CN117304182A - 一类具有嘧啶并六元环结构的化合物、包含其的药物组合物及其应用 - Google Patents
一类具有嘧啶并六元环结构的化合物、包含其的药物组合物及其应用 Download PDFInfo
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/541—Non-condensed thiazines containing further heterocyclic rings
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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
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- A—HUMAN NECESSITIES
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- 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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
本发明涉及一类具有嘧啶并六元环结构的化合物、包含其的药物组合物及其应用。所述化合物具有如下式I所示的结构。经试验验证,本申请的化合物表现出显著优异的KRAS‑G12C/SOS1相互作用抑制活性,因此,式I化合物具备作为SOS1抑制剂的潜力,可以被开发成用于与此相关的疾病的治疗药物。
Description
技术领域
本发明属于药物化学领域。具体地,本发明涉及一类具有嘧啶并六元环结构的化合物、其立体异构体、外消旋物、几何异构体、互变异构体、前药、水合物、溶剂化物或其药学上可接受的盐,以及含有它们的药物组合物,它们具有SOS1抑制剂活性。
背景技术
RAS蛋白包括KRAS(V-Ki-ras2 Kirsten rat sarcoma viral oncogenehomolog)、HRAS(neuroblastoma RAS viral oncogene homolog)和NRAS(Harvey murinesarcoma virus oncogene),其中KRAS有两个可变剪切异构体KRAS4A和KRAS4B。RAS蛋白主要分布在细胞膜内侧,膜定位是激活RAS的关键步骤。RAS蛋白的膜定位需要其C末端发生异戊烯化和棕榈酰化,但KRAS4B由于缺少棕榈酰化位点,其膜定位依赖于赖氨酸组成的多碱区与质膜之间的静电作用(Ahearn et al.,2011;Wright and Philips,2006)。RAS蛋白属于小GTPase家族,在细胞中以GTP结合方式或者是GDP结合方式存在。RAS蛋白的激活需要其从GDP结合状态转变为GTP结合状态,这一过程由鸟苷酸交化因子GEFs(guaninenucleotide exchange factors),比如SOS1(Son of Sevenless 1)来催化(Chardin etal.,1993)。RAS激活会促进下游效应分子RAF、PI3K(Phosphoinositide3-kinase)及RalGDS(Ral guanine nucleotide dissociation stimulator)的活化来影响细胞的增殖、生长、代谢、迁移、血管生成等生物学过程(Rodriguez-Viciana and McCormick,2005;Young etal.,2009)。RAS蛋白具有内在水解活性,可使GTP转化为GDP。GTPase激活蛋白GAPs(GTPaseactivating proteins),比如NF1可增加其水解速率来使RAS失活。在正常条件下,GAPs和GEFs严格调控RAS蛋白失活和激活,但是RAS蛋白发生突变后,调控机制失调。在肿瘤细胞中RAS突变主要发生在G12、G13和Q61位,这些位点的突变减弱内源和GAPs介导的水解活性,G13和Q61位点突变还会增加GEFs介导的GTP交换速率(Simanshu et al.,2017;Smith etal.,2013)。近几年的生化数据分析显示,突变的RAS仍然具有一定的内在水解活性,而且RAS突变蛋白的内在水解活性越强,其上游蛋白SHP2抑制对其活性的阻碍就越强(Hunteret al.,2015;Mainardi et al.,2018)。
SOS1蛋白有两个重要的基序,RAS exchanger motif(REM)和CDC25同源结构域(homology domain),分别为变构结合位点和催化结合位点。其中CDC25结合RAS-GDP来促进GDP和GTP的交换,REM结合RAS-GTP进一步增加SOS1的催化活性(Freedman et al.,2006;Pierre et al.,2011)。SOS1在KRAS突变肿瘤具有关键作用,敲低SOS1会使KRAS突变肿瘤细胞增殖和生存能力下降,但是对KRAS野生型细胞则无影响(Jeng et al.,2012)。SOS1在激活RAS信号通路上发挥重要作用。酪氨酸激酶受体RTKs活化后会激活SHP2,使其与衔接蛋白Grb2结合,促进Grb2与SOS1复合物形成激活SOS1,从而激活RAS蛋白(Baltanas et al.,2020)。肿瘤细胞中存在SOS1突变,比如胚胎性横纹肌肉瘤、肺腺癌等(Denayer et al.,2010),而膀胱癌和前列腺癌中则存在SOS1高表达(Timofeeva et al.,2009;Watanabe etal.,2000)。除此之外,SOS1在努南综合征Noonan syndrome(NS)、心面皮肤综合征cardio-facio-cutaneous syndrome(CFC)和hereditary gingival fibromatosis遗传性牙龈纤维瘤病及其相关综合征中也存在着突变(Pierre et al.,2011)。
SOS1的同源物SOS2也作为GEF来激活RAS蛋白,两者存在功能冗余。在老鼠中敲除SOS1会导致胚胎致死(Qian et al.,2000),在成年鼠中条件性敲除SOS1则可以存活(Baltanas et al.,2013)。而在老鼠中敲除SOS2没有明显的表型(Esteban et al.,2000)。如果在成年小鼠中同时敲除SOS1和SOS2,小鼠很快死亡(Baltanas et al.,2013)。选择性抑制单个SOS亚型比如SOS1,可能会更有效治疗SOS1-RAS激活的疾病。抑制SOS1催化位点与RAS结合,能够阻止SOS1介导的RAS-GTP的产生来抑制RAS信号通路。在RAS依赖的肿瘤中,这样的化合物理论上能够破坏RAS和SOS的结合,抑制细胞ERK的磷酸化起到抗肿瘤的效果。抑制SOS1和RAS相互作用的化合物,能够抑制RAS活性,可用来治疗头颈癌、肺癌、纵隔肿瘤、胃肠道肿瘤、前列腺癌、睾丸癌、妇科肿瘤、乳腺癌、肾脏和膀胱癌、内分泌系统肿瘤、软组织肉瘤、骨肉瘤、横纹肌样瘤、间皮细胞瘤、皮肤癌、外周神经系统肿瘤、中枢神经系统肿瘤、淋巴瘤、白血病,未知原发癌、努南综合征、心面皮肤综合征、遗传性牙龈纤维瘤病及其相关综合征。
发明内容
本发明提供了一种式(I)的化合物,其对映异构体、非对映异构体、外消旋体、前药、水合物、溶剂化物或其药学上可接受的盐:
在式I中,环A表示C6-10芳基、5-10元杂芳基或4-10元饱和或不饱和杂环基;特别地,环A为苯基;
n为0~5的整数;
每个R3独立地选自:无取代或取代的C1-4烷基、无取代或取代的C1-4烷氧基、无取代或取代的C2-4炔基、无取代或取代的C3-6环烷基、无取代或取代的4-6元饱和或不饱和杂环基、羟基、卤素、氰基、氨基、或氧代基团(=O);所述取代是指被选自卤素、羟基、氰基和氨基中的一种或多种取代基所取代;当环A为C6-10芳基或5-10元杂芳基时,R3不为氧代基团(=O);
R1选自氢、卤素、羟基、无取代或取代的C1-6烷基、无取代或取代的C3-6环烷基、无取代或取代的4-10元饱和或不饱和杂环基、无取代或取代的C1-6烷氧基、-CN、-COOH、-CONH2、-CONH-C1-6烷基、氨基、-NH-C1-6烷基;特别地,R1选自氢、卤素、羟基、无取代或取代的C1-4烷基、无取代或取代的C3-6环烷基、无取代或取代的C1-4烷氧基、-CN、-COOH、氨基;优选地,R1选自氢、卤素、羟基、-CN、甲基、乙基、甲氧基、乙氧基、氨基、环丙基;
R2为氢、无取代或取代的C1-6烷基、无取代或取代的C3-6环烷基;特别地,R2为甲基或乙基;
R4为氢、无取代或取代的C1-10烷基、无取代或取代的C6-10芳基、无取代或取代的5-10元杂芳基、无取代或取代的C3-6环烷基、无取代或取代的4-10元饱和或不饱和杂环基、无取代或取代的5-10元杂芳基并4-10元杂环基、卤素、-CN、-COOH、-OR5、-NH-R5、-CONH-R5、-NHCO-R5、-SO2-R5、-SO2NH-R5;优选地,R4选自无取代或取代的C1-10烷基、无取代或取代的C6-10芳基、无取代或取代的5-6元杂芳基、无取代或取代的C3-6环烷基、无取代或取代的4-10元杂环基;
R5选自氢、无取代或取代的C1-10烷基、无取代或取代的C6-10芳基、无取代或取代的5-10元杂芳基、无取代或取代的C3-6环烷基、无取代或取代的4-10元饱和或不饱和杂环基;
R1、R2、R4、R5中的取代是指被选自如下A组取代基中的一种或多种所取代,A组取代基包括:无取代或被B组取代基中一种或多种所取代的C1-6烷基、C1-6烷氧基、羟基、卤素、氰基、氨基、羧基、氧代基团(=O)、-NH-C1-6烷基、-NH-C3-6环烷基、无取代或被B组取代基中一种或多种取代的C6-10芳基、无取代或被B组取代基中的一种或多种所取代的5-10元杂芳基、无取代或被B组取代基中一种或多种取代的C3-6环烷基、无取代或被B组取代基中一种或多种取代的4-10元饱和或不饱和杂环基、-C(O)-R6、-C(O)-NH-R6、-NH-C(O)-R6、-SO2-R6、-SO2NH-R6;R6选自氢、无取代或被B组取代基中一种或多种所取代的C1-10烷基、无取代或被B组取代基中的一种或多种所取代的C6-10芳基、无取代或被B组取代基中的一种或多种所取代的5-10元杂芳基、无取代或被B组取代基中的一种或多种所取代的C3-6环烷基、无取代或被B组取代基中的一种或多种所取代的4-10元饱和或不饱和杂环基;B组取代基包括:C1-6烷基、C1-6烷氧基、羟基、卤素、氰基、氨基、羧基。
在具体实施方式中,R2为甲基或乙基。
在具体实施方式中,环A为苯基。在具体实施方式中,n为1或2;
每个R3独立地选自:取代或无取代的C1-4烷基、取代或无取代的C2-4炔基、取代或无取代的4-6元饱和或不饱和杂环基、卤素、氰基或氨基;所述取代是指被选自卤素、羟基、氰基、氨基中的一种或多种取代基所取代;其他取代基定义同上。
在具体实施方式中,R1为氢、卤素、羟基、无取代或取代的C1-4烷基、无取代或取代的C3-6环烷基、无取代或取代的C1-4烷氧基、-CN、-COOH、氨基;所述取代是指被选自羟基、卤素、氰基、氨基中的一种或多种所取代;优选地,R1为氢、卤素、羟基、-CN、甲基、乙基、甲氧基、乙氧基、氨基、环丙基;更优选地,R1为氢、卤素、-CN、甲基、甲氧基、环丙基;其他取代基定义同上。
在具体实施方式中,R4选自无取代或取代的C1-10烷基(例如C1-6烷基)、无取代或取代的C6-10芳基、无取代或取代的5-10元杂芳基、无取代或取代的C3-6环烷基、无取代或取代的4-10元饱和或不饱和杂环基;R4中的取代是指被选自如下A组取代基中的一种或多种所取代,A组取代基包括:无取代或被B组取代基中一种或多种所取代的C1-6烷基、C1-6烷氧基、羟基、卤素、氰基、氨基、羧基、氧代基团(=O)、-C(O)-R6、-C(O)-NH-R6;R6选自氢、无取代或被B组取代基中一种或多种所取代的C1-10烷基、无取代或被B组取代基中的一种或多种所取代的C3-6环烷基;B组取代基包括:C1-6烷基、C1-6烷氧基、羟基、卤素、氰基、氨基、羧基;
优选地,R4选自无取代或取代的C1-10烷基、无取代或取代的C6-10芳基、无取代或取代的5-6元杂芳基、无取代或取代的C3-6环烷基、无取代或取代的4-10元杂环基;
其中,
所述5-6元杂芳基选自: 优选地,所述5-6元杂芳基选自/>
所述4-10元杂环基选自: 优选地,所述4-10元杂环基选自/>
R4中的取代是指被选自如下A组取代基中的一种或多种所取代,A组取代基包括:无取代或被B组取代基中一种或多种所取代的C1-6烷基、C1-6烷氧基、羟基、卤素、氰基、氨基、羧基、-C(O)-R6、-C(O)-NH-R6;R6选自氢、无取代或被B组取代基中一种或多种所取代的C1-10烷基、无取代或被B组取代基中的一种或多种所取代的C3-6环烷基;B组取代基包括:C1-6烷基、C1-6烷氧基、羟基、卤素、氰基、氨基、羧基。
更优选地,R4选自无取代或被m个取代基R7取代的C1-10烷基、及如下结构:
m为1、2或3;
R7和R8各自独立地选自H、无取代或被B组取代基中一种或多种所取代的C1-6烷基、C1-6烷氧基、羟基、卤素、氰基、氨基、羧基、-C(O)-R9;R9选自氢、无取代或被B组取代基中一种或多种所取代的C1-10烷基、无取代或被B组取代基中的一种或多种所取代的C3-6环烷基;B组取代基包括:C1-6烷基、C1-6烷氧基、羟基、卤素、氰基、氨基、羧基;
优选地,
m为1或2;
R7选自H、无取代或被B组取代基中一种或多种所取代的C1-6烷基、C1-6烷氧基、羟基、卤素、氰基、氨基;B组取代基包括:羟基、卤素、氰基、氨基;
R8选自H、C1-6烷基、C1-6烷氧基、-C(O)-R9;R9选自C1-6烷基、C3-6环烷基;
更优选地,
m为1或2;
R7选自H、无取代或被B组取代基中一种或多种所取代的C1-6烷基、C1-6烷氧基、羟基、卤素、氰基、氨基;B组取代基包括:羟基、卤素、氰基、氨基;
R8选自H、甲基、乙基、甲氧基、乙氧基、-C(O)-R9;R9选自甲基、乙基、环丙基;
其他取代基定义同上。
在具体实施方式中,R4选自羟基取代的C1-6烷基及如下结构:
其中,R7、R7’选自H、羟基、氨基、甲基、乙基、甲氧基、羟甲基、羟乙基,R8选自H、甲基、乙基、甲氧基、-C(O)-R9;R9选自甲基、乙基、环丙基;
其他取代基定义同上。
在具体实施方式中,所述式(I)的化合物由下式II表示:
在上式II中,各取代基的定义分别如上文所定义。
在具体实施方式中,所述式(I)的化合物由下式III表示:
在上式III中,R4的定义分别如上文所定义。
在具体实施方式中,所述的式(I)的化合物选自如下化合物:
/>
本发明的另一方面,提供一种药物组合物,包括:
(1)治疗有效量的所述式(I)的化合物,其对映异构体、非对映异构体、外消旋体、前药、水合物、溶剂化物或其药学上可接受的盐作为活性成分;和
(2)药学上可接受的载体。
本发明的另一方面,提供所述的式(I)的化合物,其对映异构体、非对映异构体、外消旋体、前药、水合物、溶剂化物或其药学上可接受的盐,或所述的药物组合物在制备SOS1抑制剂中的用途。
本发明的又一方面,提供所述的式(I)的化合物,其对映异构体、非对映异构体、外消旋体、前药、水合物、溶剂化物或其药学上可接受的盐,或所述的药物组合物在制备用于预防和/或治疗与SOS1突变、活性或表达量相关的疾病的药物中的用途。
其中,所述与SOS1突变、活性或表达量相关的疾病包括头颈癌、肺癌、纵隔肿瘤、胃肠道肿瘤、前列腺癌、睾丸癌、妇科肿瘤、乳腺癌、肾脏和膀胱癌、内分泌系统肿瘤、软组织肉瘤、骨肉瘤、横纹肌样瘤、间皮细胞瘤、皮肤癌、外周神经系统肿瘤、中枢神经系统肿瘤、淋巴瘤、白血病,未知原发癌、努南综合征、心面皮肤综合征、遗传性牙龈纤维瘤病及其相关综合征。
有益效果
本申请的化合物表现出显著优异的KRAS-G12C/SOS1相互作用抑制活性,因此,具备作为SOS1抑制剂的潜力,可以被开发成用于与此相关的疾病的治疗药物。
具体实施方式
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。说明书中所揭示的各个特征,可以被任何提供相同、均等或相似目的的替代性特征取代。限于篇幅,在此不再一一累述。
术语
在本发明中,当基团价键上带有波浪线“”时,例如在“/>”中,波浪线表示该基团与分子其它部分的连接点。
在本发明中,所述卤素为F、Cl、Br或I。
在本发明中,除非特别指出,所用术语具有本领域技术人员公知的一般含义。
在本发明中,术语“C1-6”是指具有1、2、3、4、5或6个碳原子,“C1-8”是指具有1、2、3、4、5、6、7或8个碳原子,依此类推。“3元至8元”杂环基是指杂环基上具有3-8个环原子,依此类推“4元至10元杂环基”等。
在本发明中,术语“烷基”表示饱和的线性或支链烃部分,例如术语“C1-10烷基”是指具有1至10个碳原子的直链或支链烷基,非限制性地包括甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基和已基等;优选甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基和叔丁基。本发明中,如无特殊说明,所述C1-10烷基优选为C1-6烷基,更优选为C1-4烷基。
在本发明中,术语“烷氧基”表示-O-(C1-6烷基)基团。例如术语“C1-6烷氧基”是指具有1至6个碳原子的直链或支链烷氧基,非限制性地包括甲氧基、乙氧基、丙氧基、异丙氧基和丁氧基等。
在本发明中,术语“烯基”表示包含至少一个双键的直链或支链烃基部分,例如术语“C2-6烯基”是指具有2至6个碳原子的含有一个双键的直链或支链烯基,非限制性地包括乙烯基、丙烯基、丁烯基、异丁烯基、戊烯基和己烯基等。
在本发明中,术语“环烷基”表示饱和的环状烃基部分,例如术语“C3-8环烷基”是指在环上具有3至8个碳原子的环状烷基,非限制性地包括环丙基、环丁基、环戊基、环己基、环庚基、环辛基和环癸基等。
本文所用的术语“芳基”是指由一个环或多个如两个稠环组成的碳环烃基,其中至少一个环是芳族环。芳基的例子包括但不限于苯基、萘基等。
在本发明中,术语“杂环基”表示包含至少一个碳原子和至少一个(如1-3个)选自N、O、S的环杂原子的环状基团,具体为如本申请中所定义的环烷基上一个或多个环碳被选自-O-、-N=、-NR-、-C(O)-、-S-、-S(O)-和-S(O)2-的部分替换所形成的基团,其中R为氢、C1-4烷基或氮保护基(例如,苄氧羰基、对甲氧基苄基羰基、叔丁氧基羰基、乙酰基、苯甲酰基、苄基、对甲氧基-苄基、对甲氧基-苯基、3,4-二甲氧基苄基等)。“杂环基”包括单环、桥环、螺环等二环结构,例如3元至8元杂环基,3元至6元杂环基等;如四氢呋喃基、吡咯烷基、氧杂环丁基、氧杂环己基、氮杂环丁烷基、环氧乙烷基、氮丙啶基、硫杂环丁烷基、1,2-二硫杂环丁烷基、1,3-二硫杂环丁基、氮杂环庚烷基、氧杂环庚烷基等。
在本发明中,术语“5元至-10元杂芳基”是指具有5~10个环原子,例如5、6或7个环原子(即,5元至7元杂芳基)的单环或二环或稠合多环的环芳族烃基,其在环中包含至少一个(如1-3个)独立地选自N、O和S(例如N)的环杂原子,其余环原子是碳原子;如咪唑基、吡啶基、吡咯基、噻唑基、呋喃基、噁唑基、异噁唑基、吡唑基、噻吩基、嘧啶基、1,2,4-三氮唑基等;优选为五元杂芳基,如咪唑基、异噁唑基、1,2,4-三氮唑基。二环杂芳基包括,例如苯并噁唑基、咪唑并吡啶基、三唑并吡啶基、苯并呋喃基、吡唑并嘧啶基、苯并间二氧杂环戊烯基、吲哚基、喹啉基、异喹啉基等。本发明中,所述取代为单取代或多取代,所述多取代为二取代、三取代、四取代、或五取代。所述二取代就是指具有两个取代基,依此类推。在多取代的情况下,所述取代基可以彼此相同或不同。
本发明所述药学上可接受的盐可以是阴离子与式(I)化合物上带正电荷的基团形成的盐。合适的阴离子为氯离子、溴离子、碘离子、硫酸根、硝酸根、磷酸根、柠檬酸根、甲基磺酸根、三氟乙酸根、乙酸根、苹果酸根、甲苯磺酸根、酒石酸根、富马酸根、谷氨酸根、葡糖醛酸根、乳酸根、戊二酸根或马来酸根。类似地,可以由阳离子与式I化合物上的带负电荷的基团形成盐。合适的阳离子包括钠离子、钾离子、镁离子、钙离子和铵离子,例如四甲基铵离子。
在另一优选例中,“药学上可接受的盐”是指式(I)化合物同选自下组的酸形成的盐类:氢氟酸、盐酸、氢溴酸、磷酸、乙酸、草酸、硫酸、硝酸、甲磺酸、胺基磺酸、水杨酸、三氟甲磺酸、萘磺酸、马来酸、柠檬酸、醋酸、乳酸、酒石酸、琥珀酸、酢浆草酸、丙酮酸、苹果酸、谷氨酸、对甲苯磺酸、萘磺酸、乙磺酸、萘二磺酸、丙二酸、富马酸、丙酸、草酸、三氟乙酸、硬酯酸、扑酸、羟基马来酸、苯乙酸、苯甲酸、谷氨酸、抗坏血酸、对胺基苯磺酸、2-乙酰氧基苯甲酸和羟乙磺酸等;或者式(I)化合物与无机碱形成的盐,例如钠盐、镁盐、钾盐、钙盐、铝盐、锰盐或铵盐;或者通式(I)化合物与有机碱形成的盐,例如甲胺盐、乙胺盐或乙醇胺盐。
“治疗有效量”指的是:活性成分的量足以明显改善病情,而不至于产生严重的副作用。通常,药物组合物含有1-2000mg活性成分/剂,更佳地,含有10-200mg活性成分/剂。较佳地,所述的“一剂”为一个药片。
“药学上可接受的载体”指的是:一种或多种相容性固体或液体填料或凝胶物质,它们适合于人使用,而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组分能和本发明的活性成分以及它们之间相互掺和,而不明显降低活性成分的药效。药学上可以接受的载体的部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明的活性成分或药物组合物的施用方式没有特别限制,代表性的施用方式包括(但并不限于):口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)等。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性成分外,液体剂型可包含本领域中常规采用的惰性稀释剂,如水或其它溶剂,增溶剂和乳化剂,例知,乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油,特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。除了这些惰性稀释剂外,组合物也可包含助剂,如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性成分外,悬浮液可包含悬浮剂,例如,乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液,和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
本发明化合物可以单独给药,或者与其他治疗药物(如抗肿瘤药)联合给药。
使用药物组合物时,是将治疗有效量的本发明化合物适用于需要治疗的哺乳动物(如人),其中施用时剂量为药学上认为的有效给药剂量,对于60kg体重的人而言,日给药剂量通常为1~2000mg,优选20~500mg。当然,具体剂量还应考虑给药途径、病人健康状况等因素,这些都是熟练医师技能范围之内的。
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件(如Sambrook等人,分子克隆:实验室手册(New York:Cold Spring Harbor LaboratoryPress,1989)中所述的条件)或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数是重量百分比和重量份数。
除非另行定义,文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外,任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
通用合成方法
本发明通式(I)化合物的合成可通过下述的合成路线进行合成。在以下描述的合成路线中,涉及的溶剂、酸、碱、偶联催化剂及配体等信息是基于现有的有机化学知识和人名反应。
在本申请中,当化合物的名称与结构式不一致时,以化合物的结构式为准。
本发明涉及一类手性胺中间体的合成,其主要合成途径如合成路线1所示:
合成路线1:
含R3取代的芳香溴代物(Ⅰ-a)和锡试剂通过Stille偶联反应、在酸性条件下裂解得到化合物(Ⅰ-d)。亦或通过含R3取代的芳香羧酸(Ⅰ-b)和二甲基羟胺盐酸盐经缩合反应得到Weinreb酰胺(Ⅰ-c),然后和格氏试剂反应得到相应的酮(Ⅰ-d)。酮(Ⅰ-d)和(S)-(-)-叔丁基亚磺酰胺反应,生成相应的酮亚胺(Ⅰ-e),该酮亚胺经过立体选择性还原得到(Ⅰ-f)。最后,在氯化氢体系中脱去亚磺酰基,得到中间体手性胺的盐酸盐(Ⅰ-g)。
目标化合物的合成,在合成路线2中进行了详细的阐述。
合成路线2:
原料2-氯-3-硝基-4-吡啶羧酸(II-a)和甲醇钠发生取代反应,生成2-甲氧基取代的化合物(II-b)。该羧酸通过和硫酸甲醇体系,或和三甲基硅基重氮甲烷反应,得到甲酯化产物(II-c)。通过还原反应,如催化氢化、铁粉/稀盐酸体系,还原硝基得到氨基化合物(II-d),该化合物经过卤代,如用NCS,得到R1为甲氧基、6位氯代的多取代吡啶化合物(II-h)。同时,也可以从2-氯-5氨基-4-吡啶甲酸(II-e)为起始原料,经过酯化得到甲酯(II-f),再经NBS卤化,得到二卤取代的吡啶化合物(II-g)。上述卤化物和相应的硼试剂,如三甲基环三硼氧烷、环丙基硼酸,在钯试剂催化下,偶联得到不同类型R1取代基的化合物(II-h),如甲基、环丙基化合物。多取代吡啶化合物(II-h)和醋酸甲脒环合得到嘧啶并吡啶环化合物(II-i),该化合物和合成路线1制备的手性氨基化合物(II-g),经过缩合反应,得到氨基取代的化合物(II-j)。含氯的化合物(II-j),经过偶联反应,如Suzuki、Buchwald、Stille等,引入具有R4取代基的化合物(I)。R4基团中还会涉及一些官能团的引入,具体地在后续实施例中说明。
以下试剂的简写如下:
二乙胺基三氟化硫:DAST
2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯:HATU
二氧六环:dixoane
二氯甲烷:DCM
N,N-二甲基甲酰胺:DMF
实施例
实施例1:化合物Int-1的合成
合成路线:
步骤一:
在干燥的3L圆底烧瓶中加入化合物Int-1-a(100g,0.49mol)和二氯甲烷1L)。溶液冷却至0℃,氮气保护下,滴加二乙胺基三氟化硫(120g,0.17mol)。加毕,反应温度升至室温,继续搅拌16小时。TLC监测反应结束后,将反应液倒入冰水中,乙酸乙酯(500mL x 3)萃取,合并有机相,干燥,过滤,减压浓缩,所得残余物用硅胶柱层析法纯化(石油醚/乙酸乙酯=30/1)得到1-溴-3-(二氟甲基)-2-氟苯Int-1-b(90g,浅黄色油状物),产率:82%。1H NMR(CDCl3,400MHz):δ7.69–7.65(m,1H),7.56–7.52(m,1H),7.14(t,J=8.0Hz,1H),6.88(t,J=54.8Hz,1H).
步骤二:
在干燥的2L单口圆底烧瓶中依次加入化合物Int-1-b(90g,0.40mol),三丁基(1-乙氧基乙烯基)锡烷(173g,0.48mol)和无水二氧六环(900mL),搅拌下加入三乙胺(101g,1.0mol)和双(三苯基膦)氯化钯(Ⅱ)(2.8g,4.0mmol)。反应体系用氩气置换,加热至80℃,搅拌反应12小时。TLC监测反应结束后,浓缩,残余物加入饱和的氟化钾溶液(300mL),搅拌1小时,过滤,滤液用乙酸乙酯(300mL x 3)萃取,合并有机相,无水硫酸钠干燥,浓缩,所得残余物用硅胶柱层析法纯化(石油醚/乙酸乙酯=20/1)得到1-(二氟甲基)-3-(1-乙氧基乙烯基)-2-氟苯Int-1-c(100g,褐色油状物),粗品直接用于下一步。
步骤三:
在干燥的1L单口圆底烧瓶中依次加入化合物Int-1-c(100g,粗品)和无水二氧六环(200mL)。溶液降温至0℃,氮气保护下,滴加稀盐酸(200mL,0.40mol,2M)。滴加完毕,反应升至室温,继续搅拌12小时。TLC监测反应结束后,反应液倒入水中,滤液用二氯甲烷(300mLx 3)萃取,合并有机相,无水硫酸钠干燥,减压浓缩,所得残余物用硅胶柱层析法纯化(石油醚/乙酸乙酯=10/1)得到1-(3-(二氟甲基)-2-氟苯基)乙烷-1-酮Int-1-d(53g,浅黄色油状物),产率:两步50%。1H NMR(CDCl3,400MHz):δ7.69–7.98(m,1H),7.81–7.77(m,1H),7.36–7.33(m,1H),6.95(t,J=54.8Hz,1H),2.68(d,J=4.2Hz,3H).
步骤四:
在干燥的1L单口圆底烧瓶中依次加入化合物Int-1-d(17g,90mmol),(S)-2-甲基丙烷-2-亚磺酰胺(16g,0.14mol)和无水四氢呋喃(200mL),搅拌下加入四乙基氧钛(62g,0.27mol),氩气保护下,80℃搅拌反应16小时。TLC监测反应结束后,浓缩,残余物加入饱和食盐水(100mL),乙酸乙酯(100mL x 3)萃取,合并有机相,无水硫酸钠干燥,浓缩有机相,所得残余物用硅胶柱层析法纯化(石油醚/乙酸乙酯=3/1),得到(S,Z)-N-(1-(3-(二氟甲基)-2-氟苯基)亚乙基)-2-甲基丙烷-2-亚磺酰胺Int-1-e(23.7g,黄色油状物),产率:90%。LCMS(ESI):m/z 292.1[M+H]+.
步骤五:
在干燥的1L三口烧瓶中依次加入二氯(对-甲基异丙苯)钌(II)二聚体(1.4g,2.3mmol),(1S,2R)-1-氨基-2,3-二氢-1H-茚-2-醇(0.70g,4.5mmol),4A分子筛(50g)和异丙醇(100mL),氩气保护下,90℃搅拌反应20分钟。反应降温至40℃,依次加入化合物Int-1-e(13g,45mmol)的异丙醇(450mL)溶液和叔丁醇钾的异丙醇溶液(113mL,11mmol,0.1M),40℃反应2小时。TLC监测反应,反应完毕,浓缩体系,残余物加入饱和食盐水(100mL),用乙酸乙酯(100mL x 3)萃取,合并有机相,无水硫酸钠干燥。过滤、浓缩有机相,所得残余物用硅胶柱层析法纯化(石油醚/乙酸乙酯=1/2)得到(S)-N-((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)-2-甲基丙烷-2-亚磺酰胺Int-1-f(12.5g,黄色油状物),产率:95%。1H-NMR(CDCl3,400MHz):δ7.54–7.51(m,2H),7.24–7.23(m,1H),6.90(t,J=54.8Hz,1H),4.87–4.80(m,1H),3.55(d,J=5.2Hz,1H),1.55(t,J=6.4Hz,3H),1.23(s,9H).
步骤六:
在干燥的1L单口圆底烧瓶中依次加入化合物Int-1-f(12.5g,43mmol)和无水二氧六环(100mL)。溶液降温至0℃,氮气保护下,滴加稀盐酸的二氧六环溶液(50mL,0.20mol,4M)。滴加完毕,反应温度升至室温,继续搅拌12小时。LC-MS监测反应结束后,反应液浓缩,残余物加入甲基叔丁基醚(200mL),搅拌2小时,过滤析出的产品,干燥得到(R)-1-(3-(二氟甲基)-2-氟苯基)乙胺盐酸盐Int-1(8.7g,白色固体),产率:92%。1H NMR(CDCl3,400MHz):δ8.87(s,3H),7.98–7.94(m,1H),7.67–7.64(m,1H),7.45–7.41(m,1H),7.25(t,J=54.8Hz,1H),4.64(m,1H),1.55(t,d=6.4Hz,3H).Chiral HPLC:98.5%.
实施例2:化合物Int-2的合成
合成路线:
步骤一:
在干燥的3L三口瓶中加入化合物Int-2-a(100g,465mmol),干燥的N,N-二甲基甲酰胺(1.5L)和2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(195g,512mmol),室温搅拌反应30分钟后,加入甲氧基甲基胺盐酸盐(69g,512mmol)和N,N-二异丙基乙胺(180g,1.4mol),反应室温下搅拌3小时。LCMS监测反应结束后,反应降至0℃,加入2N的盐酸,然后加水(200mL)稀释,乙酸乙酯萃取(500mL×3),合并有机相,饱和食盐水(200mL×2)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,所得残余物用硅胶柱层析法(石油醚/乙酸乙酯=20/1)纯化得到3-溴-N-甲氧基-N,2-二甲基苯甲酰胺Int-2-b(110g,浅黄色油状液体),产率:92%。1H NMR(CD3Cl,400MHz):δ7.58(d,J=8.0Hz,1H),7.21(d,J=7.6Hz,1H),7.11-7.07(m,1H),3.41(s,3H),3.37(s,3H),2.37(s,3H).
步骤二:
在干燥的1L三口瓶中加入化合物Int-2-b(20g,77mmol)和无水四氢呋喃(300mL),冰浴降温至0℃,滴加甲基溴化镁(51mL,154mmol,3.0M),反应缓慢升至室温,继续搅拌3小时。TLC监测反应结束后,反应降至0℃,加入盐酸溶液(75mL,6N),搅拌30分钟后,加水(200mL)稀释,乙酸乙酯萃取(200mL×3),合并有机相,饱和食盐水(200mL×3)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,所得残余物用硅胶柱层析法(石油醚/乙酸乙酯=20/1)纯化得到1-(3-溴-2-甲基苯基)乙烷-1-酮Int-2-c(9.3,橘黄色油状液体),产率:56%。1HNMR(CD3Cl,400MHz):δ7.65(d,J=8.0Hz,1H),7.47(d,J=7.6Hz,1H),7.11(t,J=8.0Hz,1H),2.56(s,3H),2.50(s,3H).
步骤三:
在干燥的500mL单口瓶中依次加入化合物Int-2-c(9.3g,47mmol),无水四氢呋喃(250mL),(R)-(+)-叔丁基亚磺酰胺(6.4g,52mmol)和四乙醇钛(50g,218mmol),氩气保护下,80℃搅拌反应12小时。LCMS监测反应结束后,加水(200mL)稀释,乙酸乙酯萃取(200mL×3),合并有机相,饱和食盐水(200mL×3)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,所得残余物用硅胶柱层析法(石油醚/乙酸乙酯=10/1~5/1)纯化得到(R,E)-N-(1-(3-溴-2-甲基苯基)亚乙基)-2-甲基丙烷-2-亚砜酰胺Int-2-d(13g,黄色油状液体),产率:95%。LCMS(ESI):m/z 318[M+H]+.
步骤四:
在500mL的三口瓶中依次加入二氯(对-甲基异丙苯)钌(II)二聚体(0.73g,1.2mmol),(1S,2R)-1-氨基-2,3-二氢-1H-茚-2-醇(0.35g,2.4mmol),4A分子筛(29g)和异丙醇(60mL),氩气保护下,90℃反应20分钟,体系由黄色变为深红色。反应降温至40℃,依次加入(R,E)-N-(1-(3-溴-2-甲基苯基)亚乙基)-2-甲基丙烷-2-亚砜酰胺Int-2-d(7.5g,24mmol)的异丙醇(250mL)溶液和叔丁醇钾(60mL,2.4mmol,0.1M)的异丙醇溶液,氩气保护下40℃反应15小时。LCMS监测反应结束后,将反应液浓缩,残留物加水(200mL)稀释,乙酸乙酯萃取(200mL×3),合并有机相,饱和食盐水(200mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,所得残余物用硅胶柱层析法(石油醚:乙酸乙酯/二氯甲烷=2/1/1)纯化得到(R)-N-((R)-1-(3-溴-2-甲基苯基)乙基)-2-甲基丙烷-2-亚砜酰胺Int-2-e(2.0g,棕色油状液体),产率:27%。LCMS(ESI):m/z 318[M+H]+.
步骤五:
在干燥的250mL单口瓶中加入化合物Int-2-e(6.1g,19mmol)和二氧六环(50mL),冰浴降温至0℃,滴加盐酸/1,4二氧六环(25mL,100mmol,4M)溶液,室温搅拌12小时。LCMS监测反应结束后,浓缩反应液,粗产品中加入石油醚(200mL),搅拌12小时,过滤,干燥得到(R)-1-(3-溴-2-甲基苯基)乙烷-1-胺盐酸盐Int-2-f(4.8g,深灰色固体),产率:100%。LCMS(ESI):m/z 214,216[M+H]+.
步骤六:
在干燥的250mL单口瓶中依次加入化合物Int-2-f(6.5g,30mmol),二碳酸二叔丁酯(1.3g,33mmol),N,N-二异丙基乙胺(12g,31mmol)和无水二氯甲烷(150mL),室温搅拌3小时。LCMS监测反应结束后,加水(100mL)稀释,乙酸乙酯萃取(200mL×3),合并有机相,饱和食盐水(100mL×2)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,所得残余物用硅胶柱层析法(石油醚/乙酸乙酯=5/1)纯化得到(叔丁基(R)-(1-(3-溴-2-甲基苯基)乙基)氨基甲酸酯Int-2-g(7.1g,白色固体),产率:75%。LCMS(ESI):m/z 316[M+H]+.
步骤七:
在干燥的250mL单口瓶中加入化合物Int-2-g(7.1g,23mmol),氰化锌(3.2g,27mmol),四三苯基膦钯(2.6g,2.3mmol)和无水N,N-二甲基甲酰胺(100mL),氩气保护下,110℃搅拌反应3小时。LCMS监测反应结束后,加水(150mL)稀释,乙酸乙酯萃取(200mL×3),合并有机相,饱和食盐水(100mL×3)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,所得残余物用硅胶柱层析法(石油醚/乙酸乙酯=5/1)纯化得到(叔丁基(R)-(1-(3-溴-2-甲基苯基)乙基)氨基甲酸酯Int-2-h(5.0g,白色固体),产率:85%。LCMS(ESI):m/z 261[M+H]+.
步骤八:
在干燥的250mL单口瓶中加入化合物Int-2-h(5.0g,16mmol),二氧六环(50mL),冰浴降温至0℃,滴加盐酸/1,4二氧六环(25mL,100mmol,4M)溶液,反应升至室温,搅拌15小时。LC-MS监测反应结束后,反应液浓缩,加入甲基叔丁基醚(200mL),搅拌12小时,过滤,干燥得到(R)-3-(1-氨基乙基)-2-甲苯腈盐酸盐Int-2(3.0g,白色固体),产率:80%。LCMS(ESI):m/z 161[M]+;1H NMR(DMSO-d6,400MHz):δ8.75(s,3H),8.00(d,J=7.6Hz,1H),7.80(d,J=7.6Hz,1H),7.51(t,J=8.0Hz,1H),4.67–4.61(m,1H),2.56(s,3H),1.51(d,J=6.4Hz,3H).
实施例3:化合物A-1的合成
合成路线:
步骤一:
将化合物A-1-a(9.0g,52.0mmol)溶于45mL甲醇中,将氯化亚砜(12.4g,104mmol)在常温下缓慢滴加,然后在氮气保护下,在80℃下搅拌并反应48小时。反应完全后,减压浓缩,加入水并用碳酸氢钠溶液调节pH,将反应液用乙酸乙酯萃取,有机相收集后用无水硫酸钠进行干燥,得到化合物A-1-b(7.5g,黄色固体),产率:77%。LCMS(ESI):m/z=187.0[M+H]+
步骤二:
将化合物A-1-b(9.0g,48.1mmol)和N-溴代丁二酰亚胺(10.3g,57.8mmol)溶于150mL N,N-二甲基甲酰胺中,然后在氮气保护下,在85℃下搅拌并反应16小时。反应完全后,将反应液用乙酸乙酯萃取,有机相收集后用无水硫酸钠进行干燥,再在0℃向有机相中加入冷水,过滤并收集析出的产物,得到化合物A-1-c(13g,棕色固体),产率:100%。LCMS(ESI):m/z=265[M+H]+
步骤三:
将化合物A-1-c(3g,11.32mmol)和三甲基环三硼氧烷(50%四氢呋喃)(5.8mL,20.4mmol)溶于40mL二氧六环的封管中,向反应体系中依次加入碳酸钾(4.7g,34.0mmol)和Pd(dppf)Cl2(1.6g,2.3mmol),然后在氮气保护下,在90℃下搅拌并反应5小时。反应完全后,将反应液用乙酸乙酯萃取,有机相收集后用无水硫酸钠进行干燥,再将有机相过滤后减压浓缩。残余物通过制备纯化后得到化合物A-1-d(1.2g,黄色固体),产率:52%。LCMS(ESI):m/z=201.0[M+H]+.
步骤四:
将化合物A-1-d(300mg,1.6mmol)和醋酸甲脒(62mg,0.71mmol)溶于盛有6mL乙二醇二甲醚的茄形烧瓶中,然后在氮气保护下,在110℃下搅拌并反应20小时。反应完全后,将反应液减压浓缩。残余物用水洗过滤,滤饼干燥后得到化合物A-1-e(290mg,黄色固体),产率:98%。LCMS(ESI):m/z=196.0[M+H]+
步骤五:
将化合物A-1-e(250mg,1.3mmol)和化合物Int-1(226mg,1.4mmol)溶于装有10mLN,N-二甲基甲酰胺的茄形烧瓶中,向反应体系中依次加入PyBOP(733mg,1.4mmol)、N-N-二异丙基乙胺(3.3g,25.6mmol),然后在氮气保护下,在50℃下搅拌10小时。反应完全后,将反应液用乙酸乙酯萃取,有机相收集后用无水硫酸钠进行干燥,再将有机相过滤后减压浓缩。残余物通过正相柱层析纯化后得到化合物A-1-f(180mg,黄色固体),产率:39%。LCMS(ESI):m/z=367.1[M+H]+
步骤六:
将化合物A-1-f(180mg,0.14mmol)和N-Boc-哌嗪(275mg,1.5mmol)溶于3mL二氧六环的封管中,向反应体系中依次加入碳酸铯(482mg,1.5mmol)、Binap(60mg,0.1mmol)和NHC-Pd(34mg,0.05mmol),然后在氮气保护下,在110℃下搅拌并反应8h。反应完全后,将反应液用乙酸乙酯萃取,有机相收集后用无水硫酸钠进行干燥,再将有机相过滤后减压浓缩。残余物通过制备纯化后得到化合物A-1-g(80mg,黄色固体),产率:32%。
LCMS(ESI):m/z=517.2[M+H]+
步骤七:
将化合物A-1-g(80mg,0.16mmol)溶于3mL二氯甲烷中,向反应体系中加入三氟乙酸(1mL),在常温下搅拌并反应1小时。反应完全后,将反应液减压浓缩后得到化合物A-1-h(60mg,黄色油状),产率:94%。LCMS(ESI):m/z=417.2[M+H]+
步骤八:
将化合物A-1-h(60mg,0.14mmol)和乙酸(13mg,0.18mmol)、HATU(68.5mg,0.18mmol)、N,N-二异丙基乙胺(46.5mg,0.36mmol)溶于5mL N,N-二甲基甲酰胺中,然后在室温下搅拌并反应2小时。反应完全后,将反应液用乙酸乙酯萃取,有机相收集后用无水硫酸钠进行干燥,再将有机相过滤后减压浓缩。残余物通过制备纯化后得到化合物A-1(60mg,黄色固体),产率:88%。
LCMS(ESI):m/z=459.2[M+H]+.1H NMR(400MHz,DMSO-d6):δ8.40–8.42(d,J=7.6Hz,1H),8.24(s,1H),7.59–7.63(t,J=7.2Hz,1H),7.49–7.53(t,J=7.2Hz,1H),7.10–7.34(m,3H),5.74–5.78(m,1H),3.62–3.65(m,6H),3.56–3.58(m,2H),2.70(s,3H),2.08(s,3H),1.61–1.63(d,J=7.2Hz,3H).
以下化合物按照与A-1类似的方法合成:
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实施例4:化合物A-11的合成
合成路线:
步骤一:
在三口瓶中依次加入化合物A-1-f(170mg,0.46mmol),硼酸酯(140mg,0.56mmol),碳酸钾(54mg,1.38mmol),然后加入二氧六环10mL及水1mL。加毕,在氮气保护下,100℃反应过夜。反应完毕后,粗品通过硅胶柱分离,DCM/MeOH(V/V=20/1)洗脱,得到化合物A-11-a(150mg),收率:71%。LCMS(ESI):m/z=456.2[M+H]+.
步骤二:
单口瓶中加入化合物A-11-a(40mg,0.09mmol),钯碳(0.02mmol)及10mL甲醇,氢气氛围下,室温搅拌过夜,反向制备纯化得到目标化合物A-11(20mg),白色固体,收率:50%。LCMS(ESI):m/z=458.2[M+H]+.1H NMR(400MHz,DMSO-d6):δ8.68–8.70(d,J=7.2Hz,1H),8.48(s,1H),8.05(s,1H),7.61–7.65(t,J=7.6Hz,1H),7.49–7.53(t,J=7.6Hz,1H),7.27–7.31(t,J=7.6Hz,1H),7.01–7.37(t,J=54.8Hz,1H),5.77(m,1H),4.57–4.60(m,1H),3.96–3.99(m,1H),3.17–3.23(m,1H),2.99–3.05(m,1H),2.76(s,3H),2.63–2.69(m,1H),2.05(s,1H),1.93–1.97(m,1H),1.64–1.73(m,2H),1.61–1.62(d,J=6.8Hz,3H).
以下化合物按照与A-11类似的方法合成。
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实施例5:化合物A-12的合成
合成路线:
步骤一:
将化合物A-11-a(20mg,0.044mmol)溶于二氯甲烷(0.5mL)和异丙醇(5mL)中,加入三(二戊酰基甲烷)锰(8mg,0.013mmol),苯硅烷(14mg,0.13mmol),氧气置换反应体系,室温搅拌过夜。反应液减压浓缩,反向制备分离得到目标化合物A-12(3.1mg),白色固体,收率:15%。LCMS(ESI):m/z=474.2[M+H]+.1H NMR(400MHz,CD3OD):δ8.48(s,1H),8.27(s,1H),7.57–7.61(t,J=7.2Hz,1H),7.47–7.50(t,J=7.2Hz,1H),7.21–7.25(t,J=7.6Hz,1H),6.86–7.14(t,J=54.8Hz,1H),5.81–5.87(m,1H),4.47–4.51(m,1H),3.87–3.91(m,1H),3.63–3.70(m,1H),3.13–3.30(m,2H),2.85(s,1H),2.29–2.36(m,2H),2.76(s,3H),1.63–1.74(m,2H),1.60–1.62(d,J=6.8Hz,3H).
实施例6:化合物A-13的合成
合成路线:
步骤一:
将化合物A-12(80mg,0.17mmol)溶入10mL二氯甲烷中,干冰-乙酸乙酯体系冷却到低温,加入DAST(1.2eq)。加毕,自然升至室温,搅拌过夜。反应完毕,氯化铵淬灭后,用二氯甲烷-水体系,分层。收集有机相,无水硫酸镁干燥后,旋干得到化合物A-13-a粗品,直接用于下一步。
步骤二:
在封管中加入化合物A-13-a粗品,用5mL甲醇溶解,然后缓慢加入20mg甲醇钠。密闭,70℃反应2小时。滴入少量水淬灭。反应体系,经反相制备得到目标化合物A-13(13.2mg),白色固体,两步收率:16%。LCMS(ESI):m/z=488.1[M+H]+.1H NMR(400MHz,CD3OD):δ8.49(s,1H),8.22(s,1H),7.57–7.60(t,J=7.2Hz,1H),7.47–7.50(t,J=7.2Hz,1H),7.21–7.25(t,J=7.6Hz,1H),6.87–7.14(t,J=55.2Hz,1H),5.82–5.87(m,1H),4.38(m,1H),3.56–3.63(m,2H),3.30–3.31(m,1H),3.14(s,3H),2.85(s,3H),2.17–2.27(m,3H),2.15(s,3H),2.11–2.13(m,1H),1.70–1.71(d,J=6.8Hz,3H).
实施例7:化合物A-14的合成
合成路线:
步骤一:
在封管中加入化合物A-13-a(50mg,0.11mmol),氨水1mL,二氧六环2mL。密封,100℃反应2小时。反应完毕,经反相制备得到目标化合物A-14(8.3mg),白色固体,收率:16%。LCMS(ESI):m/z=473.1[M+H]+.1H NMR(400MHz,CD3OD):δ.48(s,1H),8.17(s,1H),7.57–7.61(t,J=7.2Hz,1H),7.47–7.51(t,J=7.2Hz,1H),7.21–7.25(t,J=7.6Hz,1H),6.86–7.14(t,J=55.2Hz,1H),5.81–5.86(m,1H),4.04–4.08(m,1H),3.71–3.74(m,2H),3.50–3.71(m,1H),2.85(s,3H),2.31–2.34(m,2H),2.15(s,1H),1.82–1.91(m,2H),1.70–1.72(d,J=6.8Hz,3H).
实施例8:化合物A-15的合成
步骤一:
在三口瓶中依次加入化合物A-1-f(150mg,0.41mmol),1-羟基环己-3-烯-4-硼酸酯(110mg,0.49mmol),碳酸钾(48mg,1.23mmol),然后加入二氧六环10mL及水1mL。加毕,在氮气保护下,100℃反应过夜。反应完毕后,粗品通过硅胶柱分离,DCM/MeOH(V/V=20/1~10/1)洗脱,得到化合物A-15-a(72mg),收率:41%。LCMS(ESI):m/z=429.2[M+H]+.
步骤二:
将化合物A-15-a(60mg,0.14mmol)溶于二氯甲烷(0.5mL)和异丙醇(5mL)中,加入三(二戊酰基甲烷)锰(26mg,0.042mmol),苯硅烷(45mg,0.42mmol),氧气置换反应体系,室温搅拌过夜。反应液减压浓缩,反向制备分离得到目标化合物A-15(11mg),白色固体,收率:17%。LCMS(ESI):m/z=447.1[M+H]+.1H NMR(400MHz,DMSO-d6):δ8.93–8.97(m,1H),8.48(1H),8.42–8.45(1H),7.64–7.68(m,1H),7.49–7.53(m,1H),7.10–7.38(m,2H),5.77–5.84(m,1H),4.97–5.08(1H),4.31–4.51(m,1H),3.71(m,1H),2.72–2.73(3H),2.32–2.33(m,1H),2.00–2.09(m,1H),1.88–1.94(m,1H),1.71–1.77(m,3H),1.61–1.69(m,3H),1.52–1.56(m,1H),1.23–1.43(m,1H).
测试实施例1:化合物对KRAS-G12C/SOS1抑制作用检测
实验目的:检测受试化合物对KRAS-G12C/SOS1的抑制作用,IC50表征化合物对KRAS-G12C/SOS1的抑制能力,IC50值越低,其抑制能力越强。以BI-3406作为阳性对照化合物。
实验试剂:KRASG12C/SOS Binding kit(Cisbio,cat.63ADK000CB16PEG);DMSO(Sigma,cat.D8418-1L);384-孔白板(PerkinElmer,cat.6007290)
实验方法:
1、化合物配制:用100%DMSO溶解为10mM储存液,于冰箱避光保存。
2、激酶反应过程:
(1)化合物的配制:受试化合物浓度为5000nM,384孔板中稀释成200倍终浓度的100%DMSO溶液,3倍稀释化合物,10个浓度。使用分液器Echo550向目的板384孔板转移50nL200倍终浓度的化合物。阴性对照孔和阳性对照孔中分别加50nL100%DMSO。
(2)用Diluent buffer配制4倍终浓度的Tag1-SOS1溶液。
(3)在384孔板中加入2.5μlL的4倍终浓度的Tag1-SOS1溶液。
(4)用Diluent buffer配制4倍终浓度的Tag2-KRAS-G12C溶液。
(5)在化合物孔和阳性对照孔分别加2.5μL的4倍终浓度的Tag2-KRAS-G12C溶液;在阴性对照孔中加2.5μL的diluent buffer。
(6)将384孔板1000rpm离心30秒,振荡混匀后室温孵育15分钟。
(7)用Detection buffer配制1倍终浓度的Anti-Tag1-TB3+溶液和1倍终浓度的Anti-Tag2-XL665溶液,将两溶液混匀之后得到Mix溶液,每孔加5μL的Mix溶液。
(8)将384孔板1000rpm离心30秒,振荡混匀后4℃孵育120分钟。
(9)用Envision酶标仪读数Em665/620。
数据分析
计算公式
Inhibition%=(Max signal-Compound signal)/(Max signal-Min signal)×100
其中Min signal为阴性对照孔均值,Max signal为阳性对照孔均值。
拟合量效曲线
以浓度的log值作为X轴,百分比抑制率为Y轴,采用分析软件GraphPadPrism5的log(inhibitor)vs.response-Variable slope拟合量效曲线,从而得出各个化合物对酶活性的IC50值。
拟合公式为:Y=Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))
实施例化合物对KRAS-G12C/SOS1相互作用的抑制活性如下表1所示。
表1实施例化合物对KRAS-G12C/SOS1相互作用的抑制活性
化合物编号 | IC50 |
A-1 | A |
A-2 | A |
A-3 | A |
A-5 | A |
A-6 | A |
A-11 | A |
A-12 | A |
A-13 | A |
A-14 | A |
A-15 | A |
A-16 | A |
A-17 | A |
A-23 | A |
注:IC50中“A”表示IC50≤200nM,“B”表示200nM<IC50≤2000nM,“C”表示2000nM<IC50≤5000nM,“D”表示IC50>5000nM,“//”表示未测定。
从表1中给出的数据可以看出,本申请的化合物表现出显著优异的KRAS-G12C/SOS1相互作用抑制活性,因此,具备作为SOS1抑制剂的潜力,可以被开发成用于与此相关的疾病的治疗药物。
Claims (10)
1.下式I的化合物,其对映异构体、非对映异构体、外消旋体、前药、水合物、溶剂化物或其药学上可接受的盐:
在式I中,环A表示C6-10芳基、5-10元杂芳基或4-10元饱和或不饱和杂环基;
n为0~5的整数;
每个R3独立地选自:无取代或取代的C1-4烷基、无取代或取代的C1-4烷氧基、无取代或取代的C2-4炔基、无取代或取代的C3-6环烷基、无取代或取代的4-6元饱和或不饱和杂环基、羟基、卤素、氰基、氨基、或氧代基团(=O);所述取代是指被选自卤素、羟基、氰基和氨基中的一种或多种取代基所取代;当环A为C6-10芳基或5-10元杂芳基时,R3不为氧代基团(=O);
R1为氢、卤素、羟基、无取代或取代的C1-6烷基、无取代或取代的C3-6环烷基、无取代或取代的4-10元饱和或不饱和杂环基、无取代或取代的C1-6烷氧基、-CN、-COOH、-CONH2、-CONH-C1-6烷基、氨基、或-NH-C1-6烷基;
R2为氢、无取代或取代的C1-6烷基、或无取代或取代的C3-6环烷基;
R4为氢、无取代或取代的C1-10烷基、无取代或取代的C6-10芳基、无取代或取代的5-10元杂芳基、无取代或取代的C3-6环烷基、无取代或取代的4-10元饱和或不饱和杂环基、无取代或取代的5-10元杂芳基并4-10元杂环基、卤素、-CN、-COOH、-OR5、-NH-R5、-CONH-R5、-NHCO-R5、-SO2-R5、或-SO2NH-R5;
R5选自氢、无取代或取代的C1-10烷基、无取代或取代的C6-10芳基、无取代或取代的5-10元杂芳基、无取代或取代的C3-6环烷基、无取代或取代的4-10元饱和或不饱和杂环基;
其中,R1、R2、R4、R5中的取代是指被选自如下A组取代基中的一种或多种所取代,A组取代基包括:无取代或被B组取代基中一种或多种所取代的C1-6烷基、C1-6烷氧基、羟基、卤素、氰基、氨基、羧基、氧代基团(=O)、-NH-C1-6烷基、-NH-C3-6环烷基、无取代或被B组取代基中一种或多种取代的C6-10芳基、无取代或被B组取代基中的一种或多种所取代的5-10元杂芳基、无取代或被B组取代基中一种或多种取代的C3-6环烷基、无取代或被B组取代基中一种或多种取代的4-10元饱和或不饱和杂环基、-C(O)-R6、-C(O)-NH-R6、-NH-C(O)-R6、-SO2-R6、-SO2NH-R6;R6选自氢、无取代或被B组取代基中一种或多种所取代的C1-10烷基、无取代或被B组取代基中的一种或多种所取代的C6-10芳基、无取代或被B组取代基中的一种或多种所取代的5-10元杂芳基、无取代或被B组取代基中的一种或多种所取代的C3-6环烷基、无取代或被B组取代基中的一种或多种所取代的4-10元饱和或不饱和杂环基;B组取代基包括:C1-6烷基、C1-6烷氧基、羟基、卤素、氰基、氨基、羧基。
2.根据权利要求1所述的化合物,其对映异构体、非对映异构体、外消旋体、前药、水合物、溶剂化物或其药学上可接受的盐,
其中,在式I中,R2为甲基或乙基,环A为苯基;
n为1或2,每个R3独立地选自:取代或无取代的C1-4烷基、取代或无取代的C2-4炔基、取代或无取代的4-6元饱和或不饱和杂环基、卤素、氰基或氨基;所述取代是指被选自卤素、羟基、氰基、氨基中的一种或多种取代基所取代;
其他取代基如权利要求1中所定义。
3.根据权利要求1所述的化合物,其对映异构体、非对映异构体、外消旋体、前药、水合物、溶剂化物或其药学上可接受的盐,
其中,在式I中,R1选自氢、卤素、羟基、无取代或取代的C1-4烷基、无取代或取代的C3-6环烷基、无取代或取代的C1-4烷氧基、-CN、-COOH、氨基;所述取代是指被选自羟基、卤素、氰基、氨基中的一种或多种所取代;
优选地,R1选自氢、卤素、羟基、-CN、甲基、乙基、甲氧基、乙氧基、氨基、环丙基;
更优选地,R1选自氢、卤素、-CN、甲基、甲氧基、环丙基;
其他取代基如权利要求1中所定义。
4.根据权利要求1所述的化合物,其对映异构体、非对映异构体、外消旋体、前药、水合物、溶剂化物或其药学上可接受的盐,
其中,在式I中,R4选自无取代或取代的C1-10烷基、无取代或取代的C6-10芳基、无取代或取代的5-10元杂芳基、无取代或取代的C3-6环烷基、无取代或取代的4-10元饱和或不饱和杂环基;优选地,R4选自无取代或取代的C1-10烷基、无取代或取代的C6-10芳基、无取代或取代的5-6元杂芳基、无取代或取代的C3-6环烷基、无取代或取代的4-10元杂环基;
R4中的取代是指被选自如下A组取代基中的一种或多种所取代,A组取代基包括:无取代或被B组取代基中一种或多种所取代的C1-6烷基、C1-6烷氧基、羟基、卤素、氰基、氨基、羧基、氧代基团(=O)、-C(O)-R6、-C(O)-NH-R6;R6选自氢、无取代或被B组取代基中一种或多种所取代的C1-10烷基、无取代或被B组取代基中的一种或多种所取代的C3-6环烷基;
B组取代基包括:C1-6烷基、C1-6烷氧基、羟基、卤素、氰基、氨基、羧基;
特别地,
所述5-6元杂芳基选自:
所述4-10元杂环基选自:
更优选地,R4选自无取代或被m个取代基R7取代的C1-10烷基、及如下结构:
m为1、2或3;
R7和R8各自独立地选自H、无取代或被B组取代基中一种或多种所取代的C1-6烷基、C1-6烷氧基、羟基、卤素、氰基、氨基、羧基、-C(O)-R9;R9选自氢、无取代或被B组取代基中一种或多种所取代的C1-10烷基、无取代或被B组取代基中的一种或多种所取代的C3-6环烷基;B组取代基包括:C1-6烷基、C1-6烷氧基、羟基、卤素、氰基、氨基、羧基;
其他取代基如权利要求1中所定义。
5.根据权利要求1所述的化合物,其对映异构体、非对映异构体、外消旋体、前药、水合物、溶剂化物或其药学上可接受的盐,其中,式I的化合物由下式II表示:
在上式II中,各取代基的定义分别如权利要求1中所定义。
6.根据权利要求1所述的化合物,其对映异构体、非对映异构体、外消旋体、前药、水合物、溶剂化物或其药学上可接受的盐,其中,式I的化合物由下式III表示:
在上式III中,各取代基的定义分别如权利要求1中所定义。
7.根据权利要求1所述的化合物,其对映异构体、非对映异构体、外消旋体、前药、水合物、溶剂化物或其药学上可接受的盐,其中,式(I)的化合物选自如下化合物:
8.一种药物组合物,包括:
(1)治疗有效量的如权利要求1至7中任一项所述的式I的化合物,其对映异构体、非对映异构体、外消旋体、前药、水合物、溶剂化物或其药学上可接受的盐作为活性成分;和
(2)药学上可接受的载体。
9.如权利要求1至7中任一项所述的式I的化合物,其对映异构体、非对映异构体、外消旋体、前药、水合物、溶剂化物或其药学上可接受的盐,或如权利要求8所述的药物组合物在制备SOS1抑制剂中的用途。
10.如权利要求1至7中任一项所述的式I的化合物,其对映异构体、非对映异构体、外消旋体、前药、水合物、溶剂化物或其药学上可接受的盐,或如权利要求8所述的药物组合物在制备用于预防和/或治疗与SOS1突变、活性或表达量相关的疾病的药物中的用途,
其中,所述与SOS1突变、活性或表达量相关的疾病包括头颈癌、肺癌、纵隔肿瘤、胃肠道肿瘤、前列腺癌、睾丸癌、妇科肿瘤、乳腺癌、肾脏和膀胱癌、内分泌系统肿瘤、软组织肉瘤、骨肉瘤、横纹肌样瘤、间皮细胞瘤、皮肤癌、外周神经系统肿瘤、中枢神经系统肿瘤、淋巴瘤、白血病,未知原发癌、努南综合征、心面皮肤综合征、遗传性牙龈纤维瘤病及其相关综合征。
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