CN115181106B - 喹唑啉类krasg12d突变蛋白抑制剂的制备及其应用 - Google Patents
喹唑啉类krasg12d突变蛋白抑制剂的制备及其应用 Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- 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
- C07D487/08—Bridged systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及KRASG12D抑制剂及其用途,具体地,本发明提供一种式(I)所示化合物,式中各取代在的定义如说明书中所述。此外还涉及该抑剂的组合物及其应用。本发明化合物具有良好的抑制肿瘤增长的活性。并具有良好的安全性。
Description
技术领域
本发明属于药物合成领域,具体涉及一种喹唑啉类KRASG12D突变蛋白抑制剂的制备及其应用。
背景技术
RAS代表一组紧密相关的189个氨基酸(分子量21kDa)的单体球状蛋白,其与质膜相关,并结合GDP或GTPoRAS作为分子开关。当RAS含有结合的GDP时,它处于静止或关闭状态,并且处于“非活动状态”。响应细胞暴露于某些促进生长刺激时,RAS被诱导将其结合的GDP转换成GTP。与GTP结合后,RAS被“打开”,并且能够与其它蛋白(其“下游目标”)相互作用和激活其它蛋白。RAS蛋白本身具有非常低的内在能力,无法将GTP水解回GDP,从而使其自身处于关闭状态。关闭RAS需要称为GTPase激活蛋白(GAPs)的外在蛋白,该蛋白与RAS相互作用并大大加快GTP向GDP的转化。RAS中影响其与GAP相互作用或将GTP转换回GDP的能力的任何突变都将导致蛋白质的活化时间延长,从而导致细胞信号延长,使其继续生长和分裂。因为这些信号导致细胞生长和分裂,所以过度活跃的RAS信号可能最终导致癌症。
在结构上,RAS蛋白包含一个G结构域,该结构域负责RAS的酶促活性-鸟喋吟核背酸结合和水解(GTPase反应)。它还包含一个称为CAAX盒的C末端延伸,可进行翻译后修饰,并负责将蛋白质靶向膜。G结构域的大小约为21-25kDa,它包含一个磷酸盐结合环(P-环)。P-环为核昔酸在蛋白质中结合的口袋,这是具有保守氨基酸残基((甘氨酸12、苏氨酸26和赖氨酸16))的结构域的刚性部分,对于核昔酸结合和水解至关重要。G域还包含所谓的Switch I(残基30-40)和Switch II(残基60-76)区域,这两个区域都是蛋白质的动态部分,由于它们在能够在静止和负载状态间转换,其通常被称为“弹簧负载'机制。关键相互作用是苏氨酸35和甘氨酸60形成的氢键,具有GTP的Y-磷酸酯,其分别使Switch1和Switch2区域保持其活性构象。GTP水解并释放出磷酸盐后,这两个松弛为非活性的GDP构象。
RAS亚家族最著名的成员是HRAS,KRAS和NRAS,主要是因为它们与多种类型的癌症有关。RAS的三个主要同工型(HRAS,NRAS或KRAS)基因中的任何一种突变都是人类肿瘤发生中最常见。发现人类肿瘤中约有30%携带RAS基因突变o值得注意的是,KRAS突变在25-30%的肿瘤中检测到。相比之下,在NRAS和HRAS家族成员中发生的致癌突变率要低得多(分别为8%和3%)。在P环的残基G12和G13以及残基Q61处发现了最常见的KRAS突变。G12C和G12D是KRAS基因的频繁突变(甘氨酸12突变为半胱氨酸,甘氨酸12突变为天冬胺酸)。
作为前沿靶点,KRASG12C和KRASG12D突变蛋白受到了广泛关注。其中,KRASG12C抑制剂有许多正在临床中,如:安进公司的AMG-510(WO2018217651A1)和Mirati制药公司的MRTX-849(WO2019099524A1)。但是,KRASG12D突变蛋白目前也尚无对应的靶向药物。本发明满足此需要并提供其他相关优势。
发明内容
一种具有通式(I)所示的化合物、其立体异构体、可药用的盐、多晶型物或异构体,其中通式(I)所示的化合物结构如下:
其中,
每个R1在每次出现时独立地选自氘、卤素、氧代、-C1-6烷基、-C1-6亚烷基-(卤素)1-3、C1-6杂烷基、-CN、-OR6、-C1-6亚烷基-(OR6)1-3、-O-C1-6亚烷基-(卤素)1-3、-SR6、-S-C1-6亚烷基-(卤素)1-3、-NR6R7、-C1-6亚烷基-NR6R7、-C(=O)R6、-C(=O)OR6、-OC(=O)R6、-C(=O)NR6R7、-NR6C(=O)R7、-S(O)2NR6R7或-C3-6碳环基;每个R12独立地可选地被1、2、3、4、5或6个选自氘、卤素、-C1-6烷基、-C1-6烷氧基、氧代、-OR6、-NR6R7、-CN、-C(=O)R6、-C(=O)OR6、-OC(=O)R6、-C(=O)NR6R7、-NR6C(=O)R7或-S(O)2NR6R7的取代基取代或不取代;
每个L2在每次出现时独立地选自O、NH、CO或S;
每个环B是C3-10碳环,所述的可以连接在所述环A的相同的碳原子上或不同的原子上;
每个R2是-OR6、-NR6R7、-SR6、-S(=O)R6、-S(=O)2R6、5-10元杂芳基或3-10元杂环基,每个杂环基和杂芳基在每次出现时独立地包含1、2、3或4个选自N、O、S、S=O或S(=O)2的杂原子,每个R3在每次出现时独立地可选地被1、2、3、4、5或6个R19取代或不取代;
每个R3和R4在每次出现时独立地选自氘、氢、卤素、-C1-6烷基、、-C2-6烯基、-C2-6炔基、氧代、-OR6、-NR6R7、-CN、-C(=O)R6、-C(=O)OR6、-OC(=O)R6、-C(=O)NR6R7、-NR6C(=O)R7或-S(O)2NR6R7或-C3-10碳环基、每个杂环基和杂芳基在每次出现时独立地包含1、2、3或4个选自N、0、S、S=0或S(=O)2的杂原子;每个R3和R4在每次出现时独立地可选地被1、2、3、4、5或6个选自氘、卤素、氧代、-C1-6烷基、-C1-6烷氧基、氧代、-OR6、-NR6R7、-CN、-C(=O)R6、-C(=O)OR6、-OC(=O)R6、-C(=O)NR6R7、-NR6C(=O)R7或-S(O)2NR6R7的取代基取代或不取代;
每个R5在每次出现时独立地选自氘、卤素、氧代、-C1-6烷基、-C1-6亚烷基-(卤素)1-3、C1-6杂烷基、-CN、-OR6、-C1-6亚烷基-(OR6)1-3、-O-C1-6亚烷基-(卤素)1-3、-SR6、-S-C1-6亚烷基-(卤素)1-3、-NR6R7、-C1-6亚烷基-NR6R7、-C(=O)R6、-C(=O)OR6、-OC(=O)R6、-C(=O)NR6R7、-NR6C(=O)R7、-S(O)2NR6R7或-C3-6碳环基,每个杂环基和杂芳基在每次出现时独立地包含1、2、3或4个选自N、O、S、S=O或S(=O)2的杂原子;每个R3和R4在每次出现时独立地可选地被1、2、3、4、5或6个选自氘、卤素、氧代、-C1-6烷基、-C1-6烷氧基、氧代、-OR6、-NR6R7、-CN、-C(=O)R6、-C(=O)OR6、-OC(=O)R6、-C(=O)NR6R7、-NR6C(=O)R7或-S(O)2NR6R7的取代基取代或不取代;
每个R6和R7在每次出现时独立地选自氢或-C1-6烷基,每个R6和R7独立地可选地被1、2、3、4、5或6个R19取代或不取代;或R7和R7与它们共同连接的N原子一起形成3-10元杂环,所述的3-10元杂环可进一步包含1、2、3或4个选自N、O、S、S(=O)或S(=O)2的杂原子,且所述的3-10元杂环独立地可选地被1、2、3、4、5或6个R19取代或不取代;
每个R19在每次出现时独立地选自氘、卤素、氧代、-C1-6烷基、-C1-6亚烷基-(卤素)1-3、C1-6杂烷基、-CN、-OR6、-C1-6亚烷基-(OR6)1-3、-O-C1-6亚烷基-(卤素)1-3、-SR6、-S-C1-6亚烷基-(卤素)1-3、-NR6R7、-C1-6亚烷基-NR6R7、-C(=O)R6、-C(=O)OR6、-OC(=O)R6、-C(=O)NR6R7、-NR6C(=O)R7、-S(O)2NR6R7或-C3-6碳环基;
s选自0、1、2、3、4、5或6;
p选自0、1、2、3、4、5或6;
q选自0、1、2、3、4、5或6。
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G1所取代;
G1、和G2各自独立选自氘、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、-OR11、-OC(O)NR11R12、-C(O)OR11、-C(O)NR11R12、-C(O)R11、-NR11R12、-NR11C(O)R12、-NR11C(O)NR12R13、-S(O)mR11或-NR11S(O)mR12,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个或多个氘、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、-OR14、-OC(O)NR14R15、-C(O)OR14、-C(O)NR14R15、-C(O)R14、-NR14R15、-NR14C(O)R15、-NR14C(O)NR15R16、-S(O)mR14或-NR14S(O)nR15的取代基所取代;R8、R9、R11、R12、R13、R14和R15各自独立选自氢、氘、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;
每个A1在每次出现时独立地选自N,CR20;
R20独立地选自H、D、氰基、卤素、C1-6烷基、COOH、CONH2、NHCOH、CONH2、OH或-NH2。
在一些实施方式中,式(I)所述的化合物或者其异构体、溶剂合物或其前体,或它们的药学上可接受的盐选自以下化合物、其异构体、溶剂合物或其前体,或它们的药学上可接受的盐:
另一方面,本发明还提供药物组合物,其包含式(I)所示化合物或其药学可接受的盐和药学上可接受的辅料。
另一方面,本发明涉及治疗哺乳动物中与KRAS G12D查关疾病的方法,包括对需要该治疗的哺乳动物,优选人类,给予治疗有效量的式(I)所示化合物或其药学可接受的盐、或其药物组合物。
另一方面,本发明涉及式(I)所示化合物或其药学可接受的盐预防或治疗KRASG12D相关疾病的药物中的用途。
另一方面,本发明涉及预防或治疗KRAS G12D相关疾病的式(I)所示化合物或其药学可接受的盐、或其药物组合物。
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。
具体实施方法
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。
除非另有说明,温度是摄氏温度。试剂购自Chemblocks 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BrukerAvance-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。
中间体的制备
1-(1-吡咯烷基甲基)环丙烷-1-甲醇的制备
在冰/水浴冷却搅拌下,将草酰氯(12.5mL,2M)的二氯甲烷溶液加到环丙烷-1,1-二羧酸甲酯(2.90g,20mmol)溶于二氯甲烷(50mL)溶液中,然后加入DMF(100μl),搅拌反应约2小时。在室温下,得到淡黄色溶液。溶液浓缩成黄色半固体。在冰/水冷却搅拌下,将黄色半固体溶于(20mL THF中,然后缓慢添加吡咯烷(6mL,71mmol),并搅拌约60min。加入乙酸乙酯(150mL),用水(2x75mL)和饱和氯化钠水溶液(75mL)洗涤有机相。有机相经无水硫酸镁干燥,浓缩得到黄棕色油1-(吡咯烷-1-酰基)-环丙烷羧酸甲酯(2.0g,50%)。
在氮气保护和冰/水浴下,将四氢铝锂THF溶液(20mL,1M)缓慢添加到25mL THF的1-(吡咯烷-1-酰基)-环丙烷羧酸甲酯(2.0g,10mmol)溶液中,然后升至室温,将所得溶液搅拌反应3小时。冰/水浴冷却溶液,分批加入十水合硫酸钠(4.9g,15mmol),得到白色悬浮液。加入乙醚(25mL)并搅拌悬浮液约18小时。在室温下。通过硅藻土过滤所得悬浮液,并用乙醚(2x50mL)洗涤固体。合并滤液浓缩,残液经硅胶柱层析分离纯化(洗脱液:乙酸乙酯:石油醚=1:20~1:1),得到黄色油状化合物1-(吡咯烷-1-基甲基)环丙基-1-甲醇(1.15g,64%)。
LC/MS(ESI):m/z=156[M+H]+.
(R)-1-(3-氟吡咯烷-1-甲基)环丙烷-1-甲醇的制备
在冰/水浴冷却搅拌下,将草酰氯(12.5mL,2M)的二氯甲烷溶液加到环丙烷-1,1-二羧酸甲酯(2.90g,20mmol)溶于二氯甲烷(50mL)溶液中,然后加入DMF(100μl),搅拌反应约2小时。在室温下,得到淡黄色溶液。溶液浓缩成黄色半固体。在冰/水冷却搅拌下,将黄色半固体溶于(20mL THF中,然后缓慢添加(R)-3-氟吡咯烷(3.16g,40mmol),并搅拌约60min。加入乙酸乙酯(150mL),用水(2x75mL)和饱和氯化钠水溶液(75mL)洗涤有机相。有机相经无水硫酸镁干燥,浓缩得到黄棕色油(R)-1-(3-氟吡咯烷-1-酰基)-环丙烷羧酸甲酯(2.06g,48%)。
在氮气保护和冰/水浴下,将四氢铝锂THF溶液(20mL,1M)缓慢添加到25mL THF的(R)-1-(3-氟吡咯烷-1-酰基)-环丙烷羧酸甲酯(2.0g,9.3mmol)溶液中,然后升至室温,将所得溶液搅拌反应3小时。冰/水浴冷却溶液,分批加入十水合硫酸钠(4.9g,15mmol),得到白色悬浮液。加入乙醚(25mL)并搅拌悬浮液约18小时。在室温下。通过硅藻土过滤所得悬浮液,并用乙醚(2x50mL)洗涤固体。合并滤液浓缩,残液经硅胶柱层析分离纯化(洗脱液:乙酸乙酯:石油醚=1:20~1:1),得到黄色油状化合物(R)-1-(3-氟吡咯烷-1-基甲基)环丙基-1-甲醇(0.93g,58%)。
LC/MS(ESI):m/z=174[M+H]+.
(S)-1-环丙基吡咯烷-2-甲醇的制备
在氮气保护下,将(S)-吡咯烷-2-基甲醇(5.0g 50mmol)、叔丁基二苯基氯硅烷(16.3g 59mmol)和咪唑(8.5g 125mmol)溶解于100mL DMF中,在20℃下反应4小时,直到原料转化率达到100%完成了反应后,用水淬灭,用乙酸乙酯萃取稀溶液,合并有机相,用无水硫酸钠干燥,过滤,减压浓缩滤液,硅胶柱层析分离纯化(洗脱液:乙酸乙酯:石油醚=1:20~1:1),黄色油状化合物S)-2-((((叔丁基二苯基甲硅烷基)氧基)甲基)吡咯烷(11.8g,70%)。
将(S)-2-((((叔丁基二苯基甲硅烷基)氧基)甲基)吡咯烷(3g,8.84mmol)和环丙基硼酸(3.17g,36.9mmol)溶于40mL DCE中,添加Na2CO3(1.95g,18.4mmol)、Cu(OAc)2(1.67g,9.19mmol)和2-(2-吡啶基)吡啶(1.44g,9.22mmol)。在70℃、将反应物在充15psi氧气下搅拌2h,然后过滤,滤液用40mL水释,然后用乙酸乙酯(2x50mL)萃取。用80mL饱和盐水洗涤合并的有机层,用无水Na2SO4干燥并过滤。滤液减压浓缩。通过柱层析纯化残余物(石油醚/乙酸乙酯,10:1至4:1),得到淡黄色油状(S)-2-((((叔丁基二苯基甲硅烷基)氧基)甲基)-l-环丙基吡咯烷(1.3g,38%)。
将CsF(1.75g,1.5mmol)加到(S)-2-((((叔丁基二苯基甲硅烷基)氧基)甲基)-l-环丙基吡咯烷(1.5g,3.95mmol)溶于DMF(15mL)的溶液中,在50℃下搅拌20h。然后将反应混合物冷却至室温,并用H2O(20mL)稀释并用乙酸乙酯(3x30mL)萃取。用80mL饱和盐水洗涤合并的有机层,用无水Na2SO4干燥并过滤。滤液减压浓缩。通过柱层析纯化残余物(石油醚/乙酸乙酯,10:1至1:1),得到淡黄色油状的(S)-(1-环丙基吡咯烷-2-甲醇(345mg,62%产率)。
LC/MS(ESI):m/z=142[M+H]+.
(2S,4R)-1-环丙基吡咯烷-2-甲醇的制备
根据(S)-1-环丙基吡咯烷-2-甲醇的合成方法:
在氮气保护下,将(2S,4R)-4-氟-L-脯氨醇盐酸盐(5.95g 50mmol)、叔丁基二苯基氯硅烷(16.3g 59mmol)和咪唑(17g 250mmol)溶解于100mLDMF中,在20℃下反应4小时,直到原料转化率达到100%完成了反应后,用水淬灭,用乙酸乙酯萃取稀溶液,合并有机相,用无水硫酸钠干燥,过滤,减压浓缩滤液,硅胶柱层析分离纯化(洗脱液:乙酸乙酯:石油醚=1:20~1:1),黄色油状化合物(2S,4R)-4-氟-2-((((叔丁基二苯基甲硅烷基)氧基)甲基)吡咯烷(11.9g,67%)。
将(2S,4R)-4-氟-2-((((叔丁基二苯基甲硅烷基)氧基)甲基)吡咯烷(3.16g,8.84mmol)和环丙基硼酸(3.17g,36.9mmol)溶于40mL DCE中,添加Na2CO3(1.95g,18.4mmol)、Cu(OAc)2(1.67g,9.19mmol)和2-(2-吡啶基)吡啶(1.44g,9.22mmol)。在70℃、将反应物在充15psi氧气下搅拌2h,然后过滤,滤液用40mL水释,然后用乙酸乙酯(2x50mL)萃取。用80mL饱和盐水洗涤合并的有机层,用无水Na2SO4干燥并过滤。滤液减压浓缩。通过柱层析纯化残余物(石油醚/乙酸乙酯,10:1至4:1),得到淡黄色油状(2S,4R)-4-氟-2-((((叔丁基二苯基甲硅烷基)氧基)甲基)-l-环丙基吡咯烷(1.2g,34%)。
将CsF(1.75g,1.5mmol)加到(2S,4R)-4-氟-2-((((叔丁基二苯基甲硅烷基)氧基)甲基)-l-环丙基吡咯烷(1.57g,3.95mmol)溶于DMF(15mL)的溶液中,在50℃下搅拌20h。然后将反应混合物冷却至室温,并用H2O(20mL)稀释并用乙酸乙酯(3x30mL)萃取。用80mL饱和盐水洗涤合并的有机层,用无水Na2SO4干燥并过滤。滤液减压浓缩。通过柱层析纯化残余物(石油醚/乙酸乙酯,10:1至1:1),得到淡黄色油状的(2S,4R)-4-氟-(1-环丙基吡咯烷-2-甲醇(352mg,56%产率)。
LC/MS(ESI):m/z=160[M+H]+.
8-氟萘硼酸的制备
在0℃下,将48%HBF4(100mL)添加到8-溴-1-萘胺(10g,45.2mmol)溶于100mLTHF溶液中,随后添加NaNO2(4.9g,135.8mmol)溶于20mL水的溶液。在0℃下搅拌反应1h,然后NaBF4(24.9g,226mmol)。将混合物升至室温并过滤。用乙醚洗涤固体并在高真空下干燥过夜,得到绿色固体重氮盐,将上一步骤中获得的重氮盐悬浮在二甲苯(50mL)中并回流1h。滤液减压浓缩,通过柱层析纯化残余物得到8-溴-1-氟萘(4.6g,45%)。
将8-溴-1-氟萘(2.79g,0.0124mol)溶解于无水四氢呋喃(20.0mL)中,加入硼酸三异丙酯(2.68g,0.0142mol),冷却至-78℃,添加正丁基锂(0.95g,0.0149mol),搅拌反应0.5h,然后返回至室温。加入饱和氯化铵水溶液萃灭反应。调pH至强酸性,用乙酸乙酯(20.0ml×3)萃取。合并有机相,用饱和盐水洗涤,用无水硫酸钠干燥,减压蒸馏溶剂。用正己烷打浆,并滤得8-氟萘-1-硼酸(1.98g,84%)。
LC/MS(ESI):m/z=191[M+H]+.
3-(2-(三甲硅烷基)乙氧甲氧基)-8-氟萘硼酸频哪醇酯的制备
根据文献Journal ofthe American Chemical Society,1976,vol.98,#11,p.3237-3242和KR102121583:
向Br2(5.2g,32.5mmol)溶于AcOH(15mL)溶液中添加5-氟萘胺(2.4g,15mmol)存于AcOH(10mL)中的溶液,并且在70℃下将反应搅拌1小时。反应混合物在室温下冷却并过滤。滤饼用15mLAcOH洗涤,然后加入20%NaOH水溶液(30mL)。将混合物搅拌20分钟并过滤。用20mL水洗涤分离固体并在真空下干燥以提供灰色固体形式的2,4-二溴-8-氟萘-1-胺(4.45g,93%产率)。LC/MS(ESI):m/z=320[M+H]+。
将2,4-二溴-8-氟萘-1-胺(3.84g,12mmol)溶于65mLAcOH中,并冷却至0℃。然后添加11mL丙酸并搅拌。然后,加入1.2g亚硝酸钠,搅拌30分钟几分钟。那将反应液倒入0℃的冰水中。,过滤所得固体并进一步添加到滤液中并搅拌以产生黄色沉淀将所得沉淀物过滤并干燥以获得中间体6-氟-5-溴苯并[1,2-d][1,2,3]噁二唑(1.35g,产率42%)。LC/MS(ESI):m/z=268[M+H]+。
在氮气保护下,将6-氟-5-溴萘并[1,2-d][1,2,3]噁二唑(1.34g,5mmol)溶于25mLEtOH中,然后加入将0.57g硼氢化钠,搅拌反应12小时。然后,将28mL盐酸溶液逐滴加入,并搅拌1小时。反应结束时,加入10%NaOH水溶液中和。中和完成后,用二氯甲烷萃取,浓缩有机层。快速柱纯化得到5-氟-4-溴-2-萘酚(0.92克,76%)。LC/MS(ESI):m/z=242[M+H]+。
将5-氟-4-溴-2-萘酚(0.91g,3.78mmol)溶于10mL四氢呋喃中。随后,在0℃下搅拌,分几批添加60%NaH(1.35g,5.67mmol)。然后,加SEMCl(5.6g,5.67mmol)。所得溶液在25℃搅拌反应过夜,然后加入10毫升水萃灭反应。所得溶液用2x10mL乙酸乙酯萃取,并合并有机层。混合物在无水硫酸钠上干燥并在真空下浓缩,得到粗品1-溴-3-(2-(三甲硅烷基)乙氧甲氧基)-8-氟萘(1.35克,96%)。LC/MS(ESI):m/z=272[M+H]+。
在氮气保护下,将[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(240mg,0.3mmol)和醋酸钾(726mg,7.38mmol)加入到1-溴-3-(2-(三甲硅烷基)乙氧甲氧基)-8-氟萘(816mg,3mmol)和双联频哪醇基二硼(980mg,3.9mmoll)溶于60mLDMF的溶液中,在90℃下搅拌反应5小时。然用水(100ml)稀释混合物并用乙酸乙酯(100ml)萃取,用无水干燥有机相,过滤并浓缩滤液以得到粗产物。粗品经柱层析法纯化,得白色固体(905mg,72%产率)。LC/MS(ESI):m/z=419.2[M+H]+。
3-(2-(三甲硅烷基)乙氧甲氧基)-8-氯萘硼酸频哪醇酯的制备
根据3-(2-(三甲硅烷基)乙氧甲氧基)-8-氟萘硼酸频哪醇酯的合成方法:
向Br2(5.2g,32.5mmol)溶于AcOH(15mL)溶液中添加5-氯萘胺(2.65g,15mmol)存于AcOH(10mL)中的溶液,并且在70℃下将反应搅拌1小时。反应混合物在室温下冷却并过滤。滤饼用15mLAcOH洗涤,然后加入20%NaOH水溶液(30mL)。将混合物搅拌20分钟并过滤。用20mL水洗涤分离固体并在真空下干燥以提供灰色固体形式的2,4-二溴-8-氯萘-1-胺(4.83g,96%产率)。LC/MS(ESI):m/z=336[M+H]+。
将2,4-二溴-8-氯萘-1-胺(4.03g,12mmol)溶于65mLAcOH中,并冷却至0℃。然后添加11mL丙酸并搅拌。然后,加入1.2g亚硝酸钠,搅拌30分钟几分钟。那将反应液倒入0℃的冰水中。,过滤所得固体并进一步添加到滤液中并搅拌以产生黄色沉淀将所得沉淀物过滤并干燥以获得中间体6-氯-5-溴苯并[1,2-d][1,2,3]噁二唑(1.50g,产率44%)。LC/MS(ESI):m/z=284[M+H]+。
在氮气保护下,将6-氯-5-溴萘并[1,2-d][1,2,3]噁二唑(1.42g,5mmol)溶于25mLEtOH中,然后加入将0.57g硼氢化钠,搅拌反应12小时。然后,将28mL盐酸溶液逐滴加入,并搅拌1小时。反应结束时,加入10%NaOH水溶液中和。中和完成后,用二氯甲烷萃取,浓缩有机层。快速柱纯化得到5-氯-4-溴-2-萘酚(1.02克,79%)。LC/MS(ESI):m/z=259[M+H]+。
将5-氯-4-溴-2-萘酚(0.973g,3.78mmol)溶于10mL四氢呋喃中。随后,在0℃下搅拌,分几批添加60%NaH(1.35g,5.67mmol)。然后,加SEMCl(5.6g,5.67mmol)。所得溶液在25℃搅拌反应过夜,然后加入10毫升水萃灭反应。所得溶液用2x10mL乙酸乙酯萃取,并合并有机层。混合物在无水硫酸钠上干燥并在真空下浓缩,得到粗品1-溴-3-(2-(三甲硅烷基)乙氧甲氧基)-8-氯萘(1.39克,95%)。LC/MS(ESI):m/z=388[M+H]+。
在氮气保护下,将[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(240mg,0.3mmol)和醋酸钾(726mg,7.38mmol)加入到1-溴-3-(2-(三甲硅烷基)乙氧甲氧基)-8-氟萘(1.16mg,3mmol)和双联频哪醇基二硼(980mg,3.9mmoll)溶于60mLDMF的溶液中,在90℃下搅拌反应5小时。然用水(100ml)稀释混合物并用乙酸乙酯(100ml)萃取,用无水干燥有机相,过滤并浓缩滤液以得到粗产物。粗品经柱层析法纯化,得白色固体(992mg,76%产率)。LC/MS(ESI):m/z=436[M+H]+。
实施例1
6-氯-7-(8-氟萘基)-8-氟-4-(3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)喹唑啉(化合物1)的制备
第一步:7-溴-8-氟-6-氯-2,4-喹唑啉二酮的制备
将3-氟-4-溴-5-氯-2-氨基苯甲酸(13.4g,0.05mol)和尿素(45g,0.75mol)加热到150℃,搅拌反应12小时,然后降温至95℃,然后加入200mL水,搅拌半小时过滤,用乙酸打浆,然后干燥得到黄色固体7-溴-8-氟-6-氯-2,4-喹唑啉二酮(12.62g,86%)。
LC/MS(ESI):m/z=294.5[M+H]+.
第二步:7-溴-8-氟-2,4,6-三氯喹唑啉的制备
将7-溴-8-氟-6-氯-2,4-喹唑啉二酮(1.76g 6mmol)溶于POCl3(30mL)中,加入少量N,N-二甲苯胺,加热回流搅拌反应10h。然后倒入冰水中淬灭,过滤得到固体产品,水洗,干燥得到粗品黄色固体7-溴-8-氟-2,4,6-三氯喹唑啉1f(1.70g,86%),无需再纯化进行下一反应。
LC/MS(ESI):m/z=331[M+H]+.
第三步:4-(3,8-二氮杂双环[3.2.1]辛烷-3-基)-7-溴-8-氟-2,6-二氯喹唑啉的制备
将7-溴-8-氟-2,4,6-三氯喹唑啉(1.32g,4mmol)、8-boc-3,8-二氮杂双环[3.2.1]辛烷(0.93g,4.4mmol)、碳酸钾(0.88g,6.4mmol)催化量碘化钾和DMF(80mL)混合,加热到120℃,搅拌反应4小时。冷却至室温,减压蒸溶,得到黄色固体4-(3,8-二氮杂双环[3.2.1]辛烷-3-基)-7-溴-8-氟-2,6-二氯喹唑啉1g(1.67g,83%),
LC/MS(ESI):m/z=507[M+H]+。
第四步:6-氯-7-溴-8-氟-4-(3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)喹唑啉的制备
将2,6-二氯-7-溴-8-氟-4-((8-boc-3,8-二氮杂双环[3.2.1]辛烷)-1-基)喹唑啉(152mg,0.3mmol)、N-甲基-L-脯氨醇(38mg,0.33mmol)、碳酸钾(62mg,0.45mmol)催化量碘化钾和DMF(10mL)混合,加热到120℃,搅拌反应4小时。冷却至室温,减压蒸溶,柱层析得到黄色固体6-氯-7-溴-8-氟-4-(3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)喹唑啉1h(137mg,78%)。
LC/MS(ESI):m/z=585.2[M+H]+。
第五步:6-氯-7-(8-氟萘基)-8-氟-4-(N-Boc-3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)喹唑啉的制备
将6-氯-7-溴-8-氟-4-(3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)喹唑啉1e(117mg,0.2mmol)、8-氟萘-1-硼酸(38mg,0.2mmol)、三(二亚苄基丙酮)二钯(17mg,0.018mmol)、碳酸铯、1,4-二氧六环(4mL)和水(1mL)混合后,然后回流加热到120℃,搅拌反应16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(2mL)稀释反应混合物,并通过过滤收集固体。粗产物用甲醇(10mL)打浆,然后得到黄色固体6-氯-7-(8-氟萘基)-8-氟-4-(3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)喹唑啉1f(112mg,86%),无需再纯化进行下一反应。
LC/MS(ESI):m/z=651[M+H]+.
第六步:6-氯-7-(8-氟萘基)-8-氟-4-(3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)喹唑啉的制备
反应瓶中加入6-氯-7-(8-氟萘基)-8-氟-4-(3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)喹唑啉(110mg,0.17mmol),溶于1ml乙酸乙酯和1NHCl的1,4-二氧六环溶液2ml。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6-氯-7-(8-氟萘基)-8-氟-4-(3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)喹唑啉(73mg,产率78%)。
LC/MS(ESI):m/z=551[M+H]+。
表1实施例2-12参照化合物1的制备方法与相应的中间体制备
实施例13生物活性测试肿瘤细胞增殖抑制实验
1、实验方法
将ATCC CRL-1739(KRASG12D突变)细胞消化离心重悬后用Scepter自动细胞计数仪测定细胞密度,将细胞稀释成每毫升含44,000个细胞的溶液,调整密度后的细胞溶液以每孔90微升加入96孔培养板中。将96孔板置于37℃、5%CO2培养箱中,待细胞培养24小时后,加入不同浓度的待测化合物细胞在10%胎牛血清存在下与化合物一起培养72小时,使用Cell Titer-Glo发光细胞活力检测试剂盒详见厂家说明书)测定ATP的含量来评估细胞生长抑制,简要来讲,每个孔中加入30微升Cell Titer-Glo试剂,摇板10分钟,诱导细胞裂解,用Fluoroskan Ascent FL(Thermo)检测记录萤光信号,从二甲基亚砜处理72小时的细胞得到最大的信号值。从单独的培养基(细胞数为零)得到最小信号值,抑制率%=(最大信号值化合物信号值)/(最大信号值一最小信号值×100%,使用Graphpadprism5软件处理数据。通过S形剂量反应曲线拟合计算IC50值。其中“A”表示IC50≤50nM;“B”表示50<IC50≤500nM;“C”表示500<IC50≤2000nM;“D”表示2000<IC50
2、实验结果
计算出上述实验中各化合物的1C50,结果如下表2所示
表2、化合物对肿瘤细胞增殖的抑制活性IC50(nm)。
Claims (4)
1.一种化合物,其特征在于,选自以下任一种:
2.一种药物组合物,其特征在于,包括(1)如权利要求1所述的化合物;和(2)药学上可接受的载体。
3.如权利要求1所述的化合物在制备用于抑制KRASG12D突变蛋白相关的癌症的药物中的用途。
4.如权利要求3所述的用途,其特征在于,所述癌症选自以下任一种:血液癌、肺癌、胰腺癌、结肠癌、直肠癌、结直肠癌、口腔癌。
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