4Hz,6H)。
表11.根据描述于5-氨基-N-(3-氯-4-氟苯基)-3-(5-羟基-5-(异丙氧基甲基)八氢并环戊二烯-2-基)-1-甲基-1H-吡唑-4-甲酰胺的操作合成表11中的化合物
AIA-217-3
5-氨基-3-(5-(氨基甲基)-5-羟基八氢并环戊二烯-2-基)-N-(3-氯-4-氟苯基)-1-甲基-1H-吡唑-4-甲酰胺。向5-氨基-N-(3-氯-4-氟苯基)-3-(六氢-1'H-螺[环氧乙烷-2,2'-并环戊二烯]-5'-基)-1-甲基-1H-吡唑-4-甲酰胺(200mg,0.495mmol)在THF(5mL)的溶液中加入NH4OH(5mL)。将该混合物在室温搅拌过夜。除去溶剂并通过硅胶柱色谱进行纯化(其使用乙酸乙酯)以获得作为白色固体的5-氨基-3-(5-(氨基甲基)-5-羟基八氢并环戊二烯-2-基)-N-(3-氯-4-氟苯基)-1-甲基-1H-吡唑-4-甲酰胺(80mg,38.4%)。MS理论值:421.1;MS实际值:422.3[M+1]+
AIA-218-1和AIA-218-2
5-氨基-N-(3-氯-4-氟苯基)-1-甲基-3-(2-氧代六氢-1'H-螺[噁唑烷-5,2'-并环戊二烯]-5'-基)-1H-吡唑-4-甲酰胺.非对映异构体1(CP-AIA-218-1).非对映异构体2(CP-AIA-218-2):向5-氨基-3-(5-(氨基甲基)-5-羟基八氢并环戊二烯-2-基)-N-(3-氯-4-氟苯基)-1-甲基-1H-吡唑-4-甲酰胺(80mg,0.19mmol)在DCM(6mL)的溶液中加入CDI(43mg,0.266mmol)。将该混合物在室温搅拌4h。除去溶剂并通过硅胶柱色谱进行纯化(其使用DCM/MeOH=3/1)以获得作为白色固体的CP-AIA-218(40mg,47.1%)。MS理论值:447.1;MS实际值:448.2[M+1]+。通过SFC分离CP-AIA-218以获得作为白色固体的CP-AIA-218-1(4mg)和作为白色固体CP-AIA-218-2(4mg)。CP-AIA-218-1:1H-NMR(DMSO,400MHz):δ8.95(s,1H),7.92(dd,J=2.4,2.4Hz,1H),7.55-7.51(m,1H),7.37-7.33(m,2H),5.98(s,2H),3.62-3.56(m,1H),3.49(s,3H),3.38(s,2H),2.67-2.61(m,2H),2.22-2.10(m,4H),1.55(dd,J=8.0,7.2Hz,2H),1.50-1.42(m,2H)。CP-AIA-218-2:1H-NMR(DMSO,400MHz):δ8.96(s,1H),7.91(dd,J=2.8,2.4Hz,1H),7.54-7.50(m,1H),7.40-7.32(m,2H),5.98(s,2H),3.51(s,3H),3.42-3.35(m,1H),3.34(s,2H),2.55(s,2H),2.20-2.13(m,2H),1.91(dd,J=8.8,8.0Hz,2H),1.80-1.76(m,2H),1.64-1.56(m,2H)。
AIA-255-3和AIA-255-4
5-氨基-N-(3-氯-4-氟苯基)-3-(2'-乙基六氢-1H-螺[并环戊二烯-2,4'-[1,3]二氧杂环戊基]-5-基)-1-甲基-1H-吡唑-4-甲酰胺.非对映异构体1(CP-AIA-255-3),非对映异构体2(CP-AIA-255-4).向5-氨基-N-(3-氯-4-氟苯基)-3-(六氢-1'H-螺[环氧乙烷-2,2'-并环戊二烯]-5'-基)-1-甲基-1H-吡唑-4-甲酰胺(200mg,0.49mmol)在THF(3mL)的溶液中加入环丙醇(287mg,4.90mmol)。将该混合物冷却至0℃并加入H2SO4(浓,1滴)。将获得的混合物在0℃搅拌1h,并温热至RT并维持1h,然后用Na2CO3溶液淬灭并用乙酸乙酯(15mLx3)萃取。将有机层干燥并浓缩,并将残留物通过制备型TLC,然后通过制备型HPLC纯化以获得CP-AIA-255-3(5mg,2.2%)和CP-AIA-255-4(3mg,0.7%),作为白色固体。CP-AIA-255-3:MS理论值:462.2.1H-NMR(DMSO-d6,400MHz):δ8.94(s,1H),7.91(dd,J=6.8,2.4Hz,1H),7.54-7.50(m,1H),7.34(t,J=9.2Hz,1H),5.97(s,2H),4.79(t,J=4.8Hz,1H),3.70(dd,J=34.8,8.0Hz,2H),3.57-3.51(m,1H),3.48(s,3H),2.62-2.58(m,2H),2.19-2.13(m,2H),2.05-2.00(m,1H),1.93-1.88(m,1H),1.56-1.49(m,3H),1.45-1.38(m,3H),0.84(t,J=7.2Hz,3H);MS实际值:463.2[M+1]+.CP-AIA-255-4:1H-NMR(DMSO-d6,400MHz):δ8.95(s,1H),7.91(dd,J=6.8,2.4Hz,1H),7.53-7.49(m,1H),7.34(t,J=9.2Hz,1H),5.96(s,2H),4.80(t,J=4.4Hz,1H),3.65(dd,J=48.4,8.0Hz,2H),3.48(s,3H),3.42-3.37(m,1H),2.45-2.41(m,2H),2.15-2.12(m,2H),1.87-1.77(m,2H),1.65-1.48(m,6H),0.84(t,J=7.2Hz,3H)MS理论值:462.2;MS实际值:463.2[M+1]+。
AIAI-253
5-氨基-N-(3-氯-4-氟苯基)-3-(5-((二氟甲氧基)甲基)-5-羟基八氢并环戊二烯-2-基)-1-甲基-1H-吡唑-4-甲酰胺.向5-氨基-N-(3-氯-4-氟苯基)-3-(5-羟基-5-(羟基甲基)八氢并环戊二烯-2-基)-1-甲基-1H-吡唑-4-甲酰胺.(480mg,1.14mmol)在CHCl3/H2O(20mL/4mL)的溶液中加入KHF2(450mg,5.7mmol)和(溴二氟甲基)三甲基甲硅烷(1.2g,5.7mmol)。将该混合物在室温搅拌过夜。除去溶剂,并将产物通过硅胶柱色谱进行纯化(其使用1:1乙酸乙酯/石油醚)以获得作为白色固体的5-氨基-N-(3-氯-4-氟苯基)-3-(5-((二氟甲氧基)甲基)-5-羟基八氢并环戊二烯-2-基)-1-甲基-1H-吡唑-4-甲酰胺(1.4mg,0.3%)。MS理论值:472.15;MS实际值:473.3[M+H]+.1H-NMR(DMSO,400MHz):δ8.95(s,1H),7.90-7.93(dd,J=6.8,2.4Hz,1H),7.54-7.50(m,1H),7.35(t,J=9.2Hz,1H),6.66(t,J=76Hz,1H),5.98(s,2H),4.54(s,1H),3.69(s,2H),3.59-3.51(m,1H),3.49(s,3H),2.70-2.64(m,2H),2.18-2.12(m,2H),1.79-1.74(m,2H),1.41-1.34(m,4H)。
AIA-267-1,AIA-267-2
5-氨基-N-(3-氯-4-氟苯基)-3-(5-羟基-5-(2-(甲磺酰基)乙基)八氢并环戊二烯-2-基)-1-甲基-1H-吡唑-4-甲酰胺.非对映异构体1(AIA-267-1),非对映异构体2(AIA-267-2):在-78℃,向二甲基亚砜(1.5g,15.8mmol)在干燥的THF(20mL)的溶液中缓慢加入n-BuLi在THF(6.3mL,15.8mmol,2.5M)中的溶液,并将该混合物在此温度搅拌1小时。缓慢加入5-氨基-N-(3-氯-4-氟苯基)-3-(六氢-1'H-螺[环氧乙烷-2,2'-并环戊二烯]-5'-基)-1-甲基-1H-吡唑-4-甲酰胺(800.0mg,2.0mmol)在THF(15mL)的溶液并将反应物温热至RT,并搅拌过夜。在用NH4Cl(水溶液,30mL)淬灭后,将该悬浮液用乙酸乙酯萃取(3x25mL),用Na2SO4干燥并在真空下浓缩以获得粗制产物。将粗制产物通过碱性制备型HPLC纯化以获得作为白色固体的AIA-267-1(42.0mg,4.2%)和作为白色固体的AIA-267-2(34.0mg,3.4%)。MS理论值:499.0;MS实际值:500.2[M+1]+.AIA-267-1:1H NMR(DMSO-d6,400MHz)δ8.96(s,1H),7.92-7.90(m,1H),7.54-7.50(m,1H),7.35(t,J=9.2Hz,1H),5.99(s,2H),4.33(s,1H),3.56(s,1H),3.49(s,3H),3.13-3.09(m,2H),2.96(s,3H),2.66-2.64(m,2H),2.16-2.13(m,2H),1.89-1.80(m,4H),1.45-1.40(m,2H),1.30-1.24(m,2H).AIA-267-2:1H NMR(DMSO-d6,400MHz)δ8.94(s,1H),7.93-7.91(m,1H),7.53-7.49(m,1H),7.35(t,J=9.2Hz,1H),5.99(s,2H),4.45(s,1H),3.49(s,1H),3.42-3.37(m,3H),3.13-3.09(m,2H),2.96(s,3H),2.47-2.46(m,2H),2.16-2.11(m,2H),1.81-1.62(m,6H),1.50-1.46(m,2H)。
中间体116
2-(5-(5-氨基-4-((3-氯-4-氟苯基)氨基甲酰基)-1-甲基-1H-吡唑-3-基)-2-羟基八氢并环戊二烯-2-基)乙酸乙酯.在-78℃,向EtOAc(338mg,3.9mmol)在THF(15mL)的溶液中加入LDA(1.9mL,3.9mmol)并将获得的溶液搅拌10分钟。加入AIA-002(300mg,0.8mmol)并将混合物在-78℃搅拌4h。将该混合物用MeOH淬灭并将有机层在真空下浓缩,并将残留物用硅胶柱色谱进行纯化,其使用1:5乙酸乙酯/石油醚以获得作为白色固体的2-(5-(5-氨基-4-((3-氯-4-氟苯基)氨基甲酰基)-1-甲基-1H-吡唑-3-基)-2-羟基八氢并环戊二烯-2-基)乙酸乙酯(200mg,54%)。MS理论值:478.2;MS实际值:479.2[M+1]+。
AIA-241
2-(5-(5-氨基-4-((3-氯-4-氟苯基)氨基甲酰基)-1-甲基-1H-吡唑-3-基)-2-羟基八氢并环戊二烯-2-基)乙酸.向2-(5-(5-氨基-4-((3-氯-4-氟苯基)氨基甲酰基)-1-甲基-1H-吡唑-3-基)-2-羟基八氢并环戊二烯-2-基)乙酸乙酯(200mg,0.5mmol)在THF/H2O(10/10mL)的溶液中加入LiOH-H2O(21mg,0.5mmol)并将该混合物在40℃搅拌过夜。将该混合物用乙酸乙酯萃取并将有机层在真空下浓缩以获得作为白色固体的2-(5-(5-氨基-4-((3-氯-4-氟苯基)氨基甲酰基)-1-甲基-1H-吡唑-3-基)-2-羟基八氢并环戊二烯-2-基)乙酸.(200mg)。MS理论值:450.1;MS实际值:451.2[M+1]+.1H-NMR(DMSO,400MHz):δ8.91(s,1H),7.92(dd,J=7.2,2.8Hz,1H),7.53-7.49(m,1H),7.34(t,J=9.2Hz,1H),5.98(s,2H),3.49(s,3H),3.42-3.35(m,1H),2.39(s,2H),2.12-2.08(m,4H),1.73-1.63(m,4H),1.43-1.39(m,2H)。
AIA-215
5-氨基-3-(5-(2-氨基-2-氧代乙基)-5-羟基八氢并环戊二烯-2-基)-N-(3-氯-4-氟苯基)-1-甲基-1H-吡唑-4-甲酰胺.向2-(5-(5-氨基-4-((3-氯-4-氟苯基)氨基甲酰基)-1-甲基-1H-吡唑-3-基)-2-羟基八氢并环戊二烯-2-基)乙酸(200mg 0.4mmol)在DMF(5mL)的溶液中加入HCOONH4(60mg,0.8mmol),HATU(370mg,0.8mmol)和Et3N(88mg,0.8mmol)。将该混合物在室温搅拌过夜。将该混合物用乙酸乙酯萃取并用饱和NaCl洗涤。将有机层在真空下浓缩,并将残留物通过制备型HPLC进行纯化以获得作为白色固体的AIA-215(94mg,46%)。MS理论值:449.2;MS实际值:450.2[M+1]+.1H-NMR(DMSO-d6,400MHz):δ8.94(s,1H),7.90(dd,J=2.8,4.4Hz,1H),7.53-7.49(m,1H),7.34(t,J=8.8Hz,2H),7.00(s,1H),5.96(s,2H),4.98(s,1H),3.49(s,3H),3.46-3.36(m,1H),2.43(d,J=11.6Hz,2H),2.22(s,2H),2.12(t,J=5.6Hz,2H),1.79(dd,J=7.6,12.0Hz,2H),1.64(t,J=8.8Hz,2H),1.45(dd,J=4.0,12.8Hz,2H)。
中间体117
5-氨基-N-(3-氯-4-氟苯基)-3-(5-氰基-5-(三甲基甲硅烷基氧基)八氢并环戊二烯-2-基)-1-甲基-1H-吡唑-4-甲酰胺.向AIA-002(200mg,0.51mmol)在三甲基甲硅烷基氰化物(3.0mL)的溶液中加入ZnCl2(0.05mL,0.1mmol,2M)并将该混合物在60℃搅拌4小时。将该反应混合物用水稀释,用乙酸乙酯(3x20mL)萃取,用Na2SO4干燥,过滤并在减压下浓缩。将残留物通过柱色谱进行纯化以获得作为黄色油状物的5-氨基-N-(3-氯-4-氟苯基)-3-(5-氰基-5-(三甲基甲硅烷基氧基)八氢并环戊二烯-2-基)-1-甲基-1H-吡唑-4-甲酰胺(180.0mg,72.2%)。MS理论值:489.2,MS实际值:490.2[M+1]+。
中间体118
5-(5-氨基-4-(3-氯-4-氟苯基氨基甲酰基)-1-甲基-1H-吡唑-3-基)-2-羟基八氢并环戊二烯-2-甲酸.将5-氨基-N-(3-氯-4-氟苯基)-3-(5-氰基-5-(三甲基甲硅烷基氧基)八氢并环戊二烯-2-基)-1-甲基-1H-吡唑-4-甲酰胺(180.0mg,0.37mmol)和HCl(浓)(5mL)的混合物在60℃搅拌4小时。将该反应混合物用冰冷的水稀释并用饱和NaHCO3中和。将水层在减压下除去,并将残留物通过柱色谱和碱性制备型HPLC进行纯化以获得作为白色固体的5-(5-氨基-4-(3-氯-4-氟苯基氨基甲酰基)-1-甲基-1H-吡唑-3-基)-2-羟基八氢并环戊二烯-2-甲酸(90.0mg,55.8%)。MS理论值:436.1,MS实际值:437.1[M+1]+。
AIA-274-1,AIA-274-2
5-氨基-N-(3-氯-4-氟苯基)-3-(5-(环丙基氨基甲酰基)-5-羟基八氢并环戊二烯-2-基)-1-甲基-1H-吡唑-4-甲酰胺.非对映异构体1(AIA-274-1),非对映异构体2(AIA-274-2).向5-(5-氨基-4-(3-氯-4-氟苯基氨基甲酰基)-1-甲基-1H-吡唑-3-基)-2-羟基八氢并环戊二烯-2-甲酸(90.0mg,0.21mmol)在DMF(3mL)的溶液中加入环丙胺(12.9mg,0.23mmol),HATU(119.7mg,0.32mmol)和Et3N(60.6mg,0.6mmol)。将该反应混合物在室温搅拌过夜。加入水并将混合物用乙酸乙酯(15mLx3)萃取,用Na2SO4干燥,然后浓缩以获得粗制产物。将粗制产物通过制备型TLC,然后通过制备型HPLC进行纯化以获得AIA-274-1(10.0mg,10.0%)和AIA-274-2(4.0mg,4.0%),作为白色固体。MS理论值:475.2,MS实际值:476.2[M+1]+.AIA-274-1:1H NMR(DMSO-d6,400MHz):δ8.91(s,1H),7.92(dd,J=6.8,2.4Hz,1H),7.60(d,J=4.8,1H),7.53-7.49(m,1H),7.35(t,J=8.8Hz,1H),5.99(s,2H),5.06(s,1H),3.48(s,3H),3.40-3.36(m,1H),2.67-260(m,3H),2.10-2.05(m,4H),1.82-1.74(m,2H),1.56-1.53(m,2H),0.61-0.56(m,2H),0.49-0.45(m,2H).AIA-274-2:1H NMR(DMSO-d6,400MHz):δ8.96(s,1H),7.91(dd,J=6.8,2.4Hz,1H),7.65(d,J=4.8Hz,1H),7.55-7.51(m,1H),7.35(t,J=9.2Hz,1H),5.98(s,2H),5.12(s,1H),3.61-3.57(m,1H),3.50(s,3H),2.69-2.65(m,3H),2.18-2.12(m,2H),1.82-1.70(m,4H),1.50-1.42(m,2H),0.61-0.46(m,4H)。
AIA-076
5-氨基-N-(3-氯-4-氟苯基)-3-(5-羟基-5-异丙基八氢并环戊二烯-2-基)-1-甲基-1H-吡唑-4-甲酰胺.在-10℃,将异丙基氯化镁(1.3mL,2.55mmol)30分钟缓慢加入到AIA-002(200mg,0.51mmol)在无水THF(5mL)的溶液中。将该反应混合物温热至室温并搅拌2h。然后将该混合物用NH4Cl(水溶液)淬灭,并将该溶液用DCM(10mLx3)萃取。将合并的有机层用Na2SO4干燥,浓缩并通过制备型HPLC进行纯化以获得作为浅白色的5-氨基-N-(3-氯-4-氟苯基)-3-(5-羟基-5-异丙基八氢并环戊二烯-2-基)-1-甲基-1H-吡唑-4-甲酰胺(6.6mg,3.1%产率)。MS理论值:434.1;MS实际值:435.2[M+1]+。
表12.根据描述于5-氨基-N-(3-氯-4-氟苯基)-3-(5-羟基-5-异丙基八氢并环戊二烯-2-基)-1-甲基-1H-吡唑-4-甲酰胺的操作合成表12中的化合物
中间体120和中间体121
5-氨基-N-(3-氯-4-氟苯基)-1-甲基-3-(5-(丙-2-亚基)八氢并环戊二烯-2-基)-1H-吡唑-4-甲酰胺和5-氨基-N-(3-氯-4-氟苯基)-3-(5-异丙基-1,2,3,3a,4,6a-六氢并环戊二烯-2-基)-1-甲基-1H-吡唑-4-甲酰胺.在RT,向5-氨基-N-(3-氯-4-氟苯基)-3-(5-羟基-5-异丙基八氢并环戊二烯-2-基)-1-甲基-1H-吡唑-4-甲酰胺(600mg,1.38mmol)在甲苯(40mL)的溶液中加入对甲基苯磺酸(48mg,0.28mmol),并将该混合物搅拌回流过夜。将获得的混合物倾倒入水中,并用乙酸乙酯(40mLx3)萃取。将有机层干燥并浓缩,并将残留物通过硅胶柱色谱进行纯化以获得5-氨基-N-(3-氯-4-氟苯基)-1-甲基-3-(5-(丙-2-亚基)八氢并环戊二烯-2-基)-1H-吡唑-4-甲酰胺和5-氨基-N-(3-氯-4-氟苯基)-3-(5-异丙基-1,2,3,3a,4,6a-六氢并环戊二烯-2-基)-1-甲基-1H-吡唑-4-甲酰胺(180mg)的混合。将该混合物通过制备型手性HPLC分离以获得5-氨基-N-(3-氯-4-氟苯基)-1-甲基-3-(5-(丙-2-亚基)八氢并环戊二烯-2-基)-1H-吡唑-4-甲酰胺MS理论值:416.2;MS实际值:417.2[M+1]+。5-氨基-N-(3-氯-4-氟苯基)-3-(5-异丙基-1,2,3,3a,4,6a-六氢并环戊二烯-2-基)-1-甲基-1H-吡唑-4-甲酰胺MS理论值:416.2;MS实际值:417.2[M+1]+。
AIA-257
5-氨基-N-(3-氯-4-氟苯基)-3-(5-羟基-5-(2-羟基丙-2-基)八氢并环戊二烯-2-基)-1-甲基-1H-吡唑-4-甲酰胺.将5-氨基-N-(3-氯-4-氟苯基)-1-甲基-3-(5-(丙-2-亚基)八氢并环戊二烯-2-基)-1H-吡唑-4-甲酰胺(35mg,0.08mmol),OsO4(10mg,0.04mmol),NMO(45mg,0.40mmol)在THF/H2O(5mL/1mL)中的混合物在室温搅拌4h。将该反应混合物在真空下浓缩并将残留物通过制备型HPLC进行纯化以获得作为白色固体的5-氨基-N-(3-氯-4-氟苯基)-3-(5-羟基-5-(2-羟基丙-2-基)八氢并环戊二烯-2-基)-1-甲基-1H-吡唑-4-甲酰胺(4mg,11%)。TLC:10%MeOH/DCM(Rf:0.3);MS理论值:450.2;MS实际值:451.3[M+1]+。1H-NMR(DMSO-d6,400MHz):δ8.91(s,1H),7.89(dd,J=6.8,2.0Hz,1H),7.52-7.48(m,1H),7.32(t,J=3.2Hz,1H),5.96(s,2H),4.03(s,1H),3.86(s,1H),3.54-3.39(m,4H),2.57(t,J=5.6Hz,2H),2.09(t,J=5.6Hz,2H),1.57(s,4H),1.37(dd,J=11.6,19.2Hz,2H),1.03(s,6H)。
AIA-257-1
5-氨基-N-(3-氯-4-氟苯基)-3-(4,5-二羟基-5-异丙基八氢并环戊二烯-2-基)-1-甲基-1H-吡唑-4-甲酰胺.将5-氨基-N-(3-氯-4-氟苯基)-3-(5-异丙基-1,2,3,3a,4,6a-六氢并环戊二烯-2-基)-1-甲基-1H-吡唑-4-甲酰胺(20mg,0.05mmol),OsO4(7mg,0.03mmol),NMO(23mg,0.20mmol)在THF/H2O(5mL/1mL)中的混合物在室温搅拌4h。将该反应混合物在真空下浓缩并将残留物通过制备型HPLC进行纯化以获得作为白色固体的5-氨基-N-(3-氯-4-氟苯基)-3-(4,5-二羟基-5-异丙基八氢并环戊二烯-2-基)-1-甲基-1H-吡唑-4-甲酰胺(2mg,9%)。MS理论值:450.2;MS实际值:451.3[M+1]+.1H NMR(DMSO-d6,400MHz):δ8.94(s,1H),7.91(dd,J=6.8,2.4Hz,1H),7.54-7.50(m,1H),7.35(t,J=9.2Hz,1H),5.97(s,2H),4.47(s,1H)3.58-3.45(m,6H),2.86(s,2H),2.67-2.62(m,2H),2.18-2.11(m,2H),1.89-1.84(m,2H),1.44-1.32(m,4H)。
AIA-275
5-氨基-N-(3-氯-4-氟苯基)-1-甲基-3-(3-氧代八氢环戊二烯并[c]吡喃-6-基)-1H-吡唑-4-甲酰胺.向m-CPBA(528.1mg,3.06mmol)在无水DCM(15mL)的溶液中加入TFA(247.4mg,2.55mmol),并将该混合物在室温搅拌0.5小时。加入CP-AIA-002(199.3mg,0.51mmol),并将该混合物在室温搅拌过夜。将该混合物用NaHCO3(水溶液)淬灭,用乙酸乙酯萃取。将有机相用盐水洗涤,用Na2SO4干燥,过滤并浓缩以获得粗制产物,将其通过柱色谱进行纯化以获得作为白色固体的5-氨基-N-(3-氯-4-氟苯基)-1-甲基-3-(3-氧代八氢环戊二烯并[c]吡喃-6-基)-1H-吡唑-4-甲酰胺(30mg,14.5%)。MS理论值:406.1;MS实际值:407.2[M+1]+.1H NMR(DMSO-d6,400MHz):δ9.02(s,1H),7.91(dd,J=4.4,2.4Hz,1H),7.54-7.51(m,1H),7.35(t,J=9.2Hz,1H),5.99(s,2H),4.29-4.25(m,1H),4.08-4.03(m,1H),3.50(s,3H),3.46-3.41(m,1H),2.67-2.58(m,2H),2.50-2.48(m,1H),2.33(dd,J=9.6,4.8Hz,1H),2.22-2.08(m,2H),1.51(dd,J=4.4,2.4Hz,1H),1.34-1.26(m,1H)。
中间体122
3-(5-(1,3-二硫杂环己烷-2-亚基)八氢并环戊二烯-2-基)-5-氨基-N-(3-氯-4-氟苯基)-1-甲基-1H-吡唑-4-甲酰胺.在-78℃,向(1,3-二硫杂环己烷-2-基)三甲基甲硅烷(2.1g,10.8mmol)在THF(30mL)的混合溶液加入n-BuLi(2.5M,4.3mL)。将该混合物在-78℃搅拌1小时后,缓慢加入AIA-002(600mg,1.5mmol)在THF的溶液并继续搅拌3小时。将该混合物用饱和NH4Cl淬灭,蒸发溶剂,并将残留物通过硅胶柱进行纯化(用1:1石油醚/乙酸乙酯洗脱)以获得作为白色固体的3-(5-(1,3-二硫杂环己烷-2-亚基)八氢并环戊二烯-2-基)-5-氨基-N-(3-氯-4-氟苯基)-1-甲基-1H-吡唑-4-甲酰胺(300mg,40%)。MS理论值:492.1;MS实际值:493.1[M+1]+。
中间体123
5-(5-氨基-4-(3-氯-4-氟苯基氨基甲酰基)-1-甲基-1H-吡唑-3-基)八氢并环戊二烯-2-甲酸甲酯.向3-(5-(1,3-二硫杂环己烷-2-亚基)八氢并环戊二烯-2-基)-5-氨基-N-(3-氯-4-氟苯基)-1-甲基-1H-吡唑-4-甲酰胺(200mg,0.4mmol)在MeOH(20mL)的溶液中先后加入HCl(6N,0.2mL),HgCl2(232mg,0.9mmol)和TFA(118mg,1.0mmol)。将该混合物在室温搅拌3小时,然后通过过滤。将滤饼用甲醇洗涤。在0℃将滤液用NaBH4处理,除去溶剂,并将残留物通过硅胶柱色谱进行纯化(用2:1石油醚/乙酸乙酯洗脱)以获得作为白色固体的5-(5-氨基-4-(3-氯-4-氟苯基氨基甲酰基)-1-甲基-1H-吡唑-3-基)八氢并环戊二烯-2-甲酸甲酯(120mg,68%)。MS理论值:434.2;MS实际值:435.1[M+1]+。
AIA-014
5-(5-氨基-4-(3-氯-4-氟苯基氨基甲酰基)-1-甲基-1H-吡唑-3-基)八氢并环戊二烯-2-甲酸.将5-(5-氨基-4-(3-氯-4-氟苯基氨基甲酰基)-1-甲基-1H-吡唑-3-基)八氢并环戊二烯-2-甲酸甲酯(120mg,0.28mmol)溶解在甲醇(20mL)和水(2mL)的溶液中,然后一次加入LiOH-H2O(232mg,5.5mmol)。将混合溶液在室温搅拌3小时。将溶液温热至40℃并搅拌过夜。加入1N HCl以调节pH至7。蒸发溶剂并将残留物通过硅胶柱色谱进行纯化(10:1DCM/MeOH)以获得作为白色固体的5-(5-氨基-4-(3-氯-4-氟苯基氨基甲酰基)-1-甲基-1H-吡唑-3-基)八氢并环戊二烯-2-甲酸(100mg,86%)。MS理论值:420.1;MS实际值:421.2[M+1]+;1H NMR(DMSO-d6,400MHz):δ11.98(s,1H),8.96(s,1H),7.92-7.89(m,1H),7.54-7.50(m,1H),7.34(t,J=9.2,1H),5.97(s,2H),3.49(s,3H),3.31-3.27(m,1H),2.69-2.64(m,1H),2.55-2.53(m,2H),2.17-2.02(m,2H),1.73-1.59(m,3H),1.51-1.43(m,1H),1.30-1.25(m,2H)。
AIA-015
5-氨基-3-(5-氨基甲酰基八氢并环戊二烯-2-基)-N-(3-氯-4-氟苯基)-1-甲基-1H-吡唑-4-甲酰胺.合并5-(5-氨基-4-(3-氯-4-氟苯基氨基甲酰基)-1-甲基-1H-吡唑-3-基)八氢并环戊二烯-2-甲酸(30mg,0.07mmol),HATU(33mg,0.09mmol),DIEA(14mg,0.11mmol)和HCOONH4(6mg,0.08mmol)并溶解在DMF(1mL)中。将获得的溶液在室温搅拌过夜。使用制备型HPLC(碱性)以纯化最后的目标,并获得作为白色固体的5-氨基-3-(5-氨基甲酰基八氢并环戊二烯-2-基)-N-(3-氯-4-氟苯基)-1-甲基-1H-吡唑-4-甲酰胺(19mg,64%)。MS理论值:419.2;MS实际值:420.3[M+1]+;1H NMR(DMSO-d6,400MHz):δ8.96(s,0.3H),8.95(s,0.7H),7.93-7.89(m,1H),7.54-7.50(m,1H),7.35(t,J=9.2Hz,1H),7.28(s,0.7H),7.16(s,0.3H),6.68(s,1H),5.98(s,1.4H),5.96(s,0.6H),3.53-3.49(m,4H),3.30-3.26(m,1H),2.65-2.60(m,1H),2.46-2.43(m,1H),2.18-2.12(m,2H),1.97-1.94(m,2H),1.68-1.39(m,4H),1.30-1.27(m,1H)。
表13.根据描述于5-氨基-3-(5-氨基甲酰基八氢并环戊二烯-2-基)-N-(3-氯-4-氟苯基)-1-甲基-1H-吡唑-4-甲酰胺的操作合成表13中的化合物
AIA-017
2-(5-(5-氨基-4-((3-氯-4-氟苯基)氨基甲酰基)-1-甲基-1H-吡唑-3-基)六氢并环戊二烯-2(1H)-亚基)乙酸乙酯.在0℃,向2-(二乙氧基磷酰基)乙酸乙酯(33mg,0.2mmol,2.0当量)在THF(5mL)的溶液中加入NaH(12mg,0.3mmol,3当量)。在加入AIA-002(39mg,0.1mmol,1当量)后,将获得的溶液在0℃搅拌30分钟。在用水淬灭并用乙酸乙酯萃取之前,将溶液在55℃搅拌1h。将有机相在真空下浓缩并通过制备型HPLC进行纯化以获得作为白色固体的2-(5-(5-氨基-4-((3-氯-4-氟苯基)氨基甲酰基)-1-甲基-1H-吡唑-3-基)六氢并环戊二烯-2(1H)-亚基)乙酸乙酯(22mg,48%)。TLC:30%乙酸乙酯/石油醚(Rf:0.35);MS理论值:460.2;MS实际值:461.3[M+1]+.1H-NMR(DMSO-d6,400MHz):δ8.95(s,1H),7.91(dd,J=7.2,2.8Hz,1H),7.53-7.50m,1H),7.34(t,J=8.8Hz,1H),5.96(s,2H),5.74(s,1H),4.05(q,J=7.2Hz,2H),3.49-3.47(m,1H),3.47(s,3H),2.75-2.73(m,2H),2.66-2.61(m,2H),2.49-2.13(m,4H),1.38-1.33(m,2H),1.18(t,J=7.2Hz,3H)。
AIA-018
2-(5-(5-氨基-4-((3-氯-4-氟苯基)氨基甲酰基)-1-甲基-1H-吡唑-3-基)八氢并环戊二烯-2-基)乙酸乙酯.将2-(5-(5-氨基-4-((3-氯-4-氟苯基)氨基甲酰基)-1-甲基-1H-吡唑-3-基)六氢并环戊二烯-2(1H)-亚基)乙酸乙酯(30mg,0.06mmol)溶解在THF,加入Pt/C(10mg),并在H2气氛下,将悬浮液在35℃搅拌3h。将该混合物通过过滤并用THF洗涤。将滤液在真空下浓缩并将残留物通过制备型HPLC以获得作为白色固体的2-(5-(5-氨基-4-((3-氯-4-氟苯基)氨基甲酰基)-1-甲基-1H-吡唑-3-基)八氢并环戊二烯-2-基)乙酸乙酯(15mg,50%)。MS理论值:462.2;MS实际值:463.2[M+1]+.1H-NMR(DMSO-d6,400MHz):δ8.95(s,1H),7.91(dd,J=6.8,2.4Hz,1H),7.53-7.49(m,1H),7.34(t,J=9.2Hz,1H),5.96(s,2H),4.02(q,J=7.2Hz,2H),3.56-3.52(m,1H),3.49(s,3H),2.44-2.42(m,2H),2.31-2.29(m,2H),2.21-2.10(m,3H),2.00-1.94(m,2H),1.44-1.36(m,2H),1.16(t,J=7.2Hz,3H),0.96-0.88(m,2H)。
AIA-019
5-氨基-N-(3-氯-4-氟苯基)-3-(5-(2-羟基乙基)八氢并环戊二烯-2-基)-1-甲基-1H-吡唑-4-甲酰胺.向2-(5-(5-氨基-4-((3-氯-4-氟苯基)氨基甲酰基)-1-甲基-1H-吡唑-3-基)八氢并环戊二烯-2-基)乙酸乙酯(46mg,0.1mmol,1当量)在THF(2mL)的溶液中一次性加入LiAlH4(8mg,0.2mmol,2.0当量)。该混合物变成黄色溶液。将该混合物用水和NaOH(水溶液)淬灭,然后过滤并用THF洗涤。将滤液在真空下浓缩并将残留物通过制备型HPLC以获得作为白色固体的5-氨基-N-(3-氯-4-氟苯基)-3-(5-(2-羟基乙基)八氢并环戊二烯-2-基)-1-甲基-1H-吡唑-4-甲酰胺(20mg,48%)。MS理论值:420.2;MS实际值:421.3[M+1]+.1H-NMR(DMSO-d6,400MHz):δ8.95(s,1H),7.91(dd,J=6.8,2.4Hz,1H),7.53-7.49(m,1H),7.34(t,J=9.2Hz,1H),5.96(s,2H),4.29(t,J=5.2Hz,1H),3.56-3.51(m,1H),3.49(s,3H),3.38-3.35(m,2H),2.40(s,2H),2.16-2.09(m,2H),1.97-1.94(m,3H),1.48-1.35(m,4H),0.86-0.84(m,2H)。
中间体124
2-(5-(5-氨基-4-(3-氯-4-氟苯基氨基甲酰基)-1-甲基-1H-吡唑-3-基)八氢并环戊二烯-2-基)乙酸.向2-(5-(5-氨基-4-((3-氯-4-氟苯基)氨基甲酰基)-1-甲基-1H-吡唑-3-基)八氢并环戊二烯-2-基)乙酸乙酯(462mg,1.0mmol)在MeOH/H2O(5mL/1mL)的溶液中加入LiOH-H2O(84mg,2.0mmol)。将该混合物在50℃搅拌4h。在真空下除去MeOH,并将残留物用3M HCl中和至pH~5。将获得的溶液冻干以获得作为白色固体的粗制2-(5-(5-氨基-4-(3-氯-4-氟苯基氨基甲酰基)-1-甲基-1H-吡唑-3-基)八氢并环戊二烯-2-基)乙酸(510mg,100%)。MS理论值:434.2;MS实际值:435.3[M+1]+。
表14.根据描述于5-氨基-3-(5-氨基甲酰基八氢并环戊二烯-2-基)-N-(3-氯-4-氟苯基)-1-甲基-1H-吡唑-4-甲酰胺的操作合成表14中的化合物。
中间体125
2-(5-(5-氨基-4-((3-氯-4-氟苯基)氨基甲酰基)-1-甲基-1H-吡唑-3-基)-2-(硝基甲基)八氢并环戊二烯-2-基)乙酸乙酯.在0℃,向搅拌的2-(5-(5-氨基-4-((3-氯-4-氟苯基)氨基甲酰基)-1-甲基-1H-吡唑-3-基)六氢并环戊二烯-2(1H)-亚基)乙酸酯(0.8g,1.73mmol)在DMSO(3mL)中的溶液加入K2CO3(0.703g,5.09mmol)。向该溶液缓慢加入MeNO2(0.265g,4.34mmol)。将获得的反应混合物在70℃搅拌16h。反应完成后,将该反应混合物用冰水稀释,并用乙酸乙酯萃取。将合并的有机层用无水硫酸钠干燥,过滤并在减压下浓缩以获得作为米黄色固体的2-(5-(5-氨基-4-((3-氯-4-氟苯基)氨基甲酰基)-1-甲基-1H-吡唑-3-基)-2-(硝基甲基)八氢并环戊二烯-2-基)乙酸乙酯.(0.7g,粗制)。LCMS计算值C24H29ClFN5O5:521.18;实测值:522.20[M+1]+。
HBV-AIA-039
5-氨基-N-(3-氯-4-氟苯基)-1-甲基-3-(5'-氧代六氢-1H-螺[并环戊二烯-2,3'-吡咯烷]-5-基)-1H-吡唑-4-甲酰胺.向搅拌的2-(5-(5-氨基-4-((3-氯-4-氟苯基)氨基甲酰基)-1-甲基-1H-吡唑-3-基)-2-(硝基甲基)八氢并环戊二烯-2-基)乙酸酯(0.5g,0.95mmol)在AcOH(5mL)的溶液中加入铁粉(0.321g,4.87mmol)并将获得的反应混合物在80℃搅拌16h。反应完成后,将该反应混合物在真空下浓缩。将残留物用饱和NaHCO3溶液中和并用乙酸乙酯萃取。将合并的有机层用水、盐水洗涤,用硫酸钠干燥,过滤并在真空下浓缩以获得粗制化合物,其通过制备型HPLC纯化以获得5-氨基-N-(3-氯-4-氟苯基)-1-甲基-3-(5'-氧代六氢-1H-螺[并环戊二烯-2,3'-吡咯烷]-5-基)-1H-吡唑-4-甲酰胺。HNMR(400MHz,DMSO-d6):δ8.96(s,1H),7.89(d,J=6.4Hz,1H),7.51-7.49(m,1H),7.45(s,1H),7.34(t,J=8.8Hz,1H),5.96(s,2H),3.57-3.49(m,4H),3.00(s,2H),2.53-2.45(m,2H,融合),2.17-2.11(m,4H),1.88-1.86(m,2H),1.46-1.32(m,4H)。
中间体126
5-氨基-3-溴-1H-吡唑-4-甲酸乙酯.向5-氨基-1H-吡唑-4-甲酸乙酯(20g,0.13mol)在CHCl3(200mL)的溶液中缓慢加入NBS(34.5g,0.19mol)以维持温度介于20~30℃之间。将溶液在室温搅拌3h。将该反应用水(200ml)淬灭,用DCM(100mLx3)萃取,干燥,过滤并在减压下浓缩。将粗制产物通过柱色谱进行纯化(其使用20-30%乙酸乙酯/石油醚以获得5-氨基-3-溴-1H-吡唑-4-甲酸乙酯.(12.6g,42%),作为黄色固体。MS理论值:233.0;MS实际值:234.1[M+H]+。
中间体127
5-氨基-3-溴-N-(3-氯-4-氟苯基)-1H-吡唑-4-甲酰胺.在0℃,向3-氯-4-氟-苯胺(9.3g,64mmol)在甲苯(100mL)的溶液中加入三甲基铝(2M在甲苯中,129mL,258mmol)。将浅棕色溶液搅拌30分钟。在0℃,向该溶液加入5-氨基-3-溴-1H-吡唑-4-甲酸乙酯.(10g,43mmol)并继续搅拌30分钟。将棕色溶液加热至回流并维持48h。将该混合物冷却至0℃,用H2O(200mL)、5%NaOH(100mL)淬灭,并将获得的混合物搅拌10分钟。真空下除去溶剂并将残留物通过柱色谱进行纯化(其使用20-30%乙酸乙酯/石油醚)以获得作为白色固体的5-氨基-3-溴-N-(3-氯-4-氟苯基)-1H-吡唑-4-甲酰胺(5g,36%)。MS理论值:331.9;MS实际值:333.1[M+1]+
中间体128
5-氨基-N-(3-氯-4-氟苯基)-3-(5-氧代-1,3a,4,5,6,6a-六氢并环戊二烯-2-基)-1H-吡唑-4-甲酰胺.在N2下,将5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-3,3a,6,6a-四氢并环戊二烯-2(1H)-酮(5g,20mmol),5-氨基-3-溴-N-(3-氯-4-氟苯基)-1H-吡唑-4-甲酰胺(5g,15mmol),Pd(dppf)Cl2(736mg,1.0mmol)和Na2CO3(2.4g,23mmol)在二噁烷/水(80mL/15mL)中的混合物在80℃搅拌过夜。将EtOAc(30mL)加入到混合物中。将该混合物过滤,并将滤液用H2O(35mLx2)洗涤。将有机层分离,用Na2SO4干燥并在真空下浓缩以获得黄色残留物。将残留物通过硅胶柱色谱进行纯化(其使用20-30%乙酸乙酯/石油醚)以获得作为黄色固体的5-氨基-N-(3-氯-4-氟苯基)-3-(5-氧代-1,3a,4,5,6,6a-六氢并环戊二烯-2-基)-1H-吡唑-4-甲酰胺(2.6g,46%)。MS理论值:374.1;MS实际值:375.2[M+1]+。
AIA-286
5-氨基-N-(3-氯-4-氟苯基)-3-(5-氧代八氢并环戊二烯-2-基)-1H-吡唑-4-甲酰胺向5-氨基-N-(3-氯-4-氟苯基)-3-(5-氧代-1,3a,4,5,6,6a-六氢并环戊二烯-2-基)-1H-吡唑-4-甲酰胺(500mg,1.3mmol)在THF(20mL)的溶液中加入Pd/C(500mg)和NH4OH(12滴)。将烧瓶抽空并用H2回填。将溶液在35℃搅拌8h。加入DMF(8mL)并将混合物过滤,然后在真空下浓缩。将获得的残留物通过制备型HPLC进行纯化以获得5-氨基-N-(3-氯-4-氟苯基)-3-(5-氧代八氢并环戊二烯-2-基)-1H-吡唑-4-甲酰胺(200mg,40%)MS理论值:376.1;MS实际值:377.1[M+1]+.1H-NMR(DMSO-d6,400MHz):δ12.05(s,0.55H),11.49(s,0.46H),9.54(s,0.46H),8.96(s,0.48H),7.94(d,J=4.8Hz,1H),7.55-7.50(m,1H),7.36(t,J=9.2Hz,1H),5.76(s,1H),4.97(s,1H),3.67-3.60(m,1H),2.72-2.66(m,2H),2.50-2.44(m,2H),2.33-2.25(m,2H),2.08-2.04(m,2H),1.59-1.54(m,2H)。
中间体129
(4-((3-氯-4-氟苯基)氨基甲酰基)-3-(5-氧代八氢并环戊二烯-2-基)-1H-吡唑-5-基)氨基甲酸叔丁酯.在0℃,向5-氨基-N-(3-氯-4-氟苯基)-3-(5-氧代八氢并环戊二烯-2-基)-1H-吡唑-4-甲酰胺(200mg,0.5mmol)在THF(10mL)的溶液中加入NaH(32mg,1.3mmol),将浅棕色溶液在0℃搅拌30分钟。加入Boc2O(150mg,0.7mmol)并在RT继续搅拌另外30分钟。将该混合物冷却至0℃,用H2O淬灭,用乙酸乙酯萃取(20mLx3),干燥,过滤并将滤液在减压下浓缩。将粗制产物通过柱色谱进行纯化(其使用10-20%乙酸乙酯/石油醚)以获得作为浅白色固体的(4-((3-氯-4-氟苯基)氨基甲酰基)-3-(5-氧代八氢并环戊二烯-2-基)-1H-吡唑-5-基)氨基甲酸叔丁酯(200mg,80%)。MS理论值:476.1;MS实际值:421.2[M-56+1]+。
中间体130
(4-((3-氯-4-氟苯基)氨基甲酰基)-3-(5-羟基-5-((甲磺酰基)甲基)八氢并环戊二烯-2-基)-1H-吡唑-5-基)氨基甲酸叔丁酯.于N2下,在-45℃向二甲基亚砜(237mg,2.5mmol)在THF(10mL)的溶液中加入n-BuLi(1mL,2.5M,2.5mmol)。将该混合物在-45℃搅拌30分钟。将(4-((3-氯-4-氟苯基)氨基甲酰基)-3-(5-氧代八氢并环戊二烯-2-基)-1H-吡唑-5-基)氨基甲酸叔丁酯(200mg,0.4mmol)一次性加入到该混合物中。将溶液在室温搅拌过夜。将该反应混合物用NH4Cl水溶液淬灭并用乙酸乙酯萃取(10mLx3)。将合并的有机层干燥并浓缩,将残留物通过硅胶柱色谱进行纯化,其使用95:5DCM/MeOH以获得作为白色固体的(4-((3-氯-4-氟苯基)氨基甲酰基)-3-(5-羟基-5-((甲磺酰基)甲基)八氢并环戊二烯-2-基)-1H-吡唑-5-基)氨基甲酸叔丁酯(140mg,60%)。MS理论值:570.2;MS实际值:571.2[M+1]+。
AIA-310
5-氨基-N-(3-氯-4-氟苯基)-3-(5-羟基-5-((甲磺酰基)甲基)八氢并环戊二烯-2-基)-1H-吡唑-4-甲酰胺.向(4-((3-氯-4-氟苯基)氨基甲酰基)-3-(5-羟基-5-((甲磺酰基)甲基)八氢并环戊二烯-2-基)-1H-吡唑-5-基)氨基甲酸叔丁酯(140mg,0.25mmol)在DCM(5mL)的溶液中加入三氟乙酸(1mL)。将获得的混合物在室温搅拌1h。将该反应混合物用NaHCO3调整至pH 8-9并用DMC萃取(10mLx3)。将合并的有机层干燥并浓缩。将残留物通过硅胶柱色谱(其使用95:5DCM/MeOH)和制备型HPLC进行纯化以获得作为白色固体的5-氨基-N-(3-氯-4-氟苯基)-3-(5-羟基-5-((甲磺酰基)甲基)八氢并环戊二烯-2-基)-1H-吡唑-4-甲酰胺(30mg,26%)。MS理论值:470.1;MS实际值:471.2[M+1]+.1H-NMR(DMSO-d6,400MHz):δ11.88(s,0.55H),11.44(s,0.45H),9.49(s,0.53H),8.93(s,0.41H),7.93(s,1H),7.53-7.49(m,1H),7.35(t,J=8.8Hz,1H),5.73(s,1H),4.92(t,J=12.0Hz,2H),3.47-3.45(m,1H),3.28-3.26(m,2H),2.98(s,3H),2.51-2.49(m,2H),2.17(s,2H),2.02(s,2H),1.64(d,J=10.0Hz,4H)。
中间体131
5-(三氟甲基磺酰基氧基)-3,3a,6,6a-四氢环戊二烯并[c]吡咯-2(1H)-甲酸叔丁酯:在-78℃,30分钟将LDA(10mL,20mmol)缓慢加入到5-氧代六氢环戊二烯并[c]吡咯-2(1H)-甲酸叔丁酯(3g,13.3mmol)在无水THF(50mL)的溶液中。缓慢加入1,1,1-三氟-N-苯基-N-(三氟甲磺酰基)甲烷磺酰胺(5.7g,16.1mmol)在THF(20mL),并将该溶液搅拌2h。将该反应混合物温热至室温并用NH4Cl(水溶液)淬灭。将溶液用乙酸乙酯萃取(50mLx3)。将合并的有机层用Na2SO4干燥,浓缩并通过硅胶柱色谱进行纯化(其使用5-10%乙酸乙酯/石油醚)以获得作为淡黄色固体的5-(三氟甲基磺酰基氧基)-3,3a,6,6a-四氢环戊二烯并[c]吡咯-2(1H)-甲酸叔丁酯(3.7g,78%)。
中间体132
5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-3,3a,6,6a-四氢环戊二烯并[c]吡咯-2(1H)-甲酸叔丁酯.在N2下,将5-(三氟甲基磺酰基氧基)-3,3a,6,6a-四氢环戊二烯并[c]吡咯-2(1H)-甲酸叔丁酯(2.8g,7.8mmol),4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1,3,2-二氧杂硼杂环戊烷(2.4g,9.4mmol),1,1'-双(二苯基膦基)二茂铁(0.13g,0.24mmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(II)(0.17g,0.24mmol)和乙酸钾(2.3g,23.5mmol)在二噁烷(30mL)的棕色混合物在80℃搅拌16h。观察到黑色的悬浮液。将反应通过垫过滤,并将滤饼用乙酸乙酯(20mL)洗涤。将滤液在真空下浓缩并通过硅胶柱色谱进行纯化(其使用5-10%乙酸乙酯/石油醚)以获得作为淡黄色固体的5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-3,3a,6,6a-四氢环戊二烯并[c]吡咯-2(1H)-甲酸叔丁酯(2.2g,85%产率)。
中间体133
5-(5-氨基-4-(3-氯-4-氟苯基氨基甲酰基)-1-甲基-1H-吡唑-3-基)-3,3a,6,6a-四氢环戊二烯并[c]吡咯-2(1H)-甲酸叔丁酯.在N2下,将5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-3,3a,6,6a-四氢环戊二烯并[c]吡咯-2(1H)-甲酸叔丁酯(1g,3.0mmol),5-氨基-3-溴-N-(3-氯-4-氟苯基)-1-甲基-1H-吡唑-4-甲酰胺(1g,3.0mmol),Pd(dppf)Cl2(66mg,0.09mmol)和K2CO3(0.82g,6.0mmol)在二噁烷(20mL)和H2O(4mL)中的混合物在80℃搅拌16h。将EtOAc(20mL)加入到混合物中。将该混合物过滤,并将滤液用H2O(35mLx2)洗涤。将有机层分离,用Na2SO4干燥并在真空下浓缩以获得黄色残留物。将残留物通过硅胶柱色谱进行纯化(其使用5-10%乙酸乙酯/石油醚)以获得作为黄色固体的5-(5-氨基-4-(3-氯-4-氟苯基氨基甲酰基)-1-甲基-1H-吡唑-3-基)-3,3a,6,6a-四氢环戊二烯并[c]吡咯-2(1H)-甲酸叔丁酯(0.8g,57%)。MS理论值:475.2;MS实际值:420.3[M-56+1]+,476.4[M+1]+。
AIA-005
5-(5-氨基-4-(3-氯-4-氟苯基氨基甲酰基)-1-甲基-1H-吡唑-3-基)六氢环戊二烯并[c]吡咯-2(1H)-甲酸叔丁酯.向5-(5-氨基-4-(3-氯-4-氟苯基氨基甲酰基)-1-甲基-1H-吡唑-3-基)-3,3a,6,6a-四氢环戊二烯并[c]吡咯-2(1H)-甲酸叔丁酯(800mg,1.7mmol)在THF(20mL)的溶液中加入Pt/C(160mg)。然后将烧瓶抽空并用H2回填。将溶液在30℃搅拌16h。将该混合物过滤并浓缩以获得作为白色固体的5-(5-氨基-4-(3-氯-4-氟苯基氨基甲酰基)-1-甲基-1H-吡唑-3-基)六氢环戊二烯并[c]吡咯-2(1H)-甲酸叔丁酯(600mg,75%)。MS理论值:477.2;MS实际值:422.3[M-56+1]+,478.4[M+1]+.1H-NMR(DMSO-d6,400MHz):δ8.98(s,1H),7.91(dd,J=6.8,2.4Hz,1H),7.54-7.50(m,1H),7.34(t,J=9.6Hz,1H),5.98(s,2H),3.59-3.52(m,1H),3.49(s,3H),3.32(s,2H),3.14-3.10(m,2H),2.61-2.57(m,2H),2.21-2.14(m,2H),1.56-1.48(m,2H),1.38(s,9H)
AIA-006
5-氨基-N-(3-氯-4-氟苯基)-1-甲基-3-(八氢环戊二烯并[c]吡咯-5-基)-1H-吡唑-4-甲酰胺.向5-(5-氨基-4-(3-氯-4-氟苯基氨基甲酰基)-1-甲基-1H-吡唑-3-基)六氢环戊二烯并[c]吡咯-2(1H)-甲酸叔丁酯(600mg,1.26mmol)在DCM(10mL)的溶液中加入1MHCl(0.5mL),将获得的混合物在室温搅拌1h。将该反应混合物用NaHCO3水溶液调整至pH 8~9并将溶液用DCM(10mLx3)萃取。将合并的有机层干燥,并在真空下除去溶剂。将残留物通过制备型HPLC进行纯化以获得作为白色固体的5-氨基-N-(3-氯-4-氟苯基)-1-甲基-3-(八氢环戊二烯并[c]吡咯-5-基)-1H-吡唑-4-甲酰胺(355mg,75%)。MS理论值:377.1;MS实际值:378.4[M+1]+.1H-NMR(DMSO-d6,400MHz):δ8.97(s,1H),7.91(dd,J=6.8,2.8Hz,1H),7.53-7.51(m,1H),7.34(t,J=9.2Hz,1H),5.97(s,2H),3.55-3.53(m,1H),3.49(s,3H),3.44-3.41(m,3H),3.22-3.14(m,1H),2.57(s,3H),2.19-2.13(m,2H),1.52-1.50(m,1H),1.34-1.32(m,1H)。
AIA-007
3-(2-乙酰基八氢环戊二烯并[c]吡咯-5-基)-5-氨基-N-(3-氯-4-氟苯基)-1-甲基-1H-吡唑-4-甲酰胺.在0℃,向含有搅拌的5-氨基-N-(3-氯-4-氟苯基)-1-甲基-3-(八氢环戊二烯并[c]吡咯-5-基)-1H-吡唑-4-甲酰胺(80mg,0.21mmol)和Et3N(43mg,0.42mmol)在DCM(2mL)的混合物的烧瓶中加入乙酸酐(32mg,0.32mmol)。将该混合物在室温搅拌16h然后用水淬灭,用乙酸乙酯萃取,干燥并浓缩。将粗制产物通过制备型HPLC进行纯化以获得作为白色固体的3-(2-乙酰基八氢环戊二烯并[c]吡咯-5-基)-5-氨基-N-(3-氯-4-氟苯基)-1-甲基-1H-吡唑-4-甲酰胺(30mg,34%)。MS理论值:419.2;MS实际值:420.2[M+1]+.1H-NMR(DMSO-d6,400MHz):δ8.96(s,1H),7.89(dd,J=6.8,2.8Hz,1H),7.53-7.49(m,1H),7.32(t,J=9.2Hz,1H),5.95(s,2H),3.59-3.48(m,2H),3.46(s,3H),3.36-3.33(m,1H),3.26-3.18(m,2H),2.68-2.57(m,2H),2.21-2.13(m,2H),1.88(s,3H),1.55-1.48(m,2H)。
表15.根据公布于3-(2-乙酰基八氢环戊二烯并[c]吡咯-5-基)-5-氨基-N-(3-氯-4-氟苯基)-1-甲基-1H-吡唑-4-甲酰胺的操作合成表15中的化合物。
中间体134
5-(1-甲基-1H-吡唑-4-基)-3,3a,6,6a-四氢并环戊二烯-2(1H)-酮.在N2气氛下,将4-溴-1-甲基-1H-吡唑(2.0g,8.1mmol),5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-3,3a,6,6a-四氢并环戊二烯-2(1H)-酮(1.4g,8.9mmol),K3PO4(3.4g,16.1mmol)和Pd(dppf)Cl2(589.8mg,0.8mmol)在二噁烷(10mL)和H2O(2mL)中的混合物在80℃搅拌过夜。真空下除去溶剂,并将残留物通过硅胶柱色谱进行纯化(其使用2:1石油醚/乙酸乙酯)以获得作为黄色固体的5-(1-甲基-1H-吡唑-4-基)-3,3a,6,6a-四氢并环戊二烯-2(1H)-酮(1.0g,62.5%)。MS理论值:202.1,MS实际值:203.4[M+1]+。
中间体135
5-(1-甲基-1H-吡唑-4-基)六氢并环戊二烯-2(1H)-酮.在H2下,将5-(1-甲基-1H-吡唑-4-基)-3,3a,6,6a-四氢并环戊二烯-2(1H)-酮(1.0g,4.9mmol)和Pd/C(0.1g)在乙酸乙酯(20mL)中的混合物在30℃搅拌过夜。将该混合物通过垫过滤。将滤液浓缩然后通过硅胶柱色谱进行纯化(其使用1:1石油醚/乙酸乙酯)以获得作为黄色固体的5-(1-甲基-1H-吡唑-4-基)六氢并环戊二烯-2(1H)-酮(800.0mg,80.0%)MS理论值:204.1,MS实际值:205.4[M+1]+。
中间体136
三氟甲磺酸5-(1-甲基-1H-吡唑-4-基)-1,3a,4,5,6,6a-六氢并环戊二烯-2-基酯.在-78℃,向5-(1-甲基-1H-吡唑-4-基)六氢并环戊二烯-2(1H)-酮(550.0mg,2.7mmol)在THF(20mL)的溶液中加入LiHMDS(4.0mmol,1M,4.0mL,)。将该反应混合物在-78℃搅拌1小时,然后逐滴加入1,1,1-三氟-N-苯基-N-((三氟甲基)磺酰基)甲烷磺酰胺(1.4g,4.0mmol)在THF(5mL)中的溶液。将该反应混合物温热至30℃并搅拌过夜。在25℃将该反应混合物通过加入NH4Cl(2mL)来淬灭,然后用H2O(10mL)稀释并用EtOAc(20mLx2)萃取。将合并的有机层用盐水(20mL)洗涤,用Na2SO4干燥,过滤并在减压下浓缩,并将残留物通过硅胶柱色谱进行纯化(其使用3:1石油醚/乙酸乙酯)以获得作为黄色油状物的三氟甲磺酸5-(1-甲基-1H-吡唑-4-基)-1,3a,4,5,6,6a-六氢并环戊二烯-2-基酯(800.0mg,88.4%)。MS理论值:336.1,MS实际值:337.3[M+1]+。
中间体137
1-甲基-4-(5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1,2,3,3a,4,6a-六氢并环戊二烯-2-基)-1H-吡唑.在N2气氛下,将三氟甲磺酸5-(1-甲基-1H-吡唑-4-基)-1,3a,4,5,6,6a-六氢并环戊二烯-2-基酯(90.0mg,0.3mmol),4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1,3,2-二氧杂硼杂环戊烷(81.5mg,0.3mmol),Pd(dppf)Cl2(19.6mg,0.03mmol)和乙酸钾(52.5mg,0.5mmol)在二噁烷(5mL)中的混合物在80℃搅拌4小时。将该反应混合物通过垫过滤,并将滤饼用EtOAc(10mLx3)洗涤。将滤液在真空下浓缩,并将残留物通过硅胶柱色谱进行纯化(其使用3:1石油醚/乙酸乙酯)以获得作为黄色油状物的1-甲基-4-(5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1,2,3,3a,4,6a-六氢并环戊二烯-2-基)-1H-吡唑(50.0mg,59.5%)。MS理论值:314.2,MS实际值:315.4[M+1]+。
中间体138
5-氨基-N-(3-氯-4-氟苯基)-1-甲基-3-(5-(1-甲基-1H-吡唑-4-基)-1,3a,4,5,6,6a-六氢并环戊二烯-2-基)-1H-吡唑-4-甲酰胺.在N2气氛下,将5-氨基-3-溴-N-(3-氯-4-氟苯基)-1-甲基-1H-吡唑-4-甲酰胺(55.3mg,0.2mmol),1-甲基-4-(5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1,2,3,3a,4,6a-六氢并环戊二烯-2-基)-1H-吡唑(50.0mg,0.2mmol),K3PO4(67.6mg,0.3mmol)和Pd(dppf)Cl2(11.6mg,0.02mmol)在二噁烷(5mL)和H2O(1mL)的混合物在100℃搅拌4小时。真空下除去溶剂,并将残留物通过硅胶柱色谱进行纯化(其使用1:1石油醚/乙酸乙酯)以获得作为黄色固体的5-氨基-N-(3-氯-4-氟苯基)-1-甲基-3-(5-(1-甲基-1H-吡唑-4-基)-1,3a,4,5,6,6a-六氢并环戊二烯-2-基)-1H-吡唑-4-甲酰胺(50.0mg,69.4%)。(Rf:0.2);MS理论值:454.2,MS实际值:455.3[M+1]+。
AIA-049
5-氨基-N-(3-氯-4-氟苯基)-1-甲基-3-(5-(1-甲基-1H-吡唑-4-基)八氢并环戊二烯-2-基)-1H-吡唑-4-甲酰胺.在10atm H2下,将5-氨基-N-(3-氯-4-氟苯基)-1-甲基-3-(5-(1-甲基-1H-吡唑-4-基)-1,3a,4,5,6,6a-六氢并环戊二烯-2-基)-1H-吡唑-4-甲酰胺(800.0mg,1.8mmol)和RhCl(PPh3)3(81.3mg,0.09mmol)在MeOH(50mL)中的混合物在70℃搅拌过夜。真空下除去溶剂,并将残留物通过硅胶柱色谱进行纯化(其使用1:石油醚/乙酸乙酯)以获得作为白色固体的5-氨基-N-(3-氯-4-氟苯基)-1-甲基-3-(5-(1-甲基-1H-吡唑-4-基)八氢并环戊二烯-2-基)-1H-吡唑-4-甲酰胺(55mg,6.8%)。1H-NMR(DMSO-d6,400MHz):δ8.97(s,1H),7.91(dd,J=6.8,2.4Hz,1H),7.54-7.50(m,1H),7.44(s,1H),7.35(t,J=9.2Hz,1H),7.22(s,1H),5.97(s,2H),3.74(s,3H),3.64-3.53(m,1H),3.50(m,3H),2.99-2.90(m,1H),2.51-2.50(m,2H),2.20-2.10(m,4H),1.52-1.44(m,2H),1.27-1.19(m,2H);MS理论值:456.2,MS实际值:457.4[M+1]+。
表16.根据描述于5-氨基-N-(3-氯-4-氟苯基)-1-甲基-3-(5-(1-甲基-1H-吡唑-4-基)八氢并环戊二烯-2-基)-1H-吡唑-4-甲酰胺的操作合成表16中的化合物。
中间体139
5-(1H-咪唑-4-基)-3,3a,6,6a-四氢并环戊二烯-2(1H)-酮.在N2下,将5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-3,3a,6,6a-四氢并环戊二烯-2(1H)-酮(1.5g,6.0mmol),4-溴-1H-咪唑(0.88g,6.0mmol),Pd(dppf)Cl2(0.44g,0.6mmol)和K3PO4(2.6g,12mmol)在二噁烷(50mL)和H2O(8mL)中的混合物在80℃搅拌16h。该混合物是棕色悬浮液。将EtOAc(40mL)加入到该混合物中。将该混合物过滤,并将滤液用H2O(35mLx2)洗涤。将有机层用Na2SO4干燥并在真空下蒸发以获得黄色残留物。将残留物通过硅胶柱色谱进行纯化(其使用5-50%乙酸乙酯/石油醚)以获得作为黄色固体的5-(1H-咪唑-4-基)-3,3a,6,6a-四氢并环戊二烯-2(1H)-酮(0.6g,55%)。MS理论值:188.1;MS实际值:189.2[M+1]+。
中间体140
4-(5-氧代-1,3a,4,5,6,6a-六氢并环戊二烯-2-基)-1H-咪唑-1-甲酸叔丁酯.向5-(1H-咪唑-4-基)-3,3a,6,6a-四氢并环戊二烯-2(1H)-酮(600mg,3.2mmol)在DCM(20mL)的溶液中加入Boc2O(765mg,3.5mmol)和DMAP(39mg,0.32mmol)。将溶液在室温搅拌0.5h。在真空下除去溶剂并将粗制产物通过硅胶柱色谱进行纯化(其使用5-10%乙酸乙酯/石油醚)以获得作为浅黄色固体的4-(5-氧代-1,3a,4,5,6,6a-六氢并环戊二烯-2-基)-1H-咪唑-1-甲酸叔丁酯(500mg,75%)。MS理论值:288.1;MS实际值:232.2[M-56+1]+,288.2[M+1]+。
中间体141
4-(5-氧代八氢并环戊二烯-2-基)-1H-咪唑-1-甲酸叔丁酯.向4-(5-氧代-1,3a,4,5,6,6a-六氢并环戊二烯-2-基)-1H-咪唑-1-甲酸叔丁酯(500mg,1.7mmol)在乙酸乙酯(20mL)的溶液中加入Pd/C(100mg)。然后将烧瓶抽空并用H2回填。将溶液在40℃搅拌16h。将该混合物过滤,并将滤液浓缩以获得作为浅黄色固体的4-(5-氧代八氢并环戊二烯-2-基)-1H-咪唑-1-甲酸叔丁酯(480mg,95%)。MS理论值:290.2;MS实际值:234.2[M-56+1]+,291.2[M+1]+。
中间体142
4-(5-(5-氨基-4-((3-氯-4-氟苯基)氨基甲酰基)-1-甲基-1H-吡唑-3-基)八氢并环戊二烯-2-基)-1H-咪唑-1-甲酸叔丁基酯.根据描述于5-氨基-N-(3-氯-4-氟苯基)-1-甲基-3-(5-(1-甲基-1H-吡唑-4-基)八氢并环戊二烯-2-基)-1H-吡唑-4-甲酰胺的操作合成标题化合物。MS理论值:542.2;MS实际值:487.2[M-56+1]+,543.3[M+1]+。
AIA-118
3-(5-(1H-咪唑-4-基)八氢并环戊二烯-2-基)-5-氨基-N-(3-氯-4-氟苯基)-1-甲基-1H-吡唑-4-甲酰胺.向4-(5-(5-氨基-4-((3-氯-4-氟苯基)氨基甲酰基)-1-甲基-1H-吡唑-3-基)八氢并环戊二烯-2-基)-1H-咪唑-1-甲酸叔丁酯(70mg,0.13mmol)在DCM(5mL)的溶液中加入三氟乙酸(0.5mL)并将获得的混合物在室温搅拌1h。将该反应混合物用NaHCO3调整至pH 8-9,过滤并在真空下浓缩滤液。将粗制产物通过制备型HPLC进行纯化以获得作为白色固体的3-(5-(1H-咪唑-4-基)八氢并环戊二烯-2-基)-5-氨基-N-(3-氯-4-氟苯基)-1-甲基-1H-吡唑-4-甲酰胺(30mg,53%)。MS理论值:442.2;MS实际值:443.3[M+1]+。
AIA-129
3-(5-(1H-吡唑-4-基)八氢并环戊二烯-2-基)-5-氨基-N-(3-氯-4-氟苯基)-1-甲基-1H-吡唑-4-甲酰胺。根据描述于3-(5-(1H-咪唑-4-基)八氢并环戊二烯-2-基)-5-氨基-N-(3-氯-4-氟苯基)-1-甲基-1H-吡唑-4-甲酰胺的操作合成标题化合物。MS理论值:442.2,MS实际值:443.3[M+1]+;1H-NMR(DMSO-d6,400MHz):δ12.47(brs,1H),8.97(s,1H),7.92(dd,J=6.8,2.4Hz,1H),7.55-7.51(m,1H),7.40(s,2H),7.35(t,J=9.2Hz,1H),5.97(s,2H),3.63-3.57(m,1H),3.50(s,3H),3.01-2.95(m,1H),2.50-2.51(m,2H),2.18-2.17(m,4H),1.52-1.45(m,2H),1.30-1.21(m,2H)。
AIA-394
N-(3-氯-4-氟苯基)-1-甲基-3-(5-氧代八氢并环戊二烯-2-基)-1H-吡唑-4-甲酰胺.在0℃,向AIA-002(200.0mg,0.51mmol)在无水THF(10mL)的溶液中加入t-BuNO2(210.1mg,2.04mmol),并将混合物在室温搅拌5小时。将该反应用饱和NaHSO3水溶液(5.0mL)淬灭。将溶液用水(10mL)稀释并用DCM(10mLx3)萃取。将有机层分离,用无水Na2SO4干燥并浓缩以获得粗制产物,将其通过柱色谱进行纯化以获得作为黄色固体的N-(3-氯-4-氟苯基)-1-甲基-3-(5-氧代八氢并环戊二烯-2-基)-1H-吡唑-4-甲酰胺(80.0mg,41.8%)。MS理论值:375.1;MS实际值:376.1[M+1]+.1H-NMR(CDCl3,400MHz):δ7.74(dd,J=2.4Hz,6.4Hz,1H),7.68(s,1H),7.36-7.31(m,1H),7.11(t,J=8.8Hz,1H),3.87(s,3H),3.80-3.70(m,1H),2.86-2.78(m,2H),2.57-2.42(m,4H),2.23-2.16(m,2H),1.78-1.65(m,2H)。
AIA-397
N-(3-氯-4-氟苯基)-3-(5-羟基-5-((甲磺酰基)甲基)八氢并环戊二烯-2-基)-1-甲基-1H-吡唑-4-甲酰胺将甲基砜(160mg,1.7mmol)在无水四氢呋喃(10mL)的溶液冷却至-78℃,然后用正丁基锂(0.68mL,1.7mmol,2.5M)的溶液处理。将获得的溶液在-78℃至-30℃搅拌2小时。然后,将该反应混合物冷却至-78℃并用N-(3-氯-4-氟苯基)-1-甲基-3-(5-氧代八氢并环戊二烯-2-基)-1H-吡唑-4-甲酰胺(80.0mg,0.21mmol)在无水四氢呋喃(2.0mL)中的溶液处理。将该混合物在-78℃搅拌2小时。然后将反应物温热至室温并将其在室温搅拌3小时。将该反应混合物通过饱和氯化铵(2.0mL)水溶液淬灭。将该混合物在真空下浓缩,用水稀释,并用DCM(10mLx4)萃取,用Na2SO4干燥,过滤并在减压下浓缩。将残留物通过硅胶柱色谱(其使用1:15MeOH/DCM),然后用制备型HPLC进行纯化以获得作为白色固体的N-(3-氯-4-氟苯基)-3-(5-羟基-5-((甲磺酰基)甲基)八氢并环戊二烯-2-基)-1-甲基-1H-吡唑-4-甲酰胺(40.0mg,40.6%)。MS理论值:469.1,MS实际值:470.1[M+1]+.1H NMR(DMSO-d6,400MHz):δ9.85(s,1H),8.24(s,1H),8.02(dd,J=2.8Hz,7.2Hz,1H),7.60-7.56(m,1H),7.37(t,J=9.2Hz,1H),4.90(s,1H),3.83(s,3H),3.51-3.48(m,1H),3.27(s,2H),2.99(s,3H),2.51-2.49(m,2H),2.20-2.13(m,2H),2.06-1.99(m,2H),1.80-1.63(m,4H)。
中间体143
三氟甲磺酸3,3a,4,6a-四氢-1H-环戊二烯并[c]噻吩-5-基酯在0℃,将吡啶(3.3g,42mmol)加入到四氢-1H-环戊二烯并[c]噻吩-5(3H)-酮(4.0g,28mmol)在无水DCM(50mL)的溶液中。缓慢加入Tf2O(12.2g,34mmol)并搅拌4h。将该反应混合物温热至室温并用H2O淬灭,并将溶液用乙酸乙酯萃取(50mLx3)。将合并的有机层用Na2SO4干燥,浓缩并通过硅胶柱色谱进行纯化(其使用5-10%乙酸乙酯/石油醚)以获得作为淡黄色固体的三氟甲磺酸3,3a,4,6a-四氢-1H-环戊二烯并[c]噻吩-5-基酯(3.2g,44%产率)。MS理论值:274.2;MS实际值:275.7[M+1]+。
中间体144
4,4,5,5-四甲基-2-(3,3a,4,6a-四氢-1H-环戊二烯并[c]噻吩-5-基)-1,3,2-二氧杂硼杂环戊烷.在N2下,将化合物三氟甲磺酸3,3a,4,6a-四氢-1H-环戊二烯并[c]噻吩-5-基酯(3.20g,11.34mmol),pin2B2(2.80g,11.34mmol),Pd(dppf)Cl2(0.68g,0.56mmol),dppf(0.68g,0.56mmol)和乙酸钾(3.33g,34.02mmol)在二噁烷(30mL)中的棕色混合物在80℃搅拌2h。观察到黑色悬浮液。将反应通过垫过滤,将滤饼用乙酸乙酯(20mL)洗涤。将滤液在真空下浓缩,并将残留物通过硅胶柱色谱进行纯化(其使用5-10%乙酸乙酯/石油醚)以获得为淡黄色固体的4,4,5,5-四甲基-2-(3,3a,4,6a-四氢-1H-环戊二烯并[c]噻吩-5-基)-1,3,2-二氧杂硼杂环戊烷(1.8g,60%产率)作。MS理论值:252.1;MS实际值:253.7[M+1]+。
中间体145
5-氨基-N-(3-氯-4-氟苯基)-1-甲基-3-(3,3a,4,6a-四氢-1H-环戊二烯并[c]噻吩-5-基)-1H-吡唑-4-甲酰胺.在N2下,将4,4,5,5-四甲基-2-(3,3a,4,6a-四氢-1H-环戊二烯并[c]噻吩-5-基)-1,3,2-二氧杂硼杂环戊烷(1.8g,7mmol),5-氨基-3-溴-N-(3-氯-4-氟苯基)-1-甲基-1H-吡唑-4-甲酰胺(2.4g,7mmol),Pd(dppf)Cl2(0.6g,0.35mmol)和碳酸钠(14.9g,14mmol)在二噁烷/H2O(36mL,v/v=5:1)中的混合物在80℃搅拌2h。观察到黑色悬浮液。将反应通过垫过滤,并将滤饼用乙酸乙酯(20mL)洗涤。将滤液在真空下浓缩,并将残留物通过硅胶柱色谱进行纯化(其使用1-5%乙酸乙酯/石油醚)以获得作为淡黄色固体的5-氨基-N-(3-氯-4-氟苯基)-1-甲基-3-(3,3a,4,6a-四氢-1H-环戊二烯并[c]噻吩-5-基)-1H-吡唑-4-甲酰胺.(0.3g,10%产率)。MS理论值:392.8;MS实际值:393.7[M+1]+。
AIA-055
5-氨基-N-(3-氯-4-氟苯基)-3-(六氢-1H-环戊二烯并[c]噻吩-5-基)-1-甲基-1H-吡唑-4-甲酰胺.向化合物5-氨基-N-(3-氯-4-氟苯基)-1-甲基-3-(3,3a,4,6a-四氢-1H-环戊二烯并[c]噻吩-5-基)-1H-吡唑-4-甲酰胺(300mg,0.7mmol)在EtOAc(20mL)的溶液中加入Pt/C(160mg)。然后将烧瓶抽空并用H2回填。将溶液在45℃搅拌16h。将该混合物过滤并浓缩以获得作为白色固体的5-氨基-N-(3-氯-4-氟苯基)-3-(六氢-1H-环戊二烯并[c]噻吩-5-基)-1-甲基-1H-吡唑-4-甲酰胺(280mg,93%)。MS理论值:394.8;MS实际值:395.7[M+1]+.1H-NMR(DMSO-d6,400MHz):δ8.87(s,1H),7.94(dd,J=7.2,2.8Hz,1H),7.53-7.52(m,1H),7.36(t,J=8.8Hz,1H),6.03(s,2H),3.77-3.74(m,1H),3.48(s,3H),2.92-2.87(m,2H),2.82-2.77(m,2H),2.49-2.48(m,2H),2.02-1.95(m,2H),1.73-1.67(m,2H)。
AIA-056-A和AIA-056-B
5-氨基-N-(3-氯-4-氟苯基)-1-甲基-3-(2-氧化六氢-1H-环戊二烯并[c]噻吩-5-基)-1H-吡唑-4-甲酰胺.非对映异构体1(CP-AIA-056-A),非对映异构体2(CP-AIA-056-B)向5-氨基-N-(3-氯-4-氟苯基)-3-(六氢-1H-环戊二烯并[c]噻吩-5-基)-1-甲基-1H-吡唑-4-甲酰胺(150mg,0.4mmol)在DCM(5mL)的溶液中加入m-CPBA(32mg,0.2mmol),并将获得的混合物在25℃搅拌1h。在真空下除去溶剂,将残留物通过手性HPLC进行纯化以获得CP-AIA-056-A和CP-AIA-05-6B。CP-AIA-056-A(9mg,5%产率)为白色固体。MS理论值:410.9;MS实际值:411.7[M+1]+;和CP-AIA-056-B(8.5mg,5%产率)作为灰色固体。MS理论值:410.9;MS实际值:411.7[M+1]+。
中间体146
2-(3-苯基亚环戊基)-1,3-二硫杂环己烷.在-78℃,向(1,3-二硫杂环己烷-2-基)三甲基甲硅烷(10.8g,56.3mmol)在THF的溶液中逐滴加入n-BuLi(22.5mL,2.5M于THF中,56.3mmol)。将该混合物在-78℃搅拌1h,然后加入3-苯基环戊-1-酮(6.0g,37.5mmol)。将该混合物在相同的温度搅拌2h。将该反应用NH4Cl水溶液淬灭。真空下除去溶剂,将残留物通过柱色谱进行纯化(其使用石油醚/乙酸乙酯=10:1)以获得作为微黄色油状物的2-(3-苯基亚环戊基)-1,3-二硫杂环己烷(4.5g,46%产率)。MS理论值:262.1,MS实际值:262.3[M+1]+。
中间体147
3-苯基环戊烷甲酸甲酯。将2-(3-苯基亚环戊基)-1,3-二硫杂环己烷(4.5g,17.2mmol),HgCl2(9.4g,34.4mmol),6N HCl(5.7mL,34.4mmol)和TFA(3.9g,34.4mmol)在MeOH中的混合物在室温搅拌4h。过滤后,将滤液在真空下浓缩并将残留物通过柱色谱进行纯化(其使用石油醚/乙酸乙酯=10:1)以获得作为无色油状物的3-苯基环戊烷甲酸甲酯(2.9g,83%产率)。MS理论值:204.1,MS实际值:205.3[M+1]+。
中间体148
3-苯基环戊烷甲酸.将3-苯基环戊烷甲酸甲酯(2.9g,14.2mmol)和LiOH-H2O(3.0g,71.0mmol)在THF/H2O=1:1(20mL)中的混合物加热到60℃过夜。将该反应用2N HCl中和。真空下除去溶剂,并将残留物通过硅胶柱色谱进行纯化(其使用石油醚/乙酸乙酯=1:4)以获得作为白色固体的3-苯基环戊烷甲酸(2.4g,89%产率)。MS理论值:190.1,MS实际值:191.1[M+1]+。
中间体149
3-苯基环戊烷甲酰胺.将3-苯基环戊烷甲酸(2.4g,12.6mmol),HCOONH4(1.6g,25.2mmol),HATU(7.2g,18.9mmol)和TEA(2.5g,25.2mmol)在DMF(20mL)中的混合物在室温搅拌过夜。将该反应用水(100mL)淬灭并用EtOAc(100mLx3)萃取。将合并的有机层在减压下浓缩。将残留物通过硅胶柱色谱进行纯化(其使用石油醚/乙酸乙酯=1:2)以获得作为白色固体的3-苯基环戊烷甲酰胺(2.0g,83%产率)。MS理论值:189.1,MS实际值:190.4[M+1]+。
中间体150
3-苯基环戊烷甲腈.在-40℃,向3-苯基环戊烷甲酰胺(2.0g,10.6mmol)在吡啶(20mL)的溶液中加入POCl3(4.9g,31.8mmol)并将该混合物搅拌30分钟。将该反应用水(30mL)淬灭,用EtOAc(30mLx3)萃取。将合并的有机层在真空下浓缩,并将残留物通过硅胶柱色谱进行纯化(其使用石油醚/乙酸乙酯=10:1)以获得作为无色油状物的3-苯基环戊烷甲腈(1.1g,61%产率)。MS理论值:171.1,MS实际值:172.2[M+1]+。
中间体151
3-苯基环戊烷甲亚胺酸乙酯盐酸盐.将3-苯基环戊烷甲腈(1.1g,6.4mmol)在MeOH(10mL)的溶液用HCl(气体)鼓泡,然后将反应搅拌2h。真空下除去溶剂,并且残留物无需进一步纯化即用于下一步。获得作为白色固体的3-苯基环戊烷甲亚胺酸甲酯盐酸盐(1.3g粗制,100%产率)。MS理论值:203.1,MS实际值:204.3[M+1]+。
中间体152
3-氨基-2-氰基-3-(3-苯基环戊基)丙烯酸乙酯.将3-苯基环戊烷甲亚胺酸甲酯盐酸盐(1.3g,6.4mmol),2-氰基乙酸乙酯(1.4g,12.8mmol)和TEA(1.3g,12.8mmol)在MeOH中的混合物在室温搅拌过夜。真空下除去溶剂,并将残留物通过硅胶柱色谱进行纯化(其使用石油醚/乙酸乙酯=2:1)以获得作为白色固体的3-氨基-2-氰基-3-(3-苯基环戊基)丙烯酸乙酯(500mg,28%产率)。MS理论值:284.2,MS实际值:285.3[M+1]+。
中间体153
5-氨基-3-(3-苯基环戊基)异噁唑-4-甲酸乙酯.将3-氨基-2-氰基-3-(3-苯基环戊基)丙烯酸乙酯(500mg,1.8mmol)和羟胺/EtOH(1mL)在EtOH(2mL)中的混合物在回流下加热4h。真空下除去溶剂,并将残留物通过硅胶柱色谱进行纯化(其使用石油醚/乙酸乙酯=10:1)以获得作为白色固体的5-氨基-3-(3-苯基环戊基)异噁唑-4-甲酸乙酯(200mg,38%产率)。MS理论值:300.1,MS实际值:301.3[M+1]+。
中间体154
5-氨基-3-(3-苯基环戊基)异噁唑-4-甲酸.将5-氨基-3-(3-苯基环戊基)异噁唑-4-甲酸乙酯(100mg,0.3mmol)和LiOH-H2O(140mg,71.03.3mmol)在THF/H2O=1:1(10mL)中的混合物在60℃加热过夜。将该反应用2N HCl中和。真空下除去溶剂,并将残留物通过硅胶柱色谱进行纯化(其使用石油醚/乙酸乙酯=1:4)以获得作为白色固体的5-氨基-3-(3-苯基环戊基)异噁唑-4-甲酸(70mg,78%产率)。MS理论值:272.1,MS实际值:273.1[M+1]+。
AIA-149
5-氨基-N-(3-氯-4-氟苯基)-3-(3-苯基环戊基)异噁唑-4-甲酰胺:将5-氨基-3-(3-苯基环戊基)异噁唑-4-甲酸(70mg,0.3mmol),3-氯-4-氟苯胺(60mg,0.4mmol),HATU(170mg,0.4mmol)和TEA(60mg,0.6mmol)在DCM(5mL)中的混合物在室温搅拌1h。将该反应用水(20mL)淬灭并用EtOAc(20mLx3)萃取。将合并的有机层在减压下浓缩,并将残留物通过硅胶柱色谱(其使用石油醚/乙酸乙酯=1:1)和制备型HPLC进行纯化以获得作为白色固体的5-氨基-N-(3-氯-4-氟苯基)-3-(3-苯基环戊基)异噁唑-4-甲酰胺(3mg,3%产率)。MS理论值:399.1,MS实际值:400.0[M+1]+.1H-NMR(DMSO-d6,400MHz):δ9.26-9.21(m,1H),7.89-7.85(m,1H),7.52(brs,3H),7.37-7.15(m,6H),3.85-3.66(m,1H),3.19-3.10(m,1H),2.35-2.32(m,1H),2.19-1.83(m,4H),1.67-1.62(m,1H)。
VI.生物学数据
测量测试化合物对来自HepAD38细胞的病毒产生的活性的分析
使用0.25%胰蛋白酶-EDTA(Invitrogen,货号:25200-056)剥离HepAD38细胞,所述细胞生长在含有生长培养基(DMEM/F12(1:1)(Hyclone,货号:SH30023.02)、1X Pen/Strep(Invitrogen,货号:15140-122)、10%FBS(Tissue Culture Biologics,货号:101)、250μg/mL G418(Alfa Aesar,货号:J62671)、1μg/mL四环素(Tetracycline)(Teknova,货号:T3320))的T-150烧瓶(Corning,货号:430825)中。然后向混合物中加入无四环素处理培养基(15mL DMEM/F12(1:1))、1x Pen/step、Tet系统专用2%FBS(Clontech,货号:631106),转移至50ml圆锥管(Falcon,货号:21008-918)中并在1300rpm下旋转5min。然后使用50mL1X DPBS(Invitrogen,货号:14190-136)再悬浮/洗涤粒化细胞2次并使用50mL处理培养基处理两次。然后使用10mL处理培养基再悬浮HepAD38细胞,冲洗并计数。在180μL处理培养基中,将96孔透明底部TC板(Corning,货号:3904)的孔的以50,000细胞/孔进行接种,且向处理培养基中添加20μL 10%DMSO(Sigma,货号:D4540)作为对照或测试化合物于10%DMSO中的10X溶液直至最终化合物浓度(始于10μM),且将板在37℃下在5%CO2孵育器中孵育5天。
随后,通过HBV核心序列的定量PCR(qPCR)分析病毒载量产生。制备含有正向引物HBV-f 5'-CTGTGCCTTGGGTGGCTTT-3’(IDT DNA)、反向引物HBV-r 5'-AAGGAAAGAAGTCAGAAGGCAAAA-3'(IDT DNA)、荧光TaqMantm探针HBV探针5'-FAM/AGCTCCAAA/ZEN/TTCTTTATAAGGGTC GATGTC/3IABkFQ-3'(IDT DNA)、10μL/孔qPCR(Quanta Biosciences,货号:95114-05K)和6μL/孔DEPC水(Alfa Aesar,货号:J62087)的PCR反应混合物。将4μL上清液添加至qPCR板(Applied Biosytems,货号:4309849)中的16μL反应混合物中,使用膜(Applied Biosystems,货号:4311971)密封,离心数秒,且随后在Applied Biosystems VIIA7上运行。将PCR混合物在45℃下孵育5min,然后在95℃下孵育10min,随后在95℃下孵育10秒和60℃下孵育20秒,实施40个循环。针对已知HBV DNA标准通过使用ViiATM 7软件来量化病毒载量。对含有经处理细胞的孔的上清液中的病毒载量与来自DMSO对照孔(每板≥3)的上清液中的病毒载量进行比较。使用经修改的CellTiter-Glo荧光细胞活力分析(Promega,货号:G7573)实施细胞活力分析。以1:1比例混合适当量的CellTiter-Glo(CTG)1X DPBS,将100uL混合物添加至每一孔中,随后在不触碰细胞表面下完全去除每一孔中的所有上清液。将板在室温下在定轨振荡器上孵育10min,且然后使用读板仪(TECAN M1000或Envision)读取板。通过4参数非线性逻辑回归模型(GraphPad Prism或Dotmatics)的曲线拟合来计算EC50或CC50值。CC50值皆>10μM。
表17给出本发明的示例性化合物的病毒载量降低EC50值并且以下面的范围分组:A指示EC50<0.1μM;B指示EC50是0.1-0.5μM;C指示EC50是0.5-10μM。
表17 本发明的示例性化合物的病毒载量降低
VII.实施例的立体化学
在挥发20天后,从EtOH获得尺寸为0.08x0.10x0.20mm的化合物AIA-227-2的晶体,该晶体用于X射线衍射数据采集。在室温下在Bruker SMART CCD区域-检测衍射仪上使用CuKα辐射通过扫描模式来收集数据。收集10846个反射,其中3754个反射是独特的(Rint=0.0507)。
通过直接方法解析结构,并且针对F2通过全矩阵最小平方方法使用SHELXTL程序来精修所有非H原子。将所有H原子均置放在几何理想位置上并且强制其浮在其母原子上。使用多扫描吸收校正方法,并且最大和最小透射参数分别为0.7531和0.6017。最终R、wR2、GOF分别是0.0457、0.1293和1.024。
在不对称单元中存在一个C21H26FClN4O4S分子并且可以在其间发现氢键,氢键在晶体结构的稳定堆积中发挥重要作用。
化合物AIA-227-2的ORTEP图呈现在图1中。化合物AIA-227-2的相对立体化学图展示在图2中。对相关实施例的化学结构中所描绘的立体化学是基于此指定。
通过引用并入本文
出于所有目的,本文中提及的所有出版物和专利,包括下面列出的那些,均通过引用全文并入本文,就如同每个单独的出版物或专利都被具体地和单独地通过引用并入一样。在有冲突的情况下,以本申请(包括本文的任何定义)为准。
等价物
虽然已经讨论了本公开的特定实施方案,但是以上说明书是说明性的且不是限制性的。通过阅读本说明书,本公开的许多变化对于本领域技术人员将变得显而易见。本公开的全部范围应该通过参考权利要求书,及其等价物的全部范围,说明书以及这些变化来确定。
除非另有指示,否则表示说明书和权利要求书中所用的成分数量、反应条件等的所有数字均应理解为在所有情况下由术语“约”修饰。因此,除非有相反的指示,否则在本说明书和所附权利要求书中阐述的数字参数是近似值,其可以根据本公开试图获得的所需性能而变化。
Claims (27)
1.式I化合物,或其药学上可接受的盐,
其中:
X1是NRx1、O或S;
X2是N或CRx2;
X3是O、NR7、CR4R8、C(O)、S(O)t、C=CR4R0或C=NR4;
X4和X6独立地为O或S;
X5是O、S或NR0;
L是键或C1-6亚烷基;
L1是键、C1-6亚烷基、O、NRc、C(O)、C(O)NRc、S(O)t或S(O)tNRc;
Rx1和Rx2独立地选自氢、C1-6烷基、卤代C1-6烷基和C3-6单环烷基;
Ra、Rb和Rc在每次出现时独立地选自氢、C1-6烷基、卤代C1-6烷基和C3-6单环烷基;
Rd是氢、OH、C1-6烷基或C1-6烷氧基;
R0、R6、R8和R11在每次出现时独立地选自氢、卤素、OH、CN、NO2、氧代、RdN=、肼基、甲酰基、叠氮基、甲硅烷基、甲硅烷氧基、HOC(O)-、RaRbN-、RaRbNS(O)t-、C1-6烷基、C2-6烯基、C2-6炔基、C3-6单环烷基、卤代C1-6烷基、羟基C1-6烷基-、RaRbNC1-6烷基-、HOC(O)C1-6烷基-、RaRbNC1-6烷基NRc-、C1-6烷基NRaC1-6烷基NRc-、C1-6烷氧基、卤代C1-6烷氧基、羟基C1-6烷氧基-、RaRbNC1-6烷氧基-、C1-6烷氧基C1-6烷基-、卤代C1-6烷氧基C1-6烷基-、RaRbNC(O)-、C1-6烷基C(O)-、C1-6烷氧基C(O)-、C1-6烷基C(O)O-、C1-6烷基S(O)q-、C1-6烷基S(O)tNRc-、C1-6烷基S(O)tC1-6烷基-、C1-6烷基S(O)tNRaC1-6烷基-、C3-6环烷基S(O)tC1-6烷基-、C1-6烷基C(O)C1-6烷基-和C1-6烷基C(O)OC1-6烷基-;
R0a在每次出现时独立地选自氢、卤素、OH、CN、NO2、RaRbN-、C1-6烷基和卤代C1-6烷基;
R1是苯基、萘基、C3-6单环烷基、C3-6单杂环烷基或5-6元单环杂芳基,其中:所述苯基、C3-6单环烷基、C3-6单杂环烷基或5-6元单环杂芳基任选地取代有一、二或三个独立选择的R11基团;
R2是氢、卤素、RaRbN、C1-6烷基、卤代C1-6烷基、C3-6单环烷基或C1-6烷氧基;
R3选自:
R4是R5、R6或R5-L1-;
R4a是氢或C1-6烷基;
R4b是R5、R5a、R6或R5-L1-;
R5选自:
R6a是氢或C1-6烷基;
R7是氢、C1-6烷基、C1-6卤代烷基、C1-6烷氧基C1-6烷基-、NRaRbC(O)-、R7aC(O)-、C1-6烷氧基C(O)-、C1-6烷基S(O)q-或C1-6卤代烷基S(O)q-;
R7a是C1-6烷基或C3-6单环烷基;
q、r、t、和w在每次出现时独立地选自0、1和2;且
v在每次出现时独立地选自0、1、2和3。
2.权利要求1所述的化合物或其药学上可接受的盐,其中X1是NRx1,X2是N且Rx1是氢或甲基。
3.权利要求1或2所述的化合物或其药学上可接受的盐,其中Rx1是甲基。
4.根据权利要求1-3中任一项所述的化合物或其药学上可接受的盐,其中L是键。
5.根据权利要求1-3中任一项所述的化合物或其药学上可接受的盐,其中L1是键。
6.根据权利要求1-5中任一项所述的化合物或其药学上可接受的盐,其中R2是RaRbN。
7.权利要求6所述的化合物或其药学上可接受的盐,其中R2是NH2。
9.权利要求8所述的化合物或其药学上可接受的盐,其中R11的每次出现独立地选自F、Cl、Br和I。
20.权利要求18或19所述的化合物或其药学上可接受的盐,其中R6是C1-6烷基S(O)tC1-6烷基-或C1-6烷基S(O)tNRaC1-6烷基-。
21.权利要求20所述的化合物或其药学上可接受的盐,其中R6是C1-6烷基S(O)tC1-6烷基-,并且t是1或2。
22.权利要求21所述的化合物或其药学上可接受的盐,其中t是2。
23.根据权利要求18-22中任一项所述的化合物或其药学上可接受的盐,其中R8是氢、OH或C1-6烷氧基。
24.权利要求23所述的化合物或其药学上可接受的盐,其中R8是OH。
25.药物组合物,其包含根据权利要求1-24中任一项所述的化合物或其药学上可接受的盐,和药学上可接受的赋形剂。
26.在有需要的受试者中治疗乙肝(HBV)感染的方法,所述方法包括:向所述受试者施用治疗有效量的根据权利要求1-24中任一项所述的化合物或其药学上可接受的盐。
27.在有需要的受试者中治疗乙肝(HBV)感染的方法,所述方法包括:向所述受试者施用治疗有效量的权利要求25的药物组合物。
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WO2023069547A1 (en) * | 2021-10-20 | 2023-04-27 | Assembly Biosciences, Inc. | 5-membered heteroaryl carboxamide compounds for treatment of hbv |
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