CN115124524A - 三环类衍生物及其制备方法和用途 - Google Patents
三环类衍生物及其制备方法和用途 Download PDFInfo
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- CN115124524A CN115124524A CN202110323822.3A CN202110323822A CN115124524A CN 115124524 A CN115124524 A CN 115124524A CN 202110323822 A CN202110323822 A CN 202110323822A CN 115124524 A CN115124524 A CN 115124524A
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- IVCYDMZBZVZDLU-UHFFFAOYSA-N tert-butyl 3-[8-chloro-7-[5,7-difluoro-2-[(2-methylpropan-2-yl)oxycarbonylamino]-1,3-benzothiazol-4-yl]-6-fluoropyrazolo[4,3-c]quinolin-1-yl]azetidine-1-carboxylate Chemical compound CC(C)(C)OC(NC1=NC(C(C(C(Cl)=CC2=C3N=CC4=C2N(C(C2)CN2C(OC(C)(C)C)=O)N=C4)=C3F)=C(C=C2F)F)=C2S1)=O IVCYDMZBZVZDLU-UHFFFAOYSA-N 0.000 description 1
- WPGLRFGDZJSQGI-UHFFFAOYSA-N tert-butyl 3-aminoazetidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC(N)C1 WPGLRFGDZJSQGI-UHFFFAOYSA-N 0.000 description 1
- ZVJXIYNLVGSAMP-UHFFFAOYSA-N tert-butyl 3-hydrazinylazetidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC(NN)C1 ZVJXIYNLVGSAMP-UHFFFAOYSA-N 0.000 description 1
- MOGVIYKYDYLGKU-UHFFFAOYSA-N tert-butyl N-[7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzothiazol-2-yl]carbamate Chemical compound CC(C)(C)OC(NC1=NC2=C(B3OC(C)(C)C(C)(C)O3)C=CC(F)=C2S1)=O MOGVIYKYDYLGKU-UHFFFAOYSA-N 0.000 description 1
- LFKDJXLFVYVEFG-UHFFFAOYSA-N tert-butyl carbamate Chemical compound CC(C)(C)OC(N)=O LFKDJXLFVYVEFG-UHFFFAOYSA-N 0.000 description 1
- 230000002381 testicular Effects 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- AOBORMOPSGHCAX-DGHZZKTQSA-N tocofersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2O[C@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-DGHZZKTQSA-N 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 235000019871 vegetable fat Nutrition 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
- 235000014692 zinc oxide Nutrition 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
Classifications
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- 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
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
-
- 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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- 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
- C07D471/12—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 three hetero rings
- C07D471/14—Ortho-condensed systems
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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
-
- 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
- C07D487/12—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 three hetero rings
- C07D487/14—Ortho-condensed systems
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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
Abstract
本发明涉及三环类衍生物、其制备方法及其在医药上的应用。具体而言,本发明涉及一种通式(I)所示的三环类衍生物、其制备方法及其可药用的盐,以及它们作为治疗剂,特别是作为KRas G12D抑制剂的用途,其中通式(I)中的各取代基的定义与说明书中的定义相同。
Description
技术领域
本发明涉及一种三环类衍生物、其制备方法及含有该衍生物的药物组合物以及其作为治疗剂特别是作为KRas G12D抑制剂的用途。
背景技术
RAS代表一组紧密相关的单体球状蛋白质(21kDa分子量),其具有189个氨基酸且与质膜相连并且结合GDP或GTP。在正常发育或生理条件下,RAS接收生长因子和各种其它细胞外信号而被激活,负责调节细胞生长、存活、迁移和分化等功能。RAS起分子开关作用,RAS蛋白的开/关状态通过核苷酸结合确定,活性信号传导构象结合GTP,非活性构象结合GDP。当RAS包含结合的GDP时,其处于休眠或静止或关闭状态,并且是“非活化的”。当细胞暴露于某些生长促进刺激物进行响应时,RAS被诱导将结合的GDP转换为GTP。随着GTP被结合,RAS是“开启的”,并且能够与其它蛋白相互作用且活化其它蛋白(其“下游靶标”)。RAS蛋白本身具有极低的将GTP水解回到GDP并由此将自身变为关闭状态的固有能力。将RAS转换为关闭需要称作GTP酶激活蛋白(GAPs)的外源性蛋白,其与RAS相互作用并且能大大促进GTP向GDP的转化。任何在RAS中的影响其与GAP相互作用或将GTP转化回到GDP的能力的突变,将会导致所述蛋白的延长的活化,并且因此产生到细胞的延长的信号,该信号告知其继续生长和分裂。因此这些信号会使得细胞生长和分裂,过度活化的RAS信号转导可能最终导致癌症。
在结构上,RAS蛋白包含负责RAS的酶促活性-----鸟嘌呤核苷酸结合和水解(GTP酶反应)的G结构域。其还包括含称为CAAX盒的C端延伸区,其可被转译后修饰并且使该蛋白靶向膜。G结构域在尺寸上大约为21-25kDa并含有磷酸结合环(P-环)。P-环表示蛋白中结合核苷酸的囊袋,并且这是具有保守氨基酸残基的结构域的刚性部分,所述保守氨基酸残基为核苷酸结合和水解所必需的(甘氨酸12、苏氨酸26和赖氨酸16)。G结构域还含有所谓的开关I区(残基30-40)和开关II区(残基60-76),其均为蛋白的动态部分,由于该动态部分在静止和负载状态之间进行转换的能力而常常被表示为“弹簧加载”机制。主要相互作用为由苏氨酸-35和甘氨酸-60与GTP的γ-磷酸所形成的氢键,其使开关I区和开关II区分别维持它们的活性构象。在水解GTP和释放磷酸盐之后,此两者松弛成无活性的GDP构象。
在RAS家族成员中,致癌突变最常见于KRAS(85%),而NRAS(12%)和HRAS(3%)则较为少见。KRAS突变在美国三大致命癌症类型中普遍存在:胰腺癌(95%)、结肠直肠癌(45%)和肺癌(25%),在包括多发性骨髓瘤、子宫癌、胆管癌、胃癌、膀胱癌、弥漫性大B细胞淋巴瘤、横纹肌肉瘤、皮肤鳞状细胞癌、宫颈癌、睾丸生殖细胞癌等在内的其他癌症类型中也发现KRAS突变,而在乳腺癌、卵巢癌和脑癌中很少发现(<2%)。在非小细胞肺癌(NSCLC)中,KRAS G12C是最常见的突变,占所有KRAS突变的近一半,其次是G12V和G12D。在非小细胞肺癌中,特定等位基因突变频率的增加多来自经典的由吸烟诱导的典型突变(G:C至T:A置换),从而导致了KRAS G12C(GGT至TGT)和G12V(GGT至GTT)突变。
大型基因组学研究表明,肺癌KRAS突变,包括G12C,与NSCLC中其它已知的驱动致癌突变相互排斥,包括EGFR、ALK、ROS1、RET和BRAF,表明KRAS突变在肺癌中的独特性。而同时,KRAS突变经常与某些共突变同时发生,例如STK11、KEAP1和TP53,它们与突变的RAS合作将细胞转化为高度恶性和侵袭性的肿瘤细胞。
三种RAS癌基因构成了人类癌症中突变最频繁的基因家族。令人失望的是,尽管经过三十多年的研究努力,临床上仍然没有有效的抗RAS疗法,使用小分子靶向该基因是项挑战。因此,本领域迫切需要用于靶向RAS(例如,K-RAS,H-RAS和/或N-RAS)的小分子并且利用其治疗多种疾病,例如癌症。
目前,国内外对于KRas G12D抑制剂的临床开发竞争激烈,其中MiratiTherapeutics Inc公司研发的KRas G12D抑制剂MRTX-1133已经进入临床前阶段,用于治疗大肠肿瘤、非小细胞肺癌和胰腺癌等疾病。目前公开为数不多的KRas G12D抑制剂专利申请,其中包括Mirati Therapeutics Inc公司的WO2021041671。虽然KRas G12D抑制剂的研究和应用已取得一定的进展,但是提高的空间仍然巨大,仍有必要继续研究和开发新的KRas G12D抑制剂。
发明内容
本发明的目的在于提供一种通式(I)所示的三环类衍生物,或其立体异构体、互变异构体或其可药用的盐:
其中:
G选自一个含有1-2个氮原子的4~12元的杂环基,其中所述杂环基任选进一步被一个或多个Rc所取代;
X和Y各自独立地选自N或CRf;
环A选自5~6元杂芳基;
Rc相同或不同,各自独立地选自氢原子、烷基、卤素、硝基、氰基、环烷基、杂环基、芳基、杂芳基、=O、-OR4、-C(O)OR4、-NHC(O)R4、-NHC(O)OR4、-NR5R6、-C(O)NR5R6、-CH2NHC(O)OR4、-CH2NR5R6或-S(O)rR4,其中所述的烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自烷基、卤素、硝基、氰基、环烷基、杂环基、芳基、杂芳基、=O、-OR4、-C(O)R4、-C(O)OR4、-NHC(O)R4、-NHC(O)OR4、-NR5R6、-C(O)NR5R6、-CH2NHC(O)OR5、-CH2NR6R7或-S(O)rR5的取代基所取代;
Rf选自氢原子、卤素、烷基或烷氧基;其中所述的烷基或烷氧基任选进一步被一个或多个选自卤素、羟基、氰基、烷基或烷氧基的取代基所取代;Rf优选为卤素,更优选为氟或氯;
R1选自氢原子、卤素、烷基或烷氧基;其中所述的烷基或烷氧基任选进一步被一个或多个选自卤素、羟基、氰基、烷基或烷氧基的取代基所取代;R1优选为氢原子;
R2选自芳基或杂芳基,其中所述的芳基或杂芳基任选进一步被一个或多个选自烷基、卤素、硝基、氰基、环烷基、杂环基、芳基、杂芳基、=O、-OR4、-C(O)R4、-C(O)OR4、-NHC(O)R4、-NHC(O)OR4、-NR5R6、-C(O)NR5R6、-CH2NHC(O)OR4、-CH2NR5R6或-S(O)rR4的取代基所取代;其中所述的烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自烷基、卤素、硝基、氰基、环烷基、杂环基、芳基、杂芳基、=O、-OR4、-C(O)R4、-C(O)OR4、-NHC(O)R4、-NHC(O)OR4、-NR5R6、-C(O)NR5R6、-CH2NHC(O)OR4、-CH2NR5R6或-S(O)rR4的取代基所取代;
R3选自不存在、氢原子、卤素、烷基、烷氧基、氰基、卤代烷基或卤代烷氧基,优选为不存在或氢原子;
R4选自氢原子、烷基、环烷基、杂环基、芳基或杂芳基,其中所述的烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基、杂环基、芳基、杂芳基、=O、-C(O)R7、-C(O)OR7、-OC(O)R7、-NR8R9、-C(O)NR8R9、-SO2NR8R9或-NR8C(O)R9的取代基所取代;
R5和R6各自独立地选自氢原子、羟基、卤素、烷基、烷氧基、环烷基、杂环基、芳基或杂芳基,其中所述的烷基、烷氧基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、=O、-C(O)R7、-C(O)OR7、-OC(O)R7、-NR8R9、-C(O)NR8R9、-SO2NR8R9或-NR8C(O)R9的取代基所取代;
或者,R5和R6与它们相连接的原子一起形成一个4~8元杂环基,其中4~8元杂环基内含有一个或多个N、O或S(O)r,并且所述的4~8元杂环基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、=O、-C(O)R7、-C(O)OR7、-OC(O)R7、-NR8R9、-C(O)NR8R9、-SO2NR8R9或-NR8C(O)R9的取代基所取代;
R7、R8和R9各自独立地选自氢原子、烷基、氨基、环烷基、杂环基、芳基或杂芳基,其中所述的烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氨基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧基或羧酸酯基的取代基所取代;
n选自0、1或2;
r为0、1或2。
一种通式(I)所示的三环类衍生物,或其立体异构体、互变异构体或其可药用的盐,其中:
-G-H选自:
Rc相同或不同,各自独立地选自氢原子、卤素、烷基或烷氧基,优选烷基,更优选为甲基;
m选自0、1、2、3或4。
一种通式(I)所示的三环类衍生物,或其立体异构体、互变异构体或其可药用的盐,其中X、Y各自独立地选自CRf;Rf选自氢原子、卤素、烷基、烷氧基、卤代烷基或卤代烷氧基,Rf优选为卤素,更优选为氟或氯。
一种通式(I)所示的三环类衍生物,或其立体异构体、互变异构体或其可药用的盐,其中R1选自氢原子、卤素、烷基、烷氧基、卤代烷基或卤代烷氧基,R1优选为氢原子。
一种通式(I)所示的三环类衍生物,或其立体异构体、互变异构体或其可药用的盐,其中:
R2选自苯基、萘基、吡啶基、苯并噻唑基或苯并吡唑基,其中所述的苯基、萘基、吡啶基、苯并噻唑基或苯并吡唑基任选进一步被一个或多个选自卤素、羟基、烷基、烷氧基、环烷基或-NR5R6的取代基所取代,其中所述的烷基或烷氧基任选进一步被一个或多个选自卤素或-NR5R6的取代基所取代;其中所述的卤素优选为氟;
R5和R6各自独立地选自氢原子或烷基,其中所述烷基优选为甲基。
一种通式(I)所示的三环类衍生物,或其立体异构体、互变异构体或其可药用的盐,其中R2选自:
一种通式(I)所示的三环类衍生物,或其立体异构体、互变异构体或其可药用的盐,其中R3选自不存在或氢原子。
一种通式(I)所示的三环类衍生物,或其立体异构体、互变异构体或其可药用的盐,其中环A选自:
本发明的典型化合物包括,但不限于:
或其立体异构体、互变异构体或其可药用的盐。
注:如果在画出的结构和给出的该结构的名称之间有差异,则画出的结构将给予更大的权重。
进一步,本发明提供通式(I)化合物或其立体异构体、互变异构体或其可药用的盐的制备方法,所述方法为:
通式(IA)化合物和通式(IB)化合物在钯催化剂及碱性试剂的作用下进行Suzuki偶联反应,进一步脱去保护基,得到通式(I)化合物;
其中:
X1为离去基团,优选为氯;
PG为保护基,优选为叔丁氧基羰基;
环A、R1~R3、X、Y、G和n的定义如通式(I)所述。
进一步,本发明提供一种通式(IA)所述的化合物或其立体异构体、互变异构体其可药用的盐,
其中:
X1为离去基团,优选为氯;
PG为保护基,优选为叔丁氧基羰基;
环A、R1、R3、X、Y、G和n的定义如通式(I)中所述。
通式(IA)的典型化合物包括,但不限于:
在另一方面,本发明提供一种药物组合物,所述的药物组合物含有有效剂量的通式(I)所述的化合物或其立体异构体、互变异构体或其可药用的盐,及可药用的载体、赋形剂或它们的组合。
在另一方面,本发明提供一种抑制KRas G12D酶方法,其中所述的方法包括,给予病人一种药物组合物,所述的药物组合物含有有效剂量的通式(I)所述的化合物或其立体异构体、互变异构体或其可药用的盐,及可药用的载体、赋形剂或它们的组合。
本发明还提供了一种通式(I)所述的化合物或其立体异构体、互变异构体或其可药用的盐,或其药物组合物在制备治疗由KRas G12D突变介导的疾病的药物中的用途,其中所述的由KRas G12D突变介导的疾病选自癌症,其中所述的癌症选自心脏粘液瘤、肺癌、胃癌、大肠肿瘤、直肠癌、胰腺癌、前列腺癌、膀胱癌、肝细胞癌、胆管癌、胆管癌、软骨肉瘤、多发性骨髓瘤、子宫癌、宫颈癌、精原细胞瘤、恶性黑色素瘤、皮肤鳞状细胞癌、肾上腺成神经细胞瘤、骨髓性白血病、急性淋巴细胞白血病或胶质母细胞瘤;其中所述的肺癌选自非小细胞肺癌或小细胞肺癌。
在另一方面,本发明提供一种通式(I)所述的化合物或其立体异构体、互变异构体或其可药用的盐,或其药物组合物在制KRas G12D抑制剂中的用途。
本发明的另一方面涉及一种预防和/或治疗KRas G12D突变介导的疾病的方法,其包括向患者施用治疗有效剂量的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式或其可药用盐或包含其的药物组合物。
本发明还提供了一种通式(I)所述的化合物或其立体异构体、互变异构体或其可药用的盐,或其药物组合物在制备治疗癌症的药物中的用途,其中所述的癌症选自心脏粘液瘤、肺癌、胃癌、大肠肿瘤、直肠癌、胰腺癌、前列腺癌、膀胱癌、肝细胞癌、胆管癌、胆管癌、软骨肉瘤、多发性骨髓瘤、子宫癌、宫颈癌、精原细胞瘤、恶性黑色素瘤、皮肤鳞状细胞癌、肾上腺成神经细胞瘤、骨髓性白血病、急性淋巴细胞白血病或胶质母细胞瘤;其中所述的肺癌选自非小细胞肺癌或小细胞肺癌。
本发明的药物制剂可以经局部、口服、经皮、经直肠、经阴道、非经肠、鼻内、肺内、眼内、静脉内、肌肉内、动脉内、鞘内、囊内、皮内、腹膜内、皮下、角质层下或者通过吸入进行给药。含活性成分的药物组合物可以是适用于口服的形式,例如片剂、糖锭剂、锭剂、水或油混悬液、可分散粉末或颗粒、乳液、硬或软胶囊,或糖浆剂或酏剂。片剂含有活性成分和用于混合的适宜制备片剂的无毒的可药用的赋形剂。
本发明的制剂适合以单位计量的形式存在,并且所述制剂可借由在制药技术中所众所周知的任何方法进行制备。能够通过与载体物质进行组合,从而产生单一剂型的活性成分的量可以依据所治疗的宿主及特定给药模式而变化。能够通过与载体物质进行组合从而产生单一剂型的活性成分的量通常指的是能够产生治疗效果的化合物的量。
用于本发明化合物的局部或者透皮给药的剂型可包括粉末、喷雾剂、软膏剂、糊剂、乳膏剂、洗剂、凝胶剂、溶液、贴片及吸入剂。活性化合物可在无菌条件下与药学上可接受的载剂进行混合,并且其可与可能需要的任何防腐剂、缓冲剂或者推进剂进行混合。
当本发明的化合物以药物的形式对人类及动物进行给药时,所述化合物可进行单独提供或者以药物组合物的形式提供,所述药物组合物含有与药学上可接受的载剂进行组合的活性成分,例如0.1%至99.5%(更优选地,0.5%至90%)的活性成分。
药学上可接受的载剂的实例包括但不限于:(1)糖,例如乳糖、葡萄糖及蔗糖;(2)淀粉,例如玉米淀粉及马铃薯淀粉;(3)纤维素及其衍生物,例如羧甲基纤维素钠、乙基纤维素及乙酸纤维素;(4)粉末状黄蓍胶;(5)麦芽;(6)明胶;(7)滑石;(8)赋形剂,例如可可脂及栓剂蜡;(9)油,例如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油及大豆油;(10)二醇,例如丙二醇;(11)多元醇,例如甘油、山梨糖醇、甘露糖醇及聚乙二醇;(12)酯,例如油酸乙酯及月桂酸乙酯;(13)琼脂;(14)缓冲剂,例如氢氧化镁及氢氧化铝;(15)海藻酸;(16)无热原水;(17)等渗盐水;(18)林格氏溶液(Ringer's solution);(19)乙醇;(20)磷酸盐缓冲溶液;(21)环糊精,例如连接于纳米粒子的靶向配体,例如AccurinsTM;及(22)用于药物制剂中的其它无毒兼容物质,例如聚合物基组合物。
药学上可接受的抗氧化剂的实例包括但不限于:(1)水溶性抗氧化剂,例如抗坏血酸、半胱胺酸盐酸盐、硫酸氢钠、偏亚硫酸氢钠、亚硫酸钠及其类似物;(2)油溶性抗氧化剂,例如抗坏血酸棕榈酸酯、丁基化羟基苯甲醚(BHA)、丁基化羟基甲苯(BHT)、卵磷脂、五倍子酸丙酯、α-生育酚及其类似物;及(3)金属螯合剂,例如柠檬酸、乙二胺四乙酸(EDTA)、山梨糖醇、酒石酸、磷酸及其类似物。固体剂型(例如胶囊、锭剂丸剂、糖衣锭、粉末、颗粒剂及其类似物)可包括一种或者多种药学上可接受的载剂,例如柠檬酸钠或者磷酸二钙,和/或以下任意其中之一:(1)填充剂或增量剂,例如淀粉、乳糖、蔗糖、葡萄糖、甘露糖醇及/或者硅酸;(2)黏合剂,例如羧甲基纤维素、海藻酸盐、明胶、聚乙烯吡咯啶酮、蔗糖和/或阿拉伯胶;(3)保湿剂,例如甘油;(4)崩解剂,例如琼脂、碳酸钙、马铃薯或木薯淀粉、海藻酸、某些硅酸盐及碳酸钠;(5)溶解阻滞剂,例如石蜡;(6)吸收加速剂,例如四级铵化合物;(7)湿润剂,例如十六醇及甘油单硬脂酸酯;(8)吸收剂,例如高岭土及膨润土;(9)润滑剂,例如滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、月桂基硫酸钠及其混合物;和(10)着色剂。液体剂型可包括药学上可接受的乳液、微乳液、溶液、悬浮液、糖浆及酏剂。除活性成分之外,液体剂型可含有通常用于本技术领域中的惰性稀释剂,例如水或其它溶剂;增溶剂及乳化剂,例如乙醇、异丙醇、碳酸乙酯、乙酸乙脂、苯甲醇、苯甲酸苯甲酯、丙二醇、1,3-丁二醇、油(特别是棉籽油、花生油、玉米油、胚芽油、橄榄油、蓖麻油、及芝麻油)、甘油、四氢呋喃甲醇、聚乙二醇以及脱水山梨醇的脂肪酸酯、及其混合物。
除活性化合物之外,悬浮液也可含有悬浮剂,例如乙氧基化异硬脂醇、聚氧化乙烯山梨糖醇及脱水山梨醇酯、微晶纤维素、氢氧化铝氧化物、膨润土、琼脂及黄蓍胶及其混合物。
除活性化合物之外,软膏剂、糊剂、乳膏剂以及凝胶剂也可含有赋形剂,例如动物脂肪及植物脂肪、油、蜡、石蜡、淀粉、黄蓍胶、纤维素衍生物、聚乙二醇、聚硅氧、膨润土、硅酸、滑石及氧化锌或者其混合物。
除活性化合物之外,粉末及喷雾剂也可以含有赋形剂,例如乳糖、滑石、硅酸、氢氧化铝、硅酸钙及聚酰胺粉末或者上述这些物质的混合物。所述喷雾剂可以含有其它的常用推进剂,例如氯氟烃、以及挥发性的未被取代的烃,例如丁烷及丙烷。
发明的详细说明
除非有相反陈述,否则本发明在说明书和权利要求书中所使用的部分术语定义如下:
“烷基”当作一基团或一基团的一部分时是指包括C1-C20直链或者带有支链的脂肪烃基团。优选为C1-C10烷基,更优选为C1-C6烷基。烷基基团的实施例包括但不限于甲基、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、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代或未取代的。
“烯基”指由至少两个碳原子和至少一个碳-碳双键组成的如上定义的烷基,代表性实例包括但不限于乙烯基、1-丙烯基、2-丙烯基、1-,2-或3-丁烯基等。烯基可以是任选取代的或未取代的。
“炔基”是指含有一个碳碳三键的脂肪烃基团,可为直链也可以带有支链。优先选择的是C2-C10的炔基,更优选C2-C6炔基,最优选C2-C4炔基。炔基基团的实施例包括,但不限于乙炔基、1-丙炔基、2-丙炔基、1-、2-或3-丁炔基等。炔基可以是取代或未取代的。
“环烷基”是指饱和或部分饱和的单环、稠环、桥环和螺环的碳环。优选为C3-C12环烷基,更优选为C3-C8环烷基,最优选为C3-C6环烷基。单环环烷基的实施例包括但不限于环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等,优选环丙基、环己烯基。环烷基可以是任选取代的或未取代的。
“螺环烷基”指5至18元,两个或两个以上环状结构,且单环之间彼此共用一个碳原子(称螺原子)的多环基团,环内含有1个或多个双键,但没有一个环具有完全共轭的π电子的芳香系统。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、双螺或多螺环烷基,优选为单螺和双螺环烷基,优选为4元/5元、4元/6元、5元/5元或5元/6元。“螺环烷基”的非限制性实施例包括但不限于:螺[4.5]癸基、螺[4.4]壬基、螺[3.5]壬基、螺[2.4]庚基。
“稠环烷基”指5至18元,含有两个或两个以上环状结构彼此共用一对碳原子的全碳多环基团,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电子的芳香系统,优选为6至12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元双环烷基。“稠环烷基”的非限制性实施例包括但不限于:二环[3.1.0]己基、二环[3.2.0]庚-1-烯基、二环[3.2.0]庚基、十氢化萘基或十四氢菲基。
“桥环烷基”指5至18元,含有两个或两个以上环状结构,彼此共用两个不直接相连接碳原子的全碳多环基团,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电子的芳香系统,优选为6至12元,更优选为7至10元。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、四环或多环桥环烷基,优选为双环、三环或四环,更有选为双环或三环。“桥环烷基”的非限制性实施例包括但不限于:(1s,4s)-二环[2.2.1]庚基、二环[3.2.1]辛基、(1s,5s)-二环[3.3.1]壬基、二环[2.2.2]辛基、(1r,5r)-二环[3.3.2]癸基。
“杂环基”、“杂环”或“杂环的”在本申请中可交换使用,都是指非芳香性杂环基,其中一个或多个成环的原子是杂原子,如氧、氮、硫原子等,包括单环、稠环、桥环和螺环。优选具有5至7元单环或7至10元双或三环,其可以包含1,2或3个选自氮、氧和/或硫中的原子。“杂环基”的实例包括但不限于吗啉基,氧杂环丁烷基,硫代吗啉基,四氢吡喃基,1,1-二氧代硫代吗啉基,哌啶基,2-氧代哌啶基,吡咯烷基,2-氧代吡咯烷基,哌嗪-2-酮,8-氧杂-3-氮杂-双环[3.2.1]辛基和哌嗪基。杂环基可以是取代或未取代的。
“螺杂环基”指5至18元,两个或两个以上环状结构,且单环之间彼此共用一个原子的多环基团,环内含有1个或多个双键,但没有一个环具有完全共轭的π电子的芳香系统,其中一个或多个环原子选自氮、氧或S(O)r(其中r选自0、1或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,优选为单螺杂环基和双螺杂环基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环基。“螺杂环基”的非限制性实施例包括但不限于:1,7-二氧杂螺[4.5]癸基、2-氧杂-7-氮杂螺[4.4]壬基、7-氧杂螺[3.5]壬基和5-氧杂螺[2.4]庚基。
“稠杂环基”指含有两个或两个以上环状结构彼此共用一对原子的全碳多环基团,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电子的芳香系统,其中一个或多个环原子选自氮、氧或S(O)r(其中r选自0、1或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括但不限于:八氢吡咯并[3,4-c]吡咯基、八氢-1H-异吲哚基,3-氮杂二环[3.1.0]己基,八氢苯并[b][1,4]二噁英(dioxine)。
“桥杂环基”指5至14元,5至18元,含有两个或两个以上环状结构,彼此共用两个不直接相连接的原子的多环基团,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电子的芳香系统,其中一个或多个环原子选自氮、氧或S(O)r(其中r选自0、1或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、四环或多环桥杂环基,优选为双环、三环或四环,更有选为双环或三环。“桥杂环基”的非限制性实施例包括但不限于:2-氮杂二环[2.2.1]庚基,2-氮杂二环[2.2.2]辛基和2-氮杂二环[3.3.2]癸基。
“芳基”是指含有一个或者两个环的碳环芳香系统,其中所述环可以以稠合的方式连接在一起。术语“芳基”包括单环或双环的芳基,比如苯基、萘基、四氢萘基的芳香基团。优选芳基为C6-C10芳基,更优选芳基为苯基和萘基。芳基可以是取代或未取代的。
“杂芳基”是指芳香族5至6元单环或8至10元双环,其可以包含1至4个选自氮、氧和/或硫中的原子。优选为双环杂芳基,“杂芳基”的实施例包括但不限于呋喃基,吡啶基,2-氧代-1,2-二氢吡啶基,哒嗪基,嘧啶基,吡嗪基,噻吩基,异噁唑基,噁唑基,噁二唑基,咪唑基,吡咯基,吡唑基,三唑基,四氮唑基,噻唑基,异噻唑基,1,2,3-噻二唑基,苯并间二氧杂环戊烯基,苯并噻吩基、苯并咪唑基,吲哚基,异吲哚基,1,3-二氧代-异吲哚基,喹啉基,吲唑基,苯并异噻唑基,苯并噁唑基、苯并异噁唑基、
杂芳基可以是取代或未取代的。
“烷氧基”是指(烷基-O-)的基团。其中,烷基见本文有关定义。C1-C6的烷氧基为优先选择。其实例包括,但不限于:甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基等。
“卤代烷基”是指烷基任选进一步被一个或多个卤素所取代的基团,其中烷基见本文有关定义。
“羟烷基”是指烷基任选进一步被一个或多个羟基所取代的基团,其中烷基见本文有关定义。
“卤代烷氧基”是指(烷基-O-)的烷基任选进一步被一个或多个卤素所取代的基团,其中烷氧基见本文有关定义。
“羟基”指-OH基团。
“卤素”是指氟、氯、溴和碘。
“氨基”指-NH2。
“氰基”指-CN。
“硝基”指-NO2。
“苄基”指-CH2-苯基。
“羧基”指-C(O)OH。
“羧酸酯基”指-C(O)O-烷基或-C(O)O-环烷基,其中烷基、环烷基的定义如上所述。
“DMSO”指二甲基亚砜。
“BOC”指叔丁氧基羰基。
“Ts”指对甲苯磺酰基。
“T3P”指丙基磷酸酐。
“DPPA”指叠氮磷酸二苯酯。
“DEA”指二乙胺。
“X-PHOS Pd G2”氯(2-二环己基膦基-2',4',6'-三异丙基-1,1'-联苯基)[2-(2'-氨基-1,1'-联苯)]钯(II)。
“取代的”指基团中的一个或多个氢原子,优选为最多5个,更优选为1~3个氢原子彼此独立地被相应数目的取代基取代。不言而喻,取代基仅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,具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
本说明书所述的“取代”或“取代的”,如无特别指出,均是指基团可被一个或多个选自以下的基团取代:烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、疏基、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氨基、卤代烷基、羟烷基、羧基、羧酸酯基、=O、-C(O)R5、-C(O)OR5、-NHC(O)R5、-NHC(O)OR5、-NR6R7、-C(O)NR6R7、-CH2NHC(O)OR5、-CH2NR6R7或-S(O)rR5的取代基所取代;
R5选自氢原子、烷基、环烷基、杂环基、芳基或杂芳基,其中所述的烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基、杂环基、芳基、杂芳基、=O、-C(O)R8、-C(O)OR8、-OC(O)R8、-NR9R10、-C(O)NR9R10、-SO2NR9R10或-NR9C(O)R10的取代基所取代;
R6和R7各自独立地选自氢原子、羟基、卤素、烷基、烷氧基、环烷基、杂环基、芳基或杂芳基,其中所述的烷基、烷氧基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、=O、-C(O)R8、-C(O)OR8、-OC(O)R8、-NR9R10、-C(O)NR9R10、-SO2NR9R10或-NR9C(O)R10的取代基所取代;
或者,R6和R7与它们相连接的原子一起形成一个4~8元杂环基,其中4~8元杂环基内含有一个或多个N、O或S(O)r,并且所述的4~8元杂环基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、=O、-C(O)R8、-C(O)OR8、-OC(O)R8、-NR9R10、-C(O)NR9R10、-SO2NR9R10或-NR9C(O)R10的取代基所取代;
R8、R9和R10各自独立地选自氢原子、烷基、氨基、环烷基、杂环基、芳基或杂芳基,其中所述的烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氨基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧基或羧酸酯基的取代基所取代;
r为0、1或2。
本发明化合物可以含有不对称中心或手性中心,因此以不同的立体异构体形式存在。所预期的是,本发明化合物的所有立体异构体形式,包括但不限于非对映异构体、对映异构体和阻转异构体(atropisomer)和几何(构象)异构体及它们的混合物,如外消旋体混合物,均在本发明的范围内。
除非另外指出,本发明描述的结构还包括此结构的所有异构体(如,非对映异构体、对映异构体和阻转异构体和几何(构象)异构体形式;例如,各不对称中心的R和S构型,(Z)和(E)双键异构体,以及(Z)和(E)构象异构体。因此本发明化合物的单个立体异构体以及对映体混合物、非对映异构体混合物和几何(构象)异构体混合物均在本发明范围内。
“可药用的盐”是指上述化合物能保持原有生物活性并且适合于医药用途的某些盐类。式(I)所表示的化合物的可药用的盐可以为金属盐、与合适的酸形成的胺盐。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上可药用的盐或前体药物与其他化学组分的混合物,以及其他组分例如生理学可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药,利于活性成分的吸收进而发挥生物活性。
本发明化合物的合成方法
为了完成本发明的目的,本发明采用如下技术方案:
本发明通式(I)所述的化合物或其立体异构体、互变异构体或其可药用的盐的制备方法,包括以下步骤:
通式(IA)化合物和通式(IB)化合物在钯催化剂及碱性试剂的作用下进行Suzuki偶联反应,进一步脱去保护基,得到通式(I)化合物;
其中:
X1为离去基团,优选为氯;
PG为保护基,优选为叔丁氧基羰基;
环A、R1~R3、X、Y、G和n的定义如通式(I)中所述。
具体实施方式
以下结合实施例用于进一步描述本发明,但这些实施例并非限制着本发明的范围。
实施例
实施例给出了式(I)所表示的代表性化合物的制备及相关结构鉴定数据。必须说明,下述实施例是用于说明本发明而不是对本发明的限制。1HNMR图谱是用Bruker仪器(400MHz)测定而得,化学位移用ppm表示。使用四甲基硅烷内标准(0.00ppm)。1HNMR的表示方法:s=单峰,d=双重峰,t=三重峰,m=多重峰,br=变宽的,dd=双重峰的双重峰,dt=三重峰的双重峰。若提供偶合常数时,其单位为Hz。
质谱是用LC/MS仪测定得到,离子化方式可为ESI或APCI。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板,薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm~0.2mm,薄层层析分离纯化产品采用的规格是0.4mm~0.5mm。
柱层析一般使用烟台黄海硅胶200~300目硅胶为载体。
在下列实例中,除非另有指明,所有温度为摄氏温度,除非另有指明,各种起始原料和试剂来自市售或者是根据已知的方法合成,市售原料和试剂均不经进一步纯化直接使用,除非另有指明,市售厂家包括但不限于上海皓鸿生物医药科技有限公司,上海韶远试剂有限公司,上海毕得医药科技有限公司,萨恩化学技术(上海)有限公司和上海凌凯医药科技有限公司等。
CD3OD:氘代甲醇。
CDCl3:氘代氯仿。
DMSO-d6:氘代二甲基亚砜。
实施例中无特殊说明,反应中的溶液是指水溶液。
对化合物进行纯化,采用柱层析和薄层色谱法的洗脱剂体系,其中该体系选自:A:石油醚和乙酸乙酯体系;B:二氯甲烷和甲醇体系;C:二氯甲烷和乙酸乙酯体系,D:二氯甲烷和乙醇体系,E:乙酸乙酯和四氢呋喃体系,其中溶剂的体积比根据化合物的极性不同而不同,也可以加入少量的酸性或碱性试剂进行条件,如醋酸或三乙胺等。
室温:20℃~30℃。
实施例1
2-(1-(azetidin-3-yl)-8-chloro-6-fluoro-1H-[1,2,3]triazolo[4,5-c]quinolin-7-yl)-3-fluorophenol
2-(1-(氮杂环丁烷-3-基)-8-氯-6-氟-1H-[1,2,3]三唑并[4,5-c]喹啉-7-基)-3-氟苯酚
第一步
tert-butyl 3-((7-bromo-6-chloro-8-fluoro-3-nitroquinolin-4-yl)amino)azetidine-1-carboxylate
3-((7-溴-6-氯-8-氟-3-硝基喹啉-4-基)氨基)氮杂环丁烷-1-羧酸叔丁酯
将7-溴-4,6-二氯-8-氟-3-硝基喹啉1a(550mg,1.62mmol,根据公开专利WO2019110751制备)和3-氨基氮杂环丁烷-1-羧酸叔丁酯1b(417.98mg,2.43mmol)溶于乙腈(5mL)中,冷却至0℃,滴加N,N-二异丙基乙胺(627.32mg,4.85mmol),转至室温,继续反应6小时。减压浓缩,得到的残留物用硅胶柱层析法(洗脱剂:A体系)分离纯化,得到3-((7-溴-6-氯-8-氟-3-硝基喹啉-4-基)氨基)氮杂环丁烷-1-羧酸叔丁酯1c(400mg,840.87μmol),产率:51.91%。MS m/z(ESI):474.7[M+1]+
第二步
tert-butyl 3-((3-amino-7-bromo-6-chloro-8-fluoroquinolin-4-yl)amino)azetidine-1-carboxylate
3-((3-氨基-7-溴-6-氯-8-氟喹啉-4-基)氨基)氮杂环丁烷-1-羧酸叔丁酯
将3-((7-溴-6-氯-8-氟-3-硝基喹啉-4-基)氨基)氮杂环丁烷-1-羧酸叔丁酯1c(1.2g,2.52mmol)、氯化铵(674.67mg,12.61mmol)和铁粉(704.44mg,12.61mmol)溶于甲醇(10mL)和水(2mL)的混合溶剂中,加热至90℃反应5小时。反应结束后,趁热过滤,将滤液减压浓缩,除去甲醇。体系用乙酸乙酯萃取(100mL×2),合并有机相,以无水硫酸钠干燥,过滤,减压浓缩,得到粗品3-((3-氨基-7-溴-6-氯-8-氟喹啉-4-基)氨基)氮杂环丁烷-1-羧酸叔丁酯1d(950mg,2.13mmol),产率:84.49%。
MS m/z(ESI):445.0[M+1]+
第三步
tert-butyl
3-(7-bromo-8-chloro-6-fluoro-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)azetidine-1-carboxylate
3-(7-溴-8-氯-6-氟-1H-[1,2,3]三唑并[4,5-c]喹啉-1-基)氮杂环丁烷-1-羧酸叔丁酯
将3-((3-氨基-7-溴-6-氯-8-氟喹啉-4-基)氨基)氮杂环丁烷-1-羧酸叔丁酯1d(950mg,2.13mmol)溶于乙酸(10mL)和水(2mL)的混合溶剂中,冷却至0℃,加入亚硝酸钠(220.60mg,3.20mmol),0℃下继续反应0.5小时,升温至室温反应2小时。反应结束后,体系用饱和碳酸钠溶液调至碱性,以乙酸乙酯萃取(100mL×2),合并有机相,以饱和食盐水(100mL×3)洗涤,以无水硫酸钠干燥,过滤,减压浓缩,得到的残留物用硅胶柱层析法(洗脱剂:A体系)分离纯化,得到3-(7-溴-8-氯-6-氟-1H-[1,2,3]三唑并[4,5-c]喹啉-1-基)氮杂环丁烷-1-羧酸叔丁酯1e(520mg,1.14mmol),产率:53.42%。
MS m/z(ESI):455.8[M+1]+
第四步
tert-butyl
3-(8-chloro-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)azetidine
-1-carboxylate
3-(8-氯-6-氟-7-(2-氟-6-羟基苯基)-1H-[1,2,3]三唑并[4,5-c]喹啉-1-基)氮杂环丁烷-1-羧酸叔丁酯
将3-(7-溴-8-氯-6-氟-1H-[1,2,3]三唑并[4,5-c]喹啉-1-基)氮杂环丁烷-1-羧酸叔丁酯1e(350mg,766.37μmol)、(2-氟-6-羟基苯基)硼酸1f(262.88mg,1.69mmol)、磷酸钾(325.34mg,1.53mmol)和X-PHOS Pd G2(120.44mg,153.27μmol)溶于四氢呋喃(10mL)中,氩气保护,加热至50℃,反应过夜。反应结束后,过滤,将滤液减压浓缩,得到的残留物用硅胶柱层析法(洗脱剂:A体系)分离纯化,得到3-(8-氯-6-氟-7-(2-氟-6-羟基苯基)-1H-[1,2,3]三唑并[4,5-c]喹啉-1-基)氮杂环丁烷-1-羧酸叔丁酯1g(20mg,40.99μmol),产率:5.35%。
MS m/z(ESI):487.9[M+1]+
第五步
2-(1-(azetidin-3-yl)-8-chloro-6-fluoro-1H-[1,2,3]triazolo[4,5-c]quinolin-7-yl)-3-fluorophenol
2-(1-(氮杂环丁烷-3-基)-8-氯-6-氟-1H-[1,2,3]三唑并[4,5-c]喹啉-7-基)-3-氟苯酚
将3-(8-氯-6-氟-7-(2-氟-6-羟基苯基)-1H-[1,2,3]三唑并[4,5-c]喹啉-1-基)氮杂环丁烷-1-羧酸叔丁酯1g(15mg,30.74μmol)溶于二氯甲烷(5mL)中,加入HCl的1,4-二氧六环溶液(4M,3mL),室温反应2小时。反应结束后,减压浓缩,得到粗品2-(1-(氮杂环丁烷-3-基)-8-氯-6-氟-1H-[1,2,3]三唑并[4,5-c]喹啉-7-基)-3-氟苯酚1(11mg,28.37μmol),产率:92.27%。
MS m/z(ESI):388.0[M+1]+
实施例2
4-(1-(氮杂环丁烷-3-基)-8-氯-6-氟-1H-[1,2,3]三唑并[4,5-c]喹啉-7-基)萘-2-醇
第一步
tert-butyl
3-(8-chloro-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)azetidine-1-carboxylate
3-(8-氯-6-氟-7-(3-羟基萘-1-基)-1H-[1,2,3]三唑并[4,5-c]喹啉-1-基)氮杂环丁烷-1-羧酸叔丁酯
将3-(7-溴-8-氯-6-氟-1H-[1,2,3]三唑并[4,5-c]喹啉-1-基)氮杂环丁烷-1-羧酸叔丁酯1e(354.89mg,1.31mmol)、4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)萘-2-醇2a(300mg,656.89μmol)、磷酸钾(418.30mg,1.97mmol)和X-PHOS Pd G2(51.62mg,65.69μmol)溶于四氢呋喃(5mL)中,氩气保护,加热至50℃,反应过夜。反应结束后,减压浓缩,得到的残留物用硅胶柱层析法(洗脱剂:A体系)分离纯化,得到3-(8-氯-6-氟-7-(3-羟基萘-1-基)-1H-[1,2,3]三唑并[4,5-c]喹啉-1-基)氮杂环丁烷-1-羧酸叔丁酯2b(340mg,653.90μmol),产率:99.55%。MS m/z(ESI):520.2[M+1]+
第二步
4-(1-(azetidin-3-yl)-8-chloro-6-fluoro-1H-[1,2,3]triazolo[4,5-c]quinolin-7-yl)naphthalen-2-ol
4-(1-(氮杂环丁烷-3-基)-8-氯-6-氟-1H-[1,2,3]三唑并[4,5-c]喹啉-7-基)萘-2-醇
将3-(8-氯-6-氟-7-(3-羟基萘-1-基)-1H-[1,2,3]三唑并[4,5-c]喹啉-1-基)氮杂环丁烷-1-羧酸叔丁酯2b(100mg,192.32μmol)溶于二氯甲烷(4mL)中,加入HCl的1,4-二氧六环溶液(4M,3mL),室温反应1小时。反应结束后,减压浓缩,得到粗品4-(1-(氮杂环丁烷-3-基)-8-氯-6-氟-1H-[1,2,3]三唑并[4,5-c]喹啉-7-基)萘-2-醇2(80mg,190.55μmol),产率:99.08%。
MS m/z(ESI):420.1[M+1]+
实施例3
4-(1-(azetidin-3-yl)-8-chloro-6-fluoro-1H-[1,2,3]triazolo[4,5-c]quinolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine
4-(1-(氮杂环丁烷-3-基)-8-氯-6-氟-1H-[1,2,3]三唑并[4,5-c]喹啉-7-基)-7-氟苯并[d]噻唑-2-胺
第一步
tert-butyl(7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)carbamate
(7-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯并[d]噻唑-2-基)氨基甲酸叔丁酯
将2-((叔丁氧基羰基)氨基)-7-氟苯并[d]噻唑-4-基三氟甲磺酸酯3a(8.5g,20.41mmol,根据公开专利US 20200115375制备)、醋酸钾(6.01g,61.24mmol)、联硼酸频那醇酯(41.47g,163.32mmol)和[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(2.81g,3.27mmol)溶于1,4-二氧六环(200mL)中,氮气保护下,85℃下反应16小时。LC-MS监测反应进度。反应结束后,加入300mL水稀释反应液,以乙酸乙酯(300mL×2)萃取,合并有机相,以饱和食盐水洗涤(300mL),以无水硫酸钠干燥,过滤,减压浓缩,得到的残留物用硅胶柱层析法(洗脱剂:E体系)分离纯化,得到(7-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯并[d]噻唑-2-基)氨基甲酸叔丁酯3b(1.7g),产率:21.12%。
MS m/z(ESI):256.9[M+1-139]+
1H NMR(400MHz,DMSO-d6)δ1.32(s,12H),1.51(s,9H),7.15(t,J=8.66Hz,1H),7.76(t,J=7.28Hz,1H),12.14(br s,1H).
第二步
tert-butyl
3-(7-(2-((tert-butoxycarbonyl)amino)-7-fluorobenzo[d]thiazol-4-yl)-8-chloro-6-fluoro-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)azetidine-1-carboxylate
3-(7-(2-((叔丁氧基羰基)氨基)-7-氟苯并[d]噻唑-4-基)-8-氯-6-氟-1H-[1,2,3]三唑并[4,5-c]喹啉-1-基)氮杂环丁烷-1-羧酸叔丁酯
将3-(7-溴-8-氯-6-氟-1H-[1,2,3]三唑并[4,5-c]喹啉-1-基)氮杂环丁烷-1-羧酸叔丁酯1e(512mg,1.30mmol)、(7-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯并[d]噻唑-2-基)氨基甲酸叔丁酯3b(539.15mg,1.18mmol)、磷酸钾(501.17mg,2.36mmol)、X-PHOS Pd G2(185.53mg,236.11μmol)溶于四氢呋喃(10mL)中,氩气保护,加热至50℃,反应3小时。反应结束后,减压浓缩,得到的残留物用硅胶柱层析法(洗脱剂:A体系)分离纯化,得到3-(7-(2-((叔丁氧基羰基)氨基)-7-氟苯并[d]噻唑-4-基)-8-氯-6-氟-1H-[1,2,3]三唑并[4,5-c]喹啉-1-基)氮杂环丁烷-1-羧酸叔丁酯3c(270mg,419.20μmol),产率:32.23%。
MS m/z(ESI):443.8[M+1]+
第三步
4-(1-(azetidin-3-yl)-8-chloro-6-fluoro-1H-[1,2,3]triazolo[4,5-c]quinolin-7-yl)-7-fluorobenzo[d]thiaz
ol-2-amine
4-(1-(氮杂环丁烷-3-基)-8-氯-6-氟-1H-[1,2,3]三唑并[4,5-c]喹啉-7-基)-7-氟苯并[d]噻唑-2-胺
将3-(7-(2-((叔丁氧基羰基)氨基)-7-氟苯并[d]噻唑-4-基)-8-氯-6-氟-1H-[1,2,3]三唑并[4,5-c]喹啉-1-基)氮杂环丁烷-1-羧酸叔丁酯3c(270mg,419.20μmol)溶于二氯甲烷(8mL)中,加入HCl的1,4-二氧六环溶液(4M,8mL),室温下反应1小时。反应结束后,减压浓缩,得到粗品4-(1-(氮杂环丁烷-3-基)-8-氯-6-氟-1H-[1,2,3]三唑并[4,5-c]喹啉-7-基)-7-氟苯并[d]噻唑-2-胺3(186mg,419.05μmol),直接用于下一步反应。
MS m/z(ESI):443.8[M+1]+
实施例4
4-(1-(azetidin-3-yl)-8-chloro-6-fluoro-1H-pyrazolo[4,3-c]quinolin-7-yl)-5,7-difluorobenzo[d]thiazo
l-2-amine
4-(1-(氮杂环丁烷-3-基)-8-氯-6-氟-1H-吡唑并[4,3-c]喹啉-7-基)-5,7-二氟苯并[d]噻唑-2-胺
第一步
(7-bromo-4,6-dichloro-8-fluoroquinolin-3-yl)methanol
(7-溴-4,6-二氯-8-氟喹啉-3-基)甲醇
将7-溴-4,6-二氯-8-氟喹啉-3-羧酸乙酯4a(0.05g,136.24μmol,根据公开专利WO2016164675A1制备)溶于四氢呋喃(2mL)中,降温至-78℃,滴加二异丙基氨基锂(1M,299.73μL),缓慢升温至25℃,继续反应3小时。LC-MS检测反应完全。向反应液中加入5mL水淬灭反应,以乙酸乙酯(5mL×3)萃取,合并有机相,以无水硫酸镁干燥,过滤,减压浓缩,得到黄色油状粗品(7-溴-4,6-二氯-8-氟喹啉-3-基)甲醇4b(20mg,61.55μmol),产率45.17%。MS m/z(ESI):225.9[M+3]+
第二步
7-bromo-4,6-dichloro-8-fluoroquinoline-3-carbaldehyde
7-溴-4,6-二氯-8-氟喹啉-3-甲醛
将(7-溴-4,6-二氯-8-氟喹啉-3-基)甲醇4b(0.025g,76.93μmol)溶于二氯甲烷(2mL)中,25℃下加入二氧化锰(66.88mg,769.32μmol),加热至40℃反应16小时。LC-MS检测反应完全。过滤,减压浓缩,得到的粗品7-溴-4,6-二氯-8-氟喹啉-3-甲醛4c。
MS m/z(ESI):223.6[M+3]+
第三步
tert-butyl
3-(7-bromo-8-chloro-6-fluoro-1H-pyrazolo[4,3-c]quinolin-1-yl)azetidine-1-carboxylate
3-(7-溴-8-氯-6-氟-1H-吡唑并[4,3-c]喹啉-1-基)氮杂环丁烷-1-羧酸叔丁酯
将7-溴-4,6-二氯-8-氟喹啉-3-甲醛4c(500mg,1.55mmol)和3-肼基氮杂环丁烷-1-羧酸叔丁酯4d(434.84mg,2.32mmol,根据公开专利WO2012004743 A1制备)溶于乙醇(6mL)中,加入三乙胺(470.0 0mg,4.64mmol),80℃下反应3小时。LC-MS检测反应完全。减压浓缩,得到的残留物用硅胶柱层析分离纯化(洗脱剂:A体系),得到3-(7-溴-8-氯-6-氟-1H-吡唑并[4,3-c]喹啉-1-基)氮杂环丁烷-1-羧酸叔丁酯4e(0.2g,438.88μmol),产率28.35%。
MS m/z(ESI):455.0[M+1]+
第四步
tert-butyl3-(7-(2-((tert-butoxycarbonyl)amino)-5,7-difluorobenzo[d]thiazol-4-yl)-8-chloro-6-fluoro-1H-pyrazolo[4,3-c]quinolin-1-yl)azetidine-1-carboxylate
3-(7-(2-((叔丁氧基羰基)氨基)-5,7-二氟苯并[d]噻唑-4-基)-8-氯-6-氟-1H-吡唑并[4,3-c]喹啉
-1-基)氮杂环丁烷-1-羧酸叔丁酯
将3-(7-溴-8-氯-6-氟-1H-吡唑并[4,3-c]喹啉-1-基)氮杂环丁烷-1-羧酸叔丁酯4e(300mg,658.32μmol)、(2-((叔丁氧基羰基)氨基)-5,7-二氟苯并[d]噻唑-4-基)硼酸4f(260.78mg,789.98μmol,根据公开专利US20200115375 A1制备)、磷酸钾(279.47mg,1.32mmol)和X-PHOS Pd G2(51.73mg,65.83μmol)溶于四氢呋喃(8mL)中,50℃下反应过夜。冷却至室温,反应液用硅藻土过滤,将滤液减压浓缩,加入适量的甲醇溶解残留物,再次过滤,将滤液减压浓缩,得到的残留物用硅胶柱层析分离纯化(洗脱剂:A体系),得到3-(7-(2-((叔丁氧基羰基)氨基)-5,7-二氟苯并[d]噻唑-4-基)-8-氯-6-氟-1H-吡唑并[4,3-c]喹啉-1-基)氮杂环丁烷-1-羧酸叔丁酯4g(21mg,31.77μmol),产率4.83%。
MS m/z(ESI):661.2[M+1]+
第五步
4-(1-(azetidin-3-yl)-8-chloro-6-fluoro-1H-pyrazolo[4,3-c]quinolin-7-yl)-5,7-difluorobenzo[d]thiazo
l-2-amine
4-(1-(氮杂环丁烷-3-基)-8-氯-6-氟-1H-吡唑并[4,3-c]喹啉-7-基)-5,7-二氟苯并[d]噻唑-2-胺
将3-(7-(2-((叔丁氧基羰基)氨基)-5,7-二氟苯并[d]噻唑-4-基)-8-氯-6-氟-1H-吡唑并[4,3-c]喹啉-1-基)氮杂环丁烷-1-羧酸叔丁酯4g(21mg,31.77μmol)溶于二氯甲烷(3mL)中,加入HCl/1,4-二氧六环溶液(4M,3mL),室温下反应1小时。减压浓缩,得到4-(1-(氮杂环丁烷-3-基)-8-氯-6-氟-1H-吡唑并[4,3-c]喹啉-7-基)-5,7-二氟苯并[d]噻唑-2-胺4(14.6mg,25.34μmol),产率79.78%。
MS m/z(ESI):463.0[M+3]+
生物学评价
测试例1、本发明化合物对AGS细胞中p-ERK1/2抑制活性的测定
以下方法用于测定本发明化合物对AGS细胞中p-ERK1/2抑制活性。本方法使用Cisbio公司的Advanced phospho-ERK1/2(Thr202/tyr204)试剂盒(货号64AERPEH),详细实验操作可参考试剂盒说明书。AGS细胞(含有KRAS G12D突变)购于中国科学院上海生命科学研究院细胞资源中心。
将实验流程简述如下:AGS细胞培养于含10%胎牛血清、100U青霉素和100μg/mL链霉素的F12K完全培养基中。AGS细胞按每孔40000个铺于96孔板中,培养基为完全培养基,在37℃,5%CO2培养箱内培养过夜。将受试化合物溶解于DMSO中制备为10mM贮存液,随后使用F12K完全培养基进行稀释,每孔加入100uL含对应浓度受试化合物的F12K完全培养基,受试化合物在反应体系中的终浓度范围为1000nM-0.015nM,置于细胞培养箱培养3小时后,弃去细胞上清,使用冰浴的PBS清洗细胞,之后每孔加入50μl的1×cell phospho/totalprotein lysis buffer(Advanced phospho-ERK1/2试剂盒组分)进行裂解,96孔板置于冰上裂解半小时,随后参照Advanced phospho-ERK1/2(Thr202/tyr204)试剂盒说明书检测裂解液。最后在酶标仪以TF-FRET模式上测定在304nM的激发波长下,各孔发射波长为620nM和665nM的荧光强度,并计算各孔665/620的荧光强度比值。通过与对照组(0.1%DMSO)的荧光强度比值进行比较,计算受试化合物在各浓度下的百分比抑制率,并通过GraphPad Prism5软件以受试化合物浓度对数值-抑制率进行非线性回归分析,获得化合物的IC50值。
本发明优选化合物对AGS细胞中p-ERK1/2活性具有明显的抑制作用,优选化合物的IC50<500nM,更优化合物的IC50<200nM。
测试例2、本发明化合物对AsPC-1细胞增殖抑制测定
以下方法用于测定本发明化合物对AsPC-1细胞增殖的影响。AsPC-1细胞(含有KRAS G12D突变)购于中国科学院上海生命科学研究院细胞资源中心,培养于含10%胎牛血清、100U青霉素,100μg/mL链霉素和1mM Sodium Pyruvate的RPMI 1640培养基中。细胞活力通过Luminescent Cell Viability Assay试剂盒(Promega,货号G7573)进行测定。
实验方法按照试剂盒说明书的步骤操作,简述如下:受试化合物首先溶解于DMSO中制备为10mM贮存液,随后以培养基进行稀释,配制成测试样品,化合物的终浓度范围在1000nM-0.015nM。将处于对数生长期的细胞以800个细胞每孔的密度接种至96孔细胞培养板中,在37℃,5%CO2培养箱中培养过夜,随后加入受试化合物后继续培养120小时。培养结束后,向每孔加入50uL体积的CellTiter-Glo检测液,震荡5分钟后静置10分钟,随后在酶标仪上使用Luminescence模式读取样品各孔发光值。通过与对照组(0.3%DMSO)的数值进行比较计算化合物在各浓度点的百分比抑制率,之后在GraphPad Prism 5软件中以化合物浓度对数-抑制率进行非线性回归分析,获得化合物抑制细胞增殖的IC50值。
本发明优选化合物对AsPC-1细胞增殖具有明显的抑制作用,优选化合物的IC50<500nM,更优化合物的IC50<200nM。
Claims (17)
1.一种通式(I)所示的化合物或其立体异构体、互变异构体或其可药用的盐:
其中:
G选自一个含有1-2个氮原子的4~12元的杂环基,其中所述杂环基任选进一步被一个或多个Rc所取代;
X和Y各自独立地选自N或CRf;
环A选自5~6元杂芳基;
Rc相同或不同,各自独立地选自氢原子、烷基、卤素、硝基、氰基、环烷基、杂环基、芳基、杂芳基、=O、-OR4、-C(O)OR4、-NHC(O)R4、-NHC(O)OR4、-NR5R6、-C(O)NR5R6、-CH2NHC(O)OR4、-CH2NR5R6或-S(O)rR4,其中所述的烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自烷基、卤素、硝基、氰基、环烷基、杂环基、芳基、杂芳基、=O、-OR4、-C(O)R4、-C(O)OR4、-NHC(O)R4、-NHC(O)OR4、-NR5R6、-C(O)NR5R6、-CH2NHC(O)OR5、-CH2NR6R7或-S(O)rR5的取代基所取代;
Rf选自氢原子、卤素、烷基或烷氧基;其中所述的烷基或烷氧基任选进一步被一个或多个选自卤素、羟基、氰基、烷基或烷氧基的取代基所取代;Rf优选为卤素,更优选为氟或氯;
R1选自氢原子、卤素、烷基或烷氧基;其中所述的烷基或烷氧基任选进一步被一个或多个选自卤素、羟基、氰基、烷基或烷氧基的取代基所取代;R1优选为氢原子;
R2选自芳基或杂芳基,其中所述的芳基或杂芳基任选进一步被一个或多个选自烷基、卤素、硝基、氰基、环烷基、杂环基、芳基、杂芳基、=O、-OR4、-C(O)R4、-C(O)OR4、-NHC(O)R4、-NHC(O)OR4、-NR5R6、-C(O)NR5R6、-CH2NHC(O)OR4、-CH2NR5R6或-S(O)rR4的取代基所取代;其中所述的烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自烷基、卤素、硝基、氰基、环烷基、杂环基、芳基、杂芳基、=O、-OR4、-C(O)R4、-C(O)OR4、-NHC(O)R4、-NHC(O)OR4、-NR5R6、-C(O)NR5R6、-CH2NHC(O)OR4、-CH2NR5R6或-S(O)rR4的取代基所取代;
R3选自不存在、氢原子、卤素、烷基、烷氧基、氰基、卤代烷基或卤代烷氧基,优选为不存在或氢原子;
R4选自氢原子、烷基、环烷基、杂环基、芳基或杂芳基,其中所述的烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基、杂环基、芳基、杂芳基、=O、-C(O)R7、-C(O)OR7、-OC(O)R7、-NR8R9、-C(O)NR8R9、-SO2NR8R9或-NR8C(O)R9的取代基所取代;
R5和R6各自独立地选自氢原子、羟基、卤素、烷基、烷氧基、环烷基、杂环基、芳基或杂芳基,其中所述的烷基、烷氧基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、=O、-C(O)R7、-C(O)OR7、-OC(O)R7、-NR8R9、-C(O)NR8R9、-SO2NR8R9或-NR8C(O)R9的取代基所取代;
或者,R5和R6与它们相连接的原子一起形成一个4~8元杂环基,其中4~8元杂环基内含有一个或多个N、O或S(O)r,并且所述的4~8元杂环基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、=O、-C(O)R7、-C(O)OR7、-OC(O)R7、-NR8R9、-C(O)NR8R9、-SO2NR8R9或-NR8C(O)R9的取代基所取代;
R7、R8和R9各自独立地选自氢原子、烷基、氨基、环烷基、杂环基、芳基或杂芳基,其中所述的烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氨基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧基或羧酸酯基的取代基所取代;
n选自0、1或2;
r为0、1或2。
3.根据权利要求1所述的化合物或其立体异构体、互变异构体或其可药用的盐,其中X、Y各自独立地选自CRf;Rf选自氢原子、卤素、烷基、烷氧基、卤代烷基或卤代烷氧基,Rf优选为卤素,更优选为氟或氯。
4.根据权利要求1所述的化合物或其立体异构体、互变异构体或其可药用的盐,其中R1选自氢原子、卤素、烷基、烷氧基、卤代烷基或卤代烷氧基,R1优选为氢原子。
5.根据权利要求1所述的化合物或其立体异构体、互变异构体或其可药用的盐,其中:
R2选自苯基、萘基、吡啶基、苯并噻唑基或苯并吡唑基,其中所述的苯基、萘基、吡啶基、苯并噻唑基或苯并吡唑基任选进一步被一个或多个选自卤素、羟基、烷基、烷氧基、环烷基或-NR5R6的取代基所取代,其中所述的烷基或烷氧基任选进一步被一个或多个选自卤素或-NR5R6的取代基所取代;其中所述的卤素优选为氟;
R5和R6各自独立地选自氢原子或烷基,其中所述烷基优选为甲基。
7.根据权利要求1所述的化合物或其立体异构体、互变异构体或其可药用的盐,其中R3选自不存在或氢原子。
13.一种药物组合物,所述的药物组合物含有有效剂量的根据权利要求1~9中任何一项所述的化合物或其立体异构体、互变异构体或其可药用的盐,及可药用的载体、赋形剂或它们的组合。
14.根据权利要求1~9中任何一项所述的化合物或其立体异构体、互变异构体或其可药用的盐,或根据权利要求13所述的药物组合物在制备KRas G12D抑制剂中的用途。
15.根据权利要求1~9中任何一项所述的化合物或其立体异构体、互变异构体或其可药用的盐,或根据权利要求13所述的药物组合物在制备治疗由KRas G12D突变介导的疾病的药物中的用途,其中所述的由KRas G12D突变介导的疾病选自癌症,其中所述的癌症选自心脏粘液瘤、肺癌、胃癌、大肠肿瘤、直肠癌、胰腺癌、前列腺癌、膀胱癌、肝细胞癌、胆管癌、胆管癌、软骨肉瘤、多发性骨髓瘤、子宫癌、宫颈癌、精原细胞瘤、恶性黑色素瘤、皮肤鳞状细胞癌、肾上腺成神经细胞瘤、骨髓性白血病、急性淋巴细胞白血病或胶质母细胞瘤,优选为胰腺癌、大肠肿瘤、直肠癌和肺癌。
16.根据权利要求1~9中任何一项所述的化合物或其立体异构体、互变异构体或其可药用的盐,或根据权利要求13所述的药物组合物在制备治疗癌症的药物中的用途,其中所述的癌症选自心脏粘液瘤、肺癌、胃癌、大肠肿瘤、直肠癌、胰腺癌、前列腺癌、膀胱癌、肝细胞癌、胆管癌、胆管癌、软骨肉瘤、多发性骨髓瘤、子宫癌、宫颈癌、精原细胞瘤、恶性黑色素瘤、皮肤鳞状细胞癌、肾上腺成神经细胞瘤、骨髓性白血病、急性淋巴细胞白血病或胶质母细胞瘤,优选为胰腺癌、大肠肿瘤、直肠癌和肺癌。
17.根据权利要求15或16所述的用途,其中所述的肺癌选自非小细胞肺癌或小细胞肺癌。
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