CN116332960A - 一种哒嗪类化合物、其药物组合物及应用 - Google Patents
一种哒嗪类化合物、其药物组合物及应用 Download PDFInfo
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- CN116332960A CN116332960A CN202210622049.5A CN202210622049A CN116332960A CN 116332960 A CN116332960 A CN 116332960A CN 202210622049 A CN202210622049 A CN 202210622049A CN 116332960 A CN116332960 A CN 116332960A
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Classifications
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- 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
-
- 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
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
-
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- 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
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
Abstract
本发明提供一种哒嗪类化合物、其药物组合物及应用。具体地,所述的化合物具有式I所示的结构,其能够干扰SOS1蛋白与RAS蛋白之间的相互作用,有望用于制备治疗RAS突变的肿瘤等疾病的药物。
Description
技术领域
本发明属于药物化学领域,具体涉及一种哒嗪类化合物、其药物组合物及应用。
背景技术
大鼠肉瘤蛋白(RAS蛋白)是人体内重要的信号传导调节因子,调控包括细胞增殖、分化、迁移和生存等重要生理过程。RAS属于三磷酸鸟苷水解酶(GTPase),通过RAS与三磷酸鸟苷(GTP)结合的活性状态和RAS与二磷酸鸟苷(GDP)结合的失活状体的循环调控下游RAF/MEK/ERK和PI3K/AKT等多条重要的信号通路。这一循环包括两个过程,其中负向调节通过GTPase激活蛋白(GAP)催化RAS-GTP水解为RAS-GDP,正向调节的鸟苷酸交换因子(GEF)催化RAS与GDP解离,随后RAS会与细胞内高浓度的GTP结合。SOS1(Son of Sevenless 1)是人体内表达最广泛,功能最重要的GEF之一。
RAS蛋白家族包括KRAS(kirsten rat sarcoma viral oncogene),NRAS(neuroblastoma RAS viral oncogene)和HRAS(Harvey murine sarcoma viraloncogene),其中KRAS突变导致的肿瘤最为常见。KRAS突变导致蛋白一直处于RAS-GTP的状态,持续激活下游信号通路,在这一致癌生理过程中SOS1扮演这重要的角色。敲除SOS1能有效降低KRAS突变肿瘤的生长速度,并且不影响KRAS野生型细胞系的生长。
小分子抑制剂结合在SOS1的催化口袋,影响SOS1与RAS蛋白的结合,可以有效的抑制RAS信号通路下游如ERK(extracellular regulated protein kinases)磷酸化水平,从而抑制肿瘤的生长。目前,勃林格殷格翰公司开发的小分子SOS1抑制剂BI-1701963(WO2018115380,WO2019122129)正处于I期临床研究阶段,并且与Mirati公司的KRAS G12C抑制剂MRTX-849合作开发联合用药的方案。此外,拜耳公司(WO2018172250,WO2019201848)和Revolution公司(WO2020180770,WO2020180768)也在这一领域发表了多篇专利,但是本领域仍然迫切需要研发出能够抑制SOS1与RAS突变蛋白相互作用的有效药物。
发明内容
本发明目的是提供一种新的哒嗪类化合物和包含其的药物组合物,其可以有效抑制SOS1与RAS突变蛋白相互作用。
本发明的第一方面,提供一种式I所示的化合物、其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、顺反异构体、溶剂化物、多晶型物、氘代物或其组合,
其中,
X1选自:CH、氧原子、硫原子、氮原子或-NH;优选地,X1为CH;
X2选自:硫原子、氧原子、氮原子、-NRx-或-CRx、;其中,Rx选自:H、任选取代的C1-C3烷基;优选地,X2为硫原子;其中,所述取代是指被一个或多个R取代;
R1选自:H、卤素、任选取代的C1-C3烷基、任选取代的C3-C8碳环基、任选取代的4-8元杂环基、氰基、或/>其中,R1a和R1b各自独立地选自:H、任选取代的C1-C6烷基、任选取代的C3-C8碳环基或任选取代的4-8元杂环基;其中,所述取代是指被一个或多个R取代;
R2选自:任选取代的C1-C6烷基、任选取代的C3-C16碳环基、任选取代的4-16元杂环基;其中,所述取代是指被一个或多个R取代;
A环选自:任选取代的C6-C16芳基、任选取代的5-16元杂芳基、任选取代的C3-C16碳环并C6-C10芳基、任选取代的4-16元杂环并C6-C10芳基、任选取代的C3-C16碳环并5-16元杂芳基或任选取代的4-16元杂环并5-16元杂芳基;其中,所述取代是指被一个或多个R取代;
R各自独立地选自:H、卤素、氰基、氨基、羟基、氧代基任选取代的C1-C6烷基、任选取代的C2-C6烯基、任选取代的C2-C6炔基、任选取代的C1-C6烷氧基、任选取代的C1-C6烷基砜基、任选取代的C3-C16碳环基、任选取代的4-16元杂环基、任选取代的C6-C16芳基或任选取代的5-16元杂芳基;或任意相邻的2个R和与其相连的原子形成任选取代的4-8元杂环基或任选取代的C3-C8元碳环基;其中,R中所述取代是指被选自下组的一个或多个基团取代:H、卤素、氰基、氨基、羟基、氧代基/>R’取代或未取代的C1-C6烷基、R’取代或未取代的C1-C6烷氧基、R’取代或未取代的C1-C6烷基砜基、R’取代或未取代的C3-C16碳环基、R’取代或未取代的4-16元杂环基、R’取代或未取代的C6-C16芳基、R’取代或未取代的5-16元杂芳基、-N(R’取代或未取代的C1-C6烷基)2、-CH2-N(R’取代或未取代的C1-C6烷基)2,其中,R’选自下组的一个或多个基团:H、卤素、氘(D)、卤素、-OH、氧代(=O)、巯基、氰基、-CD3、C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C8环烷基和4-8元杂环基,其中所述的烷基、烯基、炔基、环烷基和杂环基中的每一个任选被一个或多个选自以下的取代基进一步取代:H、C1-C6烷基、C1-C6烷氧基、卤素、-OH、氧代(=O)、-NH2、-N(R”取代或未取代的C1-C6烷基)2、-NH(C1-C6烷基)、-N(C1-C6烷基)(C1-C6烷基苯基)、-NH(C1-C6烷基苯基)、-N(C1-C6烷基)(芳基)、-NH(芳基)、C3-C8环烷基、4-8元杂环基、C1-C4卤代烷基-、-C1-C4烷基-OH、-C1-C4烷基-O-C1-C4烷基、-OC1-C4卤代烷基、氰基、硝基、-C(O)-OH、-C(O)OC1-C6烷基、-CON(C1-C6烷基)2、-CONH(C1-C6烷基)、-CONH2、-NHC(O)(C1-C6烷基)、-NH(C1-C6烷基)C(O)(C1-C6烷基)、-SO2(C1-C6烷基)、-SO2(苯基)、-SO2(C1-C6卤代烷基)、-SO2NH2、-SO2NH(C1-C6烷基)、-SO2NH(苯基)、-NHSO2(C1-C6烷基)、-NHSO2(苯基)、-NHSO2(C1-C6卤代烷基)和-C1-C6烷基-NH2,其中R”选自下组的一个或多个基团:H、卤素、氰基、氨基、羟基、氧代基C1-C6烷基和C1-C6烷氧基;
在另一优选例中,所述R1选自:H、卤素、任选取代的C1-C3烷基或任选取代的C3-C8碳环基,优选地,R1选自:H、卤素或甲基;其中,所述取代是指被一个或多个R取代,R的定义如上所述。
在另一优选例中,所述A环选自:任选取代的C6-C10芳基、任选取代的5-10元杂芳基、任选取代的C3-C8碳环并C6-C10芳基、任选取代的4-8元杂环并C6-C10芳基、任选取代的C3-C8碳环并5-10元杂芳基或任选取代的4-8元杂环并5-10元杂芳基;优选地A环为任选取代的苯基、5-6元杂芳基、任选取代的C3-C8碳环并苯基、任选取代的4-8元杂环并苯基、任选取代的C3-C8碳环并5-6元杂芳基或任选取代的4-8元杂环并5-6元杂芳基;更优选地,A环选自:任选取代的苯基、任选取代的吡啶基、任选取代的吡嗪基、任选取代的噻吩基、任选取代的呋喃基、任选取代的吡咯基、任选取代的噻唑基、任选取代的咪唑基、任选取代的吡唑基;其中,所述取代是指被一个或多个R取代;R的定义如上所述。
在另一优选例中,所述A环为 其中,q为0、1、2、3或4,每个Rd各自独立的选自:H、卤素、氨基、羟基、氰基、任选取代的C1-C6烷基、任选取代的C1-C6烷氧基、任选取代的C1-C6烷基砜基、任选取代的C3-C16碳环基、任选取代的4-16元杂环基、任选取代的C6-C16芳基或任选取代的5-16元杂芳基,或任意相邻的2个Rd和与其相连的碳原子形成任选取代的4-8元杂环基或任选取代的C3-C8元碳环基;
其中,所述取代是指被选自下组的一个或多个基团取代:H、卤素、氰基、氨基、羟基、氧代基R’取代或未取代的C1-C6烷基、R’取代或未取代的C1-C6烷氧基、R’取代或未取代的C1-C6烷基砜基、R’取代或未取代的C3-C16碳环基、R’取代或未取代的4-16元杂环基、-N(R’取代或未取代的C1-C6烷基)2、-CH2-N(R’取代或未取代的C1-C6烷基)2、和-CH2-(4-8元杂环基),其中,R’选自下组的一个或多个基团:H、卤素、氰基、氨基、羟基、氧代基C1-C6烷基和C1-C6烷氧基;
在另一优选例中,所述A环选自:
其中,Rd1、Rd2、Rd3分别独立地选自:H、卤素、氨基、羟基、氰基、任选取代的C1-C6烷基、任选取代的C1-C6烷氧基、任选取代的C1-C6烷基砜基、任选取代的C3-C16碳环基、任选取代的4-16元杂环基、任选取代的C6-C16芳基或任选取代的5-16元杂芳基;Rd4分别独立地选自:卤素、任选取代的C1-C6烷基和q为0、1、2或3;Rd5选自:氢、任选取代的C6-C10元芳香基或任选取代的5-16元杂芳香环基;Z选自:O或NRN;RN选自:H或任选取代的C1-C6烷基;
其中,所述取代是指被选自下组的一个或多个基团取代:H、卤素、氰基、氨基、羟基、氧代基R’取代或未取代的C1-C6烷基、C1-C6烷氧基、C1-C6烷基砜基、C3-C16碳环基、4-16元杂环基、-N(R’取代或未取代的C1-C6烷基)2、-CH2-N(R’取代或未取代的C1-C6烷基)2、和-CH2-(4-8元杂环基),其中R’选自下组的一个或多个基团:H、卤素、氰基、氨基、羟基、氧代基/>C1-C6烷基和C1-C6烷氧基;
R2’选自:甲基、乙基、丙基、单氟甲基、二氟甲基、三氟甲基、甲氧基、二氟甲氧基、三氟甲氧基、甲硫基、二氟甲硫基、三氟甲硫基、氰基、卤素、羟甲基或甲氧基甲基;
B环选自:任选取代的C3-C16碳环基或任选取代的4-16元杂环基;其中,所述取代是指被一个或多个R取代;R的定义如上所述;
在另一优选例中,B环选自:任选取代的C3-C11碳环基或任选取代的4-11元杂环基,更优选地,B环选自:任选取代的C5-C11碳环基或任选取代的5-11元杂环基,更优选地,B环选自:任选取代的C5-C8碳环基或任选取代的5-8元杂环基,更优选地,B环为任选取代的6元杂环基,如,任选取代的四氢吡喃基任选取代的哌啶基/>其中,所述取代是指被一个或多个R取代;R的定义如上所述。
在另一优选例中,X1、X2、R1、R2、A环、B环和R2’为实施例中具体化合物所对应基团。
在另一优选例中,所述化合物选自下组:
本发明第二方面,提供一种式II所示的化合物、或其盐、溶剂化物、多晶型物或氘代物,
本发明第三方面,提供一种药物组合物,其中,所述药物组合物包括:
(1)治疗有效量的选自第一方面所述的化合物、其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、顺反异构体、溶剂化物、多晶型物和氘代物中的一种或多种作为活性成分;和
(2)任选地,药学上可接受的载体。
本发明第四方面,提供一种第一方面所述的化合物、其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、顺反异构体、溶剂化物、多晶型物或氘代物或第三方面所述的药物组合物在制备预防或治疗RAS突变介导的癌症的药物中的用途。
在另一优选例中,所述癌症选自:肺癌、胰腺癌、结直肠癌、白血病、尤文氏肉瘤、乳腺癌、前列腺癌、T细胞淋巴瘤、B细胞淋巴瘤、恶性横纹肌瘤、滑膜肉瘤、子宫内膜瘤、胃癌、肝癌、肾癌、黑色素瘤、卵巢癌、脑胶质瘤、胆管癌、鼻咽癌、宫颈癌、头颈癌、食管癌、甲状腺癌和膀胱癌,特别是选自非小细胞肺癌、胰腺癌和结直肠癌。
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。限于篇幅,在此不再一一累述。
具体实施方式
本发明人经过广泛而深入地研究,开发了一种新的哒嗪类化合物,其可以有效抑制SOS1与RAS突变蛋白相互作用。在此基础上完成了本发明。
术语说明
除非另外定义,否则本文中所用的全部技术与科学术语均具有如本发明所属领域的普通技术人员通常理解的相同含义。
如本文所用,术语“含有”或“包括(包含)”可以是开放式、半封闭式和封闭式的。换言之,所述术语也包括“基本上由…构成”、或“由…构成”。
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,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数按重量计算。
基团定义
可在参考文献(包括Carey and Sundberg"ADVANCED ORGANIC CHEMISTRY 4THED."Vols.A(2000)and B(2001),Plenum Press,New York)中找到对标准化学术语的定义。除非另有说明,否则采用本领域技术范围内的常规方法,如质谱、NMR、IR和UV/VIS光谱法和药理学方法。除非提出具体定义,否则本文在分析化学、有机合成化学以及药物和药物化学的有关描述中采用的术语是本领域已知的。可在化学合成、化学分析、药物制备、制剂和递送,以及对患者的治疗中使用标准技术。例如,可利用厂商对试剂盒的使用说明,或者按照本领域公知的方式或本发明的说明来实施反应和进行纯化。通常可根据本说明书中引用和讨论的多个概要性和较具体的文献中的描述,按照本领域熟知的常规方法实施上述技术和方法。在本说明书中,可由本领域技术人员选择基团及其取代基以提供稳定的结构部分和化合物。
当通过从左向右书写的常规化学式描述取代基时,该取代基也同样包括从右向左书写结构式时所得到的在化学上等同的取代基。举例而言,-CH2O-等同于-OCH2-。
本文所用的章节标题仅用于组织文章的目的,而不应被解释为对所述主题的限制。本申请中引用的所有文献或文献部分包括但不限于专利、专利申请、文章、书籍、操作手册和论文,均通过引用方式整体并入本文。
在本文中定义的某些化学基团前面通过简化符号来表示该基团中存在的碳原子总数。例如,C1-C6烷基是指具有总共1至6个碳原子的如下文所定义的烷基。简化符号中的碳原子总数不包括可能存在于所述基团的取代基中的碳。
除前述以外,当用于本申请的说明书及权利要求书中时,除非另外特别指明,否则以下术语具有如下所示的含义。
在本申请中,术语“卤素”是指氟、氯、溴或碘。
“羟基”是指-OH基团。
“羟基烷基”是指被羟基(-OH)取代的如下文所定义的烷基。
“羰基”是指-C(=O)-基团。
“硝基”是指-NO2。
“氰基”是指-CN。
“氨基”是指-NH2。
“取代的氨基”是指被一个或两个如下文所定义的烷基、烷基羰基、芳基烷基、杂芳基烷基取代的氨基,例如,单烷基氨基、二烷基氨基、烷基酰氨基、芳基烷基氨基、杂芳基烷基氨基。
“羧基”是指-COOH。
在本申请中,作为基团或是其它基团的一部分(例如用在卤素取代的烷基等基团中),术语“烷基”是指完全饱和的直链或支链的烃链基,仅由碳原子和氢原子组成、具有例如1至12个(优选为1至8个,更优选为1至6个)碳原子,且通过1个或多个单键与分子的其余部分连接,例如包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、2-甲基丁基、2,2-二甲基丙基、正己基、庚基、2-甲基己基、3-甲基己基、辛基、壬基和癸基等。就本发明而言,术语“烷基”优选指含有1至6个碳原子的烷基。
在本申请中,作为基团或是其它基团的一部分,术语“烯基”意指仅由碳原子和氢原子组成、含有至少一个双键、具有例如2至14个(优选为2至10个,更优选为2至6个)碳原子且通过1个或多个单键与分子的其余部分连接的直链或支链的烃链基团,例如但不限于乙烯基、丙烯基、烯丙基、丁-1-烯基、丁-2-烯基、戊-1-烯基、戊-1,4-二烯基等。
本文中作为基团或是其它基团的一部分,术语“炔基”意指仅由碳原子和氢原子组成、含有至少一个碳-碳三键、具有例如2至14个(优选为2至10个,更优选为2至6个)碳原子且通过1个或多个单键与分子的其余部分连接的直链或支链的烃链基团,例如但不限于乙炔基、1-丙炔基、1-丁炔基、庚炔基、辛炔基等。
在本申请中,作为基团或是其它基团的一部分,术语“碳环(基)”意指仅由碳原子和氢原子组成的稳定的非芳香族单环或多环烃基,其可包括稠合环体系、桥环体系或螺环体系,具有3至16个碳原子,优选具有3至10个碳原子,更优选具有3至8个碳原子,更优选3至6个碳原子,且其为饱和或不饱和环(即环烷基、环烯基等)并可经由任何适宜的碳原子通过1个或多个单键与分子的其余部分连接。除非本说明书中另外特别指明,碳环基中的碳原子可以任选地被氧化。碳环基的实例包括但不限于环丙基、环丁基、环戊基、环己基、环庚基、环辛基、金刚烷基、2,3-二氢化茚基、八氢-4,7-亚甲基-1H-茚基、1,2,3,4-四氢-萘基、5,6,7,8-四氢-萘基、环戊烯基、环己烯基、环己二烯基、1H-茚基、8,9-二氢-7H-苯并环庚烯-6-基、6,7,8,9-四氢-5H-苯并环庚烯基、5,6,7,8,9,10-六氢-苯并环辛烯基、芴基、二环[1.1.1]戊烷、二环[2.2.1]庚基、7,7-二甲基-二环[2.2.1]庚基、二环[2.2.1]庚烯基、二环[2.2.2]辛基、二环[3.1.1]庚基、二环[3.2.1]辛基、二环[2.2.2]辛烯基、二环[3.2.1]辛烯基和八氢-2,5-亚甲基-并环戊二烯基等。
在本申请中,作为基团或是其它基团的一部分,术语“环烷基”是指上述完全饱和的碳环(基),典型的环烷基包括但不限于环丙基、环丁基、环戊基、环己基、环庚基、环辛基、金刚烷基等。
在本申请中,作为基团或是其它基团的一部分,术语“环烯基”是指部分不饱和的碳环(基),典型的环烯基包括但不限于环丁烯基、环戊烯基、环己烯基等。
在本申请中,作为基团或是其它基团的一部分,术语“杂环(基)”意指由2至14个碳原子以及1至6个选自氮、磷、氧和硫的杂原子组成的稳定的3元至20元非芳香族环状基团。除非本说明书中另外特别指明,否则杂环基可以为单环、双环、三环或更多环的环体系,其可包括稠合环体系、桥环体系或螺环体系;其杂环基中的氮、碳或硫原子可任选地被氧化;氮原子可任选地被季铵化;且杂环基可为部分或完全饱和。杂环基可以经由碳原子或者杂原子并通过1个或多个单键与分子其余部分连接。在包含稠环的杂环基中,一个或多个环可以是下文所定义的芳基或杂芳基,条件是与分子其余部分的连接点为非芳香族环原子。就本发明的目的而言,杂环基优选为包含1至3个选自氮、氧和硫的杂原子的稳定的4元至11元非芳香性单环、双环、桥环或螺环基团,更优选为包含1至3个选自氮、氧和硫的杂原子的稳定的4元至8元非芳香性单环、双环、桥环或螺环基团。杂环基的实例包括但不限于:吡咯烷基、吗啉基、哌嗪基、高哌嗪基、哌啶基、硫代吗啉基、2-氮杂双环[2.2.2]辛烷基、2,7-二氮杂-螺[3.5]壬烷-7-基、2-氧杂-6-氮杂-螺[3.3]庚烷-6-基、2,5-二氮杂-双环[2.2.1]庚烷-2-基、氮杂环丁烷基、吡喃基、四氢吡喃基、噻喃基、四氢呋喃基、噁嗪基、二氧环戊基、四氢异喹啉基、十氢异喹啉基、咪唑啉基、咪唑烷基、喹嗪基、噻唑烷基、异噻唑烷基、异噁唑烷基、二氢吲哚基、八氢吲哚基、八氢异吲哚基、吡咯烷基、吡唑烷基、邻苯二甲酰亚氨基等。
在本申请中,作为基团或是其它基团的一部分,术语“芳基”意指具有6至18个碳原子(优选具有6至10个碳原子)的共轭烃环体系基团。就本发明的目的而言,芳基可以为单环、双环、三环或更多环的环体系,还可以与上文所定义的碳环基或杂环基稠合,条件是芳基经由芳香环上的原子通过1个或多个单键与分子的其余部分连接。芳基的实例包括但不限于苯基、萘基、蒽基、菲基、芴基、2,3-二氢-1H-异吲哚基、2-苯并噁唑啉酮、2H-1,4-苯并噁嗪-3(4H)-酮-7-基等。
在本申请中,术语“芳基烷基”是指被上文所定义的芳基所取代的上文所定义的烷基。
在本申请中,作为基团或是其它基团的一部分,术语“杂芳基”意指环内具有1至15个碳原子(优选具有1至10个碳原子)和1至6个选自氮、氧和硫的杂原子的5元至16元共轭环系基团。除非本说明书中另外特别指明,否则杂芳基可为单环、双环、三环或更多环的环体系,还可以与上文所定义的碳环基或杂环基稠合,条件是杂芳基经由杂芳香环上的原子通过1个或多个单键与分子的其余部分连接。杂芳基中的氮、碳或硫原子可任选地被氧化;氮原子可任选地被季铵化。就本发明的目的而言,杂芳基优选为包含1至5个选自氮、氧和硫的杂原子的稳定的5元至12元芳香性基团,更优选为包含1至4个选自氮、氧和硫的杂原子的稳定的5元至10元芳香性基团或者包含1至3个选自氮、氧和硫的杂原子的5元至6元芳香性基团。杂芳基的实例包括但不限于噻吩基、咪唑基、吡唑基、噻唑基、噁唑基、噁二唑基、异噁唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、苯并咪唑基、苯并吡唑基、吲哚基、呋喃基、吡咯基、三唑基、四唑基、三嗪基、吲嗪基、异吲哚基、吲唑基、异吲唑基、嘌呤基、喹啉基、异喹啉基、二氮萘基、萘啶基、喹噁啉基、蝶啶基、咔唑基、咔啉基、菲啶基、菲咯啉基、吖啶基、吩嗪基、异噻唑基、苯并噻唑基、苯并噻吩基、噁三唑基、噌啉基、喹唑啉基、苯硫基、中氮茚基、邻二氮杂菲基、异噁唑基、吩噁嗪基、吩噻嗪基、4,5,6,7-四氢苯并[b]噻吩基、萘并吡啶基、[1,2,4]三唑并[4,3-b]哒嗪、[1,2,4]三唑并[4,3-a]吡嗪、[1,2,4]三唑并[4,3-c]嘧啶、[1,2,4]三唑并[4,3-a]吡啶、咪唑并[1,2-a]吡啶、咪唑并[1,2-b]哒嗪、咪唑并[1,2-a]吡嗪等。
在本申请中,术语“杂芳基烷基”是指被上文所定义的杂芳基所取代的上文所定义的烷基。
在本申请中,术语“不存在”是指被上文所定义的基团的两侧直接通过化学键相连。例如,“A-B-C中B是不存在”表示“A-C”。
在本申请中,除权利要求中特殊说明外,“任选地”、“任选”表示随后描述的事件或状况可能发生也可能不发生,且该描述同时包括该事件或状况发生和不发生的情况。例如,“任选取代的芳基”表示芳基上的氢被取代或未被取代,且该描述同时包括被取代的芳基与未被取代的芳基。例如,在没有明确列出取代基的情况下,本文所用的术语“任选取代的”、“被取代的”或“被……取代”意指给定的原子或基团上的一个或多个氢原子独立地被一个或多个、例如1、2、3或4个取代基取代,所述取代基独立地选自:氘(D)、卤素、-OH、氧代(=O)、巯基、氰基、-CD3、-C1-C6烷基(优选-C1-3烷基)、C2-C6烯基、C2-C6炔基、碳环基(优选C3-C8碳环基)、芳基、杂环基(优选3-8元杂环基)、杂芳基、芳基-C1-C6烷基-、杂芳基-C1-C6烷基-、C1-C6卤代烷基-、-OC1-C6烷基(优选-OC1-C3烷基)、-OC2-C6烯基、-O环烷基、-O杂环基、-O芳基、-O杂芳基、-OC1-C6烷基苯基、-C1-C6烷基-OH(优选-C1-C4烷基-OH)、-C1-C6烷基-SH、-C1-C6烷基-O-C1-C6烷基、-OC1-C6卤代烷基、-NH2、-C1-C6烷基-NH2(优选-C1-C3烷基-NH2)、-N(C1-C6烷基)2(优选-N(C1-C3烷基)2)、-NH(C1-C6烷基)(优选-NH(C1-C3烷基))、-N(C1-C6烷基)(C1-C6烷基苯基)、-NH(C1-C6烷基苯基)、-N(C1-C6烷基)(芳基)、-NH(芳基)、硝基、-C(O)-OH、-C(O)OC1-C6烷基(优选-C(O)OC1-C3烷基)、-CONRiRii(其中Ri和Rii是H、D和C1-6烷基,优选C1-3烷基)、-NHC(O)(C1-C6烷基)、-NHC(O)(苯基)、-N(C1-C6烷基)C(O)(C1-C6烷基)、-N(C1-C6烷基)C(O)(苯基)、-C(O)C1-C6烷基、-C(O)杂芳基(优选-C(O)-5-7元杂芳基)、-C(O)C1-C6烷基苯基、-C(O)C1-C6卤代烷基、-OC(O)C1-C6烷基(优选-OC(O)C1-C3烷基)、-S(O)2-C1-C6烷基、-S(O)-C1-C6烷基、-S(O)2-苯基、-S(O)2-C1-C6卤代烷基、-S(O)2NH2、-S(O)2NH(C1-C6烷基)、-S(O)2NH(苯基)、-NHS(O)2(C1-C6烷基)、-NHS(O)2(苯基)和-NHS(O)2(C1-C6卤代烷基),其中所述的烷基、烯基、炔基、环烷基、苯基、芳基、杂环基和杂芳基中的每一个任选被一个或多个选自以下的取代基进一步取代:卤素、-OH、氧代(=O)、-NH2、碳环基、3-8元杂环基、C1-C4烷基、C1-C4卤代烷基-、-OC1-C4烷基、-C1-C4烷基-OH、-C1-C4烷基-O-C1-C4烷基、-OC1-C4卤代烷基、氰基、硝基、-C(O)-OH、-C(O)OC1-C6烷基、-CON(C1-C6烷基)2、-CONH(C1-C6烷基)、-CONH2、-NHC(O)(C1-C6烷基)、-NH(C1-C6烷基)C(O)(C1-C6烷基)、-SO2(C1-C6烷基)、-SO2(苯基)、-SO2(C1-C6卤代烷基)、-SO2NH2、-SO2NH(C1-C6烷基)、-SO2NH(苯基)、-NHSO2(C1-C6烷基)、-NHSO2(苯基)和-NHSO2(C1-C6卤代烷基)。当一个原子或基团被多个取代基取代时,所述取代基可以相同或不同。本文所用术语“部分”、“结构部分”、“化学部分”、“基团”、“化学基团”是指分子中的特定片段或官能团。化学部分通常被认为是嵌入或附加到分子上的化学实体。本发明中,“任选取代的”和“取代或未取代”具有相同含义,可互换使用。
本发明中“多个”是指2、3或4个。
中间体
中间体是指半成品,是生产所需要的产品过程中形成的产物。通常,发明人可以从中间体作为起始原料进行产品的生产。因此,筛选合适的中间体可以优化工艺路线,进而达到提高收率,节约时间、成本的目的。
本发明中,所述中间体是指以下化合物
其中,R1、X1、X2的定义如上所述。
优选地,所述中间体为
中间体的制备方法
本发明中,所述中间体的制备方法包括步骤:
(i)在溶剂(如DMF)中,化合物a-1与氰化试剂(如氰化亚铜)反应,得到化合物a-2;
(ii)在溶剂(如乙醇)中,化合物a-2与肼或其盐(如盐酸肼)反应,得到化合物a-3;
(iii)在溶剂(如乙腈)中,化合物a-3在亚硝酸酯(亚硝酸叔丁酯)和氯化亚铜存在下反应,得到化合物a。
上述各步骤中,反应时间和反应温度等可以根据具体的反应物进行选择。
活性成分
如本文所用,“本发明化合物”或“活性成分”指式I所示的化合物,并且还包含其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、顺反异构体、溶剂化物、多晶型物、氘代物或其组合。
“立体异构体”是指由相同原子组成,通过相同的键键合,但具有不同三维结构的化合物。本发明将涵盖各种立体异构体及其混合物。
当本发明的化合物中含有烯双键时,除非另有说明,否则本发明的化合物旨在包含E-和Z-几何异构体。
“互变异构体”是指质子从分子的一个原子转移至相同分子的另一个原子而形成的异构体。本发明的化合物的所有互变异构形式也将包含在本发明的范围内。
本发明的化合物或其药学上可接受的盐可能含有一个或多个手性碳原子,且因此可产生对映异构体、非对映异构体及其它立体异构形式。每个手性碳原子可以基于立体化学而被定义为(R)-或(S)-。本发明旨在包括所有可能的异构体,以及其外消旋体和光学纯形式。本发明的化合物的制备可以选择外消旋体、非对映异构体或对映异构体作为原料或中间体。光学活性的异构体可以使用手性合成子或手性试剂来制备,或者使用常规技术进行拆分,例如采用结晶以及手性色谱等方法。
制备/分离个别异构体的常规技术包括由合适的光学纯前体的手性合成,或者使用例如手性高效液相色谱法拆分外消旋体(或盐或衍生物的外消旋体),例如可参见GeraldGübitz and Martin G.Schmid(Eds.),Chiral Separations,Methods and Protocols,Methods in Molecular Biology,Vol.243,2004;A.M.Stalcup,Chiral Separations,Annu.Rev.Anal.Chem.3:341-63,2010;Fumiss et al.(eds.),VOGEL’S ENCYCLOPEDIA OFPRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED.,Longman Scientific and TechnicalLtd.,Essex,1991,809-816;Heller,Acc.Chem.Res.1990,23,128。
在本申请中,术语“药学上可接受的盐”包括药学上可接受的酸加成盐和药学上可接受的碱加成盐。
“药学上可接受的酸加成盐”是指能够保留游离碱的生物有效性而无其它副作用的,与无机酸或有机酸所形成的盐。无机酸盐包括但不限于盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、磷酸盐等;有机酸盐包括但不限于甲酸盐、乙酸盐、2,2-二氯乙酸盐、三氟乙酸盐、丙酸盐、己酸盐、辛酸盐、癸酸盐、十一碳烯酸盐、乙醇酸盐、葡糖酸盐、乳酸盐、癸二酸盐、己二酸盐、戊二酸盐、丙二酸盐、草酸盐、马来酸盐、琥珀酸盐、富马酸盐、酒石酸盐、柠檬酸盐、棕榈酸盐、硬脂酸盐、油酸盐、肉桂酸盐、月桂酸盐、苹果酸盐、谷氨酸盐、焦谷氨酸盐、天冬氨酸盐、苯甲酸盐、甲磺酸盐、苯磺酸盐、对甲苯磺酸盐、海藻酸盐、抗坏血酸盐、水杨酸盐、4-氨基水杨酸盐、萘二磺酸盐等。这些盐可通过本专业已知的方法制备。
“药学上可接受的碱加成盐”是指能够保持游离酸的生物有效性而无其它副作用的、与无机碱或有机碱所形成的盐。衍生自无机碱的盐包括但不限于钠盐、钾盐、锂盐、铵盐、钙盐、镁盐、铁盐、锌盐、铜盐、锰盐、铝盐等。优选的无机盐为铵盐、钠盐、钾盐、钙盐及镁盐。衍生自有机碱的盐包括但不限于以下的盐:伯胺类、仲胺类及叔胺类,被取代的胺类,包括天然的被取代胺类、环状胺类及碱性离子交换树脂,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、三乙醇胺、二甲基乙醇胺、2-二甲氨基乙醇、2-二乙氨基乙醇、二环己胺、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、胆碱、甜菜碱、乙二胺、葡萄糖胺、甲基葡萄糖胺、可可碱、嘌呤、哌嗪、哌啶、N-乙基哌啶、聚胺树脂等。优选的有机碱包括异丙胺、二乙胺、乙醇胺、三甲胺、二环己基胺、胆碱及咖啡因。这些盐可通过本专业已知的方法制备。
本领域技术人员还应当理解,在下文所述的方法中,中间体化合物官能团可能需要由适当的保护基保护。这样的官能团包括羟基、氨基、巯基及羧酸。合适的羟基保护基包括三烷基甲硅烷基或二芳基烷基甲硅烷基(例如叔丁基二甲基甲硅烷基、叔丁基二苯基甲硅烷基或三甲基甲硅烷基)、四氢吡喃基、苄基等。合适的氨基、脒基及胍基的保护基包括叔丁氧羰基、苄氧羰基等。合适的巯基保护基包括-C(O)-R”(其中R”为烷基、芳基或芳烷基)、对甲氧基苄基、三苯甲基等。合适的羧基保护基包括烷基、芳基或芳烷基酯类。
保护基可根据本领域技术人员已知的和如本文所述的标准技术来引入和除去。保护基的使用详述于Greene,T.W.与P.G.M.Wuts,Protective Groups in OrganiSynthesis,(1999),4th Ed.,Wiley中。保护基还可为聚合物树脂。
药物组合物和施用方法
在本申请中,“药物组合物”是指本发明化合物与本领域通常接受的用于将生物活性化合物输送至哺乳动物(例如人)的介质的制剂。该介质包括药学上可接受的载体。药物组合物的目的是促进生物体的给药,利于活性成分的吸收进而发挥生物活性。
通式(I)所述化合物可以与已知的治疗或改进相似病状的其他药物联用。联合给药时,原来药物的给药方式和剂量可以保持不变,而同时或随后服用式I的化合物。当式I化合物与其它一种或几种药物同时服用时,可以优选使用同时含有一种或几种已知药物和式I化合物的药用组合物。药物联用也包括在重叠的时间段服用式I化合物与其它一种或几种已知药物。当式I化合物与其它一种或几种药物进行药物联用时,式I化合物或已知药物的剂量可能比它们单独用药的剂量低。
可以与通式(I)所述化合物进行药物联用的药物或活性成分包括但不局限为:PD-1抑制剂(如纳武单抗、派姆单抗等)、PD-L1抑制剂(如度伐单抗、阿特珠单抗atezolizumab等)、CD47抗体(如Hu5F9-G4,CC-90002等)、CD20抗体(如利妥昔单抗、伊布单抗等)、KRAS抑制剂(如AMG510等)、ALK抑制剂(如色瑞替尼、艾乐替尼、布加替尼、劳拉替尼、奥卡替尼)、EGFR抑制剂(如阿法替尼、吉非替尼、厄洛替尼、拉帕替尼、达克替尼、艾克替尼、奥希替尼等)、VEGFR抑制剂(如索拉非尼、帕唑帕尼、瑞戈非尼、卡博替尼、舒尼替尼等)、PI3K抑制剂(如Dactolisib、Taselisib等)、BTK抑制剂(如依鲁替尼、替拉布替尼、阿卡布替尼、泽布替尼、维卡布替尼等)、HDAC抑制剂(如Vorinostat、Fimepinostat、Givinostat、Tucidinostat等)、CDK抑制剂(如帕博西尼、Ribociclib、Abemaciclib等)、MEK抑制剂(如司美替尼(AZD6244)、Trametinib等)、ERK抑制剂(如BVD523、HH2710等)、mTOR抑制剂(如Vistusertib等)、SHP2抑制剂(如RMC-4630、JAB-3068)或其组合。
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。
在本申请中,“药学上可接受的载体”包括但不限于任何被相关的政府管理部门许可为可接受供人类或家畜使用的佐剂、载体、赋形剂、助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。
本发明化合物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)、和局部给药。
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。在这些固体剂型中,活性化合物与至少一种常规惰性赋形剂(或载体)混合,如柠檬酸钠或磷酸二钙,或与下述成分混合:(a)填料或增容剂,例如,淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;(b)粘合剂,例如,羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶;(c)保湿剂,例如,甘油;(d)崩解剂,例如,琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠;(e)缓溶剂,例如石蜡;(f)吸收加速剂,例如,季胺化合物;(g)润湿剂,例如鲸蜡醇和单硬脂酸甘油酯;(h)吸附剂,例如,高岭土;和(i)润滑剂,例如,滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠,或其混合物。胶囊剂、片剂和丸剂中,剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备,如肠衣和其它本领域公知的材料。它们可包含不透明剂,并且,这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时,活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
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。除了活性化合物外,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。
除了活性化合物外,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。
本发明所述“肿瘤”包括但不限于肺癌、胰腺癌、结直肠癌、白血病、尤文氏肉瘤、乳腺癌、前列腺癌、T细胞淋巴瘤、B细胞淋巴瘤、恶性横纹肌瘤、滑膜肉瘤、子宫内膜瘤、胃癌、肝癌、肾癌、黑色素瘤、卵巢癌、脑胶质瘤、胆管癌、鼻咽癌、宫颈癌、头颈癌、食管癌、甲状腺癌和膀胱癌等疾病。本文所用术语“预防的”、“预防”和“防止”包括使病患减少疾病或病症的发生或恶化的可能性。
本文所用的术语“治疗”和其它类似的同义词包括以下含义:
(i)预防疾病或病症在哺乳动物中出现,特别是当这类哺乳动物易患有该疾病或病症,但尚未被诊断为已患有该疾病或病症时;
(ii)抑制疾病或病症,即遏制其发展;
(iii)缓解疾病或病症,即,使该疾病或病症的状态消退;或者
(iv)减轻该疾病或病症所造成的症状。
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。本领域技术人员熟知可用于本文所述化合物和方法的施用技术,例如在Goodman and Gilman,ThePharmacological Basis of Therapeutics,current ed.;Pergamon;and Remington’s,Pharmaceutical Sciences(current edition),Mack Publishing Co.,Easton,Pa中讨论的那些。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。
本文所使用术语“药物组合”、“药物联用”、“联合用药”、“施用其它治疗”、“施用其它治疗剂”等是指通过混合或组合不止一种活性成分而获得的药物治疗,其包括活性成分的固定和不固定组合。术语“固定组合”是指以单个实体或单个剂型的形式向患者同时施用至少一种本文所述的化合物和至少一种协同药剂。术语“不固定组合”是指以单独实体的形式向患者同时施用、合用或以可变的间隔时间顺次施用至少一种本文所述的化合物和至少一种协同制剂。这些也应用到鸡尾酒疗法中,例如施用三种或更多种活性成分。
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是:化合物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本发明化合物/剂,更佳地,含有10-1000mg本发明化合物/剂。较佳地,所述的“一剂”为一个胶囊或药片。
化合物的制备方法
以下方案中描述了制备式I所示化合物的方法。在某些情况下,可以改变执行反应方案的步骤的顺序,以促进反应或避免不需要的副反应产物。本发明的化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便的制得,这样的组合可由本发明所属领域的技术人员容易的进行。
本领域技术人员还应当理解,在下文所述的方法中,中间体化合物官能团可能需要由适当的保护基保护。这样的官能团包括羟基、氨基、巯基及羧酸。合适的羟基保护基包括三烷基甲硅烷基或二芳基烷基甲硅烷基(例如叔丁基二甲基甲硅烷基、叔丁基二苯基甲硅烷基或三甲基甲硅烷基)、四氢吡喃基、苄基、烯丙基等。合适的氨基、脒基及胍基的保护基包括叔丁氧羰基、苄氧羰基、9-芴基甲氧基羰基、苄基、对甲氧基苄基、烯丙基、烯丙基氧羰基、对甲苯磺酰基、特戊酰基、三氟乙酰基等。合适的巯基保护基包括-C(O)-R”(其中R”为烷基、芳基或芳烷基)、对甲氧基苄基、三苯甲基等。合适的羧基保护基包括烷基、芳基或芳烷基酯类。
保护基可根据本领域技术人员已知的和如本文所述的标准技术来引入和除去。保护基的使用详述于Greene,T.W.与P.G.M.Wuts,Protective Groups in OrganiSynthesis,(1999),4th Ed.,Wiley中。保护基还可为聚合物树脂。
通常,在制备流程中,各反应通常在惰性溶剂中,在室温至回流温度(如0℃-150℃,优选10℃-100℃)下进行。反应时间通常为0.1小时-60小时,较佳地为0.5-48小时。
优选地,所述式I化合物其可通过如下方法制备:
(1)化合物a与b-1在路易斯酸的存在下发生傅克酰基化生成化合物c,所述的路易斯酸选自:三氯化铝、二氯化锡、氯化锌、三氟化硼、四氯化钛、四异丙基氧钛等;或者化合物a在强碱的存在下与化合物b-2发生反应生成化合物c,所述强碱自下组:正丁基锂、二异丙基氨基锂、叔丁基锂、仲丁基锂、六甲基二硅基氨基锂、或其组合;
(2)在碱的存在下,化合物c与化合物d芳香亲核取代反应生成化合物I,所述还原剂选自下组:氢化钠、叔丁醇钾、叔丁醇钠、氢氧化钠、氢氧化钾、正丁基锂、二异丙基氨基锂、六甲基二硅基氨基锂、六甲基二硅基氨基钠、六甲基二硅基氨基钾、碳酸钾、碳酸铯、碳酸钠、磷酸钠、磷酸钾、三乙胺、二异丙基乙基胺、1.8-二氮杂二环[5.4.0]十一烷-7-烯、或其组合;或者化合物c与化合物d发生Buchwald-Hartwig反应生成化合物I;
其中,X1、X2、R1、R2、A环的定义如上所述。
本发明主要优点:
1.本申请化合物结构新颖;
2.本申请化合物能够有效抑制SOS1与RAS蛋白结合;
3.本申请化合物具有较好的药代动力学和药效。
下面通过具体实施方式来进一步说明本发明的技术方案。本领域技术人员应该明了,所述实施例仅仅是帮助理解本发明,不应视为对本发明的具体限制。
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,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。
以下实施例中所用的实验材料和试剂如无特别说明均可从市售渠道获得。
各实施例中,1H NMR由BRUKER AVANCE NEO 400MHz型核磁共振仪记录,化学位移以δ(ppm)表示;液质联用(LCMS)由Shimadzu LC-20AD,SIL-20A,CTO-20AC,SPD-M20A,CBM-20A,LCMS-2020型质谱仪记录;制备HPLC分离使用Gilson-281型号液相色谱仪。
实施例
中间体的制备
1、中间体A的制备
(1)向化合物A-1(10.0g,48.8mmol)的N,N-二甲基甲酰胺(100mL)溶液中,加入氰化亚铜(8.73g,97.5mmol)。反应液在氮气保护下100℃搅拌16小时。反应液加入水(100mL),用乙酸乙酯(200mL×2)萃取,合并有机相,无水硫酸钠干燥,过滤并减压浓缩。粗品经硅胶柱层析法(石油醚/乙酸乙酯=1:0到5:1)分离得到化合物A-2。
1H NMR(400MHz,DMSO-d6)δ8.15(d,J=5.2Hz,1H),7.69(d,J=5.2Hz,1H),2.65(s,3H)。
(2)向化合物A-2(3.50g,23.2mmol)的乙醇(20.0mL)溶液中,加入盐酸肼(2.92g,27.78mmol)。反应液在氮气保护下80℃搅拌12小时。反应液减压浓缩,加入水(50.0mL),用乙酸乙酯(50.0mL×2)萃取,合并有机相,无水硫酸钠干燥,过滤并减压浓缩得到粗品化合物A-3。
MS-ESI[M+H]+,计算值166,实测值166。
(3)向化合物A-3(2.00g,12.1mmol)的乙腈(30.0mL)溶液中,加入亚硝酸叔丁酯(2.50g,24.2mmol)和氯化亚铜(2.40g,24.2mmol)。反应液在氮气保护下60℃搅拌12小时。反应液减压浓缩,加入水(30.0mL),用乙酸乙酯(50.0mL×2)萃取,合并有机相,无水硫酸钠干燥,过滤,减压浓缩,粗品经硅胶柱层析法(石油醚/乙酸乙酯=10:1到1:1)分离得到化合物A-4。
MS-ESI[M+H]+,计算值185,实测值185。
(4)向化合物A-4(1.00g,5.42mmol)的甲苯(10.0mL)溶液中,加入化合物A-5(1.52g,6.50mmol),醋酸钯(122mg,542μmol),碳酸铯(3.53g,10.8mmol)和1,1'-联萘-2,2'-双二苯膦(675mg,1.08mmol)。反应液在氮气保护下105℃搅拌2小时。反应液加入水(100mL),用乙酸乙酯(100mL×2)萃取,合并有机相,无水硫酸钠干燥,过滤,减压浓缩,粗品经硅胶柱层析法(石油醚/乙酸乙酯=1:0到10:1)分离得到化合物A。
MS-ESI[M+H]+,计算值383,实测值383。
2、中间体B的制备
(1)0℃下向化合物B-1(2.00g,20.0mmol)的三溴甲烷(10.0mL)溶液中,滴加氢氧化钾(3.36g,59.9mmol)的甲醇(2.43mL)溶液。反应液在氮气保护下25℃搅拌12小时。反应液加入二氯甲烷(30.0mL),用水(15.0mL×3)萃取,无水硫酸钠干燥,过滤并减压浓缩。粗品经硅胶柱层析法(石油醚/乙酸乙酯=1:0到3:1)分离得到化合物B-2。
1H NMR(400MHz,DMSO-d6)δ3.69(s,3H),3.57(dd,J=7.2,3.2Hz,4H),3.16(s,3H),1.84-1.92(m,2H),1.71-1.76(m,2H)。
(2)向化合物B-2(5.00g,28.7mmol)的四氢呋喃(30.mL)溶液中加入一水合氢氧化锂(3.61g,86.1mmol)和水(10.0mL)。反应液在25℃下搅拌12小时。反应液减压浓缩,加入水(10.0mL),用稀盐酸调节pH到5,用乙酸乙酯(15.0mL×2)萃取,合并有机相,无水硫酸钠干燥,过滤并减压浓缩得到化合物B-3。
1H NMR(400MHz,CDCl3)δ3.74-3.78(m,4H),3.33(s,3H),2.11-2.14(m,1H),2.05-2.11(m,1H),1.86-1.89(m,1H),1.82-1.86(m,1H)。
(3)向化合物B-3(3.30g,20.6mmol)的二氯甲烷(30.0mL)溶液中,加入二异丙基乙基胺(7.99g,61.8mmol),化合物B-4的盐酸盐(2.01g,20.6mmol)和丙基磷酸酐(26.2g,41.2mmol,50%)。反应液在氮气保护下25℃搅拌1小时。反应液加入二氯甲烷(20.0mL),用水(10.0mL×3)洗涤,有机相用无水硫酸钠干燥,过滤并减压浓缩,粗品经硅胶柱层析法(石油醚/乙酸乙酯=1:0到2:1)分离得到化合物B。
MS-ESI[M+H]+,计算值204,实测值204。
1H NMR(400MHz,CDCl3)δ3.73-3.79(m,4H),3.72(s,3H),3.32(s,3H),3.23(s,3H),2.05-2.15(m,2H),1.92-2.00(m,2H)。
实施例1合成化合物1
(1)向中间体A(100mg,262μmol)的四氢呋喃(6.0mL)溶液中加入二异丙基氨基锂(2.0mol/L,523μL)。反应液在氮气保护下-78℃下搅拌1小时,加入碳酸二甲酯(70.7mg,785μmol)的四氢呋喃(6.0mL)溶液,反应液在氮气保护下-0℃下搅拌2小时,然后加入饱和氯化铵水溶液(100mL),加入水(100mL),用乙酸乙酯(100mL×2)萃取,合并有机相,无水硫酸钠干燥,过滤,减压浓缩,粗品经硅胶柱层析法(二氯甲烷/甲醇=1:0到10:1)分离得到化合物1-1。
(2)向化合物1-1(40.0mg,90.8μmol)的四氢呋喃(30.mL)溶液中加入一水合氢氧化锂(6.53mg,2 73μmol)和水(1.0mL)。反应液在25℃下搅拌1小时。反应液减压浓缩,加入水(50.0mL),用乙酸乙酯(50.0mL×2)洗涤,水相用稀盐酸调节pH到5,用乙酸乙酯(50.0mL×2)萃取,合并有机相,无水硫酸钠干燥,过滤并减压浓缩得到化合物1-2。
MS-ESI[M+H]+,计算值427,实测值427。
(3)向化合物1-2(20.0mg,46.9μmol)的二氯甲烷(4.0mL)溶液中加入化合物1-3(9.68mg,56.3μmol),丙基磷酸酐(74.6mg,117μmol,50%)和二异丙基乙基胺(30.3mg,235μmol)。反应液在25℃下搅拌2小时,然后加入饱和碳酸氢钠水溶液(30.0mL),用乙酸乙酯(50.0mL×2)萃取,合并有机相,无水硫酸钠干燥,过滤,减压浓缩,得到化合物1-4。
MS-ESI[M+H]+,计算值508,实测值508。
(4)向化合物1-4(20.0mg,39.4μmol)的四氢呋喃(3.0mL)溶液中加入钯碳(0.05g,10%)。反应液在氢气氛(15psi)下25℃下搅拌10小时,反应液过滤,减压浓缩,粗品经制备高效液相色谱法(Welch Xtimate C18,150mm×30mm 5μm,A:水(碳酸氢铵);B:乙腈,25%-60%:12分钟)分离得到化合物1。
MS-ESI[M+H]+,计算值478,实测值478。
1H NMR(400MHz,MeOD)δ8.38(s,1H),6.97(s,2H),6.77(s,1H),5.31-5.45(m,2H),4.08-4.34(m,4H),3.81(d,J=13.6Hz,1H),2.65(s,3H),2.19(t,J=7.6Hz,1H),1.96(d,J=9.2Hz,1H),1.62(d,J=7.2Hz,3H)。
实施例2合成化合物2
(1)向中间体A(250mg,654μmol)的四氢呋喃(3.0mL)溶液中加入二异丙基氨基锂(2.0mol/L,1.31mL)。反应液在氮气保护下-78℃下搅拌1小时,加入化合物B(399mg,1.96mmol)的四氢呋喃(3.0mL)溶液,反应液在氮气保护下-0℃下搅拌2小时,然后加入饱和氯化铵水溶液(100mL),加入水(100mL),用乙酸乙酯(100mL×2)萃取,合并有机相,无水硫酸钠干燥,过滤,减压浓缩,粗品经制备高效液相色谱法(Welch Xtimate C18,150mm×30mm5μm,A:水(碳酸氢铵);B:乙腈,40%-80%:12分钟)分离得到化合物2-1。
MS-ESI[M+H]+,计算值525,实测值525。
(2)向化合物2-1(100mg,191μmol)的四氢呋喃(3.0mL)溶液中加入钯碳(0.10g,10%)。反应液在氢气氛(15psi)下25℃下搅拌10小时,反应液过滤,减压浓缩,粗品经制备高效液相色谱法(Welch Xtimate C18,150mm×30mm 5μm,A:水(碳酸氢铵);B:乙腈,37%-74%:12分钟)分离得到化合物2。
MS-ESI[M+H]+,计算值495,实测值495。
1H NMR(400MHz,MeOD)δ8.96(s,1H),6.98(d,J=5.6Hz,2H),6.78(s,1H),5.41(q,J=6.8Hz,1H),3.76-3.92(m,4H),3.32-3.34(m,3H),,2.66(s,3H),2.04-2.14(m,4H),1.63(d,J=7.2Hz,3H)。
实施例3合成化合物3
采用实施例1中的合成方法,使用相对应的原料合成化合物3。
实施例4和实施例5合成化合物4和化合物5
采用实施例2中的合成方法,使用相对应的原料合成化合物4和化合物5。
实施例6合成化合物6
(1)向化合物6-1(1.70g,6.56mmol)的二氯甲烷(5.0mL)溶液中,加入二异丙基乙基胺(4.24g,32.8mmol),化合物B-4的盐酸盐(959mg,9.83mmol)和丙基磷酸酐(10.4g,16.4mmol,50%)。反应液在氮气保护下25℃搅拌1小时。反应液加入二氯甲烷(30.0mL)稀释,用饱和碳酸氢钠(100.0mL)洗涤。有机相用无水硫酸钠干燥,过滤并减压浓缩得到化合物6-2。MS-ESI[M-Boc+H]+,计算值203,实测值203。
(2)向化合物6-2(500mg,2.71mmol)的四氢呋喃(6.0mL)溶液中加入二异丙基氨基锂(2.00mol/L,5.42mL)。反应液在氮气保护下-78℃下搅拌1小时,加入中间体A-4(983mg,3.25mmol),反应液在氮气保护下0℃下搅拌2小时,加入饱和氯化铵水溶液(100.0mL),加入水(100.0mL),用乙酸乙酯(100.0mL×2)萃取,合并有机相,无水硫酸钠干燥,过滤,减压浓缩,粗品经硅胶柱层析法(石油醚/乙酸乙酯=1:0到10:1)分离得到化合物6-3。MS-ESI[M+H]+,计算值426,实测值426。
(3)向化合物6-3(150mg,352μmol)的二氧六环(2.0mL)溶液中,加入化合物A-5(90.7mg,388μmol),醋酸钯(7.91mg,35.2μmol),碳酸铯(229mg,704μmol)和1,1'-联萘-2,2'-双二苯膦(43.9mg,70.4μmol)。反应液在氮气保护下80℃搅拌2小时。反应液加入水(100.0mL),用乙酸乙酯(100.0mL×2)萃取,合并有机相,无水硫酸钠干燥,过滤,减压浓缩,粗品经硅胶柱层析法(石油醚/乙酸乙酯=1:0到10:1)分离得到化合物6-4。MS-ESI[M+H]+,计算值624,实测值624。
(4)向化合物6-4(70.0mg,112μmol)的二氯甲烷(5.0mL)溶液中加入三氟乙酸(128mg,1.12mmol)。反应液在25℃下搅拌1小时。反应液减压浓缩得到化合物6-5。MS-ESI[M+H]+,计算值524,实测值524。
(5)向化合物6-5(50.0mg,78.4μmol)的乙醇(5.0mL)溶液中加入多聚甲醛(11.8mg,392μmol),三乙胺(7.94mg,78.4μmol),醋酸(471μg,7.84μmol)和氰基硼氢化钠(7.39mg,118μmol)。反应液在25℃下搅拌10小时,反应液加入水(100.0mL),用乙酸乙酯(100.0mL×2)萃取,合并有机相,无水硫酸钠干燥,过滤,减压浓缩,得到化合物6-6。MS-ESI[M+H]+,计算值538,实测值538。
(6)向化合物6-6(20.0mg,37.2μmol)的乙醇(2.0mL)溶液中加入铁(20.8mg,372μmol),氯化铵(1.99mg,37.2μmol)。反应液在60℃下搅拌1小时,反应液加入水(100.0mL),用乙酸乙酯(100.0mL×2)萃取,合并有机相,无水硫酸钠干燥,过滤,减压浓缩,粗品经制备高效液相色谱法(C18-1,150mm×30mm 5μm,A:水(碳酸氢铵);B:乙腈,25%-65%:25分钟)分离得到化合物6。MS-ESI[M+H]+,计算值508,实测值508。1H NMR(400MHz,MeOD)δ8.94(s,1H),6.97(br d,J=6.4Hz,2H),6.77(s,1H),5.40(q,J=7.2Hz,1H),3.28(s,3H),2.76(br d,J=10.8Hz,2H),2.65(s,3H),2.46-2.56(m,2H),2.34(s,3H),2.15-2.24(m,2H),2.01-2.12(m,2H),1.62(d,J=7.2Hz,3H)。
实施例7-12合成化合物7-12
采用实施例6中的合成方法,使用相对应的原料合成化合物7-12。
实施例13合成化合物13
(1))向化合物A-4(400mg,2.17mmol)的四氢呋喃(8.0mL)溶液中加入二异丙基氨基锂(2.00mol/L,1.84mL)。反应液在氮气保护下-78℃下搅拌1小时,加入化合物13-1(305mg,2.38mmol),反应液在氮气保护下-65℃下搅拌2小时,加入饱和氯化铵水溶液(30.0mL),加入水(30.0mL),用乙酸乙酯(30.0mL×2)萃取,合并有机相,无水硫酸钠干燥,过滤,减压浓缩,粗品经硅胶柱层析法(石油醚/乙酸乙酯=1:0到1:1)分离得到化合物13-2。MS-ESI[M+H]+,计算值313,实测值313。
(2)向化合物13-2(170mg,543μmol)的二氯乙烷(2.0mL)溶液中加入二氧化锰(1.89g,21.7mmol)。反应液在70℃下搅拌48小时。反应液过滤,减压浓缩,粗品经制备薄层层析法(石油醚/乙酸乙酯=2:1)分离得到化合物13-3。MS-ESI[M+H]+,计算值311,实测值311。
(3)向化合物13-3(13.5mg,16.1μmol)的二氧六环(2.00mL)溶液中,加入化合物13-4((18.3mg,96.5μmol),甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(13.5mg,16.1μmol),碳酸铯(52.4mg,161μmol)。反应液在氮气保护下100℃搅拌12小时。反应液加入水(10.0mL),用乙酸乙酯(10.0mL×2)萃取,合并有机相,无水硫酸钠干燥,过滤,减压浓缩,粗品经制备高效液相色谱法(Xtimate C18,100mm×30mm 10μm,A:水(0.225%甲酸);B:乙腈,38%-58%:10分钟)分离得到化合物13。MS-ESI[M+H]+,计算值464,实测值464。1H NMR(400MHz,MeOD)δ8.80(s,1H),7.59(t,J=7.2Hz,1H),7.45(t,J=6.8Hz,1H),7.19(t,J=7.6Hz,1H),6.83-7.14(m,1H),5.68(q,J=6.8Hz,1H),3.82(ddd,J=11.6,6.0,3.6Hz,2H),3.61(ddd,J=11.2,8.4,2.8Hz,2H),2.63(s,3H),2.37(dd,J=13.9,1.3Hz,2H),1.79-1.88(m,2H),1.69(d,J=6.8Hz,3H),1.62(s,3H)。
实施例14-16合成化合物14-16
采用实施例13中的合成方法,使用相对应的原料合成化合物14-16。
试验例
化合物对SOS1与KRAS(G12C)突变蛋白结合抑制作用的测定(HTRF方法):
1、实验原理:利用HTRF方法检测化合物对SOS1与KRAS(G12C)突变蛋白结合的抑制作用。
2、实验材料:KRAS(G12C)突变蛋白购自普建生物科技有限公司;SOS1蛋白购自Cytoskeleton有限公司;标记抗体Mab Anti 6HIS-XL665和Mab Anti GST-Eu cryptate购自Cisbio公司;
3、实验方法:1倍浓度缓冲液配制(现配现用):4-羟乙基哌嗪乙磺酸(Hepes):5mmol/L;氯化钠:150mmol/L;乙二胺四乙酸:10mmol/L;乙基苯基聚乙二醇(Igepal):0.0025%;氟化钾:100mmol/L;二硫苏糖醇(DTT):1mmol/L;牛血清白蛋白(BSA):0.05%;
化合物储备液浓度为1000μmol/L起始,5倍稀释,设置8个梯度浓度,用1倍浓度缓冲液将待测化合物各梯度稀释成2%的DMSO工作液,5μL/孔加到对应孔中,每个浓度设置复孔检测。用1倍浓度缓冲液配制KRAS(G12C)突变蛋白(200nM)和Mab Anti GST-Eu cryptate(1μg/uL)的混和工作液。将该混合工作液放置25℃中孵育5分钟,2.5μL/孔加入到对应孔。用1倍浓度缓冲液配制SOS1蛋白(80nM)和Mab Anti 6HIS-XL665(8μg/uL)的混和工作液,2.5μL/孔加入到对应孔。空白孔中加入2.5μL Mab Anti 6HIS-XL665(8μg/μL)稀释液。反应体系置于25℃反应60分钟。反应结束后采用多标记分析仪读取HTRF。
4、数据处理:
用Graphpad软件计算化合物的IC50。结果如表1所示。
表1
测试化合物 | IC50(nM) |
实施例1 | 389.4 |
实施例2 | 62.78 |
实施例4 | 125.70 |
实施例5 | 50.89 |
实施例6 | 123.30 |
实施例8 | 25.85 |
实施例9 | 18.96 |
实施例10 | 81.84 |
实施例11 | 73.93 |
实施例12 | 38.62 |
实施例13 | 152.9 |
实施例15 | 75.60 |
实施例16 | 105.80 |
由表1测试数据可知,本发明所述式I所示化合物对SOS1与KRAS(G12C)突变蛋白结合具有较佳的抑制作用,具有用于制备治疗RAS突变的肿瘤药物的潜力。
申请人声明,本发明通过上述实施例来说明所述哒嗪类化合物、包含其的药物组合物及其应用,但本发明并不局限于上述实施例,即不意味着本发明必须依赖上述实施例才能实施。所属技术领域的技术人员应该明了,对本发明的任何改进,对本发明产品各原料的等效替换及辅助成分的添加、具体方式的选择等,均落在本发明的保护范围和公开范围之内。
Claims (11)
1.一种式I所示的化合物、其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、顺反异构体、溶剂化物、多晶型物、氘代物或其组合,
其中,
X1选自:CH、氧原子、硫原子、氮原子或-NH;优选地,X1为CH;
X2选自:硫原子、氧原子、氮原子、-NRx-或-CRx;其中,Rx选自:H、任选取代的C1-C3烷基;优选地,X2为硫原子;其中,所述取代是指被一个或多个R取代;
R1选自:H、卤素、任选取代的C1-C3烷基、任选取代的C3-C8碳环基、任选取代的4-8元杂环基、氰基、其中,R1a和R1b各自独立地选自:H、任选取代的C1-C6烷基、任选取代的C3-C8碳环基或任选取代的4-8元杂环基;其中,所述取代是指被一个或多个R取代;
R2选自:任选取代的C1-C6烷基、任选取代的C3-C16碳环基、任选取代的4-16元杂环基;其中,所述取代是指被一个或多个R取代;
A环选自:任选取代的C6-C16芳基、任选取代的5-16元杂芳基、任选取代的C3-C16碳环并C6-C10芳基、任选取代的4-16元杂环并C6-C10芳基、任选取代的C3-C16碳环并5-16元杂芳基或任选取代的4-16元杂环并5-16元杂芳基;其中,所述取代是指被一个或多个R取代;
R各自独立地选自:H、卤素、氰基、氨基、羟基、氧代基任选取代的C1-C6烷基、任选取代的C2-C6烯基、任选取代的C2-C6炔基、任选取代的C1-C6烷氧基、任选取代的C1-C6烷基砜基、任选取代的C3-C16碳环基、任选取代的4-16元杂环基、任选取代的C6-C16芳基或任选取代的5-16元杂芳基;或任意相邻的2个R和与其相连的原子形成任选取代的4-8元杂环基或任选取代的C3-C8元碳环基;其中,R中所述取代是指被选自下组的一个或多个基团取代:H、卤素、氰基、氨基、羟基、氧代基/>R’取代或未取代的C1-C6烷基、R’取代或未取代的C1-C6烷氧基、R’取代或未取代的C1-C6烷基砜基、R’取代或未取代的C3-C16碳环基、R’取代或未取代的4-16元杂环基、R’取代或未取代的C6-C16芳基、R’取代或未取代的5-16元杂芳基、-N(R’取代或未取代的C1-C6烷基)2、-CH2-N(R’取代或未取代的C1-C6烷基)2,其中,R’选自下组的一个或多个基团:H、卤素、氘(D)、卤素、-OH、氧代(=O)、巯基、氰基、-CD3、C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C8环烷基和4-8元杂环基,其中所述的烷基、烯基、炔基、环烷基和杂环基中的每一个任选被一个或多个选自以下的取代基进一步取代:H、C1-C6烷基、C1-C6烷氧基、卤素、-OH、氧代(=O)、-NH2、-N(R”取代或未取代的C1-C6烷基)2、-NH(C1-C6烷基)、-N(C1-C6烷基)(C1-C6烷基苯基)、-NH(C1-C6烷基苯基)、-N(C1-C6烷基)(芳基)、-NH(芳基)、C3-C8环烷基、4-8元杂环基、C1-C4卤代烷基-、-C1-C4烷基-OH、-C1-C4烷基-O-C1-C4烷基、-OC1-C4卤代烷基、氰基、硝基、-C(O)-OH、-C(O)OC1-C6烷基、-CON(C1-C6烷基)2、-CONH(C1-C6烷基)、-CONH2、-NHC(O)(C1-C6烷基)、-NH(C1-C6烷基)C(O)(C1-C6烷基)、-SO2(C1-C6烷基)、-SO2(苯基)、-SO2(C1-C6卤代烷基)、-SO2NH2、-SO2NH(C1-C6烷基)、-SO2NH(苯基)、-NHSO2(C1-C6烷基)、-NHSO2(苯基)、-NHSO2(C1-C6卤代烷基)和-C1-C6烷基-NH2,其中,R”选自下组的一个或多个基团:H、卤素、氰基、氨基、羟基、氧代基/>C1-C6烷基和C1-C6烷氧基;
2.如权利要求1中所述的化合物,其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、顺反异构体、溶剂化物、多晶型物、氘代物或其组合,其特征在于,
所述R1选自:H、卤素、任选取代的C1-C3烷基或任选取代的C3-C8碳环基,优选地,R1选自:H、卤素或甲基;其中,所述取代是指被一个或多个R取代,R的定义如权利要求1所述。
3.如权利要求1和2所述的化合物,其药学上可接受的盐、对映异构体、互变异构体、顺反异构体、溶剂化物、多晶型物、氘代物或其组合,其特征在于,
所述A环选自:任选取代的C6-C10芳基、任选取代的5-10元杂芳基、任选取代的C3-C8碳环并C6-C10芳基、任选取代的4-8元杂环并C6-C10芳基、任选取代的C3-C8碳环并5-10元杂芳基或任选取代的4-8元杂环并5-10元杂芳基;优选地A环为任选取代的苯基、5-6元杂芳基、任选取代的C3-C8碳环并苯基、任选取代的4-8元杂环并苯基、任选取代的C3-C8碳环并5-6元杂芳基或任选取代的4-8元杂环并5-6元杂芳基;更优选地,A环选自:任选取代的苯基、任选取代的吡啶基、任选取代的吡嗪基、任选取代的噻吩基、任选取代的呋喃基、任选取代的吡咯基、任选取代的噻唑基、任选取代的咪唑基、任选取代的吡唑基;其中,所述取代是指被一个或多个R取代;R的定义如权利要求1所述。
4.如权利要求1-3中任一项所述的化合物,其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、顺反异构体、溶剂化物、多晶型物、氘代物或其组合,其特征在于,所述A环选自:
其中,Rd1、Rd2、Rd3分别独立地选自:H、卤素、氨基、羟基、氰基、任选取代的C1-C6烷基、任选取代的C1-C6烷氧基、任选取代的C1-C6烷基砜基、任选取代的C3-C16碳环基、任选取代的4-16元杂环基、任选取代的C6-C16芳基或任选取代的5-16元杂芳基;Rd4分别独立地选自:卤素、任选取代的C1-C6烷基和q为0、1、2或3;Rd5选自:氢、任选取代的C6-C10元芳香基或任选取代的5-16元杂芳香环基;Z选自:O或NRN;RN选自:H或任选取代的C1-C6烷基;
其中,所述取代是指被选自下组的一个或多个基团取代:H、卤素、氰基、氨基、羟基、氧代基R’取代或未取代的C1-C6烷基、C1-C6烷氧基、C1-C6烷基砜基、C3-C16碳环基、4-16元杂环基、-N(R’取代或未取代的C1-C6烷基)2、-CH2-N(R’取代或未取代的C1-C6烷基)2、和-CH2-(4-8元杂环基),其中R’选自下组的一个或多个基团:H、卤素、氰基、氨基、羟基、氧代基/>C1-C6烷基和C1-C6烷氧基;
9.一种药物组合物,其特征在于,所述药物组合物包括:
(1)治疗有效量的选自权利要求1~7中任一项所述的化合物、其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、顺反异构体、溶剂化物、多晶型物和氘代物中的一种或多种作为活性成分;和
(2)任选地,药学上可接受的载体。
10.如权利要求1~7中任一项所述的化合物、其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、顺反异构体、溶剂化物、多晶型物或氘代物或如权利要求9所述的药物组合物在制备预防或治疗RAS突变介导的癌症的药物中的用途。
11.如权利要求10所述的用途,其特征在于,所述癌症选自:肺癌、胰腺癌、结直肠癌、白血病、尤文氏肉瘤、乳腺癌、前列腺癌、T细胞淋巴瘤、B细胞淋巴瘤、恶性横纹肌瘤、滑膜肉瘤、子宫内膜瘤、胃癌、肝癌、肾癌、黑色素瘤、卵巢癌、脑胶质瘤、胆管癌、鼻咽癌、宫颈癌、头颈癌、食管癌、甲状腺癌和膀胱癌,特别是选自非小细胞肺癌、胰腺癌和结直肠癌。
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