CN115043841A - 一种作为btk抑制剂杂环类化合物的制备及其应用 - Google Patents
一种作为btk抑制剂杂环类化合物的制备及其应用 Download PDFInfo
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- CN115043841A CN115043841A CN202110255917.6A CN202110255917A CN115043841A CN 115043841 A CN115043841 A CN 115043841A CN 202110255917 A CN202110255917 A CN 202110255917A CN 115043841 A CN115043841 A CN 115043841A
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- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 42
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 23
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- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 229910052718 tin Inorganic materials 0.000 description 1
- 239000011135 tin Substances 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 150000004684 trihydrates Chemical class 0.000 description 1
- RMNIZOOYFMNEJJ-UHFFFAOYSA-K tripotassium;phosphate;hydrate Chemical compound O.[K+].[K+].[K+].[O-]P([O-])([O-])=O RMNIZOOYFMNEJJ-UHFFFAOYSA-K 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000012224 working solution Substances 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
本发明公开了一种作为BTK抑制剂杂环类化合物的制备及其应用，该抑制剂是一类含有多芳香杂环结构的化合物，包括化合物或其异构体、水合物、溶剂化物、多晶型物、药学上可接受的盐，同时公开了该类化合物的制备方法和使用这些新型化合物治疗或者预防Bruton's酪氨酸激酶相关疾病如急性淋巴细胞白血病(ALL)、慢性粒细胞白血病(CML)、套细胞淋巴瘤(MCL)、大肠癌、类风湿关节炎、抗器官移植排异、抗牛皮癣、红斑狼疮等。
Description
技术领域
本发明属于药物合成领域，具体涉及一种新型Bruton's酪氨酸激酶抑制剂及其制备方法与用途。
背景技术
Bruton's酪氨酸激酶是非受体蛋白酪氨酸激酶Tec家族的成员。Tec家族是人类非受体激酶中仅次于Src家族的第2大家族，其主要成员包括Bruton's酪氨酸激酶、BMX(etk)、ITK、TEC和TXK(PLK)。Bruton's酪氨酸激酶在1993年被确定为人X-连锁无丙种球蛋白血症(X-linked agammaglobulinemia，XLA)中的缺陷蛋白。这种蛋白在B细胞各个发展阶段均有表达(除了最终分化的浆细胞)，在前B淋巴细胞过渡为后期B细胞过程中，Bruton's酪氨酸激酶为细胞分化和增值所必需基因，且在B细胞淋巴瘤、急性淋巴细胞白血病(ALL)和浆细胞瘤中均有表达。此外，在骨髓细胞和红系祖细胞中也有少量表达。
目前，依鲁替尼(ibrutinib)、阿卡替尼(acalabrutinib)和泽布替尼(Zanubrutinib)等Bruton's酪氨酸激酶小分子抑制剂被美国FDA批准上市，用于治疗套细胞淋巴瘤(MCL)和CLL。
虽然依鲁替尼、阿卡替尼和泽布替尼治疗效果显著，但是临床上的B细胞淋巴瘤患者除了一部分患者在后期产生抗药耐受外，还有相当一部分患者对其治疗不敏感，比如在MCL中约有1/3患者对其治疗无应答，DLBCL中的应答率也不高。鉴于以上问题，本领域仍然需要开发活性高、特异性强的Bruton's酪氨酸激酶抑制剂。
发明内容
为解决上述问题，本发明提供了式(I)所示的一种新型Bruton's酪氨酸激酶抑制剂的化合物或其立体异构体、稳定同位素衍生物、水合物、溶剂化物、药学上可接受的盐：
其中：
X1，X2，X3，X4可以独立地选自N、CR1；
Ar1和Ar2独立地选苯环或者5-6元杂芳环，其中上述的苯环和杂芳环任选被一个或多个G1所取代；
R1独立地选自H、D、氰基、卤素、C1-6烷基、COOH、CONH2、NHCOH、CONHR2、OR2或-NHR2；
R2独立地选自H、D、氰基、卤素、C1-6烷基、C3-6环烷基、3-6元杂环烷基、-OR3、-NR3R4、-C(O)NR3R4，其中所述的烷基、环烷基或杂环烷基任选被氰基、卤素、-OR5、-NR5R6、C1-6烷基、C3-6环烷基或3-6元杂环烷基；
U和W独立地选自-C0-4烷基-、-CR7R8-、-C1-2烷基(R7)(OH)-、-C(O)-、-CR7R8O-、-OCR7R8-、-SCR7R8-、-CR7R8S-、-NR7-、-NR7C(O)-、-C(O)NR7-、-NR7C(O)NR8-、-CF2-、-O-、-S-、-S(O)m-、-NR7S(O)2-、-S(O)2NR7-；
Y不存在或选C3-8环烷基、3-8元杂环烷基、5-12元稠烷基、5-12元稠杂环基、5-12元螺环基、5-12元螺杂环基、芳香基或者杂芳香基，其中所述环烷基、杂环烷基、螺环基、稠环基、稠杂环基、螺杂环基、芳香基或者杂芳香基任选被一个或多个G2所取代；
Z独立地选自氰基、-NR9CN、
键a为双键或者三键；
当a为双键时，Ra、Rb和Rc各自独立地选自H、D、氰基，卤素、C1-6烷基、C3-6环烷基或3-6元杂环基。其中所述烷基，环烷基和杂环基任选被1个或多个G3所取代；
Ra和Rb或Rb和Rc任选与它们连接的碳原子共同形成一任选含有杂原子的3-6元环；
当键a为三键时，Ra和Rc不存在，Rb独立选自H、D、氰基，卤素、C1-6烷基、C3-6环烷基或3-6元杂环基被一个或多个G4所取代；
R9独立地选自H、D、C1-6烷基、C3-6环烷基或3-6元杂环基，其中所述烷基，环烷基和杂环基任选被1个或多个G5所取代；
G1、G2、G3、G4和G5各自独立选自H、D、氰基，卤素、C1-6烷基、C2-6烯基、C2-6炔基、C3-8环烷基或3-8元杂环基、C6-10芳基、5-10元杂芳香基、-OR10、-OC(O)NR10R11、-C(O)OR10、-C(O)NR10R11、-C(O)R10、-NR10R11、-NR10C(O)R11、-NR10C(O)NR11R12、-S(O)mR10或-NR10S(O)mR11，其中所述烷基、烯基、炔基、环烷基、杂环烷基、芳香基、杂芳香基任选被1个或多个氰基，卤素、C1-6烷基、C2-6烯基、C2-6炔基、C3-8环烷基或3-8元杂环基、C6-10芳基、5-10元杂芳香基、-OR13、-OC(O)NR13R14、-C(O)OR13、-C(O)NR13R14、-C(O)R13、-NR13R14、-NR13C(O)R14、-NR13C(O)NR14R15、-S(O)mR13或-NR13S(O)mR14的取代基所取代；
R3、R4、R5、R6、R7、R8、R10、R11、R12、R13、R14和R15各自独立选自H、D、氰基、卤素、C1-6烷基、C3-8环烷基或3-8元单环杂环基、单环杂芳香基或者苯基；且
m为1或2。
本发明的典型化合物包括，但不限于以下化合物：
本发明提供了所述的一种新型Bruton's酪氨酸激酶抑制剂或其异构体、水合物、溶剂化物、多晶型物、药学上可接受的盐，以及药学上可接受载体在制备新型Bruton's酪氨酸激酶抑制剂中的用途。
所述药物组合物为片剂、胶囊、颗粒剂、喷雾剂或者注射剂的形式。
所述药学上可接受的载体选自填充剂、崩解剂、粘合剂和润滑剂中的一种或多种。包括但不限于任何和全部的溶剂、分散介质、包衣、吸收延迟剂等，这样的介质和药剂用于药学活性物质在本领域中的应用。
本发明还提供了所述的一种新型Bruton's酪氨酸激酶抑制剂或其异构体、水合物、溶剂化物、多晶型物、药学上可接受的盐作为Bruton's酪氨酸激酶抑制剂的用途。
进一步地，所述蛋白酪氨酸激酶抑制剂为Bruton's酪氨酸激酶抑制剂。
一种新型Bruton's酪氨酸激酶抑制剂或其异构体、水合物、溶剂化物、多晶型物、药学上可接受的盐或者其药物组合物在治疗或者预防Bruton's酪氨酸激酶相关疾病的药物中的应用。
进一步地，所述Bruton's酪氨酸激酶相关疾病选自下组：急性淋巴细胞白血病(ALL)、慢性粒细胞白血病(CML)、套细胞淋巴瘤(MCL)、大肠癌、类风湿关节炎、抗器官移植排异、抗牛皮癣、红斑狼疮等。
显然，根据本发明的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本发明上述基本技术思想前提下，还可以做出其它多种形式的修改，替换或变更。
以下通过实施形式的具体实施方式，对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅于以下的实例。凡基于上述内容所实现的技术均属于本发明的范围。
某些化学术语
除非有相反陈述，否则下列用在说明书和权利要求书中的术语。
具有下述含义在本文中使用的表示方式“Cx-y”表示碳原子数的范围、其中x和y均为整数，例如C3-8环烷基表示具有3-8个碳原子的环烷基，即具有3、4、5、6、7或8个碳原子的环烷基。还应理解，“C3-8”还包含其中的任意亚范围、例如C3-7、C3-6、C4-7、C4-6、C5-6等。
“烷基”指含有1至20个碳原子，例如1至18个碳原子、1至12个碳原子、1至8个碳原子、1至6个碳原子或1至4个碳原子的直链或支链的烃基基团。烷基的非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基和2-乙基丁基。所述烷基可以是取代的或未取代的。
“烯基”指含有至少一个碳碳双键和通常2至20个碳原子例如2至8个碳原子、2至6个碳原子或2至4个碳原子的直链或支链的烃基基团。烯基的非限制性实例包括乙烯基、1-丙烯基、2-丙烯基、1-丁烯基、2-丁烯基、3-丁烯基、2-甲基-2-丙烯基、1，4-戊二烯基和1，4-丁二烯基。所述烯基可以是取代的或未取代的。
“炔基”指含有至少一个碳碳三键和通常2至20个碳原子，例如2至8个碳原子、2至6个碳原子或2至4个碳原子的直链或支链的烃基基团。炔基的非限制性实例包括乙炔基、1-丙炔基、2-丙炔基、1-丁炔基、2-丁炔基和3-丁炔基。所述炔基可以是取代的或未取代的。
“环烷基”指含有3至14个碳环原子的饱和环形烃基取代基。环烷基可以是单碳环，通常含有3至7个碳环原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环己基和环庚基。环烷基可选择地可以是稠合到一起的双或三环、如十氢萘基、所述环烷基可以是取代的或未取代的。
“杂环基”、“杂环烷基”、“杂环”是指稳定的3-18元单价非芳香环，包括2-12个碳原子，1-6个选自氮、氧和硫的杂原子。除非另作说明，杂环基基团可以是单环、双环、三环或四环系统，其可能包含稠环、螺环或桥环系统，杂环基上的氮、碳或硫可选择性的被氧化，氮原子可选择性的被季铵化，杂环基可以部分或完全饱和。杂环基可以通过环上的碳原子或杂原子与分子的其余部分通过一个单键连接。包含稠环的杂环基中可以包含一个或多个芳环或杂芳环，只要与分子的其余部分连接的是非芳香环上的原子。为了本申请，杂环基优选的是一个稳定的4-11元单价非芳香单环或二环，其包含1-3个选自氮、氧和硫的杂原子，更优选的是一个稳定的4-8元单价非芳香单环，其包含1-3个选自氮、氧和硫的杂原子。杂环基的非限制性实例包括氮杂环庚烷基、氮杂环丁基、十氢异喹啉基、二氢呋喃基、二氢吲哚基、二氧戊烷基、1,1-二氧-硫代吗啉基、咪唑烷基、咪唑啉基、异噻唑烷基、异恶唑烷基、吗啉基、八氢吲哚基、八氢异吲哚基、恶嗪基、哌嗪基、哌啶基、4-哌啶酮基、吡喃基、吡唑烷基、吡咯烷基、喹嗪基、奎宁环基、四氢呋喃基、四氢吡喃基等。
“螺杂环基”指5至20元，单环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个环原子选自氮、氧或S(O)m(其中m是整数0至2)的杂原子，其余环原子为碳。这些可以含有一个或多个双键，但没有一个环具有完全共扼的电子系统优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺环烷基分为单螺杂环基、双螺杂环基或多螺杂环基，优选为单螺环烷基和双螺环烷基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环基。螺杂环基的非限制性实施例包含：
“稠杂环基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团，一个或多个环可以含有一个或多个双键,但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子选自氮、氧或S(O)m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠杂环烷基，优选为双环或三环，更优选为5元/5元或5元/6元双环稠杂环基。稠杂环基的非限制性实施例包含：
“芳基”或“芳香基”指含有6至14个碳原子的芳香族单环或稠合多环基团，优选为6至10元，例如苯基和萘基，更优选为苯基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上、其中与母体结构连接在一起的环为芳基环。
“杂芳基”或“杂芳香基”是指5-16元环状系统，其包含1-15个碳原子，优选的1-10个碳原子，1-4个选自氮，氧和硫的杂原子，至少一个芳香环。除非另作说明，杂芳基可以是单环、双环、三环或四环系统，其可能包含稠环或桥环系统，只要与分子其它部分的连接点为芳环原子，杂芳环上的氮原子、碳原子和硫原子可以透择性的被氧化，氮原子可选择性的被季铵化。为了本发明，杂芳基优选的为稳定的4-11元单芳香环，其包含1-3个选自氮、氧和硫的杂原子，更优选的为稳定的5-8元单芳香环，其包含1-3个选自选自氮、氧和硫的杂原子。杂芳基的非限定性实例包括吖啶基、氮杂卓基、苯并咪唑基、苯并吲哚基、苯并二氧芑基、苯并二恶茂基、苯并呋喃酮基、苯并呋喃基、苯并萘并呋喃基、苯并吡喃酮基、苯并吡喃基、苯并吡唑基、苯并噻二唑基、苯并噻唑基、苯并三唑基、呋喃基、咪唑基、吲唑基、吲哚基、恶唑基、嘌呤基、吡嗪基、吡唑基、哒嗪基、吡啶基、嘧啶基、吡咯基、喹唑啉基、喹啉基、奎宁基、四唑基，噻二唑基、噻唑基、噻吩基、三嗪基，三唑基等。本申请中，杂芳基优选为5-8元杂芳基，其包含1-3选自选自氮、氧和硫的杂原子，更优选为吡啶基、嘧啶基、噻唑基。所述杂芳基可以是取代的或未取代的。
“卤素”指氟、氯、溴或碘。
“羟基”指-OH，“氨基”指-NH2，“酰胺基”指-NHCO-，“氰基”指-CN，“硝基”指-CN，“异氰基”指-NC，“三氟甲基”指-CF3。
本文单独或作为其它成分的一部分使用的术语“杂原子”或“杂”是指除碳和氢之外的原子，杂原子独立地选自氧、氮、硫、磷、硅、硒和锡，但不限于这些原子，在出现两个或更多杂原子的实施方案中，所述两个或更多杂原子可彼此相同，或者所述两个或更多杂原子中的一些或全部此不同。
本文单独或组合使用的术语“稠”或“稠环”是指两个或更多个环共享一个或更多个键的环状结构。
本文单独或组合使用的术语“螺”或“螺环”是指两个或更多个环共享一个或更多个原子的环状结构。
“任选”或“任选地”意味着随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生地场合例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。
“取代的”指基团中的一个或多个原子，较佳为5个、更佳为1～3个原子彼此独立地被相应数目的取代基取代。不言而喻，取代基处在它们的可能的化学位置本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离的胺基或羟基与具有不饱和(如烯烃)键的碳原子结合时可能是不稳定的。所述取代基包括但不限于羟基、胺基、卤素、氰基、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8环烷基等。
“药物组合物”指含有一种或多种本文所述的化合物或其可药用的盐或前药以及其他分例如可药用的载体和赋形剂的组合物。药物组合物的目的是促对生物体的给药、利于活性成分的吸收进而发挥生物活性。
“异构体”指具有相同分子式但其原子结合的性质或顺序或其原子的空间排列不同的化合物称为“异构体”、其原子空间排列不同的异构体称为“立体异构体”。立体异构体包括光学异构体、几何异构体和构象异构体。本发明的化合物可以以光学异构体形式存在。根据手性碳原子周围取代基的构型，这些光学异构体是“R”或“S”构型。光学异构体包括对映异构体和非对映异构体、制备和分离光学异构体的方法是本领域中已知的。
本发明的化合物也可以存在几何异构体。本发明考虑由碳-碳双键、碳-氮双键、环烷基或杂环基团周的取代基的分布所产生的各种几何异构体和其混合物。碳-碳双键或碳-氮键周围的取代基指定为Z或E构型、环烷基或杂环周围的取代基指定为顺式或反式构型。
本发明的化合物还可能显示互变异构现象，例如酮-烯醇互变异构。
应该理解，本发明包括任何互变异构或立体异构形式和其混合物、并且不仅限于化合物的命名或化学结式中所使用的任何一个互变异构或立体异构形式。
“同位素”是在本发明化合物中出现的原子的所有同位素。同位素包括具有相同原子序数但不同质量数的那些原子。适合并入本发明化合物中的同位素的实例是氢、碳、氮、氧、磷、氟和氯，分别例如但不限于2H、3H、13C、14C、15N、18O、31P、32P、35S、18F和36Cl。本发明的同位素标记化合物通常可通过本域技术人员已知的传统技术或通过与所附实施例中描的那些类似的方法使用适当的同位素标记的试剂代替非同位素标记的剂制。这样的化合物具有各种潜在用途、例如作为测定生物活性中的标样和试剂。在稳定同位素的情况下，这样的化合物具有有利地改变生物、药理学或药代动力学性质的潜力。
“前药”是指本发明的化合物可以以前药的形式给予。前药是指在活体内的生理条件下例如通过氧化、还原、水解等(它们各自利用酶或在没有酶参与下进行)转化成本发明的生物活性化合物的衍生物。前药的实例是下述化合物：其中本发明的化合物中的胺基被酰化、烷基化或磷酸化，例如二十烷酰基胺基、丙胺酰胺基、新戊酰氧基甲基胺基、或其中羟基被酰化、烷基化、磷酸化或转化成硼酸盐，例如乙酰氧基、棕榈酰氧基、新戊酰氧基、琥珀酰氧基、富马酰氧基、丙胺酰氧基、或其中羧基被酯化或酰胺化，或其中巯基与选择性地向靶和/或向细胞的胞质溶胶递送药物的载体分子，例如肽形成二硫桥键、这些化合物可以由本发明的化合物根据公知方法制备。
“可药用的盐”或者“药学上可接受的”是指由可药用的碱或酸，包括无机碱或酸和有机碱或酸制成的。在本发明的化合物含有一个或多个酸性或碱性基团的情况下，本发明还包含它们相应的可药用盐。因此，含有酸性基团的本发明的化合物可以以盐形式存在并可根据本发明使用，例如作为碱金属盐、碱土金属盐或作为铵盐。这样的盐的更确切实例包括钠盐、钾盐、钙盐、镁盐或与胺或有机胺，例如伯胺、仲胺、叔胺、环胺等，例如氨、异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、二乙醇胺、乙醇胺、二环己胺、乙二胺、嘌呤、哌嗪、哌啶、胆碱和咖啡因等特别优选的有机碱为异丙胺、二乙胺、乙醇胺、三甲胺、二环己胺、胆碱和咖啡因的盐。含有碱性基团的本发明的化合物可以盐形式存在并可根据本发明以它们与无机或有机酸的加成的形式使用。合适的酸的实例包括盐酸、氢溴酸、磷酸、硫酸、磷酸、甲磺酸、对甲苯磺酸、萘二磺酸、草酸、乙酸、酒石酸、乳酸、水杨酸、苯甲酸、甲酸、丙酸、特戊酸、丙二酸、琥珀酸、庚二酸、富马酸、马来酸、苹果酸、胺基磺酸、苯基丙酸、葡糖酸、抗坏血酸、异烟酸、柠檬酸、己二酸和本领域技术人员已知的其它酸。如果本发明的化合物在分子中同时含有酸性和碱性基团，本发明除所提到的盐形式外还包括内盐或内铵盐。各盐通过本领域技术人员已知的常规方法获得，例如通过在溶剂或分散剂中使这些与有机或无机酸或碱接触或通过与其它盐阴离子交换或阳离子交换。
因此，在本申请中当提及“化合物”、“本发明化合物”或“本发明所化合物”时，包括所有所述化合物形式、例如其前药、稳定同位素衍生物、可药用的盐、异构体、内消旋体、外消旋体、对映异构体、非对映异体及其混合物。
在本文中、术语“肿瘤”包括良性肿瘤和恶性肿瘤(例如癌症)。
在本文中，术语“癌症”包括Bruton's酪氨酸激酶参与其发生的各种恶性肿瘤、包括但不限于非小细胞肺癌、食管癌、黑色素瘤、横纹肌肉榴、细胞癌、多发性骨髓瘤、乳腺癌卵巢癌、子宫膜癌、宫颈癌、胃癌、结癌、膀胱癌、胰腺癌、肺癌、乳腺癌、前列腺癌和肝癌(例如肝细胞癌)，更具体为肝癌、胃癌和膀胱癌。
本文所使用术语“有效量”、“治疗有效量”或“药学有效量”是指服用后足以在某种程度上缓解所治疗的疾病或病症的一个或多个症状的至少一种药剂或化合物的量。其结果可以为迹象、症状或病因的消减和/或缓解或生物系统的任何其它所需变化。例如，用于治疗的“有效量”是在临床上提供显著的病症缓解效果所需的包含本文公开化合物的组合物的量。可使用诸如剂量递增试验的技术测定适合于任意个体病例中的有效量。
本发明使用的术语“多晶型物”或“多晶型(现象)”是指本发明的化合物具有多种晶型格形态，本发明的一些化合物可能有一个以上的晶体形式，本发明涵盖所有的多品型态或其混合物。
本发明化合物的中间体化合物及其多品形物也在本发明的范围内。
结晶经常产生本发明化合物的溶剂化物，本文所用术语“溶剂化物”是指由一个或多个本发明化合物分子和一个或多个溶剂分子组合成的合体。
溶剂可以是水，这种情况下，溶剂化物是水合物。另外还可以是有机溶剂。因此，本发明化合物可作为水合物存在，包括一水合物、二水合物、半水合物、三水合物、四水合物等，以及相应的溶剂化形态。本发明化合物可以是真溶剂化物，但在其它一些情况下，本发明化合物也可能只是偶然保留了水或水跟一些其它溶剂的混合物本发明化合物可在一种溶剂中反应或在一种溶剂中沉淀或结晶。本发明化合物的溶剂化物也包括在本发明的范围内。
本文所用的跟制剂，组合物或成分相关的术语“可接受的”是指对治疗主体的总体健康没有持续的有害影响。
本文所用术语“药学上可接受的”是指不影响本发明化合物的生物活性或性质的物质(如载体或稀释剂)，并且相对无毒，即该物质可施用于个体而不造成不良的生物反应或以不良方式与组合物中包含的任意组分相互作用。
“药学上可接受的载体”包括但不限于已经被相关政府行政部门批准的可以被用于人类和驯养动物的佐剂、载体、赋形剂、助剂、脱臭剂、稀释剂、保鲜剂、染料/着色剂、风味增强剂、表面活性剂和润湿剂、分散剂、悬浮剂、稳定剂等渗剂、溶剂、或乳化剂。
文所用术语“主体”、“患者”、“对象”或“个体”是指患有疾病、紊乱或病症等的个体，包括哺乳动物和非哺乳动物，哺乳动物的实例包括但不限于哺乳动物纲的任何成员：人，非人的灵长类动物(例如黑猩猩和其它猿类和猴)；家畜，例如牛，马、绵羊，山羊，猪；家养动物，例如兔，狗和猫；实验室动物，包括啮齿类动物，如大鼠、小鼠和豚鼠等。非人哺乳动物的实例包括但不限于鸟类和鱼类等。在本文提供的一个有关方法和组合物的实施方案中，所述哺乳动物为人。
本文所用术语“治疗”是指对哺乳动物特别是人类的相关疾病病症的治疗，包括
(i)预防哺乳动物，特别是之前已经暴露在某个疾病或病症下但尚未被诊断患有该疾病或病症的哺乳动物，产生相应的疾病或病症；
(ii)抑制疾病或病症，即，控制其发展；
(iii)缓解疾病或病症，即，使疾病或病症消退缓；
(iv)缓解疾病或病症引起的症状。
本文所用术语“疾病”和“病症”可以互相替代，也可以是不同意思，因为某些特定疾病或病症还没有已知的致病因子(所以发病原因尚不清楚)，所以还不能被认作疾病而只能被看做不想要的状况或综合症，所述综合症或多或少有一些具体症状已经被临床研究人员证实。
本文所用术语“服用”、“施用”、“给药”等是指能够将化合物或组合物递送到进行生物作用的所需位点的方法这些方法。包括但不限于口服途径、经十二指肠途径、胃肠外注射(包括静脉内、皮下、腹膜内、肌内、动脉内注射或输注)、局部给药和经直肠给药。在优选的实施方案中，本文讨论的化合物和组合物通过口服施用。
合成方法
本发明还提供制备所述化合物的方法。本发明通式(I)所述化合物的制备，可通过以下示例性方法和实施例完成，但这些方法和实施例不应以任何方式被认为是对本发明范围的限制。也可地本领域技术人员所知的合成技术合成本发明所述的化合物，或者综合使用本领域已知方法和本发明所述的方法。每步应所得的产物用本领域已知的分离技术得到，包括但不限于萃取、过滤、蒸馏、结晶、色谱分离等。合成所需要的起始原料和化学试剂可以根据文献(reaxys)常规合成或购买。
本发明通式(I)所述杂环类化合物可按照方法A所述路线合成：1、起始物A1与芳基硼酸通过suzuki偶联得到A2；2、A2与前体U-Y-P(其中U-Y-P为含有带保护胺基的官能团，P为胺基的保护基)在碱作用下发生取代反应生成A3；3、A3中胺基去保护得到A4；4、A4中的胺基被含有和激酶配体结合域内半胱胺酸残基反应的功能团的化学试剂(例如，烯丙酰氯等)衍生得到通式(I)所述化合物。
方法A：
也可以按照方法B所述路线合成，起始物A1与前体U-Y-P(其中U-Y-P为含有带保护胺基的官能团，P为胺基的保护基)在碱作用下发生取代反应生成B1；B1与芳基硼酸通过suzuki偶联得到A3，再用方法A的方法，得到通式(I)所述化合物。
方法B
也可以按照方法C所述路线合成，起始物C1与SEMCl在碱作用下上SEM保护基生成C2；C2与前体L-U-Y-P(其中L为离去基团，U-Y-P为含有带保护胺基的官能团，P为胺基的保护基)在碱作用下发生取代反应生成C3，可与一带有羟基的前体(HO-U-Y-P)通过光延反应(mitsunobu反应)得到C3，除去保护基得到A4，再用方法A的方法，得到通式(I)所述化合物。
方法C
除非另有说明，温度是摄氏温度。试剂购自Chem blocks Inc、Astatech Inc或麦克林等商业供应商，并且这些试剂可直接使用无需进一步纯化，除非另有说明。
除非另有说明，下列反应在室温、无水溶剂中、氮气或气的正压下或使用干燥管进行；玻璃器皿烘干和/或加热干燥。
除非另有说明，柱色谱纯化使用青岛海洋化工厂的200-300目硅胶；制备薄层色谱使用烟台市化学工业研究所生产的薄层色谱硅胶预制板(HSGF254)；MS的测定用ThernoLCD Fleet型(ESI)液相色谱-质谱联用仪。
核磁数据(1H NMR)使用Bruker Avance-400MHz或Varian Oxford-400Hz核磁仪，核磁数据使用的溶剂有CDCl3、CD3OD、D2O、DMS-d6等，以四甲基硅烷(0.000ppm)为基准或以残留溶剂为基准(CDCl3:7.26ppm；CD3OD:3.31ppm；D2O:4.79ppm；d6-DMSO:2.50ppm)当标明峰形多样性时，以下简写表示不同峰形：s(单峰)、d(双重峰)、t(三重峰)、q(四重峰)、m(多重峰)、br(宽峰)、dd(双双重峰)、dt(双三重峰)。如果给出了耦合常数，则以Hertz(Hz)为单位。
实施例1：(S)-4-(4-(3-(丁-2-炔酰胺基哌啶)-1-基)-7H-吡咯[2,3-d]嘧啶-5-基)-N-(吡啶-2-基)苯甲酰胺(化合物1)的制备
步骤1：化合物1b的合成
将(S)-3-Boc-氨基哌啶(2.40g，12mmol)、4-溴-7H-吡咯并[2,3-D]嘧啶(1.98g，10mmol)、碳酸铯(6.52g，20mmol)和BINAP(0.62g，1mmol)溶于1.4-二氧六环(50mL)中，然后向混合物通过鼓泡氮气脱气5min。再向反应物添加Pd2(dba)3(0.46g，0.5mmol)，回流搅拌反应混合物24小时。反应完毕后，用乙酸乙酯稀释反应混合物，再用水和饱和食盐水洗涤，无水硫酸钠干燥，有机相减压蒸干。残余物通过硅胶短柱，乙酸乙酯淋洗。然后乙腈重结晶得到中间体1b(2.70g，85％)。LC/MS(ESI):m/z＝218.1[M+H]+.
步骤2：化合物1c的合成
于反应瓶中加入化合物1b(1.59g,5mmol)，N,N-二甲基甲酰胺20mL，分批次加入NBS(1.34g,7.5mmol)，搅拌下80℃反应过夜。冷却至室温，反应液倒入100mL水中，用乙酸乙酯萃取。所得有机相再用饱和食盐水洗涤，无水硫酸钠干燥，有机相减压蒸干。残余物通过柱层析纯化，得到化合物1c(1.45g，产率73％)为黄色固体。LC/MS(ESI):m/z＝296.1[M+H]+.
步骤3：化合物1d的合成
将上一步中间体1c(1.19g，3mmol)、4-(吡啶-2-基)甲酰氨苯基硼酸(1.45g，6mmol)和磷酸三钾一水合物(10.56g，9mmol)溶解于二氧六环(10mL)和水(4mL)中。多次抽换氮气后，添加四(三苯基膦)钯(0.53g，0.45mmol)。用氮气将混合物再喷洒5分钟，然后回流加热24小时。将反应物冷却至室温并搅拌过夜，得到淡黄色沉淀物。用水稀释反应混合物，并通过过滤收集固体。粗产物用甲醇打浆，然后得到米黄色固体1d(1.20g,78％)，无需再纯化进行下一反应，LC/MS(ESI):m/z＝414.2[M+H]+。
步骤4：化合物1e的合成
于反应瓶中加入上一步中间体1d(1.03g,2.0mmol)，4mL乙酸乙酯，4N HCl的1,4-二氧六环溶液4ml。室温下搅拌2小时，反应液用1N氢氧化钠溶液中和，乙酸乙酯萃取。所得有机相再用饱和碳酸氢钠和饱和食盐水洗涤，无水硫酸钠干燥，有机相减压蒸干。得到化合物1e(0.77g，产率93％)，直接用于下一步，LC/MS(ESI):m/z＝414.2[M+H]+。
步骤5：化合物1的合成
于反应瓶中加入化合物1e(413mg,1.0mmol)，三乙胺(152mg,1.5mmol)，4mL四氢呋喃，冰水浴冷却后缓慢滴加丁-2-炔酰氯(136mg,1.5mmol)的0.5mL四氢呋喃溶液。加完后继续搅拌4小时。反应液用甲醇淬灭反应并减压蒸干。残余物通过柱层析纯化，得到化合物1(182mg，产率38％)为黄色固体。1H NMR(400MHz,DMSO-d6)δ:12.03(s,1H),10.45(s,1H),8.72(d,1H),8.45(s,1H),8.41-8.39(m,2H),8.06(s,1H),7.95-7.92(m,2H),7.75-7.48(m,3H),6.21(d,1H),4.01-3.88(s,1H),3.21-2.89(m,3H),2.82-2.72(m,1H),1.97(s,3H),1.88-1.81(m,1H),1.74-1.69(m,2H),1.35-1.29(m,1H)；LC/MS(ESI):m/z＝480.2[M+H]+.
实施例2：(S)-4-(4-(3-(丁-2-炔酰胺基哌啶)-1-基)-7H-吡咯[2,3-d]嘧啶-5-基)-N-(吡啶-3-基)苯甲酰胺(化合物2)的制备
用与实施例1相似的方法(中间体换为4-(吡啶-3-基)甲酰氨苯基硼酸)得到化合物2(173mg，产率36％)为黄色固体。1H NMR(400MHz,DMSO-d6)δ:12.03(s,1H),10.45(s,1H),8.93(s,1H),8.45(s,1H),8.31(dd,1H),8.21-8.18(m,1H),8.06-7.98(m,2H),7.64-7.36(m,4H),6.22(d,1H),4.01-3.88(s,1H),3.21-2.89(m,3H),2.82-2.72(m,1H),1.97(s,3H),1.88-1.81(m,1H),1.74-1.69(m,2H),1.35-1.29(m,1H)；LC/MS(ESI):m/z＝480.2[M+H]+.
实施例3：(S)-4-(4-(3-(丁-2-炔酰胺基哌啶)-1-基)-7H-吡咯[2,3-d]嘧啶-5-基)-N-(嘧啶-2-基)苯甲酰胺(化合物3)的制备
用与实施例1相似的方法(中间体换为4-(嘧啶-2-基)甲酰氨苯基硼酸)得到化合物3(207mg，产率43％)为黄色固体。1H NMR(400MHz,DMSO-d6)δ:12.03(s,1H),10.45(s,1H),8.45(s,1H),8.41(d,2H),8.06(s,1H),8.01-7.98(m,1H),7.65-7.36(m,3H),6.98-6.96(m,1H),6.22(d,1H),4.01-3.88(s,1H),3.21-2.89(m,3H),2.82-2.72(m,1H),1.97(s,3H),1.88-1.81(m,1H),1.74-1.69(m,2H),1.35-1.29(m,1H)；LC/MS(ESI):m/z＝481.2[M+H]+.
实施例4：(S)-4-(4-(3-(丁-2-炔酰胺基哌啶)-1-基)-7H-吡咯[2,3-d]嘧啶-5-基)-N-(吡嗪-2-基)苯甲酰胺(化合物4)的制备
用与实施例1相似的方法(中间体换为4-(吡嗪-2-基)甲酰氨苯基硼酸)得到化合物4(168mg，产率35％)为黄色固体。1H NMR(400MHz,DMSO-d6)δ:12.03(s,1H),10.45(s,1H),8.58(s,1H),8.45(s,1H),8.38-8.35(m,2H),8.06(s,1H),8.01-7.98(m,1H),7.67-7.36(m,3H),6.22(d,1H),4.01-3.88(s,1H),3.21-2.89(m,3H),2.82-2.72(m,1H),1.97(s,3H),1.88-1.81(m,1H),1.74-1.69(m,2H),1.35-1.29(m,1H)；LC/MS(ESI):m/z＝481.2[M+H]+.
实施例5：(R)-4-(4-(3-(丁-2-炔酰胺基哌啶)-1-基)-7H-吡咯[2,3-d]嘧啶-5-基)-N-(吡啶-2-基)苯甲酰胺(化合物5)的制备
用与实施例1相似的方法(中间体换为(R)-3-Boc-氨基哌啶)得到化合物5(187mg，产率39％)为黄色固体。1H NMR(400MHz,DMSO-d6)δ:12.03(s,1H),10.45(s,1H),8.72(d,1H),8.45(s,1H),8.41-8.39(m,2H),8.06(s,1H),7.95-7.92(m,2H),7.75-7.48(m,3H),6.21(d,1H),4.01-3.88(s,1H),3.21-2.89(m,3H),2.82-2.72(m,1H),1.97(s,3H),1.88-1.81(m,1H),1.74-1.69(m,2H),1.35-1.29(m,1H)；LC/MS(ESI):m/z＝480.2[M+H]+.
实施例6：(R)-4-(4-(3-(丁-2-炔酰胺基哌啶)-1-基)-7H-吡咯[2,3-d]嘧啶-5-基)-N-(吡啶-3-基)苯甲酰胺(化合物6)的制备
用与实施例2相似的方法(中间体换为(R)-3-Boc-氨基哌啶)得到化合物2(196mg，产率41％)为黄色固体。1H NMR(400MHz,DMSO-d6)δ:12.03(s,1H),10.45(s,1H),8.93(s,1H),8.45(s,1H),8.31(dd,1H),8.21-8.18(m,1H),8.06-7.98(m,2H),7.64-7.36(m,4H),6.22(d,1H),4.01-3.88(s,1H),3.21-2.89(m,3H),2.82-2.72(m,1H),1.97(s,3H),1.88-1.81(m,1H),1.74-1.69(m,2H),1.35-1.29(m,1H)；LC/MS(ESI):m/z＝480.2[M+H]+.
实施例7：(R)-4-(4-(3-(丁-2-炔酰胺基哌啶)-1-基)-7H-吡咯[2,3-d]嘧啶-5-基)-N-(嘧啶-2-基)苯甲酰胺(化合物7)的制备
用与实施例3相似的方法(中间体换为(R)-3-Boc-氨基哌啶)得到化合物3(227mg，产率45％)为黄色固体。1H NMR(400MHz,DMSO-d6)δ:12.03(s,1H),10.45(s,1H),8.45(s,1H),8.41(d,2H),8.06(s,1H),8.01-7.98(m,1H),7.65-7.36(m,3H),6.98-6.96(m,1H),6.22(d,1H),4.01-3.88(s,1H),3.21-2.89(m,3H),2.82-2.72(m,1H),1.97(s,3H),1.88-1.81(m,1H),1.74-1.69(m,2H),1.35-1.29(m,1H)；LC/MS(ESI):m/z＝481.2[M+H]+.
实施例8：(R)-4-(4-(3-(丁-2-炔酰胺基哌啶)-1-基)-7H-吡咯[2,3-d]嘧啶-5-基)-N-(吡嗪-2-基)苯甲酰胺(化合物8)的制备
用与实施例4相似的方法(中间体换为(R)-3-Boc-氨基哌啶)得到化合物8(192mg，产率38％)为黄色固体。1H NMR(400MHz,DMSO-d6)δ:12.03(s,1H),10.45(s,1H),8.58(s,1H),8.45(s,1H),8.38-8.35(m,2H),8.06(s,1H),8.01-7.98(m,1H),7.67-7.36(m,3H),6.22(d,1H),4.01-3.88(s,1H),3.21-2.89(m,3H),2.82-2.72(m,1H),1.97(s,3H),1.88-1.81(m,1H),1.74-1.69(m,2H),1.35-1.29(m,1H)；LC/MS(ESI):m/z＝481.2[M+H]+.
实施例9：(R)-N-(1-(5-(4-苯氧基苯基)-7H-吡咯[2,3-d]嘧啶-4-基)吡咯烷-3-基)丙烯酰胺(化合物9)的制备
用与实施例1相似的方法(中间体换为(R)-3-Boc-氨基吡咯烷和4-苯氧基苯硼酸和丙烯酰氯)得到化合物9(206mg，产率46％)为黄色固体。1H NMR(400MHz,DMSO-d6)δ:12.05(s,1H),8.45(d,1H),8.06(s,1H),7.43-7.08(m,9H),6.49(d,1H),6.33-6.20(m,1H),6.14-6.04(m,1H),5.58(dd,1H),4.45-4.30(m,1H),3.30-3.22(m,2H),3.14-2.97(m,2H),2.38-2.23(m,2H)；LC/MS(ESI):m/z＝426.2[M+H]+.
实施例10：(R)-N-(1-(5-(4-苯氧基苯基)-7H-吡咯[2,3-d]嘧啶-4-基)吡咯烷-3-基)-丁-2-炔酰胺(化合物10)的制备
用与实施例9相似的方法(中间体换为丁-2-炔酰氯)得到化合物9(179mg，产率39％)为黄色固体。1H NMR(400MHz,DMSO-d6)δ:12.05(s,1H),8.45(d,1H),8.06(s,1H),7.41-7.06(m,9H),6.42(d,1H),4.43-4.21(m,1H),3.26-3.20(m,2H),3.12-2.94(m,2H),2.38-2.19(m,2H),1.97(s,3H)；LC/MS(ESI):m/z＝438.2[M+H]+.
实施例11：(R)-N-(1-(5-(4-苯氧基苯基)-7H-吡咯[2,3-d]嘧啶-4-基)哌啶-3-基)-丁-2-炔酰胺(化合物11)的制备
用与实施例10相似的方法(中间体换为(R)-3-Boc-氨基哌啶)得到化合物11(175mg，产率37％)为黄色固体。1H NMR(400MHz,DMSO-d6)δ:12.08(s,1H),8.47(s,1H),8.07(s,1H),7.41-7.05(m,9H),4.02(m,1H),3.19-2.88(m,3H),2.80-2.73(m,1H),1.98(s,3H),1.88-1.80(m,1H),1.73-1.67(m,2H),1.36-1.31(m,1H)；LC/MS(ESI):m/z＝452.2[M+H]+.
实施例12：(R)-N-(1-(3-(4-苯氧基苯基)-1H-吡唑[3,4-d]嘧啶-4-基)哌啶-3-基)-丁-2-炔酰胺(化合物12)的制备
用与实施例11相似的方法(原料换为4-溴-1H-吡唑并[3,4-D]嘧啶)得到化合物12(199mg，产率42％)为黄色固体。1H NMR(400MHz,DMSO-d6)δ:13.83(s,1H),8.48(s,1H),8.23(d,1H),7.41-7.07(m,9H),3.98-3.81(s,1H),3.22-2.88(m,3H),2.82-2.69(m,1H),1.98(s,3H),1.89-1.83(m,1H),1.72-1.66(m,2H),1.35-1.29(m,1H)；LC/MS(ESI):m/z＝453.2[M+H]+.
实施例13：4-(4-(1-丙烯酰基哌啶-4-基)-7H-吡咯[2,3-d]嘧啶-5-基)-N-(吡啶-2-基)苯甲酰胺(化合物13)的制备
步骤1：化合物13b的合成
将4-溴-7H-吡咯并[2,3-D]嘧啶(1.98g，10mmol)、N-Boc-1,2,5,6-四氢吡啶-4-硼酸频哪醇酯(4.62g，15mmol)、碳酸钾(4.14g，30mmol)、四(三苯基膦)钯(0.58g，0.5mmol)、1,4-二氧六环(120mL)和水(30mL)混合后，在氮气保护加热回流，搅拌反应24小时。将反应物冷却至室温,减压蒸溶，通过柱层析纯化得到淡黄色固体13b(1.35g,45％)。LC/MS(ESI):m/z＝201.1[M+H]+.
步骤2：化合物13c的合成
将上一步化合物13b(1.20g，4mmol)溶于乙酸乙酯(10mL)和甲醇(10mL)中的溶液中添加10％Pd/C(0.2g)，并且用氢气将反应物脱气6次，然后在氢气氛下在室温下搅拌12h。过滤溶液，将滤液蒸发成棕色固体的粗产物13c(1.16g,96％)，无需再纯化直接下一步反应，LC/MS(ESI):m/z＝203.1[M+H]+.
后续步骤3-6参照实施例1中类似反应。得到化合物13(184mg，产率41％)为黄色固体。1H NMR(400MHz,DMSO-d6)δ:12.05(s,1H),10.43(s,1H),8.73(d,1H),8.46(s,1H),8.42-8.39(m,2H),8.05(s,1H),7.97-7.94(m,2H),7.75-7.48(m,3H),6.28(dd,1H),6.07(dd,1H),5.45(dd,1H),3.25-2.95(m,4H),2.71-2.64(m,1H),1.84-1.45(m,4H)；LC/MS(ESI):m/z＝453.2[M+H]+.
实施例14：1-(4-(5-(4-苯氧基苯基)-7H-吡咯[2,3-d]嘧啶-4-基)-哌啶-1-基)-2-丙烯基-1-酮(化合物14)的制备
用与实施例13相似的方法(中间体换为4-苯氧基苯基硼酸)得到化合物14(198mg，产率47％)为黄色固体。1H NMR(400MHz,DMSO-d6)δ:12.05(s,1H),8.45(s,1H),8.04(s,1H),7.43-7.08(m,9H),6.28(dd,1H),6.07(dd,1H),5.45(dd,1H),3.28-2.92(m,4H),2.72-2.65(m,1H),1.85-1.45(m,4H)；LC/MS(ESI):m/z＝425.2[M+H]+.
实施例15：4-(4-(1-丙烯酰基哌啶-3-基)-7H-吡咯[2,3-d]嘧啶-5-基)-N-(吡啶-2-基)苯甲酰胺(化合物15)的制备
用与实施例13相似的方法(中间体换为N-Boc-3,4-二氢吡啶-5-硼酸频哪醇酯)得到化合物15(193mg，产率43％)为黄色固体。1H NMR(400MHz,DMSO-d6)δ:12.05(s,1H),10.43(s,1H),8.73(d,1H),8.46(s,1H),8.42-8.39(m,2H),8.05(s,1H),7.97-7.94(m,2H),7.75-7.48(m,3H),6.33(dd,1H),6.12(dd,1H),5.51(dd,1H),3.82-3.65(m,2H),3.52-3.35(m,2H),2.76-2.71(m,1H),1.91-1.45(m,4H)；LC/MS(ESI):m/z＝453.2[M+H]+.
实施例16：1-(3-(5-(4-苯氧基苯基)-7H-吡咯[2,3-d]嘧啶-4-基)-哌啶-1-基)-2-丙烯基-1-酮(化合物16)的制备
用与实施例15相似的方法(中间体换为4-苯氧基苯基硼酸)得到化合物16(175mg，产率39％)为黄色固体。1H NMR(400MHz,DMSO-d6)δ:12.05(s,1H),8.45(s,1H),8.04(s,1H),7.43-7.08(m,9H),6.32(dd,1H),6.10(dd,1H),5.51(dd,1H),3.82-3.66(m,2H),3.53-3.35(m,2H),2.76-2.70(m,1H),1.91-1.43(m,4H)；LC/MS(ESI):m/z＝425.2[M+H]+.
实施例17：4-(4-(1-丙烯酰基哌啶-4-基)-1H-吡咯[2,3-b]吡啶-3-基)-N-(吡啶-2-基)苯甲酰胺(化合物17)的制备
用与实施例13相似的方法(原料换为4-溴-1H-吡咯并[2,3-b]吡啶)得到化合物17(193mg，产率43％)为黄色固体。1H NMR(400MHz,DMSO-d6)δ:11.62(s,1H),10.43(s,1H),8.73(d,1H),8.42-8.39(m,2H),8.10(d,1H),7.97-7.94(m,2H),7.75-7.48(m,3H),7.18(s,1H),6.98(d,1H),6.28(dd,1H),6.07(dd,1H),5.45(dd,1H),3.25-2.95(m,4H),2.71-2.64(m,1H),1.84-1.45(m,4H)；LC/MS(ESI):m/z＝452.2[M+H]+.
实施例18：1-(4-(3-(4-苯氧基苯基)-1H-吡咯[2,3-b]吡啶-4-基)-哌啶-1-基)-2-丙烯基-1-酮(化合物18)的制备
用与实施例14相似的方法(原料换为4-溴-1H-吡咯并[2,3-b]吡啶)得到化合物18(188mg，产率45％)为黄色固体。1H NMR(400MHz,DMSO-d6)δ:11.65(s,1H),8.11(d,1H),7.43-7.08(m,9H),7.19(s,1H),7.00(d,1H),6.28(dd,1H),6.07(dd,1H),5.45(dd,1H),3.27-2.90(m,4H),2.72-2.64(m,1H),1.84-1.43(m,4H)；LC/MS(ESI):m/z＝424.2[M+H]+.
实施例19：4-(4-(1-丙烯酰基哌啶-3-基)-1H-吡咯[2,3-b]吡啶-3-基)-N-(吡啶-2-基)苯甲酰胺(化合物19)的制备
用与实施例15相似的方法(原料换为4-溴-1H-吡咯并[2,3-b]吡啶)得到化合物19(175mg，产率39％)为黄色固体。1H NMR(400MHz,DMSO-d6)δ:11.62(s,1H),10.43(s,1H),8.73(d,1H),8.43-8.39(m,2H),8.12(d,1H),7.98-7.94(m,2H),7.75-7.47(m,3H),7.18(s,1H),6.99(d,1H),6.33(dd,1H),6.12(dd,1H),5.51(dd,1H),3.82-3.65(m,2H),3.52-3.35(m,2H),2.76-2.71(m,1H),1.91-1.45(m,4H)；LC/MS(ESI):m/z＝452.2[M+H]+.
实施例20：1-(3-(3-(4-苯氧基苯基)-1H-吡咯[2,3-b]吡啶-4-基)-哌啶-1-基)-2-丙烯基-1-酮(化合物20)的制备
用与实施例17相似的方法(中间体换为N-Boc-2,3-二氢吡咯-4-硼酸频哪醇酯)得到化合物20(204mg，产率47％)为黄色固体。1H NMR(400MHz,DMSO-d6)δ:11.62(s,1H),10.43(s,1H),8.73(d,1H),8.43-8.39(m,2H),8.12(d,1H),7.98-7.94(m,2H),7.75-7.47(m,3H),7.18(s,1H),6.99(d,1H),6.32(dd,1H),6.12(dd,1H),5.52(dd,1H),3.93-3.75(m,2H),3.58-3.41(m,2H),2.96-2.89(m,1H),2.11-1.85(m,2H)；LC/MS(ESI):m/z＝438.2[M+H]+.
实施例21：(R)-4-(4-(3-(丁-2-炔酰胺基吡咯烷)-1-基)-7H-吡咯[2,3-d]嘧啶-5-基)-N-(吡啶-2-基)苯甲酰胺(化合物21)的制备
用与实施例1相似的方法(中间体换为(R)-3-Boc-氨基吡咯烷)得到化合物21(179mg，产率39％)为黄色固体。1H NMR(400MHz,DMSO-d6)δ:12.03(s,1H),10.45(s,1H),8.72(d,1H),8.46(s,1H),8.41-8.39(m,2H),8.06(s,1H),7.95-7.90(m,2H),7.75-7.46(m,3H),6.22(d,1H),4.44-4.30(m,1H),3.30-3.23(m,2H),3.14-2.98(m,2H),2.36-2.23(m,1H),1.99(s,3H),1.84-1.78(m,1H)；LC/MS(ESI):m/z＝466.2[M+H]+.
实施例22：(S)-4-(4-(3-(丁-2-炔酰胺基吡咯烷)-1-基)-7H-吡咯[2,3-d]嘧啶-5-基)-N-(吡啶-2-基)苯甲酰胺(化合物22)的制备
用与实施例1相似的方法(中间体换为(S)-3-Boc-氨基吡咯烷)得到化合物22(193mg，产率42％)为黄色固体。1H NMR(400MHz,DMSO-d6)δ:12.03(s,1H),10.45(s,1H),8.72(d,1H),8.46(s,1H),8.41-8.39(m,2H),8.06(s,1H),7.95-7.90(m,2H),7.75-7.46(m,3H),6.22(d,1H),4.44-4.30(m,1H),3.30-3.23(m,2H),3.14-2.98(m,2H),2.36-2.23(m,1H),1.99(s,3H),1.84-1.78(m,1H)；LC/MS(ESI):m/z＝466.2[M+H]+.
实施例23：4-(4-(3-丙烯酰基氮杂环丁烷-1-基)-7H-吡咯[2,3-d]嘧啶-5-基)-N-(吡啶-2-基)苯甲酰胺(化合物23)的制备
用与实施例1相似的方法(中间体换为3-Boc-氨基氮杂环丁烷和丙烯酰氯)得到化合物23(139mg，产率32％)为黄色固体。1H NMR(400MHz,DMSO-d6)δ:12.05(s,1H),10.43(s,1H),8.73(d,1H),8.46(s,1H),8.42-8.39(m,2H),8.05(s,1H),7.97-7.94(m,2H),7.75-7.48(m,3H),6.52(d,1H),6.32-6.21(m,1H),6.14-6.05(m,1H),5.57(dd,1H),4.47-4.35(m,1H),3.98-3.91(m,2H),3.67-3.59(m,2H)；LC/MS(ESI):m/z＝440.2[M+H]+.
实施例24：4-(4-((1-丙烯酰基氮杂环丁烷-3-甲氨基)-7H-吡咯[2,3-d]嘧啶-5-基)-N-(吡啶-2-基)苯甲酰胺(化合物24)的制备
用与实施例1相似的方法(中间体换为1-Boc-3-氨甲基氮杂环丁烷和丙烯酰氯)得到化合物24(157mg，产率35％)为黄色固体。1H NMR(400MHz,DMSO-d6)δ:12.05(s,1H),10.43(s,1H),8.73(d,1H),8.46(s,1H),8.42-8.39(m,2H),8.05(s,1H),7.97-7.94(m,2H),7.75-7.48(m,3H),6.38(dd,1H),6.15(dd,1H),5.72(s,1H),5.47(dd,1H),4.11-4.02(m,2H),3.87-3.83(m,2H),3.07-2.96(m,2H),2.53-2.47(m,1H)；LC/MS(ESI):m/z＝454.2[M+H]+.
实施例25：4-(4-(3-丙烯酰基氮杂环丁烷-1-基)-7H-吡咯[2,3-d]嘧啶-5-基)-N-(吡啶-2-基)苯甲酰胺(化合物25)的制备
用与实施例1相似的方法(中间体换为1-Boc-3-氨甲基吡咯烷和丙烯酰氯)得到化合物25(194mg，产率42％)为黄色固体。1H NMR(400MHz,DMSO-d6)δ:12.05(s,1H),10.43(s,1H),8.73(d,1H),8.46(s,1H),8.42-8.39(m,2H),8.05(s,1H),7.97-7.94(m,2H),7.75-7.48(m,3H),6.38(dd,1H),6.17(dd,1H),5.73(s,1H),5.43(dd,1H),3.65-3.25(m,4H),3.14-2.92(m,2H),1.95-1.63(m,3H)；LC/MS(ESI):m/z＝468.2[M+H]+.
实施例26：4-(4-(3-丙烯酰基氮杂环丁烷-1-基)-7H-吡咯[2,3-d]嘧啶-5-基)-N-(吡啶-2-基)苯甲酰胺(化合物26)的制备
用与实施例1相似的方法(中间体换为1-Boc-3-氨甲基哌啶和丙烯酰氯)得到化合物26(176mg，产率37％)为黄色固体。1H NMR(400MHz,DMSO-d6)δ:12.05(s,1H),10.43(s,1H),8.73(d,1H),8.46(s,1H),8.42-8.39(m,2H),8.05(s,1H),7.97-7.94(m,2H),7.75-7.48(m,3H),6.42(dd,1H),6.19(dd,1H),5.75(s,1H),5.44(dd,1H),3.62-3.27(m,4H),3.08-2.92(m,2H),2.15-1.52(m,5H)；LC/MS(ESI):m/z＝482.2[M+H]+.
实施例27：4-(4-(3-丙烯酰基氮杂环丁烷-1-基)-7H-吡咯[2,3-d]嘧啶-5-基)-N-(吡啶-2-基)苯甲酰胺(化合物27)的制备
用与实施例1相似的方法(中间体换为1-Boc-4-氨甲基哌啶和丙烯酰氯)得到化合物27(186mg，产率39％)为黄色固体。1H NMR(400MHz,DMSO-d6)δ:12.05(s,1H),10.43(s,1H),8.73(d,1H),8.46(s,1H),8.42-8.39(m,2H),8.05(s,1H),7.97-7.94(m,2H),7.75-7.48(m,3H),6.42(dd,1H),6.19(dd,1H),5.75(s,1H),5.44(dd,1H),3.65-3.27(m,4H),3.12-2.93(m,2H),2.19-1.61(m,5H)；LC/MS(ESI):m/z＝482.2[M+H]+.
实施例28：4-(4-(6-丙烯酰基-2,6-二氮杂螺[3.4]辛烷-2-基)-7H-吡咯[2,3-d]嘧啶-5-基)-N-(吡啶-2-基)苯甲酰胺(化合物28)的制备
用与实施例1相似的方法(中间体换为叔丁基2,6-二氮杂螺[3.4]辛烷-6-甲酸酯和丙烯酰氯)得到化合物27(203mg，产率43％)为黄色固体。1H NMR(400MHz,DMSO-d6)δ:12.05(s,1H),10.43(s,1H),8.74(d,1H),8.45(s,1H),8.42-8.39(m,2H),8.05(s,1H),7.97-7.94(m,2H),7.75-7.48(m,3H),6.32-6.23(m,1H),6.14-6.07(m,1H),5.52(dd,1H),3.67-3.48(m,4H),3.27-3.12(m,4H),2.11-1.73(m,2H)；LC/MS(ESI):m/z＝480.2[M+H]+.
实施例29：对激酶BTK、BTK(R28H)的体外活性抑制作用测试
1.1BTK抑制活性筛选
用激酶缓冲液(50mM HEPES、10mM MgCl2、2mM DTT、1mM EGTA、0.01％Tween 20)将350ng/uL的BTK母液进行稀释，按每孔加入6μL 1.67×的0.134ng/μL的工作液(终浓度为0.08ng/μL)，用纳升加样仪将DMSO溶解的不同化合物1-24加入到孔中，使化合物终浓度为1000nM-0.244nM，阳性药终浓度为50nM-0.0122nM，4倍梯度，共7个浓度，同时设空白对照孔(不含酶)与阴性对照孔(含酶，加溶媒DMSO)，设2个复孔。酶与化合物或溶媒反应30min后，将用激酶缓冲液配制好的5×的250μMATP(终浓度为50uM)与5×的0.5μM底物(终浓度为0.1μM，ULight-poly GT)，按1:1混合，按每孔4μL加入孔中；封板膜封板以后，室温反应2小时后，每孔加入5μL4×的8nM检测试剂(终浓度为2nM，Ab)，室温孵育1小时；PE仪器读板(激发620nm，发射665nm)。计算抑制率，并计算IC50值。测定结果见下表，其中“A”表示IC50≤100nM；“B”表示100<IC50≤500nM；“C”表示500<IC50≤2000nM。
| BTK | BTK | ||
| 样品编号 | IC<sub>50</sub>(nM) | 样品编号 | IC<sub>50</sub>(nM) |
| 1 | A | 15 | A |
| 2 | A | 16 | B |
| 3 | A | 17 | A |
| 4 | A | 18 | B |
| 5 | A | 19 | A |
| 6 | A | 20 | A |
| 7 | A | 21 | A |
| 8 | A | 22 | A |
| 9 | A | 23 | A |
| 10 | A | 24 | B |
| 11 | B | 25 | B |
| 12 | B | 26 | B |
| 13 | A | 27 | B |
| 14 | A | 28 | A |
Claims (10)
1.一种作为BTK抑制剂杂环类化合物，其特征在于，化合物、可药用的盐、多晶型物或异构体，
其中：
X1，X2，X3，X4可以独立地选自N、CR1；
Ar1和Ar2独立地选苯环或者5-6元杂芳环，其中上述的苯环和杂芳环任选被一个或多个G1所取代；
R1独立地选自H、D、氰基、卤素、C1-6烷基、COOH、CONH2、NHCOH、CONHR2、OR2或-NHR2；
R2独立地选自H、D、氰基、卤素、C1-6烷基、C3-6环烷基、3-6元杂环烷基、-OR3、-NR3R4、-C(O)NR3R4，其中所述的烷基、环烷基或杂环烷基任选被氰基、卤素、-OR5、-NR5R6、C1-6烷基、C3-6环烷基或3-6元杂环烷基；
U和W独立地选自-C0-4烷基-、-CR7R8-、-C1-2烷基(R7)(OH)-、-C(O)-、-CR7R8O-、-OCR7R8-、-SCR7R8-、-CR7R8S-、-NR7-、-NR7C(O)-、-C(O)NR7-、-NR7C(O)NR8-、-CF2-、-O-、-S-、-S(O)m-、-NR7S(O)2-、-S(O)2NR7-；Y不存在或选C3-8环烷基、3-8元杂环烷基、5-12元稠烷基、5-12元稠杂环基、5-12元螺环基、5-12元螺杂环基、芳香基或者杂芳香基，其中所述环烷基、杂环烷基、螺环基、稠环基、稠杂环基、螺杂环基、芳香基或者杂芳香基任选被一个或多个G2所取代；
Z独立地选自氰基、-NR9CN、
键a为双键或者三键；
当a为双键时，Ra、Rb和Rc各自独立地选自H、D、氰基，卤素、C1-6烷基、C3-6环烷基或3-6元杂环基。其中所述烷基，环烷基和杂环基任选被1个或多个G3所取代；
Ra和Rb或Rb和Rc任选与它们连接的碳原子共同形成一任选含有杂原子的3-6元环；
当键a为三键时，Ra和Rc不存在，Rb独立选自H、D、氰基，卤素、C1-6烷基、C3-6环烷基或3-6元杂环基被一个或多个G4所取代；
R9独立地选自H、D、C1-6烷基、C3-6环烷基或3-6元杂环基，其中所述烷基，环烷基和杂环基任选被1个或多个G5所取代；
G1、G2、G3、G4和G5各自独立选自H、D、氰基，卤素、C1-6烷基、C2-6烯基、C2-6炔基、C3-8环烷基或3-8元杂环基、C6-10芳基、5-10元杂芳香基、-OR10、-OC(O)NR10R11、-C(O)OR10、-C(O)NR10R11、-C(O)R10、-NR10R11、-NR10C(O)R11、-NR10C(O)NR11R12、-S(O)mR10或-NR10S(O)mR11，其中所述烷基、烯基、炔基、环烷基、杂环烷基、芳香基、杂芳香基任选被1个或多个氰基，卤素、C1-6烷基、C2-6烯基、C2-6炔基、C3-8环烷基或3-8元杂环基、C6-10芳基、5-10元杂芳香基、-OR13、-OC(O)NR13R14、-C(O)OR13、-C(O)NR13R14、-C(O)R13、-NR13R14、-NR13C(O)R14、-NR13C(O)NR14R15、-S(O)mR13或-NR13S(O)mR14的取代基所取代；
R3、R4、R5、R6、R7、R8、R10、R11、R12、R13、R14和R15各自独立选自H、D、氰基、卤素、C1-6烷基、C3-8环烷基或3-8元单环杂环基、单环杂芳香基或者苯基；且
m为1或2。
2.根据权利要求1所述的一种作为BTK抑制剂杂环类化合物，其特征在于，所述多晶型物或异构体及其混合物形式。
3.根据权利要求1所述的一种作为BTK抑制剂杂环类化合物，其特征在于，其选自如下化合物
或可药用的盐、异构体及其混合和形式。
4.根据权利要求1或者3所述的一种作为BTK抑制剂杂环类化合物，其特征在于，包含Bruton's酪氨酸激酶抑制剂或其异构体、水合物、稳定同位素衍生物、溶剂化物、多晶型物、药学上可接受的盐，以及药学上可接受载体。
5.根据权利要求4所述的一种作为BTK抑制剂杂环类化合物，其特征在于，所述药物组合物为片剂、胶囊、颗粒剂、喷雾剂或者注射剂的形式。
6.根据权利要求4所述的一种作为BTK抑制剂杂环类化合物，其特征在于，所述药学上可接受的载体选自填充剂、崩解剂、粘合剂和润滑剂中的一种或多种。
7.权利要求1和或者3所述的一种作为BTK抑制剂杂环类化合物，其特征在于，Bruton's酪氨酸激酶抑制剂或其异构体、水合物、溶剂化物、多晶型物、药学上可接受的盐作为蛋白酪氨酸激酶抑制剂的用途。
8.根据权利要求7所述的一种作为BTK抑制剂杂环类化合物，其特征在于，所述蛋白酪氨酸激酶抑制剂为Bruton's酪氨酸激酶抑制剂。
9.权利要求6所述的一种作为BTK抑制剂杂环类化合物，其特征在于，新型Bruton's酪氨酸激酶抑制剂或其异构体、水合物、溶剂化物、多晶型物、药学上可接受的盐或者所述的药物组合物在治疗或者预防Bruton's酪氨酸激酶相关疾病的药物中的应用。
10.一种作为BTK抑制剂杂环类化合物的用途，其特征在于，所述Bruton's酪氨酸激酶相关疾病选自下组：
急性淋巴细胞白血病(ALL)、慢性粒细胞白血病(CML)、套细胞淋巴瘤(MCL)、大肠癌、类风湿关节炎、抗器官移植排异、抗牛皮癣、红斑狼疮等。
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| GB2515785A (en) * | 2013-07-03 | 2015-01-07 | Redx Pharma Ltd | Compounds |
| CN107556317A (zh) * | 2016-06-30 | 2018-01-09 | 杭州华东医药集团新药研究院有限公司 | 一种咪唑吡啶胺苯基衍生物及其用途 |
| CN114853723A (zh) * | 2021-02-03 | 2022-08-05 | 药雅科技(上海)有限公司 | 吲哚类化合物btk抑制剂的制备及其应用 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| GB2515785A (en) * | 2013-07-03 | 2015-01-07 | Redx Pharma Ltd | Compounds |
| CN107556317A (zh) * | 2016-06-30 | 2018-01-09 | 杭州华东医药集团新药研究院有限公司 | 一种咪唑吡啶胺苯基衍生物及其用途 |
| CN114853723A (zh) * | 2021-02-03 | 2022-08-05 | 药雅科技(上海)有限公司 | 吲哚类化合物btk抑制剂的制备及其应用 |
Non-Patent Citations (1)
| Title |
|---|
| FRANCESCA MUSUMECI，等: "Pyrrolo[2, 3-d]pyrimidines active as Btk inhibitors", 《EXPERT OPINION ON THERAPEUTIC PATENTS》, vol. 27, no. 12, pages 1305 - 1318, XP055465717, DOI: 10.1080/13543776.2017.1355908 * |
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