CN114685460A - KRAS G12C inhibitor and its application in medicine - Google Patents

KRAS G12C inhibitor and its application in medicine Download PDF

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CN114685460A
CN114685460A CN202111672313.8A CN202111672313A CN114685460A CN 114685460 A CN114685460 A CN 114685460A CN 202111672313 A CN202111672313 A CN 202111672313A CN 114685460 A CN114685460 A CN 114685460A
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alkylene
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吴颢
陈小平
路渊
何将旗
朱小惯
兰宏
王家柄
丁列明
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Betta Pharmaceuticals Co Ltd
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Abstract

The present invention relates to a novel compound having KRAS G12C modulating activity. The invention also relates to a method for preparing the compounds and a pharmaceutical composition containing the compoundsA pharmaceutical composition.

Description

KRAS G12C抑制剂及其在医药上的应用KRAS G12C inhibitor and its application in medicine

技术领域technical field

本发明涉及一种新型化合物，其具有KRAS G12C调节活性。本发明还涉及这些化合物的制备方法以及包含其的药物组合物。The present invention relates to a novel compound having KRAS G12C modulating activity. The present invention also relates to methods for the preparation of these compounds and pharmaceutical compositions containing them.

背景技术Background technique

临床数据显示，RAS是人类肿瘤中发生突变率最高的基因，所有肿瘤中，约20-30％有RAS突变，大约98％的胰腺癌，52％的结肠癌,43％的多发性骨髓瘤，及32％的肺腺癌中存在RAS基因突变。RAS最常见的突变方式是点突变，经常发生在12、13、61密码子，其中又以第12位密码子突变最常见。KRAS-G12C突变占KRAS突变的约10-20％，在非小细胞肺癌中占14％。目前针对KRAS突变的药物研发是当前新药研究热点之一。Clinical data show that RAS is the gene with the highest mutation rate in human tumors, about 20-30% of all tumors have RAS mutations, about 98% of pancreatic cancer, 52% of colon cancer, 43% of multiple myeloma, And 32% of lung adenocarcinomas have RAS gene mutations. The most common mutation of RAS is point mutation, which often occurs at codons 12, 13, and 61, of which the 12th codon mutation is the most common. KRAS-G12C mutations account for approximately 10-20% of KRAS mutations and 14% in non-small cell lung cancer. Currently, drug development targeting KRAS mutations is one of the hotspots in current new drug research.

发明内容SUMMARY OF THE INVENTION

本发明提供一种通式(I)所示的化合物，或其药用盐：The present invention provides a compound represented by the general formula (I), or a pharmaceutically acceptable salt thereof:

Figure BDA0003450229310000011
Figure BDA0003450229310000011

其中，in,

X1选自

Figure BDA0003450229310000012
Figure BDA0003450229310000013
X 1 is selected from
Figure BDA0003450229310000012
Figure BDA0003450229310000013

X2选自N或CR7，R7选自H、卤素、C1-6烷基、取代的C1-6烷基、C2-6烯基、取代的C2-6烯基、C3-6环烷基或取代的C3-6环烷基；X 2 is selected from N or CR 7 , R 7 is selected from H, halogen, C 1-6 alkyl, substituted C 1-6 alkyl, C 2-6 alkenyl, substituted C 2-6 alkenyl, C 3-6 cycloalkyl or substituted C 3-6 cycloalkyl;

X3选自N或CR8；R8选自H、羟基或氧代基、C2-6烯基、C1-6烷氧基、C3-10环烷基氧基、C1-6烷基、4-10元杂环基取代的C1-6烷基、C1-6烷基磺酰基、C1-6烷基亚磺酰基、C1-6烷硫基、C2-6炔基、C1-6烷基氨基、氨基、C1-6氨基烷基、氨基甲酰基、C1-6氨基甲酰基烷基、C1-6羧基烷基、氰基、C1-6氰基烷基、卤素、C1-6卤代烷基、取代或未取代的芳基、取代或未取代的5-10元杂芳基、取代或未取代的C3-7环烷基、取代或未取代的4-10元杂环基、氰基取代的环丙基C1-6亚烷基氧基，所述C1-6烷氧基任选地进一步被选自卤素、羟基、C1-6烷氧基、C3-8环烷基的取代基所取代；X 3 is selected from N or CR 8 ; R 8 is selected from H, hydroxyl or oxo, C 2-6 alkenyl, C 1-6 alkoxy, C 3-10 cycloalkyloxy, C 1-6 Alkyl, C 1-6 alkyl substituted by 4-10 membered heterocyclyl, C 1-6 alkylsulfonyl, C 1-6 alkylsulfinyl, C 1-6 alkylthio , C 2-6 Alkynyl, C 1-6 alkylamino, amino, C 1-6 aminoalkyl, carbamoyl, C 1-6 carbamoylalkyl, C 1-6 carboxyalkyl, cyano, C 1-6 cyanoalkyl, halogen, C 1-6 haloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C 3-7 cycloalkyl, substituted or unsubstituted Unsubstituted 4-10 membered heterocyclyl, cyano-substituted cyclopropyl C 1-6 alkyleneoxy, said C 1-6 alkoxy optionally further selected from halogen, hydroxy, C 1 -6 alkoxy, C 3-8 cycloalkyl substituents;

L选自键、C1-6亚烷基、C2-6亚烯基、C2-6亚炔基、O(CH2)0-3、S(CH2)0-3或NRa(CH2)0-3，所述C1-6亚烷基、C2-6亚烯基、C2-6亚炔基、O(CH2)0-3、S(CH2)0-3或NRa(CH2)0-3任选地进一步被一个或多个Ra取代；L is selected from bond, C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, O(CH 2 ) 0-3 , S(CH 2 ) 0-3 or NR a ( CH 2 ) 0-3 , the C 1-6 alkylene group, C 2-6 alkenylene group, C 2-6 alkynylene group, O(CH 2 ) 0-3 , S(CH 2 ) 0-3 or NR a (CH 2 ) 0-3 is optionally further substituted with one or more R a ;

R1选自H、-ORa、-OC(O)N(Ra)2、-N(Ra)2、-NRaC(O)Ra、-NRaC(O)N(Ra)2、-NRaS(O)Ra、-NRaS(O)2Ra、-S(＝O)Ra、-S(＝O)2Ra、-SRa、-S(Ra)5、-C(＝O)Ra、-C(＝O)ORa、-C(＝O)N(Ra)2、C3-14环烷基、3-14元杂环基、C6-14芳基或5-14元杂芳基，所述C3-14环烷基、3-14元杂环基、C6-14芳基或5-14元杂芳基任选地进一步被一个或多个R9取代；R9选自H、氰基、卤素、C1-6烷基、C1-6卤代烷基、-C0-6亚烷基-ORa、-C0-6亚烷基-OC(O)N(Ra)2、-C0-6亚烷基-N(Ra)2、-C0-6亚烷基-NRaC(O)Ra、-C0-6亚烷基-NRaC(O)N(Ra)2、-C0-6亚烷基-NRaS(O)Ra、-C0-6亚烷基-NRaS(O)2Ra、-C0-6亚烷基-S(＝O)Ra、-C0-6亚烷基-S(＝O)2Ra、-C0-6亚烷基-SRa、-C0-6亚烷基-S(Ra)5、-C0-6亚烷基-C(＝O)Ra、-C0-6亚烷基-C(＝O)ORa、-C0-6亚烷基-C(＝O)N(Ra)2、C2-6烯基、C2-6炔基、-C0-6亚烷基-C3-14环烷基、-C0-6亚烷基-(3-14元杂环基)、-C0-6亚烷基-C6-14芳基或-C0-6亚烷基-(5-14元杂芳基)，所述C1-6烷基、C2-6烯基、C2-6炔基、-C0-6亚烷基-C3-14环烷基、-C0-6亚烷基-(3-14元杂环基)、-C0-6亚烷基-C6-14芳基或-C0-6亚烷基-(5-14元杂芳基)任选地还可被1个或多个Ra所取代；R 1 is selected from H, -OR a , -OC(O)N(R a ) 2 , -N(R a ) 2 , -NR a C(O)R a , -NR a C(O)N(R a ) 2 , -NR a S(O)R a , -NR a S(O) 2 R a , -S(=O)R a , -S(=O) 2 R a , -SR a , -S (R a ) 5 , -C(=O)R a , -C(=O)OR a , -C(=O)N(R a ) 2 , C 3-14 cycloalkyl, 3-14 membered heterocyclic Cyclyl, C 6-14 aryl or 5-14 membered heteroaryl, the C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl optionally further substituted by one or more R 9 ; R 9 is selected from H, cyano, halogen, C 1-6 alkyl, C 1-6 haloalkyl, -C 0-6 alkylene-OR a , -C 0-6 alkylene-OC(O)N(R a ) 2 , -C 0-6 alkylene-N(R a ) 2 , -C 0-6 alkylene-NR a C(O ) R a , -C 0-6 alkylene -NR a C(O)N(R a ) 2 , -C 0-6 alkylene -NR a S(O)R a , -C 0-6 alkylene Alkyl-NR a S(O) 2 R a , -C 0-6 alkylene-S(=O)R a , -C 0-6 alkylene-S(=O) 2 R a , -C 0-6 alkylene-SR a , -C 0-6 alkylene-S(R a ) 5 , -C 0-6 alkylene-C(=O)R a , -C 0-6 alkylene base-C(=O)OR a , -C 0-6 alkylene-C(=O)N(R a ) 2 , C 2-6 alkenyl, C 2-6 alkynyl, -C 0-6 Alkylene-C 3-14 cycloalkyl, -C 0-6 alkylene-(3-14-membered heterocyclyl), -C 0-6 alkylene-C 6-14 aryl or -C 0 -6 alkylene-(5-14 membered heteroaryl), the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 0-6 alkylene-C 3 -14 cycloalkyl, -C 0-6 alkylene-(3-14 membered heterocyclyl), -C 0-6 alkylene-C 6-14 aryl or -C 0-6 alkylene- (5-14 membered heteroaryl) optionally also substituted with 1 or more R a ;

R2选自丙烯酰基、取代的丙烯酰基或

Figure BDA0003450229310000021
R 2 is selected from acryloyl, substituted acryloyl or
Figure BDA0003450229310000021

R3选自H、C2-6烯基、C1-6烷氧基、C1-6卤代烷氧基、C1-6烷基、4-10元杂环基取代的C1-6烷基、C1-6烷基磺酰基、C1-6烷基亚磺酰基、C1-6烷硫基、C2-6炔基、C1-6烷基氨基、氨基、C1-6氨基烷基、氨基甲酰基、C1-6氨基甲酰基烷基、C1-6羧基烷基、氰基、C1-6氰基烷基、卤素、C1-6卤代烷基、取代或未取代的芳基、取代或未取代的5-10元杂芳基、取代或未取代的C3-7环烷基、取代或未取代的4-10元杂环基、羟基或氧代基；优选H、卤素或C1-3烷基；更优选为H；R 3 is selected from H, C 2-6 alkenyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkyl, C 1-6 alkane substituted by 4-10-membered heterocyclyl base, C 1-6 alkylsulfonyl, C 1-6 alkylsulfinyl, C 1-6 alkylthio, C 2-6 alkynyl, C 1-6 alkylamino, amino, C 1-6 Aminoalkyl, carbamoyl, C 1-6 carbamoylalkyl, C 1-6 carboxyalkyl, cyano, C 1-6 cyanoalkyl, halogen, C 1-6 haloalkyl, substituted or unsubstituted Substituted aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C 3-7 cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclyl, hydroxy or oxo; Preferably H, halogen or C 1-3 alkyl; more preferably H;

R4、R5或R6各自独立地选自H、氰基、卤素、C1-6烷基、C1-6卤代烷基、-C0-6亚烷基-ORa、-C0-6亚烷基-OC(O)N(Ra)2、-C0-6亚烷基-N(Ra)2、-C0-6亚烷基-NRaC(O)Ra、-C0-6亚烷基-NRaC(O)N(Ra)2、-C0-6亚烷基-NRaS(O)Ra、-C0-6亚烷基-NRaS(O)2Ra、-C0-6亚烷基-S(＝O)Ra、-C0-6亚烷基-S(＝O)2Ra、-C0-6亚烷基-SRa、-C0-6亚烷基-S(Ra)5、-C0-6亚烷基-C(＝O)Ra、-C0-6亚烷基-C(＝O)ORa、-C0-6亚烷基-C(＝O)N(Ra)2、C2-6烯基、C2-6炔基、-C0-6亚烷基-C3-14环烷基、-C0-6亚烷基-(3-14元杂环基)、-C0-6亚烷基-C6-14芳基或-C0-6亚烷基-(5-14元杂芳基)，所述C1-6烷基、C2-6烯基、C2-6炔基、-C0-6亚烷基-C3-14环烷基、-C0-6亚烷基-(3-14元杂环基)、-C0-6亚烷基-C6-14芳基或-C0-6亚烷基-(5-14元杂芳基)任选地还可被1个或多个Ra所取代；R 4 , R 5 or R 6 are each independently selected from H, cyano, halogen, C 1-6 alkyl, C 1-6 haloalkyl, -C 0-6 alkylene-OR a , -C 0- 6 alkylene-OC(O)N(R a ) 2 , -C 0-6 alkylene-N(R a ) 2 , -C 0-6 alkylene-NR a C(O)R a , -C 0-6 alkylene-NR a C(O)N(R a ) 2 , -C 0-6 alkylene-NR a S(O)R a , -C 0-6 alkylene-NR a S(O) 2 R a , -C 0-6 alkylene-S(=O)R a , -C 0-6 alkylene-S(=O) 2 R a , -C 0-6 alkylene Alkyl-SR a , -C 0-6 alkylene-S(R a ) 5 , -C 0-6 alkylene-C(=O)R a , -C 0-6 alkylene-C( =O)OR a , -C 0-6 alkylene-C(=O)N(R a ) 2 , C 2-6 alkenyl, C 2-6 alkynyl, -C 0-6 alkylene- C 3-14 cycloalkyl, -C 0-6 alkylene-(3-14-membered heterocyclic group), -C 0-6 alkylene-C 6-14 aryl or -C 0-6 alkylene base-(5-14 membered heteroaryl), the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 0-6 alkylene-C 3-14 cycloalkane base, -C 0-6 alkylene-(3-14 membered heterocyclic group), -C 0-6 alkylene-C 6-14 aryl or -C 0-6 alkylene-(5-14 membered heteroaryl) optionally also substituted with 1 or more R a ;

每个Ra各自独立地选自H、卤素、羟基、氨基、氧代基、硝基、氰基、羧基、C1-6烷基、C1-6羟基烷基、C1-6氨基烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6杂烷基、C3-8环烷基、3-8元杂环基、C6-14芳基或5-14元杂芳基；Each R a is independently selected from H, halogen, hydroxy, amino, oxo, nitro, cyano, carboxyl, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkane base, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 heteroalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl;

m选自0、1、2或3。m is selected from 0, 1, 2 or 3.

一些实施方式中，式(I)中的X2选自N或CR7，R7选自H、卤素、C3-6环烷基或C1-3烯基。In some embodiments, X 2 in formula (I) is selected from N or CR 7 , and R 7 is selected from H, halogen, C 3-6 cycloalkyl or C 1-3 alkenyl.

一些实施方式中，式(I)中的X3选自N或CR8，R8选自H、卤素、C1-6烷氧基、C3-8环烷基氧基、氰基取代的环丙基C1-6亚烷基氧基，所述C1-6烷氧基任选地进一步被选自卤素、羟基、甲氧基、C3-8环烷基的取代基所取代。In some embodiments, X 3 in formula (I) is selected from N or CR 8 , and R 8 is selected from H, halogen, C 1-6 alkoxy, C 3-8 cycloalkyloxy, cyano substituted Cyclopropyl C 1-6 alkyleneoxy, said C 1-6 alkoxy optionally further substituted with a substituent selected from halogen, hydroxy, methoxy, C 3-8 cycloalkyl.

一些实施方式中，式(I)中的-L-R1选自

Figure BDA0003450229310000031
Figure BDA0003450229310000032
In some embodiments, -LR 1 in formula (I) is selected from
Figure BDA0003450229310000031
Figure BDA0003450229310000032

一些实施方式中，式(I)中的R2选自

Figure BDA0003450229310000033
Figure BDA0003450229310000034
In some embodiments, R in formula (I) is selected from
Figure BDA0003450229310000033
Figure BDA0003450229310000034

一些实施方式中，式(I)中的R4、R5或R6各自独立地选自H、＝O、卤素或C1-6烷基。In some embodiments, R 4 , R 5 or R 6 in formula (I) are each independently selected from H, =O, halogen or C 1-6 alkyl.

一些实施方式中，式(I)选自式(IA)：In some embodiments, formula (I) is selected from formula (IA):

Figure BDA0003450229310000041
Figure BDA0003450229310000041

其中，取代基如式(I)所定义。wherein the substituents are as defined in formula (I).

一些实施方式中，式(I)中的化合物选自：In some embodiments, the compound of formula (I) is selected from:

Figure BDA0003450229310000042
Figure BDA0003450229310000042

本发明还提供了一种药物组合物，其特征在于，所述药物组合物包含治疗有效量的至少一种式(I)所示的化合物和至少一种药学上可接受的辅料。The present invention also provides a pharmaceutical composition, characterized in that, the pharmaceutical composition comprises a therapeutically effective amount of at least one compound represented by formula (I) and at least one pharmaceutically acceptable adjuvant.

本发明进一步提供了一种药物组合物，其特征在于，所述的治疗有效量的至少一种式(I)所示的化合物和药学上可接受的辅料的质量百分比为0.0001:1-10。The present invention further provides a pharmaceutical composition, characterized in that the therapeutically effective amount of at least one compound represented by formula (I) and a pharmaceutically acceptable auxiliary material are in a mass percentage of 0.0001:1-10.

本发明提供了结构式(I)所示化合物或药物组合物在制备药物中的应用。The present invention provides the application of the compound represented by the structural formula (I) or the pharmaceutical composition in the preparation of medicine.

本发明进一步提供了所述应用的优选技术方案：The present invention further provides the preferred technical solution of the application:

作为优选，所述应用为制备治疗和/或预防癌症药物中的应用。Preferably, the application is in the preparation of a drug for treating and/or preventing cancer.

作为优选，所述应用为制备用于治疗由KRAS G12C介导的疾病的药物的应用。作为优选，所述疾病是癌症。Preferably, the application is for the preparation of a medicament for treating a disease mediated by KRAS G12C. Preferably, the disease is cancer.

作为优选，所述癌症选自乳腺癌、多发性骨髓瘤、膀胱癌、子宫内膜癌、胃癌、宫颈癌、横纹肌肉瘤、非小细胞肺癌、小细胞肺癌、多形性肺癌、卵巢癌、食管癌、黑色素瘤、结肠直肠癌、肝细胞瘤、头颈部肿瘤、肝胆管细胞癌、骨髓增生异常综合征、恶性胶质瘤、前列腺癌、甲状腺癌、徐旺氏细胞瘤、肺鳞状细胞癌、苔藓样角化病、滑膜肉瘤、皮肤癌、胰腺癌、睾丸癌或脂肪肉瘤。Preferably, the cancer is selected from breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small cell lung cancer, pleomorphic lung cancer, ovarian cancer, esophagus Carcinoma, melanoma, colorectal cancer, hepatoma, head and neck tumor, hepatocholangiocarcinoma, myelodysplastic syndrome, glioblastoma, prostate cancer, thyroid cancer, Schwann cell tumor, lung squamous cell Carcinoma, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer, or liposarcoma.

本发明还提供了一种治疗和/或预防的疾病的方法，包括向治疗对象施用治疗有效量的至少任意一种结构式(I)所示化合物或含其的药物组合物。The present invention also provides a method for treating and/or preventing a disease, comprising administering a therapeutically effective amount of at least any compound represented by structural formula (I) or a pharmaceutical composition containing the same to a treatment subject.

本发明还提供了一种治疗和/或预防由KRAS G12C介导的疾病的方法，包括向治疗对象施用治疗有效量的至少任意一种结构式(I)所示化合物或含其的药物组合物。The present invention also provides a method for treating and/or preventing diseases mediated by KRAS G12C, comprising administering to a subject a therapeutically effective amount of at least any compound represented by structural formula (I) or a pharmaceutical composition containing the same.

除非另有说明，所述结构通式中使用的一般化学术语具有通常的含义。Unless otherwise indicated, general chemical terms used in the structural formulae have their ordinary meanings.

例如，除非另有说明，本发明所用的术语“卤素”是指氟、氯、溴或碘。For example, unless otherwise specified, the term "halogen" as used herein refers to fluorine, chlorine, bromine or iodine.

在本发明中，除非另有说明，“烷基”包括直链或支链的一价饱和烃基。例如，烷基包括甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、3-(2-甲基)丁基、2-戊基、2-甲基丁基、新戊基、正己基、2-己基、2-甲基戊基等。类似的，“基1-8烷基”中的“1-8”是指包含有1、2、3、4、5、6、7或8个碳原子的直链或支链形式排列的基团。In the present invention, unless otherwise specified, "alkyl" includes linear or branched monovalent saturated hydrocarbon groups. For example, alkyl includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2 -pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, 2-methylpentyl, etc. Similarly, " 1-8 " in "base 1-8 alkyl" refers to a group containing 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms arranged in straight or branched chain form group.

“C1-3亚烷基”是指直链或支链的二价饱和烃基，如亚甲基、1,2-亚乙基、1,3-亚丙基或1,2-亚异丙基。"C 1-3 alkylene" refers to a linear or branched divalent saturated hydrocarbon group such as methylene, 1,2-ethylene, 1,3-propylene or 1,2-isopropylene base.

在本发明中，“一”、“一个”、“该”、“至少一个”和“一个或多个”可互换使用。因此，例如，包含“一种”药学上可接受的赋形剂的组合物可以被解释为表示该组合物包括“一种或多种”药学上可接受的赋形剂。In the present invention, "a", "an", "the", "at least one" and "one or more" are used interchangeably. Thus, for example, a composition comprising "a" pharmaceutically acceptable excipient can be interpreted to mean that the composition includes "one or more" pharmaceutically acceptable excipients.

术语“芳基”，在本发明中，除非另有说明，是指未取代或取代的包括碳环的原子的单环或稠环芳香基团，具有完全共轭的π电子体系。优选芳基为6到10元的单环或双环的芳香环基团。优选为苯基、萘基。最优选为苯基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环。The term "aryl", in the present invention, unless otherwise specified, refers to an unsubstituted or substituted mono- or fused-ring aromatic group comprising atoms of a carbocyclic ring, having a fully conjugated pi-electron system. Preferably, the aryl group is a 6- to 10-membered monocyclic or bicyclic aromatic ring group. Preferred are phenyl and naphthyl. Most preferred is phenyl. The aryl ring can be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is the aryl ring.

术语“杂环基”，在本发明中，除非另有说明，是指由碳原子和1-3个选自N、O或S的杂原子组成的未取代或取代的3-14元稳定环系统，其为饱和或部分不饱和单环或多环环状烃取代基，其中氮或硫杂原子可以选择性地被氧化，并且氮杂原子可以选择性地被季铵化。该杂环基可以被连接到任何的杂原子或碳原子上以形成稳定的结构。这些杂环基的实例包括但不限于氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、氧代哌嗪基、氧代哌啶基、四氢呋喃基、二氧戊环基、四氢咪唑基、四氢噻唑基、四氢恶唑基、四氢吡喃基、吗啉基、硫代吗啉基、硫代吗啉基亚砜、硫代吗啉基砜基和四氢恶二唑基。所述杂环基可以稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基。The term "heterocyclyl", in the present invention, unless otherwise specified, refers to an unsubstituted or substituted 3-14 membered stable ring consisting of carbon atoms and 1-3 heteroatoms selected from N, O or S. systems, which are saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituents, wherein nitrogen or sulfur heteroatoms can be selectively oxidized, and nitrogen heteroatoms can be selectively quaternized. The heterocyclyl group can be attached to any heteroatom or carbon atom to form a stable structure. Examples of such heterocyclyl groups include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone and tetrahydro oxadiazolyl. The heterocyclyl group can be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is a heterocyclyl group.

术语“杂芳基”，在本发明中，除非另有说明，是指未取代或取代的稳定的5元或6元单环芳族环系统或未取代或取代的9元-14元苯并稠合杂芳族环系统或多环杂芳族环系统，其由碳原子和1-4个选自N、O或S的杂原子组成，并且其中所述氮或硫杂原子可以选择性地被氧化，所述氮杂原子可以选择性地被季铵化。杂芳基可以连接在任何杂原子或碳原子上以形成稳定的结构。杂芳基的实例包括但不限于噻吩基、呋喃基、咪唑基、异恶唑基、恶唑基、吡唑基、吡咯基、噻唑基、噻二唑基、三唑基、吡啶基、哒嗪基、吲哚基、氮杂吲哚基、吲唑基、苯并咪唑基、苯并呋喃基、苯并噻吩基、苯并异恶唑基、苯并噻唑基、苯并噻唑基、苯并噻二唑基、苯并三唑基腺嘌呤、喹啉基或异喹啉基。所述杂芳基可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环。The term "heteroaryl", in the present invention, unless otherwise specified, refers to an unsubstituted or substituted stable 5- or 6-membered monocyclic aromatic ring system or an unsubstituted or substituted 9- to 14-membered benzo Condensed heteroaromatic ring systems or polycyclic heteroaromatic ring systems consisting of carbon atoms and 1-4 heteroatoms selected from N, O or S, and wherein the nitrogen or sulfur heteroatoms may optionally be Oxidized, the nitrogen heteroatoms can be selectively quaternized. Heteroaryl groups can be attached to any heteroatom or carbon atom to form a stable structure. Examples of heteroaryl groups include, but are not limited to, thienyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridyl Azinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzothiazolyl, benzothiazolyl, benzene thiadiazolyl, benzotriazolyl adenine, quinolinyl or isoquinolinyl. The heteroaryl group can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring.

术语“环烷基”是指具有3-14个碳原子的环状饱和或部分不饱和单环或多环环状烃取代基，例如，环丙基、环丁基、环戊基或环己基。所述环烷基可以稠合于芳基、杂环基或杂芳基环上，其中与母体结构连接在一起的环为环烷基。The term "cycloalkyl" refers to a cyclic saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent having 3 to 14 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl . The cycloalkyl group can be fused to an aryl, heterocyclyl or heteroaryl ring, wherein the ring attached to the parent structure is a cycloalkyl group.

术语“取代的”是指基团中的一个或多个氢原子分别被相同的或者不同的取代基所取代。典型的取代基包括但不限于H、-ORa、-OC(O)N(Ra)2、-N(Ra)2、-NRaC(O)Ra、-NRaC(O)N(Ra)2、-NRaS(O)Ra、-NRaS(O)2Ra、-S(＝O)Ra、-S(＝O)2Ra、-SRa、-S(Ra)5、-C(＝O)Ra、-C(＝O)ORa、-C(＝O)N(Ra)2、C3-14环烷基、3-14元杂环基、C6-14芳基或5-14元杂芳基，所述C3-14环烷基、3-14元杂环基、C6-14芳基或5-14元杂芳基任选地进一步被一个或多个R1取代；R1选自H、氰基、卤素、C1-6烷基、C1-6卤代烷基、-C0-6亚烷基-ORa、-C0-6亚烷基-OC(O)N(Ra)2、-C0-6亚烷基-N(Ra)2、-C0-6亚烷基-NRaC(O)Ra、-C0-6亚烷基-NRaC(O)N(Ra)2、-C0-6亚烷基-NRaS(O)Ra、-C0-6亚烷基-NRaS(O)2Ra、-C0-6亚烷基-S(＝O)Ra、-C0-6亚烷基-S(＝O)2Ra、-C0-6亚烷基-SRa、-C0-6亚烷基-S(Ra)5、-C0-6亚烷基-C(＝O)Ra、-C0-6亚烷基-C(＝O)ORa、-C0-6亚烷基-C(＝O)N(Ra)2、C2-6烯基、C2-6炔基、-C0-6亚烷基-C3-14环烷基、-C0-6亚烷基-(3-14元杂环基)、-C0-6亚烷基-C6-14芳基或-C0-6亚烷基-(5-14元杂芳基)，所述C1-6烷基、C2-6烯基、C2-6炔基、-C0-6亚烷基-C3-14环烷基、-C0-6亚烷基-(3-14元杂环基)、-C0-6亚烷基-C6-14芳基或-C0-6亚烷基-(5-14元杂芳基)任选地还可被1个或多个Ra所取代。每个Ra各自独立地选自H、卤素、羟基、氨基、氧代基、硝基、氰基、羧基、C1-6烷基、C1-6羟基烷基、C1-6氨基烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6杂烷基、C3-8环烷基、3-8元杂环基、C6-14芳基或5-14元杂芳基。在一些实施例中，取代基独立地选自包含-F、-Cl、-Br、-I、-OH、三氟甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、-SCH3、-SC2H5、甲醛基、-C(OCH3)、氰基、硝基、-CF3、-OCF3、氨基、二甲基氨基、甲硫基、磺酰基和乙酰基的基团。The term "substituted" refers to the replacement of one or more hydrogen atoms in a group with the same or a different substituent, respectively. Typical substituents include, but are not limited to, H, -OR a , -OC(O)N(R a ) 2 , -N(R a ) 2 , -NR a C(O)R a , -NR a C(O )N(R a ) 2 , -NR a S(O)R a , -NR a S(O) 2 R a , -S(=O)R a , -S(=O) 2 R a , -SR a , -S(R a ) 5 , -C(=O)R a , -C(=O)OR a , -C(=O)N(R a ) 2 , C 3-14 cycloalkyl, 3 -14-membered heterocyclyl, C6-14 -membered aryl or 5-14-membered heteroaryl, said C3-14 -cycloalkyl, 3-14-membered heterocyclyl, C6-14 -aryl or 5-14 Member heteroaryl is optionally further substituted with one or more R 1 ; R 1 is selected from H, cyano, halogen, C 1-6 alkyl, C 1-6 haloalkyl, -C 0-6 alkylene -OR a , -C 0-6 alkylene-OC(O)N(R a ) 2 , -C 0-6 alkylene-N(R a ) 2 , -C 0-6 alkylene-NR a C(O)R a , -C 0-6 alkylene-NR a C(O)N(R a ) 2 , -C 0-6 alkylene-NR a S(O)R a , -C 0-6 alkylene-NR a S(O) 2 R a , -C 0-6 alkylene-S(=O) R a , -C 0-6 alkylene-S(=O) 2 R a , -C 0-6 alkylene-SR a , -C 0-6 alkylene-S(R a ) 5 , -C 0-6 alkylene-C(=O)R a , -C 0 -6 alkylene-C(=O)OR a , -C 0-6 alkylene-C(=O)N(R a ) 2 , C 2-6 alkenyl, C 2-6 alkynyl, - C 0-6 alkylene-C 3-14 cycloalkyl, -C 0-6 alkylene-(3-14-membered heterocyclic group), -C 0-6 alkylene-C 6-14 aryl Or -C 0-6 alkylene-(5-14-membered heteroaryl), the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 0-6 alkylene base-C 3-14 cycloalkyl, -C 0-6 alkylene-(3-14-membered heterocyclic group), -C 0-6 alkylene-C 6-14 aryl or -C 0-6 Alkylene-(5-14 membered heteroaryl) may optionally also be substituted with 1 or more Ra . Each R a is independently selected from H, halogen, hydroxy, amino, oxo, nitro, cyano, carboxyl, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkane base, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 heteroalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl. In some embodiments, the substituents are independently selected from the group consisting of -F, -Cl, -Br, -I, -OH, trifluoromethoxy, ethoxy, propoxy, isopropoxy, n-butoxy group, isobutoxy, tert-butoxy, -SCH 3 , -SC 2 H 5 , carboxaldehyde, -C(OCH 3 ), cyano, nitro, -CF 3 , -OCF 3 , amino, dimethyl amino, methylthio, sulfonyl and acetyl groups.

取代烷基的实例包括但不限于2,3-二羟基丙基、2-氨基乙基、2-羟乙基、五氯乙基、三氟甲基、甲氧基甲基、五氟乙基、苯基甲基、二恶茂基甲基和哌嗪基甲基。Examples of substituted alkyl groups include, but are not limited to, 2,3-dihydroxypropyl, 2-aminoethyl, 2-hydroxyethyl, pentachloroethyl, trifluoromethyl, methoxymethyl, pentafluoroethyl , phenylmethyl, dioxinylmethyl and piperazinylmethyl.

取代烷氧基的实例包括但不限于2-羟基乙氧基、2-氟乙氧基、2,2-二氟乙氧基、2-甲氧基乙氧基、2-氨基乙氧基、2,3-二羟基丙氧基、环丙基甲氧基、氨基甲氧基、三氟甲氧基、2-二乙基氨基乙氧基、2-乙氧基羰基乙氧基、3-羟基丙氧基。Examples of substituted alkoxy groups include, but are not limited to, 2-hydroxyethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2-methoxyethoxy, 2-aminoethoxy, 2,3-dihydroxypropoxy, cyclopropylmethoxy, aminomethoxy, trifluoromethoxy, 2-diethylaminoethoxy, 2-ethoxycarbonylethoxy, 3- Hydroxypropoxy.

术语“药学上可接受的盐”是指从药学上可接受的无毒的碱或酸制备的盐。The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids.

由于式(I)所示化合物将作为药物应用，较优地，使用一定纯度，例如，至少为60％纯度，比较合适的纯度为至少75％，特别合适地纯度为至少98％(％是重量比)。Since the compound represented by formula (I) will be used as a medicine, it is preferable to use a certain purity, for example, at least 60% pure, more suitably at least 75% pure, particularly suitably at least 98% pure (% by weight) Compare).

本发明化合物的药物前体包含在本发明的保护范围内。通常，所述药物前体是指很容易在体内转化成所需化合物的功能性衍生物。例如，本申请化合物的任何药学上可接受的盐、酯、酯的盐或其它衍生物，其在向受体施用后能够直接或间接地提供本申请的化合物或其具有药学活性的代谢物或残基。Prodrugs of the compounds of the present invention are included within the scope of the present invention. In general, the prodrugs refer to functional derivatives that are readily converted into the desired compound in vivo. For example, any pharmaceutically acceptable salt, ester, salt of ester or other derivative of a compound of the present application which, upon administration to a recipient, is capable of providing, directly or indirectly, a compound of the present application or a pharmaceutically active metabolite thereof or Residues.

当式(I)所示化合物存在互变异构体时，除非特别声明，本发明包括任何可能的互变异构体和其药学上可接受的盐，及它们的混合物。When the compound represented by formula (I) exists as a tautomer, unless otherwise stated, the present invention includes any possible tautomer and pharmaceutically acceptable salts thereof, and mixtures thereof.

当式(I)所示化合物用较重的同位素(例如氘)替代可能提供某些治疗优势，这是由于更大的代谢稳定性，例如增加体内半衰期或减少剂量要求。Substitution of compounds of formula (I) with heavier isotopes (eg deuterium) may provide certain therapeutic advantages due to greater metabolic stability, eg increased in vivo half-life or reduced dosage requirements.

当式(I)所示化合物及其药学上可接受的盐存在溶剂化物或多晶型时，本发明包括任何可能的溶剂化物和多晶型。形成溶剂化物的溶剂类型没有特别的限定，只要该溶剂是药学上可以接受的。例如，水、乙醇、丙醇、丙酮等类似的溶剂都可以采用。When the compounds of formula (I) and their pharmaceutically acceptable salts exist as solvates or polymorphs, the present invention includes any possible solvates and polymorphs. The type of solvent that forms the solvate is not particularly limited as long as the solvent is pharmaceutically acceptable. For example, water, ethanol, propanol, acetone and similar solvents can be used.

术语“组合物”，在本发明中，是指包括包含指定量的各指定成分的产品，以及直接或间接地由指定量的各指定成分的组合生产的任何产品。因此，含有本发明的化合物作为活性成分的药物组合物以及制备本发明化合物的方法也是本发明的一部分。此外，化合物的一些结晶形式可以多晶型存在，并且此多晶型包括在本发明中。另外，一些化合物可以与水(即水合物)或常见的有机溶剂形成溶剂化物，并且此类溶剂化物也落入本发明的范围内。The term "composition", in the present invention, refers to a product comprising a specified amount of each of the specified ingredients, as well as any product produced directly or indirectly from a combination of the specified amounts of each of the specified ingredients. Accordingly, pharmaceutical compositions containing the compounds of the present invention as active ingredients and methods of preparing the compounds of the present invention are also part of the present invention. In addition, some of the crystalline forms of the compounds may exist as polymorphs, and such polymorphs are included in the present invention. In addition, some of the compounds may form solvates with water (ie, hydrates) or common organic solvents, and such solvates are also within the scope of this invention.

本发明提供的药物组合物包括作为活性组分的式(I)所示化合物(或其药学上可接受的盐)、一种药学上可接受的赋形剂及其他可选的治疗组分或辅料。The pharmaceutical composition provided by the present invention comprises a compound represented by formula (I) (or a pharmaceutically acceptable salt thereof) as an active component, a pharmaceutically acceptable excipient and other optional therapeutic components or Accessories.

具体实施方式Detailed ways

为使上述内容更清楚、明确，本发明将用以下实施例来进一步阐述本发明的技术方案。以下实施例仅用于说明本发明的具体实施方式，以使本领域的技术人员能够理解本发明，但不用于限制本发明的保护范围。本发明的具体实施方式中，未作特别说明的技术手段或方法等为本领域的常规技术手段或方法等。In order to make the above content clearer and clearer, the present invention will further illustrate the technical solutions of the present invention with the following examples. The following examples are only used to illustrate the specific embodiments of the present invention, so that those skilled in the art can understand the present invention, but are not intended to limit the protection scope of the present invention. In the specific embodiments of the present invention, the technical means or methods that are not specifically described are conventional technical means or methods in the field.

除非另有说明，本发明所有的一部分和百分比均按重量计算，所有温度均指摄氏度。All parts and percentages herein are by weight and all temperatures are in degrees Celsius unless otherwise indicated.

中间体M的合成Synthesis of Intermediate M

Figure BDA0003450229310000081
Figure BDA0003450229310000081

步骤1：化合物M-2的合成Step 1: Synthesis of Compound M-2

把商业可得的原料M-1(10.0g)溶解在THF中(60mL)，然后加DIEA(14mL)和羰基二咪唑(10.4g)，室温反应3h。LCMS确定原料转化完全到中间体。在另外一个瓶子里加氨水(90mL),降温至0℃，搅拌下把前面的反应液滴加到反应瓶中，加完反应10min，取样检测显示都转化为产物了。加入乙酸乙酯100mL萃取，再用饱和氯化钠水溶液60mL×2洗涤、分液。加入无水硫酸钠干燥。过滤，浓缩，得到黄色固体M-2(9.6g,96.9％yield)ESI-MS m/z:233.21[M+H]+。The commercially available raw material M-1 (10.0 g) was dissolved in THF (60 mL), then DIEA (14 mL) and carbonyldiimidazole (10.4 g) were added, and the reaction was carried out at room temperature for 3 h. LCMS confirmed complete conversion of starting material to intermediate. Ammonia water (90 mL) was added to another bottle, the temperature was lowered to 0°C, and the previous reaction was added dropwise to the reaction bottle under stirring. 100 mL of ethyl acetate was added for extraction, and then washed with 60 mL of saturated aqueous sodium chloride solution × 2, and the solution was separated. Add anhydrous sodium sulfate to dry. Filtration and concentration gave M-2 as a yellow solid (9.6 g, 96.9% yield) ESI-MS m/z: 233.21 [M+H] + .

步骤2：化合物M-3的合成Step 2: Synthesis of Compound M-3

在反应瓶中加入原料M-2(9.6g)，加DMF(100mL)溶解，降温至0℃，然后加NaH(4.1g)，0℃下反应0.5h，再加羰基二咪唑(10.1g)，75℃反应5h。取样检测显示都转化为产物了。冷却，然后加水析出固体，过滤，滤饼用水和EA洗三次，最后干燥得到黄色固体M-3(8.1g,75.5％yield)ESI-MS m/z:259.31[M+H]+。Add raw material M-2 (9.6g) to the reaction flask, add DMF (100mL) to dissolve, cool to 0°C, then add NaH (4.1g), react at 0°C for 0.5h, add carbonyldiimidazole (10.1g) , 75 ℃ reaction 5h. Sampling and testing showed that all were converted to product. Cool, then add water to precipitate solid, filter, wash the filter cake with water and EA three times, and finally dry to obtain yellow solid M-3 (8.1 g, 75.5% yield) ESI-MS m/z: 259.31 [M+H] + .

步骤3：化合物M-4的合成Step 3: Synthesis of Compound M-4

在反应瓶中加入原料M-3(8.0g)，搅拌下加入POCl3(60mL)，再加DIEA(12mL)，110℃下反应2h。取样检测显示大部分都转化为产物了，将溶剂旋干，然后加到碎冰中，用EA萃取。有机相浓缩后再用PE:EA＝2:1打浆，过滤，得到黄色固体M-4(3.8g,41.7％yield)ESI-MS m/z:295.33[M+H]+。The raw material M-3 (8.0 g) was added to the reaction flask, POCl 3 (60 mL) was added under stirring, DIEA (12 mL) was added, and the reaction was carried out at 110° C. for 2 h. Sampling showed most conversion to product, the solvent was spun dry, added to crushed ice and extracted with EA. The organic phase was concentrated and then slurried with PE:EA=2:1, and filtered to obtain a yellow solid M-4 (3.8 g, 41.7% yield) ESI-MS m/z: 295.33 [M+H] + .

步骤4：化合物M-5的合成Step 4: Synthesis of Compound M-5

在反应瓶中加入原料M-4(3.75g)，加DCM(30mL)和THF(10mL)溶解，再加DIEA(6mL)，降温至0℃，然后加(S)-2-(piperazin-2-yl)acetonitrile(2.1g)。加完在该温度下继续反应0.3h。取样检测显示原料基本上都转化为产物了，将溶剂旋干，得到粗品黄色固体M-5(6.8g,crude)ESI-MS m/z:384.07[M+H]+。Add raw material M-4 (3.75g) to the reaction flask, add DCM (30mL) and THF (10mL) to dissolve, add DIEA (6mL), cool down to 0°C, then add (S)-2-(piperazin-2 -yl)acetonitrile (2.1 g). After the addition, the reaction was continued for 0.3 h at this temperature. Sampling and testing showed that the raw materials were basically converted into products, and the solvent was spin-dried to obtain a crude yellow solid M-5 (6.8 g, crude) ESI-MS m/z: 384.07 [M+H] + .

步骤5：化合物M-6的合成Step 5: Synthesis of Compound M-6

在反应瓶中加入粗品M-5(6.8g,crude)，加DCM(50mL)溶解，再加DIEA(6mL)，0℃下加(Boc)2O(3.5g)。加完恢复室温反应14h。取样检测显示原料基本上都转化为产物了，加水和DCM，萃取，干燥，浓缩。用flash过柱，展开剂用DCM:MeOH＝40:1，得到黄色固体M-6(5.4g,87.4％yield)ESI-MS m/z:484.02[M+H]+。Crude M-5 (6.8 g, crude) was added to the reaction flask, DCM (50 mL) was added to dissolve, DIEA (6 mL) was added, and (Boc) 2 O (3.5 g) was added at 0°C. After the addition was completed, the reaction was returned to room temperature for 14h. Sampling and testing showed that the starting material was substantially converted to product, water and DCM were added, extracted, dried, and concentrated. Pass the column with flash and use DCM:MeOH=40:1 as the developing solvent to obtain yellow solid M-6 (5.4 g, 87.4% yield) ESI-MS m/z: 484.02 [M+H] + .

步骤6：中间体M的合成Step 6: Synthesis of Intermediate M

在反应瓶中加入原料M-6(5.4g)，加CH3CN(50mL)溶解，再加DIEA(6mL)和(s)-1-甲基-2-吡咯烷甲醇(3.8g)。加完80℃反应14h。取样检测显示原料大部分都转化为产物了，先将溶剂旋干，然后加水和DCM萃取，干燥，浓缩。用flash过柱，展开剂用DCM:MeOH＝15:1，得到黄色固体M(4.1g,65.8％yield)ESI-MS m/z:563.28[M+H]+。The raw material M-6 (5.4 g) was added to the reaction flask, CH 3 CN (50 mL) was added to dissolve, and DIEA (6 mL) and (s)-1-methyl-2-pyrrolidine methanol (3.8 g) were added. The reaction was completed at 80°C for 14h. Sampling and testing showed that most of the raw materials were converted into products, the solvent was spin-dried, then extracted with water and DCM, dried and concentrated. Pass the column with flash, and use DCM:MeOH=15:1 as the developing solvent to obtain yellow solid M (4.1 g, 65.8% yield) ESI-MS m/z: 563.28 [M+H] + .

实施例1：化合物1的合成Example 1: Synthesis of Compound 1

Figure BDA0003450229310000101
Figure BDA0003450229310000101

步骤1：化合物1-2的合成Step 1: Synthesis of Compounds 1-2

在反应瓶中加入商业可得的原料1-1(2.11g)和甲基三苯基溴化膦(7.14g)，加THF(25mL)溶解，取叔丁醇钾(2.24g)溶于THF(25mL)中，0℃下加到反应液中，加完恢复室温反应3h。取样点板检测，显示原料反应完全。加EA和水萃取，干燥，浓缩。用flash过柱，展开剂用石油醚，得到无色液体1-2(1.65g,79.3％yield)。Commercially available raw materials 1-1 (2.11g) and methyltriphenylphosphine bromide (7.14g) were added to the reaction flask, dissolved in THF (25mL), and potassium tert-butoxide (2.24g) was dissolved in THF (25mL), added to the reaction solution at 0°C, and returned to room temperature after the addition for 3h. Sampling point plate detection shows that the reaction of the raw materials is complete. Add EA and water for extraction, dry and concentrate. Pass the column with flash, and use petroleum ether as the developing solvent to obtain 1-2 (1.65 g, 79.3% yield) as a colorless liquid.

步骤2：化合物1-3的合成Step 2: Synthesis of Compounds 1-3

在反应瓶中加入DCM(30mL)，降温至0℃，加二乙基锌溶液(28.7mL)和三氟乙酸(2.1mL)，加完0℃反应15min，加CH2I2(7.69g)，0℃下继续反应15min，再取化合物1-2(1.5g)溶于DCM(15mL)后加到反应液中，加完0℃继续反应15min，最后恢复室温反应3h，取样点板检测，显示原料反应完全。加氯化铵水溶液淬灭反应，然后加DCM萃取，干燥，浓缩。用flash过柱，展开剂用石油醚，拿到无色液体1-3(1.4g,87.6％yield)。DCM (30 mL) was added to the reaction flask, the temperature was lowered to 0 °C, diethylzinc solution (28.7 mL) and trifluoroacetic acid (2.1 mL) were added, and the reaction at 0 °C was completed for 15 min, and CH 2 I 2 (7.69 g) was added. , continue the reaction at 0°C for 15min, then take compound 1-2 (1.5g) and dissolve it in DCM (15mL) and add it to the reaction solution. After adding 0°C, continue the reaction for 15min, and finally return to room temperature for 3h. The reaction of the starting material was shown to be complete. The reaction was quenched with aqueous ammonium chloride, then extracted with DCM, dried and concentrated. Pass through the column with flash, and use petroleum ether as the developing solvent to obtain colorless liquid 1-3 (1.4 g, 87.6% yield).

步骤3：化合物1-4的合成Step 3: Synthesis of Compounds 1-4

在反应瓶中加入1-3(1.4000g)，联硼酸频那醇酯(3.18g)，[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(0.51g)，醋酸钾(1.85g)和1,4-dioxane(25mL)，氮气置换后氮气保护下95℃反应8h。取样点板检测，显示原料反应完全，加EA和水萃取，干燥，浓缩。用flash过柱，展开剂从PE到PE:EA＝50:1，得到淡黄色液体1-4(1.1g,64.8％yield)。1-3 (1.4000g), biboronic acid pinacol ester (3.18g), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane were added to the reaction flask for complexation Compound (0.51 g), potassium acetate (1.85 g) and 1,4-dioxane (25 mL) were replaced with nitrogen and reacted at 95°C for 8 h under nitrogen protection. Sampling point plate detection shows that the reaction of the raw materials is complete, add EA and water for extraction, dry and concentrate. The column was flashed, and the developing solvent was from PE to PE:EA=50:1 to obtain pale yellow liquid 1-4 (1.1 g, 64.8% yield).

步骤4：化合物1-5的合成Step 4: Synthesis of Compounds 1-5

在反应瓶中加入中间体M(0.2g)，1-4(0.14g)，磷酸钾(0.23g)，Sphos-Pd-G2(0.026g)，环戊基甲基醚(4mL)和水(0.4mL)，氮气置换后氮气保护下100℃反应4h。取样检测，显示原料反应完全，加EA和水萃取，干燥，浓缩。用大板分离，展开剂用DCM:MeOH:氨水＝15:1：0.15，拿到黄色固体1-5(0.14g，yield:62.9％)ESI-MS m/z:627.42[M+H]+。Intermediate M (0.2g), 1-4 (0.14g), potassium phosphate (0.23g), Sphos-Pd-G2 (0.026g), cyclopentyl methyl ether (4mL) and water ( 0.4 mL), replaced with nitrogen and reacted at 100 °C for 4 h under nitrogen protection. Sampling and testing showed that the reaction of the raw materials was complete, and EA and water were added for extraction, drying and concentration. Separate with a large plate, use DCM:MeOH:ammonia=15:1:0.15 as the developing agent, get yellow solid 1-5 (0.14g, yield: 62.9%) ESI-MS m/z: 627.42[M+H] + .

步骤5：化合物1-6的合成Step 5: Synthesis of Compounds 1-6

在反应瓶中加入化合物1-5(0.14g)，加DCM(1.5mL)和三氟乙酸(1.5mL)，室温反应0.5h。取样检测，显示原料反应完全。加DCM和水萃取，干燥，浓缩。拿到粗品化合物1-6(120mg,crude)ESI-MS m/z:527.25[M+H]+。Compound 1-5 (0.14 g) was added to the reaction flask, DCM (1.5 mL) and trifluoroacetic acid (1.5 mL) were added, and the reaction was carried out at room temperature for 0.5 h. Sampling and testing showed that the reaction of the raw materials was complete. Extracted with DCM and water, dried and concentrated. Obtained crude compound 1-6 (120 mg, crude) ESI-MS m/z: 527.25 [M+H] + .

步骤6：化合物1的合成Step 6: Synthesis of Compound 1

在反应瓶中加入1-5(120mg)，加DCM(3mL)溶解，加DIEA(81mg)，降温至0度，取丙烯酰氯(23mg)，稀释后缓慢加到反应液中，加完后继续在该温度下反应10min。LCMS显示原料反应完全，加入二氯甲烷10mL，再用饱和氯化钠水溶液20mL×2洗涤、分液。加入无水硫酸钠干燥，过滤，浓缩，用制备板分离，展开剂用DCM:MeOH:氨水＝18:1:0.18，拿到白色固体1(60mg,49.3％yield)ESI-MS m/z:581[M+H]+，1H NMR(500MHz,CDCl3)δ7.55–7.47(m,1H),7.21(d,J＝7.7Hz,1H),7.09(t,J＝7.5Hz,1H),7.04(ddd,J＝8.8,6.5,2.7Hz,1H),6.80(d,J＝7.3Hz,1H),6.53(s,1H),6.34(d,J＝16.7Hz,1H),5.77(d,J＝10.4Hz,1H),4.55(ddd,J＝10.8,4.6,1.8Hz,1H),4.38–4.18(m,3H),4.07–3.87(m,1H),3.83–3.47(m,2H),3.40–3.28(m,1H),3.08(t,J＝7.3Hz,1H),2.95(ddt,J＝23.6,16.1,7.9Hz,3H),2.72(s,2H),2.47(t,J＝5.6Hz,3H),2.31–2.20(m,1H),2.04–1.90(m,3H),1.83–1.65(m,3H),1.29–1.15(m,1H),0.63–0.53(m,2H),0.52–0.46(m,1H),0.45–0.38(m,1H).Add 1-5 (120mg) to the reaction flask, add DCM (3mL) to dissolve, add DIEA (81mg), cool to 0 degrees, take acryloyl chloride (23mg), dilute and slowly add it to the reaction solution, continue after adding React at this temperature for 10 min. LCMS showed that the reaction of the raw materials was complete, and 10 mL of dichloromethane was added, followed by washing with a saturated aqueous sodium chloride solution 20 mL×2, and separation. Add anhydrous sodium sulfate to dry, filter, concentrate, separate with a preparative plate, use DCM:MeOH:ammonia=18:1:0.18 as the developing solvent, get white solid 1 (60mg, 49.3% yield) ESI-MS m/z: 581[M+H] + , 1 H NMR (500MHz, CDCl 3 ) δ 7.55-7.47 (m, 1H), 7.21 (d, J=7.7Hz, 1H), 7.09 (t, J=7.5Hz, 1H) ),7.04(ddd,J=8.8,6.5,2.7Hz,1H),6.80(d,J=7.3Hz,1H),6.53(s,1H),6.34(d,J=16.7Hz,1H),5.77 (d, J=10.4Hz, 1H), 4.55 (ddd, J=10.8, 4.6, 1.8Hz, 1H), 4.38–4.18 (m, 3H), 4.07–3.87 (m, 1H), 3.83–3.47 (m ,2H),3.40–3.28(m,1H),3.08(t,J=7.3Hz,1H),2.95(ddt,J=23.6,16.1,7.9Hz,3H),2.72(s,2H),2.47( t, J=5.6Hz, 3H), 2.31–2.20 (m, 1H), 2.04–1.90 (m, 3H), 1.83–1.65 (m, 3H), 1.29–1.15 (m, 1H), 0.63–0.53 ( m, 2H), 0.52–0.46 (m, 1H), 0.45–0.38 (m, 1H).

实施例2：化合物2的合成Example 2: Synthesis of Compound 2

Figure BDA0003450229310000111
Figure BDA0003450229310000111

在反应瓶中加入1-6粗产品(100mg)，加DMF(4mL)溶解，加DIEA(0.2mL)，然后加入2-氟丙烯酸(18mg)，最后加入HATU(72mg)，加完后继续在该温度下反应10min。LCMS显示原料反应完全，反应结束后，往体系中加入EA(100mL)，然后饱和碳酸氢钠水溶液洗两次，再用饱和氯化钠水溶液20mL×2洗涤、分液。加入无水硫酸钠干燥，过滤，浓缩，用制备板分离，展开剂用DCM:MeOH:氨水＝18:1:0.18，拿到白色固体2(43mg,37.7％yield)ESI-MS m/z:599[M+H]+，1H NMR(500MHz,CDCl3)δ7.57(dd,J＝8.5,3.7Hz,1H),7.29(d,J＝7.5Hz,1H),7.21–7.10(m,2H),6.88(d,J＝7.5Hz,1H),5.45(d,J＝47.5Hz,1H),5.27(dd,J＝17.0,3.7Hz,1H),4.68(dt,J＝10.4,4.8Hz,1H),4.45(dt,J＝11.8,6.5Hz,1H),4.42–4.26(m,2H),3.30(s,1H),3.04(qt,J＝16.7,8.2Hz,4H),2.89(s,2H),2.64(d,J＝3.9Hz,3H),2.46(d,J＝9.2Hz,1H),2.19–2.09(m,1H),2.03(q,J＝9.9,8.7Hz,2H),1.97–1.80(m,3H),0.64(dp,J＝13.4,5.0Hz,2H),0.60–0.53(m,2H),0.48(ddt,J＝10.1,6.8,3.6Hz,1H)。Add 1-6 crude product (100mg) to the reaction flask, add DMF (4mL) to dissolve, add DIEA (0.2mL), then add 2-fluoroacrylic acid (18mg), and finally add HATU (72mg), after adding, continue in The reaction was carried out at this temperature for 10 min. LCMS showed that the reaction of the raw materials was complete. After the reaction was completed, EA (100 mL) was added to the system, then washed twice with saturated aqueous sodium bicarbonate solution, and then washed with saturated aqueous sodium chloride solution 20 mL×2 and separated. Anhydrous sodium sulfate was added to dry, filtered, concentrated, separated with a preparative plate, and the developing solvent was DCM:MeOH:ammonia=18:1:0.18 to obtain a white solid 2 (43 mg, 37.7% yield) ESI-MS m/z: 599 [M+H] + , 1 H NMR (500 MHz, CDCl 3 ) δ 7.57 (dd, J=8.5, 3.7 Hz, 1H), 7.29 (d, J=7.5 Hz, 1H), 7.21-7.10 (m ,2H),6.88(d,J＝7.5Hz,1H),5.45(d,J＝47.5Hz,1H),5.27(dd,J＝17.0,3.7Hz,1H),4.68(dt,J＝10.4, 4.8Hz, 1H), 4.45 (dt, J=11.8, 6.5Hz, 1H), 4.42–4.26 (m, 2H), 3.30 (s, 1H), 3.04 (qt, J=16.7, 8.2Hz, 4H), 2.89(s, 2H), 2.64(d, J=3.9Hz, 3H), 2.46(d, J=9.2Hz, 1H), 2.19–2.09(m, 1H), 2.03(q, J=9.9, 8.7Hz) ,2H),1.97–1.80(m,3H),0.64(dp,J=13.4,5.0Hz,2H),0.60–0.53(m,2H),0.48(ddt,J=10.1,6.8,3.6Hz,1H ).

下述的实施例采用上述方法合成，或使用相应中间体的类似方法合成。The following examples were synthesized using the methods described above, or analogously using the corresponding intermediates.

Figure BDA0003450229310000121
Figure BDA0003450229310000121

Figure BDA0003450229310000131
Figure BDA0003450229310000131

Figure BDA0003450229310000141
Figure BDA0003450229310000141

药理实验Pharmacological experiments

实施例1：细胞增殖抑制检测Example 1: Detection of Cell Proliferation Inhibition

将MIA PaCa-2细胞按600细胞、160μL/孔铺96孔超低吸附板。孵育隔夜后，配制梯度浓度的化合物溶液，分别向各孔细胞中加入40μL各浓度的待测化合物DMSO溶液，化合物终浓度为10000、2000、400、80、16、3.2、0.64、0.12、0.025、0nM(DMSO终浓度均为0.25％)。37℃，5％CO2孵育96h。向各孔中加入50μL Cell-titer Glo工作液，震荡混匀后室温孵育10min，多功能酶标仪读取Luminescence发光值，将发光值读数转换为抑制百分数：MIA PaCa-2 cells were plated in a 96-well ultra-low adsorption plate at 600 cells and 160 μL/well. After overnight incubation, compound solutions with gradient concentrations were prepared, and 40 μL of DMSO solutions of the compounds to be tested were added to each well of cells respectively. 0 nM (all final concentrations of DMSO were 0.25%). Incubate for 96h at 37°C, 5% CO2 . Add 50 μL of Cell-titer Glo working solution to each well, incubate at room temperature for 10 min after shaking and mixing, read the Luminescence luminescence value with a multi-function microplate reader, and convert the luminescence value reading into the inhibition percentage:

抑制百分数＝(最大值-读数)/(最大值-最小值)*100。Percent Inhibition=(Max-Reading)/(Max-Min)*100.

“最大值”为DMSO对照；“最小值”表示无细胞对照组。"Max" is the DMSO control; "Min" is the cell-free control.

用Graphpad Prism软件进行曲线拟合并得到IC50值。Curve fitting was performed with Graphpad Prism software and IC50 values were obtained.

本发明的化合物具有良好活性。实施例部分化合物对MIA PaCa-2细胞抑制的IC50数据参见表1。The compounds of the present invention have good activity. See Table 1 for IC50 data of some compounds in the examples for inhibition of MIA PaCa-2 cells.

表1Table 1

化合物名称Compound name IC<sub>50</sub>(nM)IC<sub>50</sub>(nM) 11 1.091.09 22 1111

实施例2：细胞增殖抑制检测Example 2: Detection of Cell Proliferation Inhibition

将H358细胞按2000细胞、190μL/孔铺96孔超低吸附板。孵育隔夜后，配制梯度浓度的化合物溶液，分别向各孔细胞中加入10μL各浓度的待测化合物DMSO溶液，化合物终浓度为10000、3333.3、1111.1、370.4、123.5、41.2、13.7、4.6、1.5、0nM(DMSO终浓度均为0.25％)。37℃，5％CO2孵育96h。向各孔中加入50μL Cell-titer Glo工作液，震荡混匀后室温孵育10min，多功能酶标仪读取Luminescence发光值，将发光值读数转换为抑制百分数：H358 cells were plated in 96-well ultra-low adsorption plates at 2000 cells and 190 μL/well. After overnight incubation, compound solutions with gradient concentrations were prepared, and 10 μL of DMSO solution of each concentration of the test compound was added to each well of cells respectively. 0 nM (all final concentrations of DMSO were 0.25%). Incubate for 96h at 37°C, 5% CO2. Add 50 μL of Cell-titer Glo working solution to each well, incubate at room temperature for 10 min after shaking and mixing, read the Luminescence luminescence value with a multi-function microplate reader, and convert the luminescence value reading into the inhibition percentage:

抑制百分数＝(最大值-读数)/(最大值-最小值)*100。Percent Inhibition=(Max-Reading)/(Max-Min)*100.

“最大值”为DMSO对照；“最小值”表示无细胞对照组。"Max" is the DMSO control; "Min" is the cell-free control.

用Graphpad Prism软件进行曲线拟合并得到IC50值。Curve fitting was performed with Graphpad Prism software and IC50 values were obtained.

本发明的化合物具有良好活性。实施例部分化合物对H358细胞抑制的IC50数据参见表2。The compounds of the present invention have good activity. Table 2 shows the IC50 data of some compounds in the examples for inhibition of H358 cells.

表2Table 2

化合物名称Compound name IC<sub>50</sub>(nM)IC<sub>50</sub>(nM) 11 2.32.3 22 22twenty two

虽然本发明已通过其实施方式进行了全面的描述，但是值得注意的是，各种变化和修改对于本领域技术人员都是显而易见的。这样的变化和修改都应该包括在本发明所附权利要求的范围内。Although the present invention has been fully described in terms of its embodiments, it is worth noting that various changes and modifications will be apparent to those skilled in the art. Such changes and modifications are intended to be included within the scope of the appended claims of the present invention.

Claims (10)

1.一种通式(I)所示的化合物、其互变异构体、氘代物或药用盐：1. a compound shown in general formula (I), its tautomer, deuterated substance or pharmaceutically acceptable salt:
Figure FDA0003450229300000011
Figure FDA0003450229300000011
 其中，in, X1选自
Figure FDA0003450229300000012
Figure FDA0003450229300000013
X 1 is selected from
Figure FDA0003450229300000012
Figure FDA0003450229300000013
 X2选自N或CR7，R7选自H、卤素、C1-6烷基、取代的C1-6烷基、C2-6烯基、取代的C2-6烯基、C3-6环烷基或取代的C3-6环烷基；X 2 is selected from N or CR 7 , R 7 is selected from H, halogen, C 1-6 alkyl, substituted C 1-6 alkyl, C 2-6 alkenyl, substituted C 2-6 alkenyl, C 3-6 cycloalkyl or substituted C 3-6 cycloalkyl; X3选自N或CR8；R8选自H、羟基或氧代基、C2-6烯基、C1-6烷氧基、C3-10环烷基氧基、C1-6烷基、4-10元杂环基取代的C1-6烷基、C1-6烷基磺酰基、C1-6烷基亚磺酰基、C1-6烷硫基、C2-6炔基、C1-6烷基氨基、氨基、C1-6氨基烷基、氨基甲酰基、C1-6氨基甲酰基烷基、C1-6羧基烷基、氰基、C1-6氰基烷基、卤素、C1-6卤代烷基、取代或未取代的芳基、取代或未取代的5-10元杂芳基、取代或未取代的C3-7环烷基、取代或未取代的4-10元杂环基、氰基取代的环丙基C1-6亚烷基氧基，所述C1-6烷氧基任选地进一步被选自卤素、羟基、C1-6烷氧基、C3-8环烷基的取代基所取代；X 3 is selected from N or CR 8 ; R 8 is selected from H, hydroxyl or oxo, C 2-6 alkenyl, C 1-6 alkoxy, C 3-10 cycloalkyloxy, C 1-6 Alkyl, C 1-6 alkyl substituted by 4-10 membered heterocyclyl, C 1-6 alkylsulfonyl, C 1-6 alkylsulfinyl, C 1-6 alkylthio , C 2-6 Alkynyl, C 1-6 alkylamino, amino, C 1-6 aminoalkyl, carbamoyl, C 1-6 carbamoylalkyl, C 1-6 carboxyalkyl, cyano, C 1-6 cyanoalkyl, halogen, C 1-6 haloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C 3-7 cycloalkyl, substituted or unsubstituted Unsubstituted 4-10 membered heterocyclyl, cyano-substituted cyclopropyl C 1-6 alkyleneoxy, said C 1-6 alkoxy optionally further selected from halogen, hydroxy, C 1 -6 alkoxy, C 3-8 cycloalkyl substituents; L选自键、C1-6亚烷基、C2-6亚烯基、C2-6亚炔基、O(CH2)0-3、S(CH2)0-3或NRa(CH2)0-3，所述C1-6亚烷基、C2-6亚烯基、C2-6亚炔基、O(CH2)0-3、S(CH2)0-3或NRa(CH2)0-3任选地进一步被一个或多个Ra取代；L is selected from bond, C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, O(CH 2 ) 0-3 , S(CH 2 ) 0-3 or NR a ( CH 2 ) 0-3 , the C 1-6 alkylene group, C 2-6 alkenylene group, C 2-6 alkynylene group, O(CH 2 ) 0-3 , S(CH 2 ) 0-3 or NR a (CH 2 ) 0-3 is optionally further substituted with one or more R a ; R1选自H、-ORa、-OC(O)N(Ra)2、-N(Ra)2、-NRaC(O)Ra、-NRaC(O)N(Ra)2、-NRaS(O)Ra、-NRaS(O)2Ra、-S(＝O)Ra、-S(＝O)2Ra、-SRa、-S(Ra)5、-C(＝O)Ra、-C(＝O)ORa、-C(＝O)N(Ra)2、C3-14环烷基、3-14元杂环基、C6-14芳基或5-14元杂芳基，所述C3-14环烷基、3-14元杂环基、C6-14芳基或5-14元杂芳基任选地进一步被一个或多个R9取代；R9选自H、氰基、卤素、C1-6烷基、C1-6卤代烷基、-C0-6亚烷基-ORa、-C0-6亚烷基-OC(O)N(Ra)2、-C0-6亚烷基-N(Ra)2、-C0-6亚烷基-NRaC(O)Ra、-C0-6亚烷基-NRaC(O)N(Ra)2、-C0-6亚烷基-NRaS(O)Ra、-C0-6亚烷基-NRaS(O)2Ra、-C0-6亚烷基-S(＝O)Ra、-C0-6亚烷基-S(＝O)2Ra、-C0-6亚烷基-SRa、-C0-6亚烷基-S(Ra)5、-C0-6亚烷基-C(＝O)Ra、-C0-6亚烷基-C(＝O)ORa、-C0-6亚烷基-C(＝O)N(Ra)2、C2-6烯基、C2-6炔基、-C0-6亚烷基-C3-14环烷基、-C0-6亚烷基-(3-14元杂环基)、-C0-6亚烷基-C6-14芳基或-C0-6亚烷基-(5-14元杂芳基)，所述C1-6烷基、C2-6烯基、C2-6炔基、-C0-6亚烷基-C3-14环烷基、-C0-6亚烷基-(3-14元杂环基)、-C0-6亚烷基-C6-14芳基或-C0-6亚烷基-(5-14元杂芳基)任选地还可被1个或多个Ra所取代；R 1 is selected from H, -OR a , -OC(O)N(R a ) 2 , -N(R a ) 2 , -NR a C(O)R a , -NR a C(O)N(R a ) 2 , -NR a S(O)R a , -NR a S(O) 2 R a , -S(=O)R a , -S(=O) 2 R a , -SR a , -S (R a ) 5 , -C(=O)R a , -C(=O)OR a , -C(=O)N(R a ) 2 , C 3-14 cycloalkyl, 3-14 membered heterocyclic Cyclyl, C 6-14 aryl or 5-14 membered heteroaryl, the C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl optionally further substituted by one or more R 9 ; R 9 is selected from H, cyano, halogen, C 1-6 alkyl, C 1-6 haloalkyl, -C 0-6 alkylene-OR a , -C 0-6 alkylene-OC(O)N(R a ) 2 , -C 0-6 alkylene-N(R a ) 2 , -C 0-6 alkylene-NR a C(O ) R a , -C 0-6 alkylene -NR a C(O)N(R a ) 2 , -C 0-6 alkylene -NR a S(O)R a , -C 0-6 alkylene Alkyl-NR a S(O) 2 R a , -C 0-6 alkylene-S(=O)R a , -C 0-6 alkylene-S(=O) 2 R a , -C 0-6 alkylene-SR a , -C 0-6 alkylene-S(R a ) 5 , -C 0-6 alkylene-C(=O)R a , -C 0-6 alkylene base-C(=O)OR a , -C 0-6 alkylene-C(=O)N(R a ) 2 , C 2-6 alkenyl, C 2-6 alkynyl, -C 0-6 Alkylene-C 3-14 cycloalkyl, -C 0-6 alkylene-(3-14-membered heterocyclyl), -C 0-6 alkylene-C 6-14 aryl or -C 0 -6 alkylene-(5-14 membered heteroaryl), the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 0-6 alkylene-C 3 -14 cycloalkyl, -C 0-6 alkylene-(3-14 membered heterocyclyl), -C 0-6 alkylene-C 6-14 aryl or -C 0-6 alkylene- (5-14 membered heteroaryl) optionally also substituted with 1 or more R a ; R2选自丙烯酰基、取代的丙烯酰基或
Figure FDA0003450229300000021
R 2 is selected from acryloyl, substituted acryloyl or
Figure FDA0003450229300000021
 R3选自H、C2-6烯基、C1-6烷氧基、C1-6卤代烷氧基、C1-6烷基、4-10元杂环基取代的C1-6烷基、C1-6烷基磺酰基、C1-6烷基亚磺酰基、C1-6烷硫基、C2-6炔基、C1-6烷基氨基、氨基、C1-6氨基烷基、氨基甲酰基、C1-6氨基甲酰基烷基、C1-6羧基烷基、氰基、C1-6氰基烷基、卤素、C1-6卤代烷基、取代或未取代的芳基、取代或未取代的5-10元杂芳基、取代或未取代的C3-7环烷基、取代或未取代的4-10元杂环基、羟基或氧代基；优选H、卤素或C1-3烷基；更优选为H；R 3 is selected from H, C 2-6 alkenyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkyl, C 1-6 alkane substituted by 4-10-membered heterocyclyl base, C 1-6 alkylsulfonyl, C 1-6 alkylsulfinyl, C 1-6 alkylthio, C 2-6 alkynyl, C 1-6 alkylamino, amino, C 1-6 Aminoalkyl, carbamoyl, C 1-6 carbamoylalkyl, C 1-6 carboxyalkyl, cyano, C 1-6 cyanoalkyl, halogen, C 1-6 haloalkyl, substituted or unsubstituted Substituted aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C 3-7 cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclyl, hydroxy or oxo; Preferably H, halogen or C 1-3 alkyl; more preferably H; R4、R5或R6各自独立地选自H、氰基、卤素、C1-6烷基、C1-6卤代烷基、-C0-6亚烷基-ORa、-C0-6亚烷基-OC(O)N(Ra)2、-C0-6亚烷基-N(Ra)2、-C0-6亚烷基-NRaC(O)Ra、-C0-6亚烷基-NRaC(O)N(Ra)2、-C0-6亚烷基-NRaS(O)Ra、-C0-6亚烷基-NRaS(O)2Ra、-C0-6亚烷基-S(＝O)Ra、-C0-6亚烷基-S(＝O)2Ra、-C0-6亚烷基-SRa、-C0-6亚烷基-S(Ra)5、-C0-6亚烷基-C(＝O)Ra、-C0-6亚烷基-C(＝O)ORa、-C0-6亚烷基-C(＝O)N(Ra)2、C2-6烯基、C2-6炔基、-C0-6亚烷基-C3-14环烷基、-C0-6亚烷基-(3-14元杂环基)、-C0-6亚烷基-C6-14芳基或-C0-6亚烷基-(5-14元杂芳基)，所述C1-6烷基、C2-6烯基、C2-6炔基、-C0-6亚烷基-C3-14环烷基、-C0-6亚烷基-(3-14元杂环基)、-C0-6亚烷基-C6-14芳基或-C0-6亚烷基-(5-14元杂芳基)任选地还可被1个或多个Ra所取代；R 4 , R 5 or R 6 are each independently selected from H, cyano, halogen, C 1-6 alkyl, C 1-6 haloalkyl, -C 0-6 alkylene-OR a , -C 0- 6 alkylene-OC(O)N(R a ) 2 , -C 0-6 alkylene-N(R a ) 2 , -C 0-6 alkylene-NR a C(O)R a , -C 0-6 alkylene-NR a C(O)N(R a ) 2 , -C 0-6 alkylene-NR a S(O)R a , -C 0-6 alkylene-NR a S(O) 2 R a , -C 0-6 alkylene-S(=O)R a , -C 0-6 alkylene-S(=O) 2 R a , -C 0-6 alkylene Alkyl-SR a , -C 0-6 alkylene-S(R a ) 5 , -C 0-6 alkylene-C(=O)R a , -C 0-6 alkylene-C( =O)OR a , -C 0-6 alkylene-C(=O)N(R a ) 2 , C 2-6 alkenyl, C 2-6 alkynyl, -C 0-6 alkylene- C 3-14 cycloalkyl, -C 0-6 alkylene-(3-14-membered heterocyclic group), -C 0-6 alkylene-C 6-14 aryl or -C 0-6 alkylene base-(5-14 membered heteroaryl), the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 0-6 alkylene-C 3-14 cycloalkane base, -C 0-6 alkylene-(3-14 membered heterocyclic group), -C 0-6 alkylene-C 6-14 aryl or -C 0-6 alkylene-(5-14 membered heteroaryl) optionally also substituted with 1 or more R a ; 每个Ra各自独立地选自H、卤素、羟基、氨基、氧代基、硝基、氰基、羧基、C1-6烷基、C1-6羟基烷基、C1-6氨基烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6杂烷基、C3-8环烷基、3-8元杂环基、C6-14芳基或5-14元杂芳基；Each R a is independently selected from H, halogen, hydroxy, amino, oxo, nitro, cyano, carboxyl, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkane base, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 heteroalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl; m选自0、1、2或3。m is selected from 0, 1, 2 or 3. 2.根据权利要求1所述的化合物，其特征在于，X2选自N或CR7，R7选自H、卤素、C3-6环烷基或C1-3烯基。2 . The compound according to claim 1 , wherein X 2 is selected from N or CR 7 , and R 7 is selected from H, halogen, C 3-6 cycloalkyl or C 1-3 alkenyl. 3 . 3.根据权利要求1或2所述的化合物，其特征在于，X3选自N或CR8，R8选自H、卤素、C1-6烷氧基、C3-8环烷基氧基、氰基取代的环丙基C1-6亚烷基氧基，所述C1-6烷氧基任选地进一步被选自卤素、羟基、甲氧基、C3-8环烷基的取代基所取代。3. The compound according to claim 1 or 2, wherein X 3 is selected from N or CR 8 , and R 8 is selected from H, halogen, C 1-6 alkoxy, C 3-8 cycloalkyloxy cyclopropyl, cyano-substituted cyclopropyl C 1-6 alkyleneoxy, said C 1-6 alkoxy optionally further selected from halogen, hydroxy, methoxy, C 3-8 cycloalkyl substituted by the substituents. 4.根据权利要求1-3任一项所述的化合物，其特征在于，-L-R1选自
Figure FDA0003450229300000031
Figure FDA0003450229300000032
4. The compound according to any one of claims 1-3, wherein -LR 1 is selected from
Figure FDA0003450229300000031
Figure FDA0003450229300000032
 5.根据权利要求1-4任一项所述的化合物，其特征在于，R2选自
Figure FDA0003450229300000033
Figure FDA0003450229300000034
Figure FDA0003450229300000035
5. The compound according to any one of claims 1-4, wherein R 2 is selected from
Figure FDA0003450229300000033
Figure FDA0003450229300000034
Figure FDA0003450229300000035
 6.根据权利要求1-5任一项所述的化合物，其特征在于，R4、R5或R6各自独立地选自H、＝O、卤素或C1-6烷基。6. The compound of any one of claims 1-5, wherein R 4 , R 5 or R 6 are each independently selected from H, =O, halogen or C 1-6 alkyl. 7.根据权利要求1-6任一项所述的化合物，或其药用盐，其特征在于，选自式(IA)化合物7. The compound according to any one of claims 1-6, or a pharmaceutically acceptable salt thereof, characterized in that it is selected from the compound of formula (IA)
Figure FDA0003450229300000036
Figure FDA0003450229300000036
 其中，取代基如权利要求1所定义。wherein the substituents are as defined in claim 1 . 8.一种化合物，其互变异构体或药用盐，其中，所述化合物选自：8. A compound, its tautomer or pharmaceutically acceptable salt, wherein the compound is selected from:
Figure FDA0003450229300000041
Figure FDA0003450229300000041
 9.一种药物组合物，其特征在于，所述药物组合物含有治疗有效量的权利要求1-8任一项所述的化合物和至少一种药学上可接受的辅料。9. A pharmaceutical composition, characterized in that, the pharmaceutical composition contains a therapeutically effective amount of the compound according to any one of claims 1-8 and at least one pharmaceutically acceptable adjuvant. 10.权利要求1-8任一项所述的化合物或权利要求9所述的药物组合物在制备药物中的应用。10. Use of the compound of any one of claims 1-8 or the pharmaceutical composition of claim 9 in the preparation of a medicine.
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