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CN119219608A - Polycyclic derivative inhibitor, preparation method and application thereof - Google Patents

Polycyclic derivative inhibitor, preparation method and application thereof Download PDF

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Publication number
CN119219608A
CN119219608A CN202410865246.9A CN202410865246A CN119219608A CN 119219608 A CN119219608 A CN 119219608A CN 202410865246 A CN202410865246 A CN 202410865246A CN 119219608 A CN119219608 A CN 119219608A
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alkyl
cyano
alkoxy
substituted
cycloalkyl
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Inventor
吴建睿
董加强
俞文胜
郑露露
丁露
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Jiangsu Hansoh Pharmaceutical Group Co Ltd
Shanghai Hansoh Biomedical Co Ltd
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Jiangsu Hansoh Pharmaceutical Group Co Ltd
Shanghai Hansoh Biomedical Co Ltd
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Abstract

本发明涉及多环类衍生物抑制剂、其制备方法和应用。特别地，本发明涉及多环类衍生物化合物、其制备方法及含有该化合物的药物组合物，及其在治疗癌症的用途。The present invention relates to polycyclic derivative inhibitors, preparation methods and applications thereof, and in particular, to polycyclic derivative compounds, preparation methods thereof, pharmaceutical compositions containing the compounds, and applications thereof in treating cancer.

Description

Polycyclic derivative inhibitor, preparation method and application thereof
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to a polycyclic derivative inhibitor, a preparation method and application thereof.
Background
Protein arginase methyltransferases (PRMTs) are classified into three major classes, type I, type II, and type III, based on catalytic activity and type of product. Type I mainly comprises PRMT1/2/3/4/6/8, which catalyzes the formation of Asymmetric Dimethylarginine (ADMA) by the substrate, type II comprises PRMT5/9, which catalyzes the formation of Symmetric Dimethylarginine (SDMA) by the substrate, and type III only comprises PRMT7, which is responsible for catalyzing the formation of monomethylarginine (MMA) by the substrate. PRMT5 uses S-adenosyl-L-methionine (SAM) as methyl donor, transfers methyl to DNA, RNA, histone and other substrates, and the arginine residue of the substrates is symmetrically and dimethyl to generate SDMA, so as to regulate and control a plurality of key cell processes including transcription, translation and DNA repair, maintain cell homeostasis, and simultaneously can participate in regulating and controlling the growth and survival pathways of tumor cells and promote tumorigenesis and development. Elevated expression of PRMT5 has also been shown to be associated with poor prognosis for a variety of cancers, a very potential epigenetic target.
Methylthioadenosine phosphorylase (MTAP) catalyzes the production of methionine from Methylthioadenosine (MTA), which is critical to maintaining normal cellular function. Deletion mutations in the MTAP gene compete for intracellular accumulation of MTA, MTA and substrate SAM of PRMT5, decrease PRMT5 activity, and produce a large amount of PRMT5-MTA complex. Deletion of MTAP gene can increase dependence of tumor on PRMT5, inhibit PRMT5 from playing a role of 'synthetic death' in MTAP deleted tumor, and PARP inhibitor based on 'synthetic death' theory has been greatly successful in accurate treatment field of tumor field. MTAP gene is adjacent to the most common tumor suppressor gene CDKN2A in human cancers and is often co-deleted with CDKN2A, and the co-deletion accounts for 10% -15% of all cancers, mainly occurs in non-small cell lung cancer (12% -20%), glioma (53%), pancreatic cancer (30%), DLBCL (20%), and has a huge market prospect.
At present, no PRMT5 inhibitor is marketed, and early PRMT5 inhibitors are nonselective substrate SAM competitive inhibitors, and have serious clinical blood toxic and side effects and small safety window. Clinical progress with the primary PRMT5 inhibitors GSK-3326595, JNJ-64619178 and PF-06939999 was poor. The new generation PRMT5 inhibitor of the target PRMT5-MTA complex is effective only on MTAP-deficient and MTA-enriched tumors, has higher selectivity on MTAP wild type, reduces blood toxicity in mechanism, is verified in preclinical research, and is expected to greatly improve the safety window.
The patent relates to a novel PRMT5-MTA selective inhibitor which only has activity on MTAP-deleted cells, has weak inhibition on MTAP wild type cells, and can avoid side effects such as blood toxicity and the like caused by clinical nonselective PRMT5 inhibitors on MTAP wild type inhibition. The high-selectivity PRMT5-MTA inhibitor can be used as a novel PRMT5-MTA inhibitor for treating various tumors, cancers and other diseases.
Disclosure of Invention
The invention aims to provide a compound shown in a general formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound shown in the general formula (I) has the following structure:
L 1 is selected from the group consisting of cycloalkyl- (CR aRb)n2-、-(CRaRb)n1 -3-12 membered heterocyclyl- (CR aRb)n2-、-(CRaRb)n1-C6-12 aryl- (CR aRb)n2) -or- (CR aRb)n1 -5-12 membered heteroaryl- (CR aRb)n2) -having a bond 、-(CRaRb)n1-、-(CRaRb)n1O(CRaRb)n2-、-(CRaRb)n1S(CRaRb)n2-、-(CRaRb)n1NRc(CRaRb)n2-、-(CRaRb)n1C(O)(CRaRb)n2-、-(CRaRb)n1S(O)m2(CRaRb)n2-、-(CRaRb)n1C(O)NRc(CRaRb)n2-、-(CRaRb)n1NRcC(O)(CRaRb)n2-、-(CRaRb)n1-C3-12, said C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally substituted by deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, - (CH 2)n3 -substituted or unsubstituted C 3-12 cycloalkyl, - (CH 2)n3 -substituted or unsubstituted 3-12 membered heterocyclic group, - (CH 2)n3 -substituted or unsubstituted C 6-12 aryl and- (CH 2)n3 -substituted or unsubstituted 5-12 membered heteroaryl), preferably substituted by one or more substituents, bond 、-(CRaRb)n1-、-(CRaRb)n1O(CRaRb)n2-、-(CRaRb)n1S(CRaRb)n2-、-(CRaRb)n1NRc(CRaRb)n2-、-(CRaRb)n1C(O)(CRaRb)n2-、-(CRaRb)n1S(O)m2(CRaRb)n2-、-(CRaRb)n1C(O)NRc(CRaRb)n2-、-(CRaRb)n1NRcC(O)(CRaRb)n2-、-(CRaRb)n1-C3-8 cycloalkyl- (CR aRb)n2-、-(CRaRb)n1 -3-8 membered heterocyclyl- (CR aRb)n2-、-(CRaRb)n1-C6-10 aryl- (CR aRb)n2 -or- (CR aRb)n1 -5-10 membered heteroaryl- (CR aRb)n2 -, said C 3-8 cycloalkyl), 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted by deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, Oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, - (CH 2)n3 -substituted or unsubstituted C 3-8 cycloalkyl, Substituted with one or more substituents selected from the group consisting of- (CH 2)n3 -substituted or unsubstituted 3-8 membered heterocyclyl, - (CH 2)n3 -substituted or unsubstituted C 6-10 aryl, and- (CH 2)n3 -substituted or unsubstituted 5-10 membered heteroaryl);
R 1a、R1b、R1c and R 1e are each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, Halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, - (CH 2)n4-C3-12 cycloalkyl), - (CH 2)n4 -3-12 membered heterocyclyl, - (CH 2)n4-C6-12 aryl, - (CH 2)n4 -5-12 membered heteroaryl 、-(CH2)n4ORd、-(CH2)n4NRdRe、-(CH2)n4C(O)Rd、-(CH2)n4C(O)NRdRe or- (CH 2)n4P(O)RdRe), said amino group, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, Substituted with one or more substituents selected from the group consisting of 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, preferably hydrogen, deuterium, fluoro, chloro, bromo, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, Oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, - (CH 2)n4-C3-8 cycloalkyl, - (CH 2)n4 -3-8 membered heterocyclyl), - (CH 2)n4-C6-10 aryl, - (CH 2)n4 -5-10 membered heteroaryl 、-(CH2)n4ORd、-(CH2)n4NRdRe、-(CH2)n4C(O)Rd、-(CH2)n4C(O)NRdRe or- (CH 2)n4P(O)RdRe), said amino group, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, c 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thioxo, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl, one or more substituents of 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl;
r 1d is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, - (CH 2)n4-C3-12 cycloalkyl, - (CH 2)n4 -3-12 membered heterocyclyl), - (CH 2)n4-C6-12 aryl, - (CH 2)n4 -5-12 membered heteroaryl 、-(CH2)n4ORd、-(CH2)n4NRdRe、-(CH2)n4C(O)Rd、-(CH2)n4S(O)m3Rd、-(CH2)n4N＝S(O)m3RdRe、-(CH2)n4N＝S(O)m3Rd、-(CH2)n4C(O)NRdRe or- (CH 2)n4P(O)RdRe), said amino group, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, Substituted with one or more substituents selected from the group consisting of 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, preferably hydrogen, deuterium, fluoro, chloro, bromo, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, Oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, - (CH 2)n4-C3-8 cycloalkyl, - (CH 2)n4 -3-8 membered heterocyclyl), - (CH 2)n4-C6-10 aryl, - (CH 2)n4 -5-10 membered heteroaryl 、-(CH2)n4ORd、-(CH2)n4NRdRe、-(CH2)n4C(O)Rd、-(CH2)n4C(O)NRdRe or- (CH 2)n4P(O)RdRe), said amino group, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, c 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thioxo, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl, one or more substituents of 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl;
Or R 1d and R 1e are adjacent to each other, R 1c and R 1d are adjacent to each other, an atom, R 1b and R 1c are linked to their adjacent atoms or R 1a and R 1b are linked to their adjacent atoms to form a C 3-12 cycloalkyl group, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, Substituted by one or more substituents selected from C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, preferably forming C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, Oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, One or more substituents selected from the group consisting of C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl;
R 2 is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-to 12-membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl 、-(CH2)n4ORd、-(CH2)n4NRdRe、-(CH2)n4C(O)Rd、-(CH2)n4C(O)NRdRe or- (CH 2)n4P(O)RdRe) said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally deuterated, Halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, Substituted by one or more substituents selected from C 3-12 cycloalkyl, 3-12 heterocyclyl, C 6-12 aryl and 5-12 heteroaryl, preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thioxo, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl 、-(CH2)n4ORd、-(CH2)n4NRdRe、-(CH2)n4C(O)Rd、-(CH2)n4C(O)NRdRe or- (CH 2)n4P(O)RdRe), said amino, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted by deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, Oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, One or more substituents selected from the group consisting of C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl;
R a、Rb、Rc、Rd and R e are each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, -C (O) -C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, Cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl, =N-O-R aa and=R aaRbb, preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, -C (O) -C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, said amino, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted by deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, Oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, One or more substituents selected from the group consisting of C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl;
or R d and R e are linked to their adjacent atoms to form C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, Halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, preferably forms C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, Halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thioxo, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, One or more substituents of C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl;
R aa and R bb are each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, -C (O) -C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, Cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, Substituted by one or more substituents selected from C 3-12 cycloalkyl, 3-12 heterocyclyl, C 6-12 aryl and 5-12 heteroaryl, preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, -C (O) -C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, said amino, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, Cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thioxo, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, One or more substituents of C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl;
m1 is selected from 0,1 or 2;
m2 is selected from 0,1 or 2;
n1 is selected from 0, 1, 2, 3 or 4;
n2 is selected from 0, 1, 2, 3 or 4;
n3 is selected from 0, 1, 2, 3 or 4;
n4 is selected from 0, 1, 2, 3 or 4;
m3 is selected from 0,1 or 2, and
X is selected from 0, 1,2, 3 or 4.
In a preferred embodiment of the invention, the compound, stereoisomer or pharmaceutically acceptable salt thereof, is characterized in that L 1 is selected from -(CRaRb)NRc-、-NRc(CRaRb)-、-C(O)NRc-、-NRcC(O)-、5-10 membered heteroaryl, - (CR aRb) -5-10 membered heteroaryl or 5-10 membered heteroaryl- (CR aRb) -, said 5-10 membered heteroaryl optionally substituted with one or more substituents from deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted C 6-10 aryl and substituted or unsubstituted 5-10 membered heteroaryl;
in a preferred embodiment of the invention, the compound, stereoisomer or pharmaceutically acceptable salt thereof, is characterized in that the compound is further represented by the general formula (II):
Ring A is selected from
R 3 is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, - (CH 2)n5-C3-12 cycloalkyl, - (CH 2)n5 -3-12 membered heterocyclyl), - (CH 2)n5-C6-12 aryl, - (CH 2)n5 -5-12 membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally deuterated, Halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, Substituted with one or more substituents selected from C 3-12 cycloalkyl, 3-12 heterocyclyl, C 6-12 aryl and 5-12 heteroaryl, preferably hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thioxo, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, c 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, - (CH 2)n5-C3-8 cycloalkyl), - (CH 2)n5 -3-8 membered heterocyclyl, - (CH 2)n5-C6-10 aryl or- (CH 2)n5 -5-10 membered heteroaryl), said amino, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted by deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, Oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, One or more substituents selected from the group consisting of C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl;
n5 is selected from 0, 1, 2, 3 or 4;
R 1a、R1b、R1c、R1d、R1e、R2 and x are as described in any one embodiment.
Another object of the present invention is to provide a compound represented by the general formula (III):
Ring B is selected from C 3-12 saturated or unsaturated cycloalkyl, 3-12 membered saturated or unsaturated heterocyclyl, C 6-14 aryl, or 5-14 membered heteroaryl;
R 2 is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-to 12-membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl 、-(CH2)n4ORd、-(CH2)n4NRdRe、-(CH2)n4C(O)Rd、-(CH2)n4C(O)NRdRe or- (CH 2)n4P(O)RdRe) said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally deuterated, Halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, Substituted by one or more substituents selected from C 3-12 cycloalkyl, 3-12 heterocyclyl, C 6-12 aryl and 5-12 heteroaryl, preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thioxo, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl 、-(CH2)n4ORd、-(CH2)n4NRdRe、-(CH2)n4C(O)Rd、-(CH2)n4C(O)NRdRe or- (CH 2)n4P(O)RdRe), said amino, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted by deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, Oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, One or more substituents selected from the group consisting of C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl;
R 4 is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, Cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, Halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally substituted by deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-to 12-membered heterocyclyl, C 6-12 aryl and 5-to 12-membered heteroaryl, preferably hydrogen, Deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, said amino, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally deuterated, Halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thioxo, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, One or more substituents of C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl;
R 5 is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, c 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, - (CH 2)n6-C3-12 cycloalkyl, - (CH 2)n6 -3-12 membered heterocyclyl), - (CH 2)n6-C6-12 aryl, - (CH 2)n6 -5-12 membered heteroaryl 、-(CH2)n6ORf、-(CH2)n6NRfRg、-(CH2)n4C(O)Rd、-(CH2)n6S(O)m4Rf、-(CH2)n6N＝S(O)m4Rf、-(CH2)n6C(O)NRfRg or- (CH 2)n6P(O)RfRg), said amino group, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, Substituted with one or more substituents selected from the group consisting of 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, preferably selected from the group consisting of hydrogen, deuterium, fluoro, chloro, bromo, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, Oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, - (CH 2)n6-C3-8 cycloalkyl, - (CH 2)n6 -3-8 membered heterocyclyl), - (CH 2)n6-C6-10 aryl, - (CH 2)n6 -5-10 membered heteroaryl 、-(CH2)n6ORf、-(CH2)n6NRfRg、-(CH2)n6C(O)Rf、-(CH2)n6C(O)NRfRg or- (CH 2)n6P(O)RfRg), said amino group, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, c 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thioxo, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl, one or more substituents of 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl;
Or two R 5 on the same carbon atom form =o, =nr h、＝CRhRi、C3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, Substituted with one or more substituents selected from C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, preferably to form =O, =NR h、＝CRhRi、C3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, Halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thioxo, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, One or more substituents of C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl;
r d、Re、Rf、Rg、Rh and R i are each independently selected from
Hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, -C (O) -C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, Halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally substituted by deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-to 12-membered heterocyclyl, C 6-12 aryl, 5-to 12-membered heteroaryl, =n-O-R aa and=r aaRbb, preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, -C (O) -C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, said amino, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, Cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thioxo, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, One or more substituents of C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl;
R aa and R bb are each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, -C (O) -C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, Cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, Substituted by one or more substituents selected from C 3-12 cycloalkyl, 3-12 heterocyclyl, C 6-12 aryl and 5-12 heteroaryl, preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, -C (O) -C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, said amino, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, Cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thioxo, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, One or more substituents of C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl;
n4 is selected from 0, 1, 2, 3 or 4;
n6 is selected from 0, 1, 2, 3 or 4;
m4 is selected from 0,1 or 2;
x is selected from 0, 1,2, 3 or 4;
q is selected from 0, 1, 2, 3 or 4, and
Z is selected from 0,1, 2, 3, 4 or 5.
In a preferred embodiment of the invention, the compound, stereoisomer or pharmaceutically acceptable salt thereof is characterized in that ring B is selected from the group consisting of benzoC 3-8 cycloalkyl, benzo3-8 membered heterocyclyl or benzo5-8 membered heteroaryl, preferably
In a preferred embodiment of the invention, the compounds, stereoisomers or pharmaceutically acceptable salts thereof, are characterized in that ring B is selected from C 7-10 saturated or unsaturated bridged cycloalkyl, C 3-8 cycloalkyl and 3-8 membered heterocyclyl, C 3-8 cycloalkyl and phenyl or C 3-8 cycloalkyl and 5-8 membered heteroaryl, preferably
In a preferred embodiment of the invention, the compounds, stereoisomers or pharmaceutically acceptable salts thereof, are characterized in that ring B is selected from 7-10 membered saturated or unsaturated bridged heterocyclyl, 3-8 membered heterocyclo C 3-8 cycloalkyl, 3-8 membered heterocyclo 3-8 membered heterocyclyl, 3-8 membered heterocyclo phenyl or 3-8 membered heterocyclo 5-8 membered heteroaryl, preferably
In a preferred embodiment of the invention, the compound, stereoisomer or pharmaceutically acceptable salt thereof is characterized in that ring B is selected from the group consisting of 5-10 membered heteroaryl, 5-10 membered heteroaryl and 3-10 membered cycloalkyl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl, 5-10 membered heteroarylphenyl or 5-10 membered heteroaryl and 5-10 membered heteroaryl, preferably from 5-membered heteroaryl or 6 membered heteroaryl, more preferably from
Another object of the present invention is to provide a compound represented by the general formula (IV) or (V):
ring C is selected from 6-14 membered spiroheterocyclyl groups, preferably from
Ring D is selected from C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, preferably C 3-6 cycloalkyl or 3-6 membered heterocyclyl;
Ring E is selected from C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, preferably C 3-8 cycloalkylphenyl, C 3-8 cycloalkyl 5-8 membered heteroaryl, 3-8 membered heterocyclylphenyl or 3-8 membered heterocyclyl 5-8 membered heteroaryl;
R 2 is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-to 12-membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl 、-(CH2)n4ORd、-(CH2)n4NRdRe、-(CH2)n4C(O)Rd、-(CH2)n4C(O)NRdRe or- (CH 2)n4P(O)RdRe) said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally deuterated, Halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, Substituted by one or more substituents selected from C 3-12 cycloalkyl, 3-12 heterocyclyl, C 6-12 aryl and 5-12 heteroaryl, preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thioxo, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl 、-(CH2)n4ORd、-(CH2)n4NRdRe、-(CH2)n4C(O)Rd、-(CH2)n4C(O)NRdRe or- (CH 2)n4P(O)RdRe), said amino, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted by deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, Oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, One or more substituents selected from the group consisting of C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl;
R 6、R7 or R 8 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, Halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl, -OR j、-NRjRk、-C(O)Rj、-C(O)NRjRk OR-P (O) R jRk, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, Halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally substituted by deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-to 12-membered heterocyclyl, C 6-12 aryl and 5-to 12-membered heteroaryl, preferably hydrogen, Deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thioxo, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -OR j、-NRjRk、-C(O)Rj、-C(O)NRjRk OR-P (O) R jRk, said amino group, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, c 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thioxo, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl, one or more substituents of 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl;
R d、Re、Rj and R k are each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, -C (O) -C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, Cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, Substituted by one or more substituents selected from C 3-12 cycloalkyl, 3-12 heterocyclyl, C 6-12 aryl and 5-12 heteroaryl, preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, -C (O) -C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, said amino, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, Cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thioxo, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, One or more substituents of C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl;
n4 is selected from 0, 1, 2, 3 or 4;
x is selected from 0, 1,2, 3 or 4;
p is selected from 0, 1,2, 3 or 4;
r is selected from 0, 1, 2, 3 or 4, and
S is selected from 0, 1,2, 3 or 4.
Another object of the present invention is to provide a compound represented by the general formula (VI):
R 1a、R1b、R1c and R 1e are each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, Halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, - (CH 2)n4-C3-12 cycloalkyl), - (CH 2)n4 -3-12 membered heterocyclyl, - (CH 2)n4-C6-12 aryl, - (CH 2)n4 -5-12 membered heteroaryl 、-(CH2)n4ORd、-(CH2)n4NRdRe、-(CH2)n4C(O)Rd、-(CH2)n4C(O)NRdRe or- (CH 2)n4P(O)RdRe), said amino group, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, Substituted with one or more substituents selected from the group consisting of 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, preferably hydrogen, deuterium, fluoro, chloro, bromo, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, Oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, - (CH 2)n4-C3-8 cycloalkyl, - (CH 2)n4 -3-8 membered heterocyclyl), - (CH 2)n4-C6-10 aryl, - (CH 2)n4 -5-10 membered heteroaryl 、-(CH2)n4ORd、-(CH2)n4NRdRe、-(CH2)n4C(O)Rd、-(CH2)n4C(O)NRdRe or- (CH 2)n4P(O)RdRe), said amino group, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, c 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thioxo, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl, one or more substituents of 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl;
r 1d is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, - (CH 2)n4-C3-12 cycloalkyl, - (CH 2)n4 -3-12 membered heterocyclyl), - (CH 2)n4-C6-12 aryl, - (CH 2)n4 -5-12 membered heteroaryl 、-(CH2)n4ORd、-(CH2)n4NRdRe、-(CH2)n4C(O)Rd、-(CH2)n4S(O)m3Rd、-(CH2)n4N＝S(O)m3RdRe、-(CH2)n4N＝S(O)m3Rd、-(CH2)n4C(O)NRdRe or- (CH 2)n4P(O)RdRe), said amino group, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, Substituted with one or more substituents selected from the group consisting of 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, preferably hydrogen, deuterium, fluoro, chloro, bromo, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, Oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, - (CH 2)n4-C3-8 cycloalkyl, - (CH 2)n4 -3-8 membered heterocyclyl), - (CH 2)n4-C6-10 aryl, - (CH 2)n4 -5-10 membered heteroaryl 、-(CH2)n4ORd、-(CH2)n4NRdRe、-(CH2)n4C(O)Rd、-(CH2)n4C(O)NRdRe or- (CH 2)n4P(O)RdRe), said amino group, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, c 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thioxo, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl, one or more substituents of 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl;
Or R 1d and R 1e are adjacent to each other, R 1c and R 1d are adjacent to each other, an atom, R 1b and R 1c are linked to their adjacent atoms or R 1a and R 1b are linked to their adjacent atoms to form a C 3-12 cycloalkyl group, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, Substituted by one or more substituents selected from C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, preferably forming C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, Oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, One or more substituents selected from the group consisting of C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl;
R 2a and R 2b are each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, Halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, - (CH 2)n7C3-12 cycloalkyl), - (CH 2)n7 -12 membered heterocyclyl, - (CH 2)n7C6-12 aryl, - (CH 2)n7 5-12 membered heteroaryl 、-(CH2)n7ORm、-(CH2)n7NRmRn、-(CH2)n7C(O)Rm、-(CH2)n7C(O)NRmRn or- (CH 2)n7P(O)RmRn), said amino group, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, Substituted with one or more substituents selected from the group consisting of 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, preferably hydrogen, deuterium, fluoro, chloro, bromo, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, Oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, - (CH 2)n7C3-8 cycloalkyl, - (CH 2)n7 3-8 membered heterocyclyl), - (CH 2)n7C6-10 aryl, - (CH 2)n7 5-10 membered heteroaryl 、-(CH2)n7ORm、-(CH2)n7NRmRn、-(CH2)n7C(O)Rm、-(CH2)n7C(O)NRmRn or- (CH 2)n7P(O)RmRn), said amino group, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, c 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thioxo, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl, one or more substituents of 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl;
R 3a is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, - (CH 2)n8-C3-12 cycloalkyl, - (CH 2)n8 -3-12 membered heterocyclyl), - (CH 2)n8-C6-12 aryl, - (CH 2)n8 -5-12 membered heteroaryl 、-(CH2)n8ORp、-(CH2)n8NRpRq、-(CH2)n8C(O)Rp、-(CH2)n8C(O)NRpRq or- (CH 2)n8P(O)RpRq), said amino group, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, Substituted with one or more substituents selected from the group consisting of 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, preferably hydrogen, deuterium, fluoro, chloro, bromo, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, Oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, - (CH 2)n8-C3-8 cycloalkyl, - (CH 2)n8 -3-8 membered heterocyclyl), - (CH 2)n8-C6-10 aryl, - (CH 2)n8 -5-10 membered heteroaryl 、-(CH2)n8ORp、-(CH2)n8NRpRq、-(CH2)n8C(O)Rp、-(CH2)n8C(O)NRpRq or- (CH 2)n8P(O)RpRq), said amino group, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, c 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thioxo, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl, one or more substituents of 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl;
R 3b and R 3c are selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, Halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, - (CH 2)n8-C3-12 cycloalkyl), - (CH 2)n8 -3-12 membered heterocyclyl, - (CH 2)n8-C6-12 aryl, - (CH 2)n8 -5-12 membered heteroaryl 、-(CH2)n8ORp、-(CH2)n8NRpRq、-(CH2)n8C(O)Rp、-(CH2)n8C(O)NRpRq or- (CH 2)n8P(O)RpRq), said amino group, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, Substituted with one or more substituents selected from the group consisting of 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, preferably hydrogen, deuterium, fluoro, chloro, bromo, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, Oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, - (CH 2)n8-C3-8 cycloalkyl, - (CH 2)n8 -3-8 membered heterocyclyl), - (CH 2)n8-C6-10 aryl, - (CH 2)n8 -5-10 membered heteroaryl 、-(CH2)n8ORp、-(CH2)n8NRpRq、-(CH2)n8C(O)Rp、-(CH2)n8C(O)NRpRq or- (CH 2)n8P(O)RpRq), said amino group, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, c 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thioxo, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl, one or more substituents of 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl;
r d、Re、Rm、Rn、Rp and R q are each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, -C (O) -C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, Cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl, =N-O-R aa and=R aaRbb, preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, -C (O) -C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, said amino, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted by deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, Oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, One or more substituents selected from the group consisting of C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl;
or R d and R e are linked to their adjacent atoms to form C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, Halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl, =N-O-R aa and=R aaRbb, preferably to form C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, Oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl, 3-to 8-membered heterocyclyl, C 6-10 aryl, A 5-10 membered heteroaryl, =n-O-R aa, and=r aaRbb;
R aa and R bb are each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, -C (O) -C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, Cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, Substituted by one or more substituents selected from C 3-12 cycloalkyl, 3-12 heterocyclyl, C 6-12 aryl and 5-12 heteroaryl, preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, -C (O) -C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, said amino, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, Cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thioxo, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, One or more substituents of C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl;
n4 is selected from 0, 1, 2, 3 or 4;
n7 is selected from 0,1, 2, 3 or 4, and
N8 is selected from 0, 1, 2, 3 or 4;
m3 is selected from 0,1 or 2.
Another object of the present invention is to provide a compound represented by the general formula (VII):
R 1a、R1b、R1c and R 1e are each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, Halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, - (CH 2)n4-C3-12 cycloalkyl), - (CH 2)n4 -3-12 membered heterocyclyl, - (CH 2)n4-C6-12 aryl, - (CH 2)n4 -5-12 membered heteroaryl 、-(CH2)n4ORd、-(CH2)n4NRdRe、-(CH2)n4C(O)Rd、-(CH2)n4C(O)NRdRe or- (CH 2)n4P(O)RdRe), said amino group, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, Substituted with one or more substituents selected from the group consisting of 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, preferably hydrogen, deuterium, fluoro, chloro, bromo, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, Oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, - (CH 2)n4-C3-8 cycloalkyl, - (CH 2)n4 -3-8 membered heterocyclyl), - (CH 2)n4-C6-10 aryl, - (CH 2)n4 -5-10 membered heteroaryl 、-(CH2)n4ORd、-(CH2)n4NRdRe、-(CH2)n4C(O)Rd、-(CH2)n4C(O)NRdRe or- (CH 2)n4P(O)RdRe), said amino group, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, c 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thioxo, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl, one or more substituents of 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl;
r 1d is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, - (CH 2)n4-C3-12 cycloalkyl, - (CH 2)n4 -3-12 membered heterocyclyl), - (CH 2)n4-C6-12 aryl, - (CH 2)n4 -5-12 membered heteroaryl 、-(CH2)n4ORd、-(CH2)n4NRdRe、-(CH2)n4C(O)Rd、-(CH2)n4S(O)m3Rd、-(CH2)n4N＝S(O)m3RdRe、-(CH2)n4N＝S(O)m3Rd、-(CH2)n4C(O)NRdRe or- (CH 2)n4P(O)RdRe), said amino group, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, Substituted with one or more substituents selected from the group consisting of 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, preferably hydrogen, deuterium, fluoro, chloro, bromo, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, Oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, - (CH 2)n4-C3-8 cycloalkyl, - (CH 2)n4 -3-8 membered heterocyclyl), - (CH 2)n4-C6-10 aryl, - (CH 2)n4 -5-10 membered heteroaryl 、-(CH2)n4ORd、-(CH2)n4NRdRe、-(CH2)n4C(O)Rd、-(CH2)n4C(O)NRdRe or- (CH 2)n4P(O)RdRe), said amino group, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, c 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thioxo, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl, one or more substituents of 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl;
Or R 1d and R 1e are adjacent to each other, R 1c and R 1d are adjacent to each other, an atom, R 1b and R 1c are linked to their adjacent atoms or R 1a and R 1b are linked to their adjacent atoms to form a C 3-12 cycloalkyl group, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, Substituted by one or more substituents selected from C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, preferably forming C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, Oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, One or more substituents selected from the group consisting of C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl;
R 2a and R 1e and their use adjacent atoms, R 2a and R 1d are linked to their adjacent atoms or R 2a and R 1c are linked to their adjacent atoms to form a C 3-12 cycloalkyl group, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, Substituted by one or more substituents selected from C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, preferably forming C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, Oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, One or more substituents selected from the group consisting of C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl;
R 2b is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, - (CH 2)n7C3-12 cycloalkyl, - (CH 2)n7 3-12 membered heterocyclyl), - (CH 2)n7C6-12 aryl, - (CH 2)n7 5-12 membered heteroaryl 、-(CH2)n7ORm、-(CH2)n7NRmRn、-(CH2)n7C(O)Rm、-(CH2)n7C(O)NRmRn or- (CH 2)n7P(O)RmRn), said amino group, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, Substituted with one or more substituents selected from the group consisting of 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, preferably hydrogen, deuterium, fluoro, chloro, bromo, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, Oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, - (CH 2)n7C3-8 cycloalkyl, - (CH 2)n7 3-8 membered heterocyclyl), - (CH 2)n7C6-10 aryl, - (CH 2)n7 5-10 membered heteroaryl 、-(CH2)n7ORm、-(CH2)n7NRmRn、-(CH2)n7C(O)Rm、-(CH2)n7C(O)NRmRn or- (CH 2)n7P(O)RmRn), said amino group, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, c 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thioxo, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl, one or more substituents of 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl;
R 3a is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, - (CH 2)n8-C3-12 cycloalkyl, - (CH 2)n8 -3-12 membered heterocyclyl), - (CH 2)n8-C6-12 aryl, - (CH 2)n8 -5-12 membered heteroaryl 、-(CH2)n8ORp、-(CH2)n8NRpRq、-(CH2)n8C(O)Rp、-(CH2)n8C(O)NRpRq or- (CH 2)n8P(O)RpRq), said amino group, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, Substituted with one or more substituents selected from the group consisting of 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, preferably hydrogen, deuterium, fluoro, chloro, bromo, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, Oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, - (CH 2)n8-C3-8 cycloalkyl, - (CH 2)n8 -3-8 membered heterocyclyl), - (CH 2)n8-C6-10 aryl, - (CH 2)n8 -5-10 membered heteroaryl 、-(CH2)n8ORp、-(CH2)n8NRpRq、-(CH2)n8C(O)Rp、-(CH2)n8C(O)NRpRq or- (CH 2)n8P(O)RpRq), said amino group, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, c 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thioxo, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl, one or more substituents of 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl;
R 3b and R 3c are selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, Halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, - (CH 2)n8-C3-12 cycloalkyl), - (CH 2)n8 -3-12 membered heterocyclyl, - (CH 2)n8-C6-12 aryl, - (CH 2)n8 -5-12 membered heteroaryl 、-(CH2)n8ORp、-(CH2)n8NRpRq、-(CH2)n8C(O)Rp、-(CH2)n8C(O)NRpRq or- (CH 2)n8P(O)RpRq), said amino group, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, Substituted with one or more substituents selected from the group consisting of 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, preferably hydrogen, deuterium, fluoro, chloro, bromo, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, Oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, - (CH 2)n8-C3-8 cycloalkyl, - (CH 2)n8 -3-8 membered heterocyclyl), - (CH 2)n8-C6-10 aryl, - (CH 2)n8 -5-10 membered heteroaryl 、-(CH2)n8ORp、-(CH2)n8NRpRq、-(CH2)n8C(O)Rp、-(CH2)n8C(O)NRpRq or- (CH 2)n8P(O)RpRq), said amino group, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, c 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thioxo, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl, one or more substituents of 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl;
Or R 2b and R 3b are linked to their adjacent atoms to form C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, Halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, preferably forms C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, Halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thioxo, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, One or more substituents of C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl;
r d、Re、Rm、Rn、Rp and R q are each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, -C (O) -C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, Cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl, =N-O-R aa and=R aaRbb, preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, -C (O) -C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, said amino, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted by deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, Oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, One or more substituents selected from the group consisting of C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl;
or R d and R e are linked to their adjacent atoms to form C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, Halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl, =N-O-R aa and=R aaRbb, preferably to form C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, Oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl, 3-to 8-membered heterocyclyl, C 6-10 aryl, A 5-10 membered heteroaryl, =n-O-R aa, and=r aaRbb;
Or R p and R q are linked to their adjacent atoms to form C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, Halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl, =N-O-R aa and=R aaRbb, preferably to form C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, Oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl, 3-to 8-membered heterocyclyl, C 6-10 aryl, A 5-10 membered heteroaryl, =n-O-R aa, and=r aaRbb;
R aa and R bb are each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, -C (O) -C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, Cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, Substituted by one or more substituents selected from C 3-12 cycloalkyl, 3-12 heterocyclyl, C 6-12 aryl and 5-12 heteroaryl, preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, -C (O) -C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, said amino, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, Cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thioxo, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, One or more substituents of C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl;
n4 is selected from 0, 1, 2, 3 or 4;
n7 is selected from 0,1, 2, 3 or 4, and
N8 is selected from 0, 1, 2, 3 or 4;
m3 is selected from 0,1 or 2.
In a preferred embodiment of the present invention, the compound, stereoisomer or pharmaceutically acceptable salt thereof is characterized by the further formula (VIII):
Ring F is selected from 5-12 membered heterocyclyl or 5-12 membered heteroaryl, preferably 5-6 membered monocyclic heterocyclyl, 5-10 membered spiroheterocyclyl, 7-10 membered fused heterocyclyl or 7-10 membered bridged heterocyclyl;
R 1a、R1b、R1c and R 1e are each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, Halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, - (CH 2)n4-C3-12 cycloalkyl), - (CH 2)n4 -3-12 membered heterocyclyl, - (CH 2)n4-C6-12 aryl, - (CH 2)n4 -5-12 membered heteroaryl 、-(CH2)n4ORd、-(CH2)n4NRdRe、-(CH2)n4C(O)Rd、-(CH2)n4C(O)NRdRe or- (CH 2)n4P(O)RdRe), said amino group, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, Substituted with one or more substituents selected from the group consisting of 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, preferably hydrogen, deuterium, fluoro, chloro, bromo, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, Oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, - (CH 2)n4-C3-8 cycloalkyl, - (CH 2)n4 -3-8 membered heterocyclyl), - (CH 2)n4-C6-10 aryl, - (CH 2)n4 -5-10 membered heteroaryl 、-(CH2)n4ORd、-(CH2)n4NRdRe、-(CH2)n4C(O)Rd、-(CH2)n4C(O)NRdRe or- (CH 2)n4P(O)RdRe), said amino group, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, c 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thioxo, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl, one or more substituents of 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl;
R 2a and R 2b are each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, Halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, - (CH 2)n7C3-12 cycloalkyl), - (CH 2)n7 -12 membered heterocyclyl, - (CH 2)n7C6-12 aryl, - (CH 2)n7 5-12 membered heteroaryl 、-(CH2)n7ORm、-(CH2)n7NRmRn、-(CH2)n7C(O)Rm、-(CH2)n7C(O)NRmRn or- (CH 2)n7P(O)RmRn), said amino group, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, Substituted with one or more substituents selected from the group consisting of 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, preferably hydrogen, deuterium, fluoro, chloro, bromo, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, Oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, - (CH 2)n7C3-8 cycloalkyl, - (CH 2)n7 3-8 membered heterocyclyl), - (CH 2)n7C6-10 aryl, - (CH 2)n7 5-10 membered heteroaryl 、-(CH2)n7ORm、-(CH2)n7NRmRn、-(CH2)n7C(O)Rm、-(CH2)n7C(O)NRmRn or- (CH 2)n7P(O)RmRn), said amino group, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, c 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thioxo, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl, One or more substituents selected from the group consisting of 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, more preferably methyl or cyclopropyl;
R 3a is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, - (CH 2)n8-C3-12 cycloalkyl, - (CH 2)n8 -3-12 membered heterocyclyl), - (CH 2)n8-C6-12 aryl, - (CH 2)n8 -5-12 membered heteroaryl 、-(CH2)n8ORp、-(CH2)n8NRpRq、-(CH2)n8C(O)Rp、-(CH2)n8C(O)NRpRq or- (CH 2)n8P(O)RpRq), said amino group, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, Substituted with one or more substituents selected from the group consisting of 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, preferably hydrogen, deuterium, fluoro, chloro, bromo, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, Oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, - (CH 2)n8-C3-8 cycloalkyl, - (CH 2)n8 -3-8 membered heterocyclyl), - (CH 2)n8-C6-10 aryl, - (CH 2)n8 -5-10 membered heteroaryl 、-(CH2)n8ORp、-(CH2)n8NRpRq、-(CH2)n8C(O)Rp、-(CH2)n8C(O)NRpRq or- (CH 2)n8P(O)RpRq), said amino group, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, c 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thioxo, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl, Substituted with one or more substituents selected from the group consisting of 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, more preferably -CH2NH2、-CH2NHCH3、-CH2NHCH2CH3、-CH2OH、-C(O)NH2、
R 3b and R 3c are selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, Halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, - (CH 2)n8-C3-12 cycloalkyl), - (CH 2)n8 -3-12 membered heterocyclyl, - (CH 2)n8-C6-12 aryl, - (CH 2)n8 -5-12 membered heteroaryl 、-(CH2)n8ORp、-(CH2)n8NRpRq、-(CH2)n8C(O)Rp、-(CH2)n8C(O)NRpRq or- (CH 2)n8P(O)RpRq), said amino group, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, Substituted with one or more substituents selected from the group consisting of 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, preferably hydrogen, deuterium, fluoro, chloro, bromo, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, Oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, - (CH 2)n8-C3-8 cycloalkyl, - (CH 2)n8 -3-8 membered heterocyclyl), - (CH 2)n8-C6-10 aryl, - (CH 2)n8 -5-10 membered heteroaryl 、-(CH2)n8ORp、-(CH2)n8NRpRq、-(CH2)n8C(O)Rp、-(CH2)n8C(O)NRpRq or- (CH 2)n8P(O)RpRq), said amino group, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, c 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thioxo, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl, one or more substituents of 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl;
R 9 is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, Cyano-substituted C 1-6 alkyl, -C (O) -C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl, -COOR aa、＝N-O-Raa or = R aaRbb, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally deuterated, Halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, Substituted by one or more substituents selected from C 3-12 cycloalkyl, 3-12 heterocyclyl, C 6-12 aryl and 5-12 heteroaryl, preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, -C (O) -C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, =n-O-R aa or=r aaRbb, said amino, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted by deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, Oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, One or more substituents selected from the group consisting of C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl;
r d、Re、Rm、Rn、Rp and R q are each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, -C (O) -C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, Cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, Substituted by one or more substituents selected from C 3-12 cycloalkyl, 3-12 heterocyclyl, C 6-12 aryl and 5-12 heteroaryl, preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, -C (O) -C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, said amino, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, Cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thioxo, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, One or more substituents of C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl;
Or R p and R q are linked to their adjacent atoms to form C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, Halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl, =N-O-R aa and=R aaRbb, preferably to form C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, Oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl, 3-to 8-membered heterocyclyl, C 6-10 aryl, A 5-10 membered heteroaryl, =n-O-R aa, and=r aaRbb;
R aa and R bb are each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, -C (O) -C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, Cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, Substituted by one or more substituents selected from C 3-12 cycloalkyl, 3-12 heterocyclyl, C 6-12 aryl and 5-12 heteroaryl, preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, -C (O) -C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, said amino, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, Cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thioxo, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, One or more substituents of C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl;
n4 is selected from 0, 1, 2, 3 or 4;
n7 is selected from 0,1, 2, 3 or 4, and
N8 is selected from 0, 1, 2, 3 or 4;
m3 is selected from 0,1 or 2.
The invention further relates to a pharmaceutical composition comprising a therapeutically effective dose of a compound as shown in any one of the embodiments, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
The invention further relates to the use of a compound as shown in any one of the embodiments, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition in the preparation of a PRMT5 inhibitor medicament.
The invention further relates to the use of a compound as shown in any one of the embodiments, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for the treatment of a cancer, wherein the cancer is selected from MTAP-associated cancers.
The invention further relates to a method of preparing a compound as set forth in any one of the embodiments, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for treating a cancer, wherein the cancer is selected from MTAP-associated cancers.
In some embodiments, the cancer is selected from lung cancer, hepatocellular carcinoma, breast cancer, skin cancer, bladder cancer, liver cancer, pancreatic cancer, head and neck cancer, glioma, glioblastoma, esophageal cancer, pancreatic cancer, mesothelioma, melanoma, astrocytoma, undifferentiated multiforme sarcoma, diffuse large B-cell lymphoma, leukemia, gastric adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, brain cancer, gastric cancer, renal cancer, endometrial cancer, ovarian cancer, prostate cancer, lymphoma, non-hodgkin's lymphoma, urinary tract cancer, soft tissue cancer, pleural cancer, colorectal cancer, or cholangiocarcinoma, the lung cancer is selected from non-small cell lung cancer, lung squamous carcinoma, or lung adenocarcinoma, and the esophageal cancer is selected from esophageal squamous cell carcinoma or esophageal adenocarcinoma.
The present invention also relates to a method of treatment for preventing and/or treating cancer comprising administering to a patient a therapeutically effective dose of a compound as shown in any one of the embodiments, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
The invention also relates to a method of treating cancer in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof.
In certain embodiments of the invention, the pharmaceutical composition comprises, on a free base basis, 0.1% -95%, preferably 90%, 85%, 80%, 75%, 70%, 60%, 50% by weight of the compound, stereoisomer or pharmaceutically acceptable salt thereof.
In certain embodiments of the invention, the pharmaceutical composition is selected from a tablet, a capsule, a liquid formulation or an injection, preferably further comprising a filler, optionally further comprising a disintegrant, or further comprising one or more of a glidant or a lubricant.
In certain embodiments of the invention, the pharmaceutical composition is an immediate release formulation or a sustained release formulation.
In certain embodiments of the invention, the pharmaceutical composition has a unit dose of 1-1000mg, preferably 1-500mg, or preferably 1mg, 2mg, 3mg,5mg, 10mg, 20mg, 40mg, 50mg, 60mg, 80mg, 100mg, 200mg, 300mg, 400mg or 500mg of the compound, stereoisomer or pharmaceutically acceptable salt thereof, as the free base.
In certain embodiments of the invention, the compound, stereoisomer or pharmaceutically acceptable salt thereof, can be administered by any convenient method, for example, orally, parenterally, buccally, sublingually, nasally, rectally, intrathecally, or transdermally, and pharmaceutical compositions adapted accordingly.
In certain embodiments of the invention, the compounds, stereoisomers or pharmaceutically acceptable salts thereof, may be formulated as liquid or solid formulations, such as syrups, suspensions, emulsions, tablets, capsules, powders, granules or lozenges.
In some embodiments, the methods relate to the treatment of a condition such as lung cancer, hepatocellular carcinoma, breast cancer, skin cancer, bladder cancer, liver cancer, pancreatic cancer, head and neck cancer, glioma, glioblastoma, esophageal cancer, pancreatic cancer, mesothelioma, melanoma, astrocytoma, undifferentiated multiforme sarcoma, diffuse large B-cell lymphoma, leukemia, gastric adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, brain cancer, gastric cancer, renal cancer, endometrial cancer, ovarian cancer, prostate cancer, lymphoma, non-hodgkin's lymphoma, urinary tract cancer, soft tissue cancer, pleural cancer, colorectal cancer, or cholangiocarcinoma.
In some embodiments, the lung cancer is selected from non-small cell lung cancer, lung squamous carcinoma, or lung adenocarcinoma, and the esophageal cancer is selected from esophageal squamous cell carcinoma or esophageal adenocarcinoma.
Detailed description of the invention
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art, and in particular, the terms used in the specification and claims have the following meanings.
The term "alkyl" refers to a straight or branched chain saturated aliphatic hydrocarbon group, which alkyl group may be optionally substituted with one or more substituents. In particular embodiments, alkyl refers to having 1 to 20 (C 1-20), 1 to 15 (C 1-15), 1 to 12 (C 1-12), 1 to 10 (C 1-10), 1 to 8 (C 1-8), 1 to 6 (C 1-6) or 1 to 3 (C 1-3) carbon atoms, or having 3 to 20 (C 3-20), Branched saturated hydrocarbyl of 3 to 15 (C 3-15), 3 to 12 (C 3-12), 3 to 10 (C 3-10), 3 to 8 (C 3-8) or 3 to 6 (C 3-6) carbon atoms. As used herein, straight chain C 1-6 alkyl and branched C 3-6 alkyl groups are also referred to as "lower alkyl". For example, a C 1-6 alkyl group refers to a linear saturated monovalent hydrocarbon group having 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon group having 3 to 6 carbon atoms. In one embodiment, the C 1-6 alkyl contains 1 to 6 (e.g., 1,2, 3,4, 5, 6) carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 2-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof, and the like. In one embodiment, the alkyl is an optionally substituted alkyl as described elsewhere herein.
The term "alkylene" means that one hydrogen atom of the alkyl group is further substituted, wherein the definition of "alkyl" is as previously described. Non-limiting examples of "alkylene" include methylene (-CH 2 -), ethylene (- (CH 2)2 -), propylene (- (CH 2)3 -), or butylene (- (CH 2)4 -). In one embodiment, the alkylene is an optionally substituted alkyl group as described elsewhere herein.
The term "alkenyl" refers to a straight or branched chain unsaturated aliphatic hydrocarbon group containing at least one carbon-carbon double bond and the carbon-carbon double bond may be located anywhere within the alkenyl group, which may be optionally substituted with one or more substituents. In particular embodiments, alkenyl groups are those having 2 to 20 (C 2-20), 2 to 15 (C 2-15), 2 to 12 (C 2-12), 2 to 10 (C 2-10), 2 to 8 (C 2-8), 2 to 6 (C 2-6) or 2 to 4 (C 2-4) of a straight-chain unsaturated hydrocarbon radical having carbon atoms, or having 3 to 20 (C 3-20), 3 to 15 (C 3-15), 3 to 12 (C 3-12), 3 to 10 (C 3-10), 3 to 8 (C 3-8) or 3 to 6 (C 3-6) branched unsaturated hydrocarbon groups. The term "alkenyl" as used herein includes both straight chain and branched alkenyl groups unless otherwise indicated. For example, C 2-6 alkenyl refers to a straight chain unsaturated hydrocarbon group having 2 to 6 carbon atoms or a branched unsaturated hydrocarbon group having 3 to 6 carbon atoms. In one embodiment, the C 2-6 alkenyl group contains 2 to 6 (e.g., 2, 3,4, 5, 6) carbon atoms. non-limiting examples of alkenyl groups include: those of ordinary skill in the art will appreciate that the term "alkenyl" may also include groups having "cis" and "trans" configurations, or alternatively, groups having "E" and "Z" configurations. In one embodiment, the alkenyl is an optionally substituted alkenyl as described elsewhere herein.
The term "alkynyl" refers to a straight or branched chain unsaturated aliphatic hydrocarbon group containing at least one carbon-carbon triple bond and which may be located anywhere within the alkynyl group, which may be optionally substituted with one or more substituents. in particular embodiments, alkynyl groups are those having 2 to 20 (C 2-20), 2 to 15 (C 2-15), 2 to 12 (C 2-12), 2 to 10 (C 2-10), 2 to 8 (C 2-8), 2 to 6 (C 2-6) or 2 to 4 (C 2-4) of a straight-chain unsaturated hydrocarbon radical having carbon atoms, or having 3 to 20 (C 3-20), 3 to 15 (C 3-15), 3 to 12 (C 3-12), 3 to 10 (C 3-10), 3 to 8 (C 3-8) or 3 to 6 (C 3-6) branched unsaturated hydrocarbon groups. The term "alkynyl" as used herein includes both straight and branched chain alkynyl groups, unless otherwise indicated. For example, C 2-6 alkynyl refers to a straight chain unsaturated hydrocarbon group having 2 to 6 carbon atoms or a branched unsaturated hydrocarbon group having 3 to 6 carbon atoms. In one embodiment, the C 2-6 alkynyl contains 2 to 6 (e.g., 2, 3,4, 5, 6) carbon atoms. non-limiting examples of alkynyl groups include: In one embodiment, the alkynyl is an optionally substituted alkynyl as described elsewhere herein.
The term "cycloalkyl" refers to a saturated or partially unsaturated aliphatic hydrocarbon monocyclic, polycyclic (two or more) cyclic group, which may be optionally substituted with one or more substituents. In particular embodiments, the cycloalkyl ring contains 3 to 20 (C 3-20), 3 to 12 (C 3-12), 3 to 10 (C 3-10), 3 to 8 (C 3-8), or 3 to 6 (C 3-6) carbon atoms, in one embodiment, the cycloalkyl ring contains 6 to 14 (C 6-14) or 7 to 10 (C 7-10) carbon atoms, which may contain one or more double bonds, but does not have a fully conjugated pi-electron system. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like, and polycyclic cycloalkyl groups include spirocycloalkyl groups, fused ring alkyl groups, and bridged cycloalkyl groups in one embodiment. In one embodiment, the cycloalkyl is optionally substituted cycloalkyl or cycloalkyl optionally fused with heterocyclyl, aryl, or heteroaryl as described elsewhere herein, non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, and the like.
The term "spirocycloalkyl" refers to an aliphatic hydrocarbon polycyclic group having one carbon atom (referred to as the spiro atom) shared between the monocyclic rings, which may contain one or more double bonds, but no ring has a fully conjugated pi-electron system. In particular embodiments, the spirocycloalkyl group comprises 5 to 20 (C 5-20), 6 to 14 (C 6-14), or 7 to 10 (C 7-10) (e.g., 7, 8, 9, 10) carbon atoms. The spirocycloalkyl groups are classified as mono-, di-or multicycloalkyl groups according to the number of common spiro atoms between rings, in one embodiment mono-and bisspirocycloalkyl groups. In one embodiment 4/4, 3/5, 4/6, 5/5 or 5/6 mono-spirocycloalkyl. In one embodiment, the spirocycloalkyl is an optionally substituted spirocycloalkyl as described elsewhere herein. Non-limiting examples of spirocycloalkyl groups include:
The term "fused ring alkyl" refers to an all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with the other rings in the system, wherein one or more of the rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. In particular embodiments, the fused ring alkyl groups comprise 5 to 20 (C 5-20), 6 to 14 (C 6-14), or 7 to 10 (C 7-10) (e.g., 7, 8, 9, 10) carbon atoms. The number of constituent rings may be classified as a bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyl group, further in one embodiment as a bicyclic or tricyclic ring, further in one embodiment as a 3-membered/5-membered, 4-membered/5-membered, 5-membered/5-membered or 5-membered/6-membered bicyclic alkyl group. In one embodiment, the fused ring alkyl is an optionally substituted fused ring alkyl or fused ring alkyl optionally fused with a heterocyclyl, aryl or heteroaryl group as described elsewhere herein, further in one embodiment is a bicyclic or tricyclic ring, further in one embodiment is a C 3-8 cycloalkyl and 3-8 membered heterocyclyl, a C 3-8 cycloalkyl-acenyl or a C 3-8 cycloalkyl and 5-8 membered heteroaryl, further in one embodiment is a C 3-6 cycloalkyl and 3-6 membered heterocyclyl, a C 3-6 cycloalkyl-acenyl or a C 3-6 cycloalkyl and 5-6 membered heteroaryl. Non-limiting examples of fused ring alkyl groups include:
The term "bridged cycloalkyl" refers to an all-carbon polycyclic group wherein any two rings share two carbon atoms not directly attached, which may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. In particular embodiments, bridged cycloalkyl groups comprise 5 to 20 (C 5-20), 6 to 14 (C 6-14), or 7 to 10 (C 7-10) (e.g., 7, 8, 9, 10) carbon atoms. The number of constituent rings may be classified as a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group, with bicyclic or tricyclic being preferred. In one embodiment, the bridged cycloalkyl is an optionally substituted bridged cycloalkyl as described elsewhere herein. Non-limiting examples of bridged cycloalkyl groups include:
The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus or sulfur, in which the nitrogen, phosphorus or sulfur atoms may be optionally oxidized, the nitrogen atoms may be optionally quaternized, the ring carbon atoms may be optionally substituted with oxygen, but excluding the ring portions of-O-, -O-S-, the remaining ring atoms being carbon, which may contain one or more double bonds, but not have a fully conjugated pi-electron system. In particular embodiments, the heterocyclyl contains 3 to 20, 3 to 12, 3 to 10, 3 to 8, or 3 to 6 ring atoms, 1 to 4 of which are heteroatoms, in one embodiment the heterocyclyl contains 3 to 6, 4 to 6, 3 to 8, 3 to 10, 6 to 10, or 7 to 11 ring atoms, in one embodiment the heterocyclyl contains 3 to 8 (e.g., 3, 4, 5, 6, 7, 8) ring atoms. Non-limiting examples of monocyclic heterocyclyl groups include tetrahydropyrrolyl, azetidinyl, oxetanyl, oxacyclohexanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, and the like. Polycyclic heterocyclic groups include spiro heterocyclic groups, fused heterocyclic groups, and bridged heterocyclic groups. In one embodiment, the heterocyclyl is an optionally substituted heterocyclyl as described elsewhere herein, or further ring-attached through any two or more atoms in the ring to other cycloalkyl, heterocyclyl, aryl and heteroaryl groups.
The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group having one atom in common between the rings (referred to as the spiro atom), wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen, boron, phosphorus or sulfur, and the remaining ring atoms are carbon, which may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. In particular embodiments, the spiroheterocyclyl contains 5 to 20 or 6 to 14 ring atoms, in one embodiment 7 to 10 (e.g., 7, 8, 9, 10) ring atoms, the spiroheterocyclyl is classified as a mono-, di-or poly-spiroheterocyclyl based on the number of common spiro atoms between rings, preferably mono-and di-spiroheterocyclyl, in one embodiment 4-, 5-, 4-, 6-, 5-, or 5/6-membered mono-spiroheterocyclyl, in one embodiment the spiroheterocyclyl is an optionally substituted spiroheterocyclyl as described elsewhere herein, non-limiting examples of spiroheterocyclyl include:
The term "fused heterocyclyl" refers to a polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with the other rings in the system, one or more of which may contain one or more double bonds, but none of which has a fully conjugated pi-electron system in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus or sulfur and the remaining ring atoms are carbon. In particular embodiments, the fused heterocyclyl is an optionally substituted fused heterocyclyl, preferably bicyclic or tricyclic, comprising from 5 to 20 or 6 to 14 ring atoms, in one embodiment from 7 to 10 (e.g., 7, 8, 9, 10) ring atoms, which may be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclyl groups, depending on the number of constituent rings, preferably bicyclic or tricyclic, in one embodiment 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclyl groups, which in one embodiment is an optionally substituted fused heterocyclyl group as described elsewhere herein, or which may be fused with cycloalkyl, heterocyclyl, aryl or heteroaryl groups, preferably bicyclic or tricyclic, in one embodiment is a 3-8 membered heterocyclyl C 3-8 cycloalkyl, 3-8 membered heterocyclyl, 3-8 heterocyclyl 3-8 membered heterocyclyl 3-6 heterocyclyl heteroaryl, further in one embodiment is a 3-6 heterocyclyl C 3-6 cycloalkyl, 3-6 heterocyclyl, 3-6 heterocyclyl or 3-6 heterocyclyl including, examples of non-limiting heterocyclyls:
The term "bridged heterocyclyl" refers to a polycyclic heterocyclic group in which any two rings share two atoms not directly connected, which may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system in which one or more of the ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus or sulfur and the remaining ring atoms are carbon. In particular embodiments, the bridged heterocyclyl contains 5 to 20 or 6 to 14 ring atoms, in one embodiment 7 to 10 (e.g., 7, 8, 9, 10) ring atoms, can be classified as bicyclic, tricyclic, tetra, or polycyclic, depending on the number of constituent rings, is preferably bicyclic, tricyclic, or tetra, in one embodiment, is bicyclic or tricyclic, in one embodiment, is an optionally substituted bridged heterocyclyl as described elsewhere herein, non-limiting examples of bridged heterocyclyl include:
The term "aryl" refers to an all-carbon monocyclic or fused-polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group containing at least one ring having a conjugated pi-electron system, which may be optionally substituted with one or more substituents. In particular embodiments, aryl groups contain 6 to 20, 6 to 14, or 6 to 10 ring atoms, and in one embodiment, aryl groups may further refer to bicyclic, tricyclic, or tetracyclic ring systems, wherein at least one ring is an aromatic ring, and the other rings may be saturated, partially unsaturated carbocyclic, or rings containing one or more heteroatoms independently selected from O, S and N, and in one embodiment, the aryl groups are selected from benzo 5-8 membered heteroaryl, benzo 3-8 membered cycloalkyl, or benzo 3-8 membered heterocyclyl. In one embodiment, the aryl group is selected from a benzo 5-6 membered heteroaryl, a benzo 3-6 membered cycloalkyl or a benzo 3-6 membered heterocyclyl wherein the heterocyclyl is a heterocyclyl containing 1-3 nitrogen, oxygen or sulfur atoms. Non-limiting examples thereof include phenyl, naphthyl, fluorenyl, azulenyl, anthracenyl, phenanthryl, pyrenyl, biphenyl, terphenyl, dihydronaphthyl, indenyl, tetrahydronaphthyl (tetralinyl), and,
The term "arylene" refers to a divalent aryl group formed by further substitution of one hydrogen atom of the aryl group, wherein arylene is optionally substituted or unsubstituted, and aryl is as defined above.
The term "heteroaryl" refers to an optionally substituted monocyclic, multicyclic group or ring system comprising at least one aromatic ring, wherein the aromatic ring has one or more heteroatoms independently selected from O, S and N. In particular embodiments, heteroaryl comprises 5 to 20, 5 to 14, or 5 to 10 ring atoms, 1 to 4 of which are heteroatoms, in one embodiment, 5 or 6 ring atoms, and in particular embodiments, heteroaryl may further refer to bicyclic, tricyclic, or tetracyclic rings, at least one of which is an aromatic ring having one or more heteroatoms independently selected from O, S and N, and the other rings may be saturated, partially unsaturated carbocyclic or contain one or more heteroatoms independently selected from O, S and N. In one embodiment, the heteroaryl is selected from heteroaryl-6-10 membered aryl, heteroaryl-3-10 membered cycloalkyl or heteroaryl-3-10 membered heterocyclyl, further in one embodiment, the heteroaryl is selected from 5-or 6-membered heteroaryl-6-10 membered aryl, 5-or 6-membered heteroaryl-3-6-membered cycloalkyl, 5-or 6-membered heteroaryl-3-6-membered heterocyclyl, wherein heterocyclyl is a heterocyclyl containing 1-3 nitrogen, oxygen or sulfur atoms. Non-limiting examples of which include: furyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, triazolyl, pyridyl, pyrimidinyl, thiazolyl, thienyl, and thienyl benzofuranyl, benzimidazolyl, benzisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothienyl, benzotriazole, imidazopyridinyl, imidazothiazolyl, indolizinyl, and benzofuranyl, benzimidazolyl, benzisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothienyl, benzofuranyl benzothienyl, benzotriazole, imidazopyridinyl, imidazothiazolyl, indolizinyl,
The term "heteroarylene" refers to a divalent heteroaryl group formed by further substitution of one hydrogen atom of a cyclic alkyl group, wherein the heteroarylene group is optionally substituted or unsubstituted, and the heteroaryl group is as defined above.
The term "heteroalkyl" refers to a stable straight or branched chain, or cyclic hydrocarbon group, or a combination thereof, consisting of the indicated number of carbon atoms and one or more (one to three in one embodiment) heteroatoms selected from O, N, si and S, and wherein the nitrogen and sulfur atoms are optionally oxidized, which nitrogen heteroatoms may optionally be quaternized. In one embodiment, heteroatoms O, N and S may be placed at any internal position of the heteroalkyl group. In one embodiment, the heteroatom Si may be placed at any position (e.g., internal or terminal) of the heteroalkyl group, including where the alkyl group is attached to the remainder of the molecule. Non-limiting examples thereof include ：-CH2-CH2-O-CH3、-CH2-CH2-NH-CH3、-CH2-CH2-N(CH3)-CH3、-CH2-S-CH2-CH3、-CH2-CH2-S(O)-CH3、-CH2-CH2-S(O)2-CH3、-CH＝CH-O-CH3、-Si(CH3)3、-CH2-CH＝N-OCH3 and-ch=ch-N (CH 3)-CH3. Up to two heteroatoms may be consecutive, e.g., -CH 2-NH-O-CH3 and-CH 2-O-Si(CH3)3. In particular embodiments, the heteroalkyl is an optionally substituted heteroalkyl as described elsewhere herein.
The term "alkoxy" refers to-O- (alkyl) and-O- (unsubstituted cycloalkyl), wherein the alkyl or cycloalkyl is as defined above. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, or cyclohexyloxy. In one embodiment, the alkoxy is an optionally substituted alkoxy as described elsewhere herein.
The term "alkanoyl" refers to a-C (O) -alkyl group, wherein alkyl is as defined above.
The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein the alkyl group is as defined above. Non-limiting examples of such haloalkyl groups include trifluoromethyl, -CH 2CF3,
The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above.
The term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein the alkyl group is as defined above.
The term "alkylthio" refers to-S- (alkyl) and-S- (unsubstituted cycloalkyl), wherein the alkyl or cycloalkyl is as defined above. Non-limiting examples of alkylthio groups include methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio or cyclohexylthio. In one embodiment, the alkylthio group is an optionally substituted alkylthio group as described elsewhere herein.
The term "haloalkylthio" refers to an alkylthio group substituted with one or more halogens, wherein the alkylthio group is as defined above.
The term "alkenylcarbonyl" refers to-C (O) - (alkenyl), wherein alkenyl is as defined above. Non-limiting examples of alkenylcarbonyl groups include vinylcarbonyl, propenylcarbonyl, or butenylcarbonyl. In one embodiment, the alkenylcarbonyl is an optionally substituted alkenylcarbonyl as described elsewhere herein.
The term "aminocarbonyl" refers to NH 2 -C (O) -.
The term "alkylaminocarbonyl" refers to an aminocarbonyl (NH 2 -C (O) -) in which one or both of the two hydrogens are replaced with an alkyl group, where the definition of alkyl is as previously described.
The term "alkylamino" refers to an amino group in which one or both of the hydrogens are replaced with an alkyl group, where the alkyl group is as defined above.
The term "carbonyl" refers to a-C (O) -, - (CO) -or-C (=o) -group. All references are used interchangeably throughout the specification.
The term "=r aaRbb" meansA substituent.
The term "hydroxy" refers to an-OH group.
The term "halogen" refers to fluorine, chlorine, bromine or iodine.
The term "oxo" or "lateral oxygen" refers to = O.
The term "hydrogen" includes protons (1 H), deuterium (2 H), tritium (3 H), and/or mixtures thereof. In certain embodiments, one or more hydrogen-occupied positions in the compound may be enriched with deuterium and/or tritium. Such isotopically enriched analogs can be prepared by suitable isotopically labeled starting materials obtained from commercial sources or by known literature procedures.
The alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, arylene, heteroaryl, heteroarylene, heteroalkyl, alkoxy, alkylthio, hydroxyalkyl, alkenylcarbonyl, aminocarbonyl, alkylaminocarbonyl, alkylamino, alkanoyl may be substituted or unsubstituted, and in one embodiment the substituents are selected from one or more of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, alkanoyl, halogen, mercapto, hydroxy, nitro, cyano, azido, oximo, phosphate, oxo, thio, carboxyl, carboxylate, cycloalkyl, heterocyclyl, aryl, heteroaryl, heterocycloalkoxy, cycloalkylthio, or heterocycloalkylthio.
The different expressions of X being selected from A, B or C, X being selected from A, B and C, X being A, B or C, X being A, B and C, etc. all express the same meaning, namely that X can be any one or more than one of A, B, C.
"Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may be, but is not necessarily, present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.
In the various parts of the invention, linking substituents are described. When the structure clearly requires a linking group, the markush variables recited for that group are understood to be linking groups. For example, if the structure requires a linking group and the markush group definition for that variable enumerates an "alkyl" or "aryl" group, it will be understood that the "alkyl" or "aryl" represents a linked alkylene group or arylene group, respectively.
"Substituted" means that any one or more hydrogen atoms on a particular atom is replaced with a substituent, so long as the valence of the particular atom is normal and the substituted compound is stable in one embodiment. When the substituent is oxo (i.e., =o), it means that two hydrogen atoms are substituted. The term "optionally substituted" means that the substituents may or may not be substituted, and the types and numbers of substituents may be arbitrary on the basis that they can be chemically achieved unless otherwise specified. It goes without saying that substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable when bound to carbon atoms having unsaturated (e.g., olefinic) bonds.
The indefinite articles "a" and "an" and the definite article "the" in the specification and claims include both plural and singular forms unless stated to the contrary.
"Pharmaceutical composition" means a mixture comprising one or more of the compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and thus exert biological activity.
By "pharmaceutically acceptable salts" is meant salts of the compounds of the present invention which are safe and effective when used in a mammal, and which possess the desired biological activity.
"Stereoisomers" include all enantiomeric/diastereomeric/stereomeric pure and enantiomeric/diastereomeric/stereomeric enriched compounds of the invention.
"Stereoisomerically pure" refers to a composition comprising one stereoisomer of a compound and substantially free of the other stereoisomer of the compound. For example, a stereomerically pure composition of a compound having one chiral center will be substantially free of the opposite enantiomer of the compound. A stereomerically pure composition of a compound having two chiral centers will be substantially free of the other diastereomers of the compound. A typical stereoisomerically pure compound comprises more than about 80% by mass of one stereoisomer of the compound and less than about 20% by mass of the other stereoisomer of the compound, more than about 90% by mass of one stereoisomer of the compound and less than about 10% by mass of the other stereoisomer of the compound, more than about 95% by mass of one stereoisomer of the compound and less than about 5% by mass of the other stereoisomer of the compound, more than about 97% by mass of one stereoisomer of the compound and less than about 3% by mass of the other stereoisomer of the compound or more than about 99% by mass of the one stereoisomer of the compound and less than about 1% by mass of the other stereoisomer of the compound.
"Stereoisomerically enriched" refers to a composition comprising a stereoisomer of a compound having a mass content of greater than about 55%, a mass content of greater than about 60%, a mass content of greater than about 70%, or a mass content of greater than about 80%.
"Enantiomerically pure" refers to a stereoisomerically pure composition of a compound having one chiral center. Similarly, the term "enantiomerically enriched" refers to a stereomerically enriched composition of a compound having one chiral center.
"Optically active" and "enantiomerically active" refer to a combination of molecules having an enantiomeric or diastereomeric excess of not less than about 50%, not less than about 70%, not less than about 80%, not less than about 90%, not less than about 91%, not less than about 92%, not less than about 93%, not less than about 94%, not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 99%, not less than about 99.5%, or not less than about 99.8%. In particular embodiments, the compound comprises about 95% or more of the desired enantiomer or diastereomer and about 5% or less of the less preferred enantiomer or diastereomer, based on the total weight of the racemate. In describing optically active compounds, the prefixes R and S are used to represent the absolute configuration of the molecule relative to its chiral center. (+) and (-) are used to denote the optical rotation of the compound, i.e., the direction of the plane of polarized light rotated by the optically active compound. The prefix (-) indicates that the compound is left-handed, i.e., the compound rotates the plane of polarized light to the left or counter-clockwise. The prefix (+) indicates that the compound is right-handed, i.e., the compound rotates the plane of polarized light to the right or clockwise. However, the sign (+) and (-) of the optical rotation is independent of the absolute configuration R and S of the molecule.
Detailed Description
The invention is further described below in connection with examples, which are not intended to limit the scope of the invention.
Examples
The structure of the compounds of the invention is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). The NMR shift (. Delta.) is given in units of 10 -6 (ppm). NMR was performed using a Bruker AVANCE-400 nuclear magnetic resonance apparatus with deuterated dimethyl sulfoxide (DMSO-d 6), deuterated chloroform (CDCl 3), deuterated methanol (CD 3 OD) and Tetramethylsilane (TMS) as the internal standard.
MS was determined using FINNIGAN LCQAD (ESI) mass spectrometer (manufacturer: thermo, model: FINNIGAN LCQ ADVANTAGE MAX).
HPLC was performed using Agilent 1200DAD high pressure liquid chromatograph (Sunfire C 18 X4.6 mm column) and Waters 2695-2996 high pressure liquid chromatograph (Gimini C 18 X4.6 mm column).
The average inhibition rate of kinase and IC 50 were measured by NovoStar microplate reader (BMG, germany).
The thin layer chromatography silica gel plate uses a smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used by the Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.
Column chromatography generally uses a tobacco stand yellow sea silica gel of 200-300 meshes as a carrier.
The known starting materials of the present invention may be synthesized using or following methods known in the art, or may be purchased from the companies ABCR GmbH & Co.KG, acros Organics, ALDRICH CHEMICAL Company, shao Yuan chemical technology (Accela ChemBio Inc), darui chemical, and the like.
The examples are not particularly described, and the reaction can be carried out under an argon atmosphere or a nitrogen atmosphere.
An argon or nitrogen atmosphere means that the reactor flask is connected to a balloon of argon or nitrogen of about 1L volume.
The hydrogen atmosphere is defined as the reaction flask being connected to a balloon of hydrogen gas of about 1L volume.
The pressure hydrogenation reaction uses Parr 3916EKX type hydrogenometer and clear blue QL-500 type hydrogen generator or HC2-SS type hydrogenometer.
The hydrogenation reaction is usually vacuumized, filled with hydrogen and repeatedly operated for 3 times.
The microwave reaction used was a CEM Discover-S908860 type microwave reactor.
The examples are not specifically described, and the solution refers to an aqueous solution.
The reaction temperature is room temperature and is 20-30 ℃ without special description in the embodiment.
The reaction progress was monitored by Thin Layer Chromatography (TLC) using a developing solvent system of A methylene chloride and methanol, B n-hexane and ethyl acetate, C petroleum ether and ethyl acetate, D acetone, and the volume ratio of the solvents was adjusted according to the polarities of the compounds.
The eluent system for column chromatography and the developing agent system for thin-layer chromatography used for purifying the compound comprise a n-hexane and ethyl acetate system, a n-hexane and tetrahydrofuran system, an acetonitrile and water system, and the volume ratio of the solvent can be adjusted according to the polarity of the compound, and can also be adjusted by adding a small amount of alkaline or acidic reagents such as triethylamine and acetic acid.
Examples resolution of chiral isomers an OZ column was used and HPLC chiral analysis conditions were as follows:
Example 1
2- (4- (4- (Aminomethyl) -1-carbonyl-1, 2-dihydro-phthalazin-6-yl) -4H-1,2, 4-triazol-3-yl) -4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile
First step
3-Chloro-6-cyano-5-cyclopropyloxy-2-fluorobenzamide
4-Chloro-6-cyclopropyloxy-3-fluoro-2-iodobenzonitrile 1a (2 g,5.93mmol, synthesized by known method "patent WO 2022192745"), methoxyamine hydrochloride (0.60 g,7.12 mmol), sodium iodide (178 mg,1.19 mmol) and triethylenediamine (1.33 g,11.85 mmol) were dissolved in 35mL acetonitrile, nitrogen was exchanged three times, palladium dichloride (105 mg,0.59 mmol) was added, carbon monoxide was exchanged three times, and the system was reacted at 90℃C of carbon monoxide (5 atm) for 8 hours. Cooled to room temperature, concentrated, water was added, extracted with ethyl acetate (80 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride solution (50 mL. Times.1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title product 3-chloro-6-cyano-5-cyclopropyloxy-2-fluorobenzamide 1B (0.90 g), yield: 59.6%. MS m/z (ESI) 255[ M+1]
Second step
4-Chloro-6-cyclopropyloxy-3-fluoro-2- (4H-1, 2, 4-triazol-3-yl) benzonitrile
3-Chloro-6-cyano-5-cyclopropyloxy-2-fluorobenzamide 1b (0.5 g,1.96 mmol) was dissolved in N, N-dimethylformamide dimethyl acetal (2.34 g,19.64 mmol), nitrogen was purged three times, and the system was heated to 120℃for 2 hours. Cooled to room temperature, concentrated, the residue was dissolved in acetic acid (10 mL), hydrazine hydrate (139 mg,2.36 mmol) was added dropwise, and the system was heated to 90℃for 2 hours. The mixture was concentrated, diethyl ether was added to the residue, and the system was stirred at0℃for 30 minutes. The residue was filtered, washed with a small amount of diethyl ether and dried by spin-drying with a pump to give the title product 4-chloro-6-cyclopropyloxy-3-fluoro-2- (4H-1, 2, 4-triazol-3-yl) benzonitrile 1c (0.30 g) in 54.8% yield.
MS m/z(ESI):280[M+1]
Third step
(7- (3- (3-Chloro-6-cyano-5-cyclopropyloxy-2-fluorophenyl) -4H-1,2, 4-triazol-4-yl) -4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) carbamic acid tert-butyl ester
4-Chloro-6-cyclopropyloxy-3-fluoro-2- (4H-1, 2, 4-triazol-3-yl) benzonitrile 1C (0.20 g,0.72 mmol), (7-bromo-4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) carbamic acid tert-butyl ester 1d (0.28 g,0.79mmol, obtained by synthesis using the well known method "patent WO 2022192745") and cesium carbonate (935 mg,2.87 mmol) were dissolved in 10mL toluene, nitrogen was exchanged three times, and bis (dibenzylideneacetone) palladium (41 mg,0.072 mmol) was added and the system heated to 80℃for reaction for 16 hours. Cooled to room temperature, concentrated, water was added, the organic phases were combined, washed with saturated sodium chloride solution (20 mL. Times.1), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product (tert-butyl 7- (3- (3-chloro-6-cyano-5-cyclopropyloxy-2-fluorophenyl) -4H-1,2, 4-triazol-4-yl) -4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) carbamate 1e (70 mg), yield: 17.7%.
MS m/z(ESI):553[M+1]
Fourth step
2- (4- (4- (Aminomethyl) -1-carbonyl-1, 2-dihydro-phthalazin-6-yl) -4H-1,2, 4-triazol-3-yl) -4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile
(7- (3- (3-Chloro-6-cyano-5-cyclopropyloxy-2-fluorophenyl) -4H-1,2, 4-triazol-4-yl) -4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) carbamic acid tert-butyl ester 1e (70 mg,0.13 mmol) was dissolved in 5mL of 1, 4-dioxane, 5mL of 4M dioxane hydrochloride was added, and the reaction was carried out at room temperature for 1 hour. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography with eluent system C, and the residue was resolved by SFC chiral column to give 2- (4- (4- (aminomethyl) -1-carbonyl-1, 2-dihydro-phthalazin-6-yl) -4H-1,2, 4-triazol-3-yl) -4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile 1 (16 mg), yield: 27.9%.
MS m/z(ESI):453[M+1]
Synthesis of the following examples reference example 1.
Example 9
2- (4- (4- (Aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-cyclopropyl-1H-pyrazol-5-yl) -4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile
First step
4-Bromo-1-cyclopropyl-1H-pyrazole
In a single-port flask were charged 4-bromo-1-hydropyrazole 1 (3 g,20.41 mmol), cyclopropylboronic acid 9b (7.01 g,81.65 mmol), copper acetate (4.89 g,24.49 mmol), 2' -bipyridine (3.51 g,22.45 mmol), sodium carbonate (4.76 g,44.91 mmol) and DME (45 mL) reacted at 80℃for 24 hours. Aqueous ammonia (25 mL) was added dropwise to the reaction solution, EA was extracted three times, and the organic phases were combined. The resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 4-bromo-1-cyclopropyl-1H-pyrazole 9c (1.3 g) in 34% yield.
1H NMR(400MHz,CDCl3)δ7.44(d,2H),3.57(dq,1H),1.14-1.05(m,2H),1.05-0.94(m,2H).
Second step
4-Bromo-1-cyclopropyl-5-boronic acid-1H-pyrazole
4-Bromo-1-cyclopropyl-1H-pyrazole 9C (2.10 g,11.23 mmol) was dissolved in THF (4.85 mL) in a three-necked flask, cooled to-65℃and then n-butyllithium solution (2.5M, 6.76 mL) was added dropwise, and the mixture was reacted at-65℃for 1 hour, triisopropylborate (6.33 g,33.68 mmol) was added dropwise to the reaction mixture, and the temperature was raised to 10℃for 2 hours. The reaction mixture was quenched by addition of saturated ammonium chloride solution (5 mL), extracted three times with EA and the organic phases were combined. The resulting residue was purified by silica gel column chromatography with eluent system A to give 4-bromo-1-cyclopropyl-5-boronic acid-1H-pyrazole 9d (1 g) in 38.6% yield.
MS m/z(ESI):231[M+1]
Third step
4-Chloro-6-cyclopropyloxy-2- (1-cyclopropyl-1H-pyrazol-5-yl) -3-fluorobenzonitrile
4-Bromo-1-cyclopropyl-5-boronic acid-1H-pyrazole 9d (0.5 g,2.17 mmol), 4-chloro-6-cyclopropyloxy-3-fluoro-2-iodobenzonitrile (220mg,0.65mmol)、K3PO4(1.84g,4.33mmol)、Pd(dtbpf)Cl2(140mg,0.22mmol)、H2O(2.5mL) and 1' 4-dioxane (10 mL) were added to the single-necked flask, and reacted under nitrogen protection at microwave 85℃for 45 minutes. The system was concentrated to dryness, and the resulting residue was purified by silica gel column chromatography with eluent system a to give the title product 4-chloro-6-cyclopropyloxy-2- (1-cyclopropyl-1H-pyrazol-5-yl) -3-fluorobenzonitrile 9e (230 mg), yield: 33.0%.
MS m/z(ESI):318[M+1]
Fourth step
2- (4-Bromo-1-cyclopropyl-1H-pyrazol-5-yl) -4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile
4-Chloro-6-cyclopropyloxy-2- (1-cyclopropyl-1H-pyrazol-5-yl) -3-fluorobenzonitrile 9e (230 mg,0.72 mmol) and N-bromosuccinimide (248 mg,1.40 mmol) were dissolved in 5mL of dichloromethane and reacted at room temperature under stirring for 0.5H. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system a to give the title product 2- (4-bromo-1-cyclopropyl-1H-pyrazol-5-yl) -4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile 9f (161 mg), yield: 56.1%.
MS m/z(ESI):396[M+1]
The synthesis of the fourth to fifth steps of reference example 1 gave the title product 2- (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-cyclopropyl-1H-pyrazol-5-yl) -4-chloro-6-cyclopropoxy-3-fluorobenzonitrile 9 (7 mg) in 5.0% yield by 2- (4-bromo-1-cyclopropyl-1H-pyrazol-5-yl) -4-chloro-6-cyclopropoxy-3-fluorobenzonitrile 9f (80 mg,0.29 mmol).
MS m/z(ESI):491[M+1]
1H NMR(400MHz,DMSO)δ12.52(s,1H),8.31(s,1H),8.24(s,1H),8.16(d,1H),8.03(d,1H),7.76(d,1H),7.67(dd,1H),4.20(dq,1H),3.88(s,2H),3.57-3.54(m,1H),1.10-1.00(m,2H),0.92(dp,4H),0.82(q,2H).
Example 17
2- (4- (4- (Aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -6-ethyl-2-methyl-2, 6-dihydro-pyrrolo [2,3-c ] pyrazol-5-yl) -4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile
First step
2-Chloro-1-ethyl-1H-pyrrole-3-carbaldehyde
1-Ethyl-1H-pyrrole-3-carbaldehyde 17a (5 g,40.65 mmol) was dispersed in 50mL of acetonitrile, N-chlorosuccinimide (6.65 g,50 mmol) was added thereto, and the reaction was stirred at 40℃for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 2-chloro-1-ethyl-1H-pyrrole-3-carbaldehyde 17B (5.1 g) in 79.4% yield.
MS m/z(ESI):158[M+1]
Second step
6-Ethyl-2-methyl-2, 6-dihydropyrrol [2,3-c ] pyrazole
2-Chloro-1-ethyl-1H-pyrrole-3-carbaldehyde 17b (5.10 g,32.48 mmol) was dispersed in 30mL of ethanol, methyl hydrazine (1.84 g,40 mmol) was added thereto, and the reaction was stirred at 60℃for 12 hours. The residue obtained was purified by silica gel column chromatography with eluent system B after cooling, filtration and concentration of the filtrate under reduced pressure to give the title product 6-ethyl-2-methyl-2, 6-dihydropyrrole [2,3-c ] pyrazole 17c (3.10 g), yield: 64.0%.
MS m/z(ESI):150[M+1]
Third step
5-Chloro-6-ethyl-2-methyl-2, 6-dihydropyrrole [2,3-c ] pyrazole
6-Ethyl-2-methyl-2, 6-dihydropyrrole [2,3-C ] pyrazole 17C (3.10 g,20.81 mmol) was dissolved in 30mL of acetonitrile, N-chlorosuccinimide (3.32 g,25 mmol) was added, and the reaction was stirred at 25℃for 16 hours. The residue obtained was purified by silica gel column chromatography with eluent system B, followed by filtration, concentration of the filtrate under reduced pressure, to give the title product 5-chloro-6-ethyl-2-methyl-2, 6-dihydropyrrole [2,3-c ] pyrazole 17d (2.15 g), yield: 56.4%. MS m/z (ESI): 184[ M+1]
Fourth step
5-Chloro-6-ethyl-4-iodo-2-methyl-2, 6-dihydropyrrole [2,3-c ] pyrazole
5-Chloro-6-ethyl-2-methyl-2, 6-dihydropyrrole [2,3-C ] pyrazole 17d (2 g,10.87 mmol) was dissolved in 20mL of acetonitrile, N-iodosuccinimide (2.70 g,12 mmol) was added, and the reaction was stirred at 25℃for 16 hours. The residue obtained was purified by silica gel column chromatography with eluent system B, followed by filtration, concentration of the filtrate under reduced pressure, to give the title product, 5-chloro-6-ethyl-4-iodo-2-methyl-2, 6-dihydropyrrole [2,3-c ] pyrazole 17e (1.7 g), yield: 50.3%.
MS m/z(ESI):310[M+1]
The synthesis of the third step of reference example 1 gave 17g (510 mg) of ((7- (6-ethyl-2-methyl-5-chloro-2, 6-dihydropyrrol [2,3-c ] pyrazol-4-yl) -4-oxo-3, 4-dihydropyrazin-1-yl) methyl) carbamic acid tert-butyl ester by 5-chloro-6-ethyl-4-iodo-2-methyl-2, 6-dihydropyrrol [2,3-c ] pyrazole 17e (1 g,3.23 mmol) and 34.5% yield.
MS m/z(ESI):457[M+1]
Sixth step
((7- (6-Ethyl-2-methyl-5- (boric acid pinacol ester) -2, 6-two hydrogen pyrrole [2,3-C ] pyrazole-4-base) -4-oxo-3, 4-two hydrogen phthalazin-1-base) methyl) carbamic acid tert-butyl ester
17G (510 mg,1.12 mmol) of tert-butyl ((7- (6-ethyl-2-methyl-5-chloro-2, 6-dihydropyrrol [2,3-c ] pyrazol-4-yl) -4-oxo-3, 4-dihydropyrazin-1-yl) methyl) carbamate (510 ml of 1, 4-dioxane) was dissolved, and pinacol biborate (381 mg,1.5 mmol), potassium acetate (254 mg,3 mmol) and [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride (44 mg,0.06 mmol) were added. The reaction was stirred at 100 ℃ for 2 hours under nitrogen atmosphere. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product ((7- (6-ethyl-2-methyl-5- (pinacol borate) -2, 6-dihydropyrrol [2,3-c ] pyrazol-4-yl) -4-oxo-3, 4-dihydropyrazin-1-yl) methyl) carbamic acid tert-butyl ester 17h (410 mg) in 66.9% yield.
MS m/z(ESI):549[M+1]
The synthesis of the third to fourth steps of reference example 1 gave the title product 2- (4- (4- (aminomethyl) -1-oxo-1, 2-dihydropyrazin-6-yl) -6-ethyl-2-methyl-2, 6-dihydropyrrol [2,3-c ] pyrazol-5-yl) -4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile 17 (52 mg) in 13.1% yield by ((7- (6-ethyl-2-methyl-5- (boronate) -2, 6-dihydropyrrol [2,3-c ] pyrazol-4-yl) -4-oxo-3, 4-dihydropyrazin-1-yl) methyl) carbamic acid tert-butyl ester 17h (410 mg,0.75 mmol) and 2-bromo-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile 17i (289 mg,1 mmol).
MS m/z(ESI):532[M+1]
Example 18
2- [4- [4- (Aminomethyl) -1-oxo-2H-phthalazin-6-yl ] -2-methylpyrazol-3-yl ] -4- (o-tolyl) benzonitrile
First step
2-Bromo-4- (o-tolyl) benzonitrile
Compound 2-bromo-4-iodo-benzonitrile 18a (2 g,6.50 mmol) and o-tolylboronic acid 18b (971 mg,7.14 mmol) were dissolved in DMF (30 mL), pd (dtbpf) Cl 2·CH2Cl2 (227 mg,0.65 mmol) and K 3PO4 (4.14 g,19.49 mmol) were added and the system stirred at 80℃for 16hr. To the reaction solution was added water (30 mL), which was quenched, extracted with ethyl acetate (3X 50 mL), and the organic phases were combined, washed with saturated brine (3X 50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give 2-bromo-4- (o-tolyl) benzonitrile 18c (876 mg), yield: 49.6%. MS m/z (ESI): 272[ M+1]
Second step
2 '-Methyl-3- (1-methyl-1H-pyrazol-5-yl) - [1,1' -biphenyl ] -4-carbonitrile
The compound 2-bromo-4- (o-tolyl) benzonitrile 18C (500 mg,1.84 mmol) and 1-methyl-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazole 18d (573 mg,2.76 mmol) were dissolved in a mixed solvent of 1, 4-dioxane (10 mL) and water (1 mL), and potassium acetate (541 mg,5.51 mmol) and 1,1' -di-t-butylphosphino-ferrocene palladium dichloride (119 mg,0.18 mmol) were added to stir the system at 100℃for 16hr. The reaction solution was cooled to 25℃and concentrated under reduced pressure, water (20 mL) was added to the residue, the extracts were performed with ethyl acetate (3X 30 mL), the organic phases were combined, washed with saturated brine (2X 30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give 2- (2-methylpyrazol-3-yl) -4- (o-tolyl) benzonitrile 18e (431 mg), yield 85.9%.
MS m/z(ESI):274[M+1]
Third step
2- (4-Iodo-2-methylpyrazol-3-yl) -4- (o-tolyl) benzonitrile
The compound 2- (2-methylpyrazol-3-yl) -4- (o-tolyl) benzonitrile 18e (330 mg,1.21 mmol) was dissolved in acetic acid (7 mL), N-iodosuccinimide (543 mg,2.41 mmol) was added, and the system was stirred at 80℃for 2hr. The reaction solution was cooled to 25℃and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give 2- (4-iodo-2-methylpyrazol-3-yl) -4- (o-tolyl) benzonitrile 18f (400 mg) in 82.8% yield.
MS m/z(ESI):400[M+1]
Fourth step
N- [ [7- [5- [ 2-cyano-5- (o-tolyl) phenyl ] -1-methyl-pyrazol-4-yl ] -4-oxo-3H-phthalazin-1-yl ] methyl ] carbamic acid tert-butyl ester
The compound 2- (4-iodo-2-methylpyrazol-3-yl) -4- (o-tolyl) benzonitrile 18f (100 mg,0.25 mmol) and [4- [ (tert-butoxycarbonylamino) methyl ] -1-oxo-2H-phthalic acid-6-yl ] boronic acid 18G (ref. J. Med. Chem.2022,65,1749-1766 "were synthesized by dissolving 96mg,0.30 mmol) in 1, 4-dioxane (5 mL), cesium fluoride (228 mg,1.50 mmol), potassium phosphate (160 mg,0.75 mmol) and cataCXium-A-Pd-G3 (36 mg,0.05 mmol) were added and the system was stirred under microwave conditions at 85℃for 1hr. The reaction solution was cooled to 25℃and concentrated under reduced pressure, water (20 mL) was added to the concentrated residue, which was extracted with ethyl acetate (3X 30 mL), and the organic phases were combined, washed with saturated brine (2X 30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give tert-butyl N- [ [7- [5- [ 2-cyano-5- (o-tolyl) phenyl ] -1-methyl-pyrazol-4-yl ] -4-oxo-3H-phthalazin-1-yl ] methyl ] carbamate (117 mg), yield: 85.3%.
MS m/z(ESI):548[M+1]
Fifth step
2- [4- [4- (Aminomethyl) -1-oxo-2H-phthalazin-6-yl ] -2-methylpyrazol-3-yl ] -4- (o-tolyl) benzonitrile
The compound tert-butyl N- [ [7- [5- [ 2-cyano-5- (o-tolyl) phenyl ] -1-methyl-pyrazol-4-yl ] -4-oxo-3H-phthalazin-1-yl ] methyl ] carbamate (175.1 mg, 320.33. Mu. Mol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (37 mg,0.32 mmol) was added, and the system was stirred at 25℃for 1hr. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by reverse phase chromatography with eluent system D to give 2- [4- [4- (aminomethyl) -1-oxo-2H-phthalazin-6-yl ] -2-methylpyrazol-3-yl ] -4- (o-tolyl) benzonitrile 18 (30 mg), yield: 21.0%.
MS m/z(ESI):447[M+1]
1H NMR(400MHz,DMSO)δ12.86(s,1H),8.29(s,2H),8.13(dd,3H),7.79-7.71(m,3H),7.49(dd,1H),7.37-7.30(m,4H),4.26(d,2H),3.80(s,3H),2.20(s,3H).
Synthesis of the following example reference example 18
Example 40
1'- (4- (Aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -7-cyclopropoxy-spiro [ indoline-3, 3' -pyrrol ] -2-one
First step
3- ((2, 6-Dibromobenzene) carbamoyl) pyrrole-1-carboxylic acid tert-butyl ester
1- (Tert-Butoxycarbonyl) pyrrole-3-carboxylic acid 40a (3 g,13.95 mmol) and 2, 6-dibromoaniline 40b (3.48 g,14 mmol) were dispersed in 30mL of dichloromethane, triethylamine (2.02 g,20 mmol) and urea N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) hexafluorophosphate (7.60 g,20 mmol) were added and the reaction stirred at 40℃for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 3- ((2, 6-dibromobenzene) carbamoyl) pyrrole-1-carboxylic acid tert-butyl ester 40c (4.48 g), yield: 72.1%. MS m/z (ESI): 447[ M+1]
Second step
7-Bromo-2-oxospiro [ indoline-3, 3 '-pyrrole ] -1' -carboxylic acid tert-butyl ester
3- ((2, 6-Dibromobenzene) carbamoyl) pyrrole-1-carboxylic acid tert-butyl ester 40c (2 g,4.48 mmol) was dispersed in 30mL 1, 4-dioxane, and dichloro [1, 3-bis (2, 6-di-3-pentylphenyl) imidazol-2-ylidene ] (3-chloropyridinyl) palladium (II) (174 mg,0.22 mmol) and sodium tert-butoxide (576 mg,6 mmol) were added. The reaction was stirred at 100 ℃ for 2 hours under nitrogen atmosphere. The residue obtained was purified by silica gel column chromatography with eluent system B to give the title product, 7-bromo-2-oxospiro [ indoline-3, 3 '-pyrrole ] -1' -carboxylic acid tert-butyl ester 40d (573 mg), yield: 35.1%.
MS m/z(ESI):367[M+1]
Third step
7-Cyclopropoxy-2-oxospiro [ indoline-3, 3 '-pyrrole ] -1' -carboxylic acid tert-butyl ester
7-Bromo-2-oxospiro [ indoline-3, 3 '-pyrrole ] -1' -carboxylic acid tert-butyl ester 40d (573 mg,1.57 mmol) and cyclopropane (116 mg,2 mmol) were dispersed in 20mL tetrahydrofuran, and tetrakis (triphenylphosphine) palladium (92 mg,0.08 mmol) and sodium tert-butoxide (284 mg,4 mmol) were added. The reaction was stirred at 70 ℃ for 16 hours under nitrogen atmosphere. The residue obtained was purified by silica gel column chromatography with eluent system B to give the title product, 7-cyclopropoxy-2-oxospiro [ indoline-3, 3 '-pyrrole ] -1' -carboxylic acid tert-butyl ester 40e (222 mg, yellow solid), yield: 41.1%.
MS m/z(ESI):345[M+1]
Fourth step
7-Cyclopropoxy-spiro [ indoline-3, 3' -pyrrole ] -2-one
The eighth procedure of reference example 3 was followed by 7-cyclopropoxy-2-oxospiro [ indoline-3, 3' -pyrrole ] -1' -carboxylic acid tert-butyl ester 40e (222 mg,0.65 mmol) to give the title product 7-cyclopropoxy-spiro [ indoline-3, 3' -pyrrole ] -2-one 40f (158 mg) in 100% yield.
MS m/z(ESI):245[M+1]
Fifth step ((7- (7-Cyclopropoxy-2-oxospiro [ indoline-3, 3 '-pyrrole ] -1' -yl) -4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) carbamic acid tert-butyl ester
7-Cyclopropoxy-spiro [ indoline-3, 3' -pyrrole ] -2-one 40f (158 mg,0.64 mmol) and tert-butyl ((7-bromo-4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) carbamate 1d (353 mg,1mmol, synthesized using well known methods "patent WO 2021050915A 1") were dispersed in 5mL of tetrahydrofuran, and tetrakis (triphenylphosphine) palladium (34 mg,0.03 mmol) and sodium tert-butoxide (192 mg,2 mmol) were added. The reaction was stirred at 70 ℃ for 16 hours under nitrogen atmosphere. The filtrate was filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product ((7- (7-cyclopropoxy-2-oxospiro [ indolin-3, 3 '-pyrrole ] -1' -yl) -4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) carbamic acid tert-butyl ester 40g (58 mg), yield: 17.8%.
MS m/z(ESI):518[M+1]
The fourth step of the synthesis method of reference example 1 was carried out by ((7- (7-cyclopropyloxy-2-oxospiro [ indolin-3, 3 '-pyrrole ] -1' -yl) -4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) carbamic acid tert-butyl ester 40g (58 mg,0.11 mmol) to give the title product 1'- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -7-cyclopropoxy spiro [ indolin-3, 3' -pyrrole ] -2-one 40 (25 mg) in 53.4% yield.
MS m/z(ESI):418[M+1]
Synthesis of the following example, reference example 40
Example 47
2- (4- (4- (2-Aminocyclopropyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) -4-chloro-6-cyclopropyl-3-fluorobenzonitrile
First step
(2-Hydroxymethyl) cyclopropylcarbamic acid tert-butyl ester
Methyl 2- (tert-butoxycarbonyl) aminocyclopropane-1-carboxylate 47a (2.28 g,9.70 mmol) was dispersed in 25mL of diethyl ether, cooled to 0℃and lithium aluminum hydride (0.55 g,14.55 mmol) was added thereto, and the mixture was allowed to warm to room temperature and stirred for reaction for 1 hour. 5mL of saturated ammonium chloride solution was added to quench, extraction was performed with ethyl acetate (10 mL. Times.3), the organic phases were combined, washed with saturated sodium bicarbonate solution (50 mL), saturated sodium chloride solution (50 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product (2-hydroxymethyl) tert-butyl cyclopropylcarbamate 47B (1.38 g), yield: 76.0%.
MS m/z(ESI):188[M+1]
Second step
(2-Formyl-cyclopropyl) carbamic acid tert-butyl ester
Tert-butyl (2-hydroxymethyl) cyclopropylcarbamate 47b (1.38 g,7.37 mmol) was dispersed in 25mL chloroform, manganese dioxide (1.28 g,14.74 mmol) was added and the reaction stirred at 60℃for 12 hours. The residue obtained was purified by silica gel column chromatography with eluent system B after cooling, filtration and concentration of the filtrate under reduced pressure to give the title product (2-formylcyclopropyl) tert-butyl carbamate 47c (1.08 g) in 79.2% yield.
MS m/z(ESI):186[M+1]
Third step
4-Bromo-2- (hydroxy (2- ((tert-butoxycarbonyl) amino) cyclopropyl) methyl) benzoic acid
2, 4-Dibromobenzoic acid 47d (1.63 g,5.84 mmol) was dissolved in 25mL dry tetrahydrofuran, cooled to-78℃and a 2M solution of n-butyllithium in tetrahydrofuran (8.8 mL,17.6 mmol) was added and the reaction stirred at-78℃for 0.5 h. Tert-butyl (2-formylcyclopropyl) carbamate (1.08 g,5.84 mmol) was then added and the reaction was stirred at 78℃for 0.5 h, followed by natural warming to room temperature and stirring for 12h. 5mL of saturated ammonium chloride solution was added to quench, extraction was performed with ethyl acetate (10 mL. Times.3), the organic phases were combined, washed with saturated sodium bicarbonate solution (50 mL), saturated sodium chloride solution (50 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product, 47e (1.04 g), 46.1% yield.
MS m/z(ESI):386[M+1]
Fourth step
4-Bromo-2- (2- ((tert-butoxycarbonyl) amino) cyclopropane-1-carbonyl) benzoic acid
4-Bromo-2- (hydroxy (2- ((tert-butoxycarbonyl) amino) cyclopropyl) methyl) benzoic acid 47e (1.04 g,2.69 mmol) was dissolved in 20mL dichloromethane, dess-martin oxidant (2.28 g,5.38 mmol) was added and the reaction stirred at 20℃for 12 hours. 5mL of saturated sodium sulfite solution was added to quench, extracted with ethyl acetate (10 mL. Times.3), the organic phases were combined, washed with saturated sodium bicarbonate solution (50 mL), saturated sodium chloride solution (50 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product, 47f (0.58 g), 4-bromo-2- (2- ((tert-butoxycarbonyl) amino) cyclopropane-1-carbonyl) benzoic acid in 56.5% yield.
MS m/z(ESI):384[M+1]
Fifth step
(2- (7-Bromo-4-oxo-3, 4-dihydro-phthalazin-1-yl) cyclopropyl) carbamic acid tert-butyl ester
4-Bromo-2- (2- ((tert-butoxycarbonyl) amino) cyclopropane-1-carbonyl) benzoic acid 47f (0.58 g,1.52 mmol) was dissolved in 20mL ethanol, 80% hydrazine hydrate (313. Mu.L, 7.60 mmol) was added and the reaction was stirred at 78℃for 12 hours. The reaction solution was cooled, filtered and dried to give 47g (0.42 g) of the title product (tert-butyl 2- (7-bromo-4-oxo-3, 4-dihydro-phthalazin-1-yl) cyclopropyl) carbamate in a yield of 72.0%.
MS m/z(ESI):380[M+1]
Sixth step
(2- (4-Oxo-7- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -3, 4-dihydro-phthalazin-1-yl) cyclopropyl) carbamic acid tert-butyl ester
47G (0.42 g,1.09 mmol) of tert-butyl (2- (7-bromo-4-oxo-3, 4-dihydro-phthalazin-1-yl) cyclopropyl) carbamate, pinacol ester of biboronic acid (416 mg,1.64 mmol), a complex of { 1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride } dichloromethane (89 mg,0.11 mmol) and potassium acetate (321 mg,3.27 mmol) were dissolved in 20mL dioxane and replaced with a nitrogen atmosphere, and the reaction was stirred at 100℃for 2 hours. The resulting residue was purified by silica gel column chromatography with eluent system B to give the title product (tert-butyl 2- (4-oxo-7- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -3, 4-dihydrophthalazin-1-yl) cyclopropyl) carbamate 47h (258 mg) in 55.3% yield.
MS m/z(ESI):428[M+1]
Seventh step
(2- (7- (5- (3-Chloro-6-cyano-5-cyclopropyl-2-fluorophenyl) -1-methyl-1H-pyrazol-4-yl) -4-oxo-3, 4-dihydro-phthalazin-1-yl) cyclopropyl) carbamic acid tert-butyl ester
Tert-butyl (2- (4-oxo-7- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -3, 4-dihydropyrazin-1-yl) cyclopropyl) carbamate 47H (258 mg,0.60 mmol), 2- (4-iodo-1-methyl-1H-pyrazol-5-yl) -4-chloro-6-cyclopropyl-3-fluorobenzonitrile 47i (667 mg,1.80mmol, obtained by synthesis using well known method "patent WO 22022192745"), SPhos-Pd-G2 (86.4 mg,0.12 mmol) and cesium carbonate (58 mg,1.80 mmol) were dissolved in a mixed solvent of 5mL dioxane and 1mL water, replaced with a nitrogen atmosphere, and the reaction was stirred at 90℃for 3H. The reaction solution was cooled, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product (tert-butyl 2- (7- (5- (3-chloro-6-cyano-5-cyclopropyl-2-fluorophenyl) -1-methyl-1H-pyrazol-4-yl) -4-oxo-3, 4-dihydro-phthalazin-1-yl) cyclopropyl) carbamate 47j (177 mg) in 50.0% yield.
MS m/z(ESI):591[M+1]
Eighth step
2- (4- (4- (2-Aminocyclopropyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) -4-chloro-6-cyclopropyl-3-fluorobenzonitrile
Tert-butyl (2- (7- (5- (3-chloro-6-cyano-5-cyclopropyl-2-fluorophenyl) -1-methyl-1H-pyrazol-4-yl) -4-oxo-3, 4-dihydro-phthalazin-1-yl) cyclopropyl) carbamate 47j (177 mg,0.30 mmol) was dissolved in 10mL acetonitrile, and ceric ammonium nitrate (159 mg,0.60 mmol) was added. Quench by adding 5mL of saturated sodium sulfite solution, extract with ethyl acetate (10 mL. Times.3), combine the organic phases, wash with saturated sodium bicarbonate solution (50 mL), saturated sodium chloride solution (50 mL. Times.2), dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, purify the resulting residue by silica gel column chromatography on eluent system A to give the title product 2- (4- (4- (2-aminocyclopropyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) -4-chloro-6-cyclopropyl-3-fluorobenzonitrile 47 (41 mg, white solid), yield 28.0%.
MS m/z(ESI):491[M+1]
Example 55
2- (4- (4-Aminomethyl-1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) -4-chloro-3-fluoro-6- (tetrahydro-2H-pyran-2-yl) benzonitrile
First step
4-Chloro-2- (3, 4-dihydro-2H-pyran-2-yl) -5-fluorobenzonitrile
2-Bromo-4-chloro-5-fluorobenzonitrile 55a (2.33 g,10.00mmol, synthesized using well-known method "patent US 2017291892"), palladium acetate (166 mg,1.00 mmol), triethylamine (2.02 g,20.00 mmol) were dissolved in 50mL of N, N-dimethylformamide and reacted at 140℃with stirring for 6 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product, 4-chloro-2- (3, 4-dihydro-2H-pyran-2-yl) -5-fluorobenzonitrile 55B (2.12 g), yield: 89.2%.
MS m/z(ESI):238[M+1]
Second step
4-Chloro-2- (tetrahydro-2H-pyran-2-yl) -5-fluorobenzonitrile
4-Chloro-2- (3, 4-dihydro-2H-pyran-2-yl) -5-fluorobenzonitrile 55b (2.12 g,8.92 mmol) and 10% palladium on charcoal (212 mg) were dispersed in 50mL of methanol, replaced with a hydrogen atmosphere, and reacted at room temperature with stirring for 12 hours. The reaction solution was filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product, 4-chloro-2- (tetrahydro-2H-pyran-2-yl) -5-fluorobenzonitrile 55c (2.09 g), yield: 97.8%.
MS m/z(ESI):240[M+1]
Third step
2-Bromo-4-chloro-3-fluoro-6- (tetrahydro-2H-pyran-2-yl) benzonitrile
4-Chloro-2- (tetrahydro-2H-pyran-2-yl) -5-fluorobenzonitrile 55C (2.09 g,8.72 mmol), N-bromosuccinimide (3.10 g,17.44 mmol), palladium acetate (144 mg,0.87 mmol) and p-toluene sulfonic acid (751mg, 4.36 mmol) were dispersed in 50mL of 1, 2-dichloroethane and reacted at 75℃with stirring under heating for 12 hours. The reaction solution was cooled to room temperature, 20mL of water was added, the organic phases were combined, washed with dichloromethane (20 mL. Times.3), washed with saturated sodium hydrogen carbonate solution (20 mL. Times.1), saturated sodium chloride solution (20 mL. Times.1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product, 2-bromo-4-chloro-3-fluoro-6- (tetrahydro-2H-pyran-2-yl) benzonitrile 55d (1.21 g), yield: 43.6%.
MS m/z(ESI):319[M+1]
Fourth step
4-Chloro-3-fluoro-2- (1-methyl-1H-pyrazol-5-yl) -6- (tetrahydro-2H-pyran-2-yl) benzonitrile
2-Bromo-4-chloro-3-fluoro-6- (tetrahydro-2H-pyran-2-yl) benzonitrile 55d (1.21 g,3.80 mmol), 1-methyl-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole 55e (3.65 g,11.40 mmol), sodium carbonate (1.61 g,15.20 mmol) and Pd (dtbpf) Cl 2 (245 mg,0.38 mmol) were dispersed in a mixed solvent of 25mL dioxane and 5mL water, and the mixture was heated and stirred at 80℃for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product, 4-chloro-3-fluoro-2- (1-methyl-1H-pyrazol-5-yl) -6- (tetrahydro-2H-pyran-2-yl) benzonitrile 55f (551 mg), yield: 45.2%.
MS m/z(ESI):320[M+1]
Fifth step
4-Chloro-3-fluoro-2- (4-iodo-1-methyl-1H-pyrazol-5-yl) -6- (tetrahydro-2H-pyran-2-yl) benzonitrile
4-Chloro-3-fluoro-2- (1-methyl-1H-pyrazol-5-yl) -6- (tetrahydro-2H-pyran-2-yl) benzonitrile 55f (553mg, 1.72 mmol) was dissolved in 20mL of acetonitrile, and N-iodosuccinimide (2.32 g,10.32 mmol) was added thereto, and the reaction was heated and stirred at 80℃for 16 hours. The reaction solution was cooled to room temperature, 20mL of water was added, the organic phases were combined, washed with a saturated sodium chloride solution (20 mL. Times.3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give 55g (481 mg) of the title product 4-chloro-3-fluoro-2- (4-iodo-1-methyl-1H-pyrazol-5-yl) -6- (tetrahydro-2H-pyran-2-yl) benzonitrile in a yield of 62.8%.
MS m/z(ESI):446[M+1]
Sixth step ((7- (5- (3-chloro-6-cyano-2-fluoro-5- (tetrahydro-2H-pyran-2-yl) phenyl) -1-methyl-1H-pyrazol-4-yl) -4-oxo-3, 4-dihydropyrazin-1-yl) methyl) carbamic acid tert-butyl ester
55G (481mg, 1.08 mmol) of 4-chloro-3-fluoro-2- (4-iodo-1-methyl-1H-pyrazol-5-yl) -6- (tetrahydro-2H-pyran-2-yl) benzonitrile, sodium carbonate (284 mg,2.70 mmol), pd (dppf) Cl 2 (80 mg,0.11 mmol) were dissolved in a mixed solvent of 5mL of 1, 4-dioxane and 1mL of water, and the mixture was heated at 80℃to react for 3 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product ((tert-butyl 7- (5- (3-chloro-6-cyano-2-fluoro-5- (tetrahydro-2H-pyran-2-yl) phenyl) -1-methyl-1H-pyrazol-4-yl) -4-oxo-3, 4-dihydropyrazin-1-yl) methyl) carbamate 55H (260 mg) in 40.6% yield.
MS m/z(ESI):593[M+1]
Seventh step
2- (4- (4-Aminomethyl-1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) -4-chloro-3-fluoro-6- (tetrahydro-2H-pyran-2-yl) benzonitrile
Tert-butyl ((7- (5- (3-chloro-6-cyano-2-fluoro-5- (tetrahydro-2H-pyran-2-yl) phenyl) -1-methyl-1H-pyrazol-4-yl) -4-oxo-3, 4-dihydropyrazin-1-yl) methyl) carbamate 55H (260 mg,0.44 mmol) was dissolved in 5mL of 1, 4-dioxane, 5mL of 4M dioxane hydrochloride was added, and the reaction was carried out at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 2- (4- (4-aminomethyl-1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) -4-chloro-3-fluoro-6- (tetrahydro-2H-pyran-2-yl) benzonitrile 55 (152 mg) in a yield of 70.1%.
MS m/z(ESI):493[M+1]
Synthesis of the following example reference example 55.
Example 63
2- (4- (4- (Aminomethyl) -1-carbonyl-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) -4-chloro-6- ((dimethyl (carbonyl) -lambda 6 -sulfanylidene) amino) -3-fluorobenzonitrile
First step
2-Bromo-5-chloro-4-fluorophenol
3-Chloro-4-fluorophenol 63a (10 g,68.24 mmol) was dissolved in 50ml chloroform followed by the addition of bromine water (10.90 g,68.24 mmol) and the reaction stirred at 20℃for 12 hours. The reaction solution was cooled, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system A to give 63b (12 g) of 2-bromo-5-chloro-4-fluorophenol in a yield of 78.0%.
MS m/z(ESI):225[M+1]
Second step
1-Bromo-4-chloro-5-fluoro-2-methoxybenzene
2-Bromo-5-chloro-4-fluorophenol 63b (12 g,53.23 mmol) and cesium carbonate (17 g,52.18 mmol) were dissolved in 100mL of N, N-dimethylformamide, followed by addition of methyl iodide (7.70 g,54.25 mmol) and reaction stirred at 20℃for 2 hours. The reaction solution was cooled, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system A to give 1-bromo-4-chloro-5-fluoro-2-methoxybenzene 63c (10 g), yield: 78.4%.
MS m/z(ESI):239[M+1]
Third step
4-Chloro-5-fluoro-2-methoxybenzonitrile
1-Bromo-4-chloro-5-fluoro-2-methoxybenzene 63C (10 g,41.76 mmol), zinc cyanide (2.5 g,21.29 mmol), and palladium tetraphenylphosphine (4.8 g,4.15 mmol) were dissolved in 100mL of N, N-dimethylformamide, and reacted at 100℃with stirring for 12 hours. The reaction solution was cooled, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system A to give 63d (5 g) of 4-chloro-5-fluoro-2-methoxybenzonitrile in a yield of 64.5%.
MS m/z(ESI):186[M+1]
Fourth step
4-Chloro-3-fluoro-2-iodo-6-methoxybenzonitrile
4-Chloro-5-fluoro-2-methoxybenzonitrile 63d (5 g,26.94 mmol) was dissolved in 50mL of tetrahydrofuran solvent and subsequently condensed to-60 ℃. LDA in tetrahydrofuran (13.5 ml,27mmol, 2M) was added at-60℃and reacted at this temperature for 2 hours, iodine was added, and then the reaction was stirred at 20℃for 2 hours. The reaction solution was cooled, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system A to give 4-chloro-3-fluoro-2-iodo-6-methoxybenzonitrile 63e (5.5 g), yield: 65.5%.
MS m/z(ESI):312[M+1]
Fifth step
4-Chloro-3-fluoro-6-methoxy-2- (1-methyl-1H-pyrazol-5-yl) benzonitrile
4-Chloro-3-fluoro-2-iodo-6-methoxybenzonitrile 63e (5.50 g,17.66 mmol), 1-methyl-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (3.74 g,18.0 mmol), [1,1' -bis (di-t-butylphosphino) ferrocene ] palladium dichloride (1.1 g,1.70 mmol) and potassium carbonate (9.76 g,70.62 mmol) were dissolved in a mixed solvent of 50mL dioxane and 10mL water, and reacted at 80℃for 12 hours with stirring. The reaction mixture was cooled, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give 4-chloro-3-fluoro-6-methoxy-2- (1-methyl-1H-pyrazol-5-yl) benzonitrile 63f (1.5 g), yield: 32.0%.
MS m/z(ESI):266[M+1]
Sixth step
4-Chloro-3-fluoro-6-hydroxy-2- (1-methyl-1H-pyrazol-5-yl) benzonitrile
4-Chloro-3-fluoro-6-methoxy-2- (1-methyl-1H-pyrazol-5-yl) benzonitrile 63f (1.5 g,5.64 mmol) was dissolved in 50ml of boron tribromide dichloromethane (1M) and reacted at 50℃for 12 hours with stirring. The reaction solution was cooled, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system A to give 63g (900 mg) of 4-chloro-3-fluoro-6-hydroxy-2- (1-methyl-1H-pyrazol-5-yl) benzonitrile in 63.3% yield.
MS m/z(ESI):252[M+1]
Seventh step
5-Chloro-2-cyano-4-fluoro-3- (1-methyl-1H-pyrazol-5-yl) phenyl triflic acid
63G (900 mg,3.58 mmol) of 4-chloro-3-fluoro-6-hydroxy-2- (1-methyl-1H-pyrazol-5-yl) benzonitrile, triethylamine (44 mg,0.12 mmol) and trifluoromethanesulfonic anhydride (7.3 mg,4.3 mmol) were dissolved in 10mL of dichloromethane solvent, and the reaction was stirred at 20℃for 2 hours. The reaction mixture was cooled, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system A to give 63H (1 g) of 5-chloro-2-cyano-4-fluoro-3- (1-methyl-1H-pyrazol-5-yl) phenyltrifluoromethanesulfonic acid in a yield of 72.9%.
MS m/z(ESI):384[M+1]
Eighth step
4-Chloro-6- ((dimethyl (carbonyl) -l 6-sulfanylidene) amino) -3-fluoro-2- (1-methyl-1H-pyrazol-5-yl) benzonitrile
5-Chloro-2-cyano-4-fluoro-3- (1-methyl-1H-pyrazol-5-yl) phenyl triflic acid 63H (300 mg,0.78 mmol), dimethyl sulfimide (146 mg,1.567 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (90 mg,0.16 mmol), tris (dibenzylideneacetone) dipalladium (72 mg,0.079 mmol) and cesium carbonate (510 mg,1.56 mmol) were dissolved in 10mL dioxane solvent and reacted at 100℃with stirring for 12 hours. The reaction solution was cooled, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give 4-chloro-6- ((dimethyl (carbonyl) -l 6-sulfanylidene) amino) -3-fluoro-2- (1-methyl-1H-pyrazol-5-yl) benzonitrile 63i (150 mg), yield: 58.7%.
MS m/z(ESI):327[M+1]
Ninth step
2- (4-Bromo-1-methyl-1H-pyrazol-5-yl) -4-chloro-6- ((dimethyl (carbonyl) -lambda 6 -sulfanylidene) amino) -3-fluorobenzonitrile
4-Chloro-6- ((dimethyl (carbonyl) -l 6-sulfanylidene) amino) -3-fluoro-2- (1-methyl-1H-pyrazol-5-yl) benzonitrile 63i (150 mg,0.46 mmol), N-bromosuccinimide (90 mg,0.51 mmol) were dissolved in 10mL acetonitrile and reacted at 20℃for 12 hours with stirring. The reaction solution was cooled, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give 2- (4-bromo-1-methyl-1H-pyrazol-5-yl) -4-chloro-6- ((dimethyl (carbonyl) - λ 6 -sulfanylidene) amino) -3-fluorobenzonitrile 63j (90 mg), yield: 48.3%.
MS m/z(ESI):405[M+1]
Tenth step
((7- (5- (3-Chloro-6-cyano-5- ((dimethyl (carbonyl) -lambda 6 -sulfanylidene) amino) -2-fluorophenyl) -1-methyl-1H-pyrazol-4-yl) -4-carbonyl-3, 4-dihydro-phthalazin-1-yl) methyl) carbamic acid tert-butyl ester
Tert-butyl 2- (4-bromo-1-methyl-1H-pyrazol-5-yl) -4-chloro-6- ((dimethyl (carbonyl) -lambda 6 -sulfanylidene) amino) -3-fluorobenzonitrile 63j (90 mg,0.22 mmol), ((4-carbonyl-7- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 4-dihydropyrazin-1-yl) methyl) carbamate (120 mg,0.30mmol, synthesized using well known methods "patent WO 22022192745"), [1,1' -bis (di-tert-butylphosphino) ferrocene ] palladium dichloride (15 mg,0.023 mmol) and sodium carbonate (95 mg,0.90 mmol) were dissolved in a mixed solvent of 5mL dioxane and 1mL water and reacted for 1 hour with stirring at 80 ℃. The reaction solution was cooled, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system a to give tert-butyl ((7- (5- (3-chloro-6-cyano-5- ((dimethyl (carbonyl) - λ 6 -sulfanylidene) amino) -2-fluorophenyl) -1-methyl-1H-pyrazol-4-yl) -4-carbonyl-3, 4-dihydropyrazin-1-yl) methyl) carbamate 63k (68 mg) in a yield of 51.5%.
MS m/z(ESI):601[M+1]
Eleventh step
2- (4- (4- (Aminomethyl) -1-carbonyl-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) -4-chloro-6- ((dimethyl (carbonyl) -lambda 6 -sulfanylidene) amino) -3-fluorobenzonitrile
Tert-butyl ((7- (5- (3-chloro-6-cyano-5- ((dimethyl (carbonyl) - λ 6 -sulfanylidene) amino) -2-fluorophenyl) -1-methyl-1H-pyrazol-4-yl) -4-carbonyl-3, 4-dihydro-phthalazin-1-yl) methyl) carbamate 63k (45 mg,0.075 mmol), 0.2mL trifluoroacetic acid were dissolved in 5mL dichloromethane and the reaction was stirred at 20 ℃ for 2 hours. The reaction solution was cooled, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system a to give 2- (4- (4- (aminomethyl) -1-carbonyl-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) -4-chloro-6- ((dimethyl (carbonyl) - λ 6 -sulfanylidene) amino) -3-fluorobenzonitrile (9 mg), yield: 24.0%.
MS m/z(ESI):500[M+1]
1H NMR(400MHz,MeOD)δ8.43(s,1H),8.29(d,1H),8.08(s,1H),7.72(s,1H),7.68-7.58(m,1H),4.17(s,2H),3.83(s,3H),1.32(d,6H).
Example 64
2- (4- (4- (Aminomethyl) -1-carbonyl-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) -4-chloro-3-fluoro-6- (pyrrolidin-1-yl) benzonitrile
First step
4-Chloro-5-fluoro-2- (pyrrolidin-1-yl) benzonitrile
4-Chloro-2, 5-difluorobenzonitrile 64a (5 g,28.81 mmol) and pyrrolidine (2.2 g,30.93 mmol) were dissolved in 50mL acetonitrile and reacted for 2 hours at 80 ℃. The reaction solution was cooled, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system A to give 4-chloro-5-fluoro-2- (pyrrolidin-1-yl) benzonitrile 64b (4.6 g) in a yield of 71.0%.
MS m/z(ESI):225[M+1]
With reference to the fourth to fifth and ninth to eleventh steps of example 63 in sequence, through 4-chloro-5-fluoro-2- (pyrrolidin-1-yl) benzonitrile 64b (4.6 g,20.48 mmol), 2- (4- (4- (aminomethyl) -1-carbonyl-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) -4-chloro-3-fluoro-6- (pyrrolidin-1-yl) benzonitrile 64 (15 mg) was obtained in a yield of 0.2%.
MS m/z(ESI):478[M+1]
1H NMR(400MHz,MeOD)δ8.48(d,1H),8.17(s,1H),8.08(d,1H),7.61(d,1H),7.12(d,1H),4.26(s,2H),3.83(s,3H),3.69(s,4H),2.13-1.89(m,4H).
Example 73
4- (Aminomethyl) -6- (5- (benzo [ c ] [1,2,5] oxadiazol-5-yl) -1-methyl-1H-pyrazol-4-yl) phthalazin-1 (2H) -one
The synthesis of the first to fifth steps of reference example 20 gave the title product 4- (aminomethyl) -6- (5- (benzo [ c ] [1,2,5] oxadiazol-4-yl) -1-methyl-1H-pyrazol-4-yl) phthalazin-1 (2H) -one 73 (23 mg) in 4.8% yield by 5-bromobenzo [ c ] [1,2,5] oxadiazol 73a (250 mg,1.26 mmol).
MS m/z(ESI):373[M+1]
1H NMR(400MHz,DMSO)δ12.48(s,1H),8.32(dd,1H),8.28(s,1H),8.10(d,1H),7.91-7.79(m,3H),7.69(dd,1H),3.86(s,3H),3.77(s,2H).
Example 76
2- (4- (4- (Aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) -4- (1H-pyrazol-1-yl) benzonitrile
First step
2-Bromo-4- (1H-pyrazol-1-yl) benzonitrile
2-Bromo-4-iodobenzonitrile 76a (1.85 g,6 mmol), 1H-pyrazole (247 mg,1.26 mmol), (1R, 2R) -N 1,N2 -dimethylcyclohexane-1, 2-diamine (416 mg,2.40 mmol) and cuprous iodide (228 mg,1.20 mmol) were dispersed in 20mL DMF and reacted at 120℃with stirring for 16H. Cooled to room temperature, the system was concentrated to dryness and the resulting residue was purified by silica gel column chromatography with eluent system a to give the title product 2-bromo-4- (1H-pyrazol-1-yl) benzonitrile 76b (420 mg), yield 28.2%.
MS m/z(ESI):249[M+1]
Second step
2- (4-Bromo-1-methyl-1H-pyrazol-5-yl) -4- (1H-pyrazol-1-yl) benzonitrile
4-Bromo-1-methyl-pyrazole (314.11 mg,1.95 mmol), 2-bromo-4- (1H-pyrazol-1-yl) benzonitrile 76b (550 mg,2.22 mmol), tricyclohexylphosphine fluoroborate (163 mg, 443.41. Mu. Mol) and palladium acetate (50 mg,0.22 mmol) were dispersed in 20mL of DMF and reacted at 140℃for 2 hours. The mixture was cooled to room temperature, the system was concentrated to dryness, and the resulting residue was purified by silica gel column chromatography with eluent system a to give the title product 2- (4-bromo-1-methyl-1H-pyrazol-5-yl) -4- (1H-pyrazol-1-yl) benzonitrile 76c (53 mg), yield 7.3%.
MS m/z(ESI):328[M+1]
Third step ((7- (5- (2-cyano-5- (1H-pyrazol-1-yl) phenyl) -1-methyl-1H-pyrazol-4-yl) -4-oxo-3, 4-dihydro-phthalazin-1-yl) carbamic acid tert-butyl ester
2- (4-Bromo-1-methyl-1H-pyrazol-5-yl) -4- (1H-pyrazol-1-yl) benzonitrile 76C (33 mg,0.10 mmol), N- [ [ 4-oxo-7- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3H-phthalazin-1-yl ] methyl ] carbamic acid tert-butyl ester (44 mg,0.11 mmol), potassium phosphate (64 mg,0.30 mmol) and cataCXium-A-Pd-G3 (10 mg,0.01 mmol) were dispersed in a mixed solvent of 1mL water and 5mL dioxane and reacted at 80℃for 1H. The reaction mixture was cooled to room temperature, the system was concentrated to dryness, and the resulting residue was purified by silica gel column chromatography with eluent system a to give the title product ((tert-butyl 7- (5- (2-cyano-5- (1H-pyrazol-1-yl) phenyl) -1-methyl-1H-pyrazol-4-yl) -4-oxo-3, 4-dihydro-phthalazin-1-yl) carbamate 76d (20 mg) in 38.3% yield.
MS m/z(ESI):524[M+1]
The fourth step of reference example 1 was performed by using ((7- (5- (2-cyano-5- (1H-pyrazol-1-yl) phenyl) -1-methyl-1H-pyrazol-4-yl) -4-oxo-3, 4-dihydro-phthalazin-1-yl) carbamic acid tert-butyl ester 76d (63 mg,0.12 mmol) to give the title product 2- (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) -4- (1H-pyrazol-1-yl) benzonitrile 76 (2.6 mg) in 5.1% yield.
MS m/z(ESI):423[M+1]
1H NMR(400MHz,DMSO-d6)δ12.40(s,1H),8.78(d,1H),8.33-8.23(m,3H),8.19(d,1H),8.11(d,1H),7.89(d,1H),7.74(d,1H),7.68(dd,1H),6.66(t,1H),3.79(s,3H),3.69(s,2H).
Example 77
3- (4- (4- (Aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) -5-cyclopropyl-2 '-methyl- [1,1' -biphenyl ] -4-carbonitrile
First step
4-Bromo-2-chloro-6-cyclopropoxy-benzonitrile
Cyclopropyl alcohol (139 mg,2.40 mmol) was dissolved in 20mL tetrahydrofuran, sodium cyanide (96 mg,4 mmol) was added at 0deg.C and the reaction stirred at 0deg.C for 1h. 4-bromo-2-chloro-6-fluorobenzonitrile 77a (469 mg,2 mmol) was then added and the reaction stirred at 60℃for 12h. Cooled to room temperature, quenched by the sequential addition of methanol (5 mL) and 0.5M dilute hydrochloric acid (5 mL), concentrated to dryness, and the resulting residue purified by silica gel column chromatography with eluent system A to give the title product 4-bromo-2-chloro-6-cyclopropoxybenzonitrile 77b (330 mg), yield: 70.4%.
MS m/z(ESI):272[M+1]
The synthesis of the first to fifth steps of reference example 18 gave the title product 3- (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) -5-cyclopropyl-2 '-methyl- [1,1' -biphenyl ] -4-carbonitrile 77 (12 mg) in 2.3% yield by 4-bromo-2-chloro-6-cyclopropoxybenzonitrile 77b (282 mg,1.03 mmol).
MS m/z(ESI):503[M+1]
1H NMR(400MHz,DMSO-d6)δ12.88(s,1H),8.34(t,2H),8.26(s,1H),8.13(d,1H),7.78(d,1H),7.63(d,1H),7.49(dd,1H),7.43-7.29(m,4H),7.26(d,1H),4.33(s,2H),4.25-4.15(m,1H),3.79(s,3H),2.24(s,3H),0.97-0.77(m,4H).
Example 86
3- (4- (4- (Aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) -4-chloro-3-fluoro-6- (4-azaspiro [2.4] heptane-4-yl) benzonitrile
The synthesis of the second to third steps of reference example 18 gave, by 2-bromo-4-chloro-3, 6-difluorobenzonitrile 86a (1.56 g,6.18mmol, synthesized by the well-known method "patent WO 22022192745"), the product 4-chloro-3, 6-difluoro-2- (4-iodo-1-methyl-1H-pyrazol-5-yl) benzonitrile 86c (300 mg), in 12.8% yield.
MS m/z(ESI):380[M+1]
Third step
4-Chloro-3-fluoro-2- (4-iodo-1-methyl-1H-pyrazol-5-yl) -6- (4-azaspiro [2.4] heptan-4-yl) benzonitrile
4-Azaspiro [2.4] heptane hydrochloride (147 mg,1.10 mmol), 4-chloro-3, 6-difluoro-2- (4-iodo-1-methyl-1H-pyrazol-5-yl) benzonitrile 86C (190 mg,0.50 mmol) and 1, 8-diazabicyclo [5.4.0] undec-7-ene (224 μl,1.50 mmol) were dissolved in 5mL of acetonitrile and reacted at 80℃with stirring for 16H. The mixture was cooled to room temperature, the system was concentrated to dryness, and the resulting residue was purified by silica gel column chromatography with eluent system a to give the title product 4-chloro-3-fluoro-2- (4-iodo-1-methyl-1H-pyrazol-5-yl) -6- (4-azaspiro [2.4] heptan-4-yl) benzonitrile 86d (60 mg), yield: 26.2%.
MS m/z(ESI):457[M+1]
The synthesis of the fourth to fifth steps of reference example 18 gave the title product 3- (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) -4-chloro-3-fluoro-6- (4-azaspiro [2.4] heptan-4-yl) benzonitrile 86 (9.5 mg), yield 14.4% by the synthesis of 4-chloro-3-fluoro-2- (4-iodo-1-methyl-1H-pyrazol-5-yl) -6- (4-azaspiro [2.4] heptan-4-yl) benzonitrile 86d (60 mg,0.13 mmol).
MS m/z(ESI):504[M+1]
1H NMR(400MHz,DMSO-d6)δ12.40(broad s,1H),8.27(d,J＝2.7Hz,1H),8.8.18(d,1H),8.11(d,1H),7.74(d,1H),7.43(d,1H),4.29(qd,1H),3.78(d,3H),3.75-3.69(m,2H),3.56-3.44(m,1H),2.08-1.79(m,4H),0.99-0.69(m,4H).
Example 88
2- (4- (4- (Aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) -4-chloro-6- (3- (difluoromethylene) pyrrolidin-1-yl) -3-fluorobenzonitrile
The synthesis of the third to fifth steps of reference example 86 gave the title product 2- (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) -4-chloro-6- (3- (difluoromethylene) pyrrolidin-1-yl) -3-fluorobenzonitrile 88 (16 mg) in 5.9% yield by the synthesis of 4-chloro-3, 6-difluoro-2- (4-iodo-1-methyl-1H-pyrazol-5-yl) benzonitrile 86c (190 mg,0.50 mmol).
MS m/z(ESI):526[M+1]
1H NMR(400MHz,DMSO-d6)δ12.88(s,1H),8.36(s,2H),8.35(s,1H),8.16(d,1H),7.87(s,1H),7.52(d,1H),7.43(d,1H),4.35(d,4H),3.78(s,3H),3.74(t,J＝7.6Hz,2H),2.71(s,2H).
Example 90
2- (4- (4- (Aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) -4-chloro-6- (3, 3- (difluoropyrrolidin-1-yl) -3-fluorobenzonitrile
The synthesis of the third to fifth steps of reference example 86 gave the title product 2- (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) -4-chloro-6- (3, 3- (difluoropyrrolidin-1-yl) -3-fluorobenzonitrile 90 (14 mg) in 5.2% yield by the synthesis of 4-chloro-3, 6-difluoro-2- (4-iodo-1-methyl-1H-pyrazol-5-yl) benzonitrile 86c (190 mg,0.50 mmol).
MS m/z(ESI):514[M+1]
1H NMR(400MHz,DMSO-d6)δ12.87(s,1H),8.67(s,2H),8.41(s,1H),8.16(d,1H),7.84(d,1H),7.55(d,1H),7.42(d,1H),4.35(d,4H),3.78(s,3H),3.74(t,2H),2.71(s,2H).
Example 95
2- (4- (4- (Aminomethyl) -1-oxo-1, 2-dihydro-phthalic acid-6-yl) -1-methyl-1H-pyrazol-5-yl) -4-chloro-6- (4- (difluoromethylene) piperidin-1-yl) -3-fluorobenzonitrile
The synthesis of the third to fifth steps of reference example 86 gave 2- (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalic acid-6-yl) -1-methyl-1H-pyrazol-5-yl) -4-chloro-6- (4- (difluoromethylene) piperidin-1-yl) -3-fluorobenzonitrile 95 (3 mg) in 0.6% yield by the synthesis of 4-chloro-3, 6-difluoro-2- (4-iodo-1H-pyrazol-5-yl) benzonitrile 86c (0.30 g,0.79 mmol) and 4- (difluoromethylene) piperidine (105 mg,0.79mmol, reference "J.org. chem.2022,87, 16676-16690").
MS m/z(ESI):540[M+1]
1H NMR(400MHz,DMSO-d6)δ12.44(s,1H),8.23(s,1H),8.09(d,1H),7.75-7.51(m,4H),3.75(d,5H),3.11(dq,4H),2.22(s,4H).
Example 98
2- (4- (4- (Aminomethyl) -1-oxo-1, 2-dihydro-phthalic acid-6-yl) -1-methyl-1H-pyrazol-5-yl) -4-chloro-3-fluoro-6- (4, 4-trifluorobutoxy) benzonitrile
First step
4-Chloro-5-fluoro-2- (4, 4-trifluorobutoxy) benzonitrile
Sodium hydride (645.36 mg,16.13mmol,60% purity) was dispersed in tetrahydrofuran (10 mL), 4-trifluorobutan-1-ol (1.77 g,13.83 mmol) was slowly added, stirred at 25℃for 30 minutes, a solution of 4-chloro-2, 5-difluorobenzonitrile 98a (2 g,11.52 mmol) in tetrahydrofuran (20 mL) was slowly added, and the reaction stirred at 60℃for 12 hours. To the reaction solution was added water (50 mL), which was quenched, extracted with ethyl acetate (3X 100 mL), and the organic phases were combined, washed with saturated brine (3X 100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give 4-chloro-5-fluoro-2- (4, 4-trifluorobutoxy) benzonitrile 98b (2.4 g), yield: 74.0%.
MS m/z(ESI):282[M+1]
Second step
4-Chloro-3-fluoro-2-iodo-6- (4, 4-trifluorobutoxy) benzonitrile
The compound 4-chloro-5-fluoro-2- (4, 4-trifluorobutoxy) benzonitrile 98b (1 g,3.55 mmol) was dissolved in tetrahydrofuran (10 mL), the reaction system was cooled to-78℃and lithium diisopropylamide solution (2M, 2.66 mL) was added, nitrogen was replaced 3 times, stirring was carried out at-78℃for 30 minutes, and a solution of iodine (1.08 g,4.26 mmol) in tetrahydrofuran (10 mL) was added dropwise at-78℃followed by natural warming to room temperature and stirring for 16 hours. To the reaction solution was added water (50 mL), which was quenched, extracted with ethyl acetate (3×80 mL), and the organic phases were combined, washed with saturated brine (3×80 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with an eluent (petroleum ether: tetrahydrofuran=10:1) to give 4-chloro-3-fluoro-2-iodo-6- (4, 4-trifluorobutoxy) benzonitrile 98c (1.4 g), yield: 96.8%.
MS m/z(ESI):408[M+1]
Third step
4-Chloro-3-fluoro-2- (1-methyl-1H-pyrazol-5-yl) -6- (4, 4-trifluoro-butoxy) benzonitrile
The compound 4-chloro-3-fluoro-2-iodo-6- (4, 4-trifluorobutoxy) benzonitrile 98C (400 mg,0.98 mmol) and 1-methyl-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazole (245 mg,1.18 mmol) were dissolved in 1 '4-dioxane (15 mL) and water (3 mL), sodium carbonate (312 mg,2.94 mmol) and [1,1' -bis (di-t-butylphosphine) ferrocene ] palladium dichloride (63 mg,0.01mol,184 μl) were added, and the reaction was stirred under 100 ℃ microwaves for 1 hour. The reaction solution was cooled to room temperature, concentrated under reduced pressure, water (20 mL) was added to the obtained residue to wash, an organic phase was separated, an aqueous layer was extracted with ethyl acetate (2X 30 mL), the organic phases were combined, washed with saturated brine (2X 30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was concentrated by silica gel column chromatography with eluent system A to give 4-chloro-3-fluoro-2- (1-methyl-1H-pyrazol-5-yl) -6- (4, 4-trifluorobutoxy) benzonitrile 98d (312 mg), yield: 70.3%.
MS m/z(ESI):362[M+1]
Fourth step
4-Chloro-3-fluoro-2- (4-iodo-1-methyl-1H-pyrazol-5-yl) -6- (4, 4-trifluoro-butoxy) benzonitrile
The compound 4-chloro-3-fluoro-2- (1-methyl-1H-pyrazol-5-yl) -6- (4, 4-trifluorobutoxy) benzonitrile 98d (300 mg,0.83 mmol) was dissolved in acetic acid (10 mL), N-iodosuccinimide (373 mg,1.66 mmol) was added, and the system was stirred at 80℃for 2 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system C to give 4-chloro-3-fluoro-2- (4-iodo-1-methyl-1H-pyrazol-5-yl) -6- (4, 4-trifluorobutoxy) benzonitrile 98e (274 mg) in 67.8% yield.
MS m/z(ESI):488[M+1]
Fifth step
((7- (5- (3-Chloro-6-cyano-2-fluoro-5- (4, 4-trifluorobutoxy))) phenyl) -1-methyl-1H-pyrazol-4-yl) -4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) carbamic acid tert-butyl ester
The compound 4-chloro-3-fluoro-2- (4-iodo-1-methyl-1H-pyrazol-5-yl) -6- (4, 4-trifluorobutoxy) benzonitrile 98e and [4- [ (tert-butoxycarbonylamino) methyl ] -1-oxo-2H-phthalazin-6-yl ] boronic acid 18f (ref. J.Med. Chem.2022,65, 1749-1766) were synthesized, 78mg,0.25 mmol) were dissolved in 1' 4-dioxane (5 mL) and water (1 mL), cesium fluoride (81 mg,1.23 mmol), potassium phosphate (130 mg,0.62 mmol) and cataCXium-A-Pd-G3 (30 mg,0.04 mmol) were added, the reaction was stirred for 1hr at 80℃under microwaves, the organic phase was separated, the aqueous phase was extracted with ethyl acetate (2X 15 mL), the organic phase was combined, washed with saturated brine (2X 15 mL), dried over sodium sulfate, and the resulting residue was purified by filtration to give a thin layer of anhydrous sodium sulfate ((4, 4-fluoro-6-methyl-1-pyrazol-5-yl) -6-hydroxy-phenyl) -1- (4, 4-trifluoro-hydroxy-1-methyl-6-p-hydroxy-1-phenyl) -3 (30 mg,0.62 mmol), and the resulting residue was purified by dry chromatography (4-chloro-4-methyl-4-hydroxy-6-methyl-6-p-hydroxy-6-methyl-6-hydroxy-butan-6-yl) under conditions of water.
MS m/z(ESI):635[M+1]
Sixth step
2- (4- (4- (Aminomethyl) -1-oxo-1, 2-dihydro-phthalic acid-6-yl) -1-methyl-1H-pyrazol-5-yl) -4-chloro-3-fluoro-6- (4, 4-trifluorobutoxy) benzonitrile
The compound ((7- (5- (3-chloro-6-cyano-2-fluoro-5- (4, 4-trifluorobutoxy))) phenyl) -1-methyl-1H-pyrazol-4-yl) -4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) carbamic acid tert-butyl ester 98f (59 mg, 92.91. Mu. Mol) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (1 mL) at 25℃under stirring for 0.5 hours, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system C to give 2- (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalic acid-6-yl) -1-methyl-1H-pyrazol-5-yl) -4-chloro-3-fluoro-6- (4, 4-trifluorobutoxy) benzonitrile 98 (26 mg) in a yield of 52.3%.
MS m/z(ESI):535[M+1]
1H NMR(400MHz,DMSO-d6)δ12.23(s,1H),8.24-8.14(m,2H),7.83(d,1H),7.76(d,1H),7.68(dd,1H),4.33(t,2H),3.83(d,2H),3.79(s,3H),2.49-2.30(m,4H),2.07-1.96(m,2H).
Example 99
2- (4- (4- (Aminomethyl) -1-oxo-1, 2-dihydro-phthalic acid-6-yl) -1-methyl-1H-pyrazol-5-yl) -6- (tert-butoxy) -4-chloro-3-fluorobenzonitrile
The first, third to seventh steps of example 55 were successively referred to, and 4-chloro-2, 5-difluorobenzonitrile (600 mg,3.47 mmol) was used to give the title product 2- (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalic acid-6-yl) -1-methyl-1H-pyrazol-5-yl) -6- (tert-butoxy) -4-chloro-3-fluorobenzonitrile 99 (2.5 mg), yield: 0.15%.
MS m/z(ESI):481[M+1]
1H NMR(400MHz,DMSO)δ12.55(s,1H),8.30(d,2H),8.14(d,1H),7.90-7.76(m,2H),7.58(dd,1H),3.94(s,2H),3.80(s,3H),1.39(s,9H).
Example 102
2- (4- (4- (Aminomethyl) -1-oxo-1, 2-dihydro-phthalic acid-6-yl) -1-methyl-1H-pyrazol-5-yl) -4-chloro-6- (3- (difluoromethylene) cyclobutoxy) -m-fluorobenzonitrile
First step
((3- (Difluoromethylene) cyclobutoxy) methyl) benzene
Tetrahydrofuran (70 mL) was added to a three-necked flask, nitrogen was replaced 3 times, and cooled to 0 ℃, dibromo (difluoromethane) (10.36 g,49.37mmol,4.51 mL) was quickly added, stirred for 10 minutes under ice bath, tris (dimethylamino) phosphine (8.06 g,49.37mmol,8.97 mL) was slowly added dropwise, stirring was continued for 1 hour at 0 ℃, 3-benzyloxycyclobutanone 102a (2 g,11.35 mmol) in tetrahydrofuran (10 mL) was slowly added dropwise, stirring was continued for 1 hour at 25 ℃, zn (2.97 g,45.40 mmol) was added, and 0.15mL HMPT was supplemented, and the mixture was transferred to 75 ℃ and stirred for 5 hours. To the reaction solution was added water (100 mL), the organic phase was separated, the aqueous layer was extracted with ethyl acetate (2X 100 mL), the organic phases were combined, washed with saturated brine (2X 100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue obtained by the eluent system A was subjected to silica gel column chromatography to give ((3- (difluoromethylene) cyclobutoxy) methyl) benzene 102b (580 mg), yield: 24.3%.
1H NMR(400MHz,DMSO-d6)δ7.40-7.25(m,5H),4.40(s,2H),4.18(tt,1H),2.92(ddq,2H),2.67-2.55(m,2H).
Second step
3- (Difluoromethylene) cyclobutan-1-ol
The compound ((3- (difluoromethylene) cyclobutoxy) methyl) benzene 102b (100 mg,0.48 mmol) was dissolved in dichloromethane (5 mL), the reaction system cooled to-78 ℃ and boron tribromide (238 mg,0.95mmol,92 μl) was slowly added dropwise, the reaction stirred at-78 ℃ for 0.5 hours, quenched by adding saturated aqueous sodium bicarbonate solution at-78 ℃ to the reaction droplets, water (10 mL) was added, extracted with dichloromethane (3×20 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give crude 3- (difluoromethylene) cyclobutan-1-ol 102C (90 mg) which was directly taken to the next step without isolation and purification.
MS m/z(ESI):121[M+1]
The synthesis of the third to fifth steps of reference example 86 gave the title product 2- (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalic acid-6-yl) -1-methyl-1H-pyrazol-5-yl) -4-chloro-6- (3- (difluoromethylene) cyclobutoxy) -m-fluorobenzonitrile 102 (10 mg) in 2.5% yield by the crude 3- (difluoromethylene) cyclobutan-1-ol 102c (90 mg,0.75 mmol).
MS m/z(ESI):527[M+1]
1H NMR(400MHz,DMSO)δ12.50(s,1H),8.30(d,3H),8.15(d,1H),7.77(s,1H),7.72-7.62(m,2H),5.12(p,1H),3.87(s,2H),3.78(s,3H),2.87(dp,4H).
19F NMR(377MHz,DMSO)δ-94.91,-122.15.
Example 103
2-4- (4- (Aminomethyl) -1-oxo-1, 2-dihydro-phthalic acid-6-yl) -1-methyl-1H-pyrazol-5-yl) -4-chloro-6- (1, 1-isothiazolin-2-yl) -3-fluorobenzonitrile
First step
4-Chloro-6- (1, 1-dioxido isothiazolin-2-yl) -3-fluoro-2- (4-iodo-1-methyl-1H-pyrazol-5-yl) benzonitrile
4-Chloro-3, 6-difluoro-2- (4-iodo-1-methyl-1H-pyrazol-5-yl) benzonitrile 86C (0.20 g,0.53 mmol) and potassium carbonate (218 mg,1.58 mmol) were dissolved in acetonitrile (10 mL), 1, 2-thiazolidine 1, 1-dioxide (96 mg,0.79 mmol) was added, nitrogen was purged three times, and the system was heated to 80℃for 16 hours. The reaction was cooled to room temperature, concentrated, and the residue was dissolved in water, extracted with ethyl acetate (30 mL. Times.3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the resulting residue was purified by silica gel column chromatography using eluent system A to give 4-chloro-6- (1, 1-isothiazolin-2-yl) -3-fluoro-2- (4-iodo-1-methyl-1H-pyrazol-5-yl) benzonitrile 103a (80 mg), yield: 31.6%.
MS m/z(ESI):481[M+1]
Second step (7- (5- (3-chloro-6-cyano-5- (1, 1-dioxaisothiazolin-2-yl) -2-fluorophenyl) -1-methyl-1H-pyrazol-4-yl) -4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) carbamic acid tert-butyl ester
[4- [ (Tert-Butoxycarbonylamino) methyl ] -1-oxo-2H-phthalazin-6-yl ] boronic acid 18f (46 mg,0.15mmol, ref. J.Med. Chem.2022,65,1749-1766 "synthesis), 4-chloro-6- (1, 1-isothiazolin-2-yl) -3-fluoro-2- (4-iodo-1-methyl-1H-pyrazol-5-yl) benzonitrile (70 mg,0.15 mmol), potassium phosphate (93 mg,0.44 mmol) and cesium fluoride (58 mg,0.87 mmol) were dissolved in water (1 mL) and 1 '4-dioxane (5 mL), nitrogen was exchanged three times, methanesulfonic acid [ n-butylbis (1-adamantyl) phosphine ] (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (11 mg, 15. Mu. Mol) was added and the system was heated to 80℃in a microwave reactor for reaction for 1 hour. Cooled to room temperature, dissolved in water, extracted with ethyl acetate (30 mL. Times.3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the resulting residue was purified by silica gel column chromatography with eluent system A to give tert-butyl 7- (5- (3-chloro-6-cyano-5- (1, 1-isothiazolin-2-yl) -2-fluorophenyl) -1-methyl-1H-pyrazol-4-yl) -4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) carbamate 103b (16 mg) in 17.5% yield.
MS m/z(ESI):628[M+1]
Third step
2-4- (4- (Aminomethyl) -1-oxo-1, 2-dihydro-phthalic acid-6-yl) -1-methyl-1H-pyrazol-5-yl) -4-chloro-6- (1, 1-isothiazolin-2-yl) -3-fluorobenzonitrile
7- (5- (3-Chloro-6-cyano-5- (1, 1-isothiazolin-2-yl) -2-fluorophenyl) -1-methyl-1H-pyrazol-4-yl) -4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) carbamic acid tert-butyl ester 103b (16 mg, 25. Mu. Mol) was dissolved in methylene chloride (2 mL), and trifluoroacetic acid (0.5 mL) was added and the system was reacted at 25℃for 1 hour. The residue was concentrated and the resulting residue was purified by silica gel column chromatography with eluent system C to give 2-4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalic acid-6-yl) -1-methyl-1H-pyrazol-5-yl) -4-chloro-6- (1, 1-isothiazolin-2-yl) -3-fluorobenzonitrile 103 (2 mg), yield: 14.9%.
MS m/z(ESI):528[M+1]
1H NMR(400MHz,DMSO-d6)δ12.40(s,1H),8.28-8.18(m,2H),8.08(d,1H),7.71-7.60(m,2H),6.50(s,1H),4.34(t,1H),3.80(t,2H),3.73(d,4H),3.45(s,2H),2.39(d,2H).
Example 112
2- [4- [4- (Aminomethyl) -1-oxo-2H-phthalazin-6-yl ] ] -methyl epichlorohydrin-pyrazol-3-yl ] -4-chloro-3-fluoro-6- (2-hydroxy-methyl epichlorohydrin-propoxy) benzonitrile
First step
2-Methylpropane-1, 2-diol
Ethyl 2-hydroxy-2-methylpropionate 112a (500 mg,3.78 mmol) was dissolved in THF (5 mL), the reaction system was cooled to 0℃and LiAlH4 (1M in THF,7.57 mL) was slowly added dropwise, the reaction was stirred at 0℃for 1hr, the reaction was quenched with 2M aqueous sodium hydroxide solution, the slow dropwise addition was noted, the quenching was completed, direct filtration was performed, and the filtrate was concentrated under reduced pressure to give 2-methylpropan-1, 2-diol 112b (330 mg) in 96.8% yield.
MS m/z(ESI):91[M+1]
Second step
4-Chloro-3-fluoro-6- (2-hydroxy-2-methyl-propoxy) -2- (4-iodo-2-methyl-pyrazol-3-yl) benzonitrile
The compound cesium carbonate (343mg, 1.05 mmol) was suspended in THF (5 mL), 2-methylpropan-1, 2-diol (95 mg,1.05 mmol), 4-chloro-3, 6-difluoro-2- (4-iodo-2-methyl-pyrazol-3-yl) benzonitrile 1i (100 mg,263 μmol, obtained by synthesis in reference example 1) was added to the reaction solution under stirring at 25 ℃ for 12 hours, water (15 mL) was added, extraction was performed with ethyl acetate (30 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the concentrated residue was separated and purified by Pre-TLC (developer PE: ea=10:1) to give 4-chloro-3-fluoro-6- (2-hydroxy-2-methyl-propoxy) -2- (4-iodo-2-methyl-pyrazol-3-yl) benzonitrile 112C (88 mg) in 74.4% yield.
MS m/z(ESI):450[M+1]
The synthesis of the fifth to sixth steps of reference example 9 gave the title product 2- [4- [4- (aminomethyl) -1-oxo-2H-phthalazin-6-yl ] ] -methyl epichlorohydrin-pyrazol-3-yl ] -4-chloro-3-fluoro-6- (2-hydroxy-methyl epichlorohydrin-propoxy) benzonitrile 112 (7 mg) in 10.5% yield by the synthesis method of 4-chloro-3-fluoro-6- (2-hydroxy-2-methyl-propoxy) -2- (4-iodo-2-methyl-pyrazol-3-yl) benzonitrile 112c (60 mg, 134. Mu. Mol).
MS m/z(ESI):498[M+1]
1H NMR(400MHz,DMSO-d6)δ12.47(s,1H),8.29(s,1H),8.15(d,1H),7.90(d,1H),7.78(d,1H),7.72-7.65(m,1H),4.79(s,2H),4.05-3.97(m,2H),3.82(s,2H),3.79(s,3H),1.20(d,6H).
Example 120
2- (4- (4- (Aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) -4-chloro-6- (3- (fluoromethylene) pyrrolidin-1-yl) -3-fluorobenzonitrile
The synthesis of the third to fifth steps of reference example 86 gave the title product 2- (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) -4-chloro-6- (3- (fluoromethylene) pyrrolidin-1-yl) -3-fluorobenzonitrile 120 (3 mg) in 4.7% yield by the synthesis of 4-chloro-3, 6-difluoro-2- (4-iodo-1-methyl-1H-pyrazol-5-yl) benzonitrile 86c (47 mg,0.13 mmol).
MS m/z(ESI):508[M+1]
1H NMR(400MHz,DMSO-d6)δ12.44(s,1H),8.27(s,1H),8.16(d,1H),7.81(d,1H),7.72(dd,1H),7.39(d,1H),7.01(s,1H),4.42-4.25(m,2H),3.79(s,3H),3.75-3.59(m,4H),2.63(t,2H).
Example 123
2- (4- (4- (Aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) -4-chloro-6- (3, 3- (difluoropyrrolidin-1-yl) -3-fluorobenzonitrile
The synthesis of the third to fifth steps of reference example 86 gave the title product 2- (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) -4-chloro-6- (3, 3- (difluoropyrrolidin-1-yl) -3-fluorobenzonitrile 123 (6 mg) in 2.4% yield by the synthesis of 4-chloro-3, 6-difluoro-2- (4-iodo-1-methyl-1H-pyrazol-5-yl) benzonitrile 86c (190 mg,0.50 mmol).
MS m/z(ESI):500[M+1]
1H NMR(400MHz,DMSO-d6)δ12.70(broad s,1H),8.34(s,2H),8.16(d,1H),7.87(s,1H),7.58(d,1H),7.31(d,1H),4.66(hept,4H),4.16(s,2H),3.78(s,3H).
Example 131
2- (4- (4- (Aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) -4-chloro-3-fluoro-6- (1H-pyrazol-1-yl) benzonitrile
The synthesis of the third to fifth steps of reference example 86 gave the title product 2- (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) -4-chloro-3-fluoro-6- (1H-pyrazol-1-yl) benzonitrile 131 (16 mg) in 13.5% yield by the synthesis of 4-chloro-3, 6-difluoro-2- (4-iodo-1-methyl-1H-pyrazol-5-yl) benzonitrile 86c (95 mg,0.25 mmol).
MS m/z(ESI):475[M+1]
1H NMR(400MHz,DMSO-d6)δ12.91(s,1H),8.50(d,1H),8.49(d,1H),8.37(s,1H),8.35(t,2H),8.15(d,1H),7.90(dd,2H),7.56(dd,1H),6.69(dd,1H),4.46-4.39(m,2H),3.85(s,3H).
Example 132
2- (4- (4- (Aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) -4-chloro-3-fluoro-6- (5-azaspiro [2.4] heptane-5-yl) benzonitrile
The synthesis of the third to fifth steps of reference example 86 gave the title product 2- (4- (4- (aminomethyl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) -4-chloro-3-fluoro-6- (5-azaspiro [2.4] heptan-5-yl) benzonitrile 132 (15 mg) in 11.9% yield by the synthesis of 4-chloro-3, 6-difluoro-2- (4-iodo-1-methyl-1H-pyrazol-5-yl) benzonitrile 86c (95 mg,0.25 mmol).
MS m/z(ESI):504[M+1]
1H NMR(400MHz,DMSO-d6)δ12.88(s,1H),8.45(s,2H),8.36(s,1H),8.17(d,1H),7.90(d,1H),7.52(dd,1H),7.24(d,1H),4.40(dd,2H),3.91-3.63(m,2H),3.78(s,3H),3.49(s,2H),1.89(ddt,2H),0.63(dd,4H).
Synthesis of the following example reference example 136.
Example 150 can also be synthesized with reference to the following procedure:
Example 150
1- (Aminomethyl) -7- (5- (2-cyano-3-cyclopropyloxy-6-fluoro-5- (prop-1-yn-1-yl) phenyl) -1-methyl-1H-pyrazol-4-yl) -4-carbonyl-3, 4-dihydro-phthalazine-5-carbonitrile
First step
2- (Benzyloxy) -4-chlorobenzoic acid methyl ester
Methyl 4-chloro-2-hydroxy-benzoate 150a (15 g,80.39 mmol) and potassium carbonate (22.22 g,160.78 mmol) were dissolved in N, N-dimethylformamide (100 mL), nitrogen was purged three times, and benzyl bromide (16.50 g,96.47mmol,11.5 mL) was added and the system reacted at 90℃for 4 hours. The reaction was cooled to room temperature, filtered and concentrated. The mixture was extracted with ethyl acetate (150 mL. Times.3), and the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography with eluent system B to give methyl 2- (benzyloxy) -4-chlorobenzoate 150B (21 g) in 94.4% yield.
MS m/z(ESI):277[M+1]
Second step
2- (Benzyloxy) -4-chlorobenzoic acid
Methyl 2- (benzyloxy) -4-chlorobenzoate 150b (21 g,75.89 mmol) was dissolved in water (20 mL) and ethylene glycol dimethyl ether (100 mL), cooled to 0℃and lithium hydroxide (4.54 g,189.73 mmol) was added and the system reacted at 25℃for 1 hour. The mixture is filtered and the mixture is filtered, the filter residue was washed with a small amount of ethyl acetate. Spin-drying to give 150c (18.0 g, crude) of 2- (benzyloxy) -4-chlorobenzoic acid, which was directly added to the next step.
MS m/z(ESI):263[M+1]
Third step
2- (Benzyloxy) -4-chlorobenzoyl chloride
2- (Benzyloxy) -4-chlorobenzoic acid 150C (16 g,60.91 mmol) was dissolved in dichloromethane (100 mL), nitrogen was purged three times, cooled to 0℃and oxalyl chloride (2M, 36.55 mL) and N, N-dimethylformamide (445 mg,6.09mmol,0.45 mL) were added and the system was reacted at 0℃for 0.5 hours and then warmed to 25℃for 1 hour. Concentration gives 2- (benzyloxy) -4-chlorobenzoyl chloride 150d (17 g, crude product) which is directly fed to the next step.
Fourth step
2- (Benzyloxy) -4-chloro-N, N-diisopropylaniline
Diisopropylamine (13.46 g,133.03mmol,18.64 mL) was dissolved in 2-methyltetrahydrofuran (150 mL), nitrogen was purged three times, cooled to 0℃and 2- (benzyloxy) -4-chlorobenzoyl 150d (17 g,60.47 mmol) was dissolved in 2-methyltetrahydrofuran (50 mL) and added dropwise to the system, after which the system was reacted at 25℃for 1 hour. 1M sodium hydroxide (50 mL) was added to the reaction, stirred to separate layers, extracted with ethyl acetate (100 mL. Times.2), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography with eluent system B to give 2- (benzyloxy) -4-chloro-N, N-diisopropylaniline 150e (18 g), yield 86.7%.
MS m/z(ESI):346[M+1]
Fifth step
2- (Benzyloxy) -4-chloro-6- (2-chloroacetyl) -N, N-diisopropylaniline
2- (Benzyloxy) -4-chloro-N, N-diisopropylaniline 150e (10 g,28.91 mmol) was dissolved in 2-methyltetrahydrofuran (200 mL), nitrogen was purged three times, cooled to below-60 ℃, N-butyllithium (2.5M, 23.1 mL) was added dropwise to the system, the internal temperature was kept below-50 ℃, after the addition was allowed to react at-50℃for 30 minutes, znCl 2 (8.28 g,60.7 mmol) was added dropwise to the system, the internal temperature was kept below-50℃and after the addition was allowed to react at-30℃for 10 minutes, cuCl.2LiCl (0.1M, 2.9 mL) and chloroacetyl chloride (8.16 g,72.28mmol,5.8 mL) were added dropwise to the system, the internal temperature was kept below-10℃at the time of the addition, and the system was allowed to react at 0℃for 20 minutes after the addition. Water (20 mL) and 30% aqueous ammonia (15 mL) were added to the system, and the system was maintained at 10℃or below while stirring at room temperature for 30 minutes after the addition was completed. The layers were separated, the organic phase was neutralized with 1M HCl, separated, and the organic phase was dried by spinning. The residue was purified by silica gel column chromatography using eluent system B to give 2- (benzyloxy) -4-chloro-6- (2-chloroacetyl) -N, N-diisopropylaniline 150f (8.60 g) in a yield of 70.43%.
MS m/z(ESI):423[M+1]
Sixth step
(1 R,3R,5S,7 r) -1- (2- (3- (benzyloxy) -5-chloro-2- (diisopropylcarbamoyl) phenyl) -2-oxoethyl) -1,3, 5-triazaadamantane-1-iodonium
2- (Benzyloxy) -4-chloro-6- (2-chloroacetyl) -N, N-diisopropylaniline 150f (8.9 g,21.07 mmol) and urotropine (3.25 g,23.18 mmol) were dissolved in acetone (42 mL), nitrogen was purged three times, the system was cooled to 0℃and sodium iodide (4.74 g,31.61 mmol) dissolved in acetone (28 mL) was added dropwise to the system, after the addition, the system was warmed to 25℃and reacted for 30 minutes. A large amount of solid is precipitated in the system, the solid is filtered, a filter cake is washed by acetone, and the filter cake is dried by spin to obtain 150g (11 g) of (1 r,3R,5S,7 r) -1- (2- (3- (benzyloxy) -5-chloro-2- (diisopropylcarbamoyl) phenyl) -2-oxyethyl) -1,3, 5-triazaadamantane-1-iodonium with the yield of 79.8%. MS m/z (ESI): 526[ M ]
Seventh step
2- (Benzyloxy) -4-chloro-6-glycyl-N, N-diisopropylaniline hydrochloride
(1 R,3R,5S,7 r) -1- (2- (3- (benzyloxy) -5-chloro-2- (diisopropylcarbamoyl) phenyl) -2-oxoethyl) -1,3, 5-triazaadamantane-1-iodonium 150g (9.1 g,13.91 mmol) was dissolved in water (30 mL), the system was cooled to 0℃and concentrated hydrochloric acid (9.3 mL) was added, after which the system was warmed to 40℃for 16 hours. Cooled to room temperature, and the reaction solution was directly used for the next reaction.
MS m/z(ESI):403[M+1]
Eighth step
(2- (3- (Benzyloxy) -5-chloro-2- (diisopropylcarbamoyl) phenyl) -2-oxoethyl) carbamic acid tert-butyl ester
Di-tert-butyl dicarbonate (3.86 g,17.68mmol,4.1 mL) was dissolved in toluene (45 mL), nitrogen was purged three times, the system was cooled to 0℃and aqueous ammonia (36 mL) was added to the system, after the addition, an aqueous solution of 2- (benzyloxy) -4-chloro-6-glycyl-N, N-diisopropylaniline hydrochloride (5.7 g,14.15 mmol) was added dropwise to the system, the temperature of the system was kept below 5℃at the time of the dropwise addition, and after the addition, the system was warmed to 25℃and reacted for 1 hour. The aqueous phase was discarded and the organic phase concentrated. The residue was purified by silica gel column chromatography using eluent system B to give (2- (3- (benzyloxy) -5-chloro-2- (diisopropylcarbamoyl) phenyl) -2-oxoethyl) carbamic acid tert-butyl ester 150i (5.60 g) in 78.7% yield.
MS m/z(ESI):503[M+1]
Ninth step
(5- (Benzyloxy) -7-chloro-4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) carbamic acid tert-butyl ester
Tert-butyl (2- (3- (benzyloxy) -5-chloro-2- (diisopropylcarbamoyl) phenyl) -2-oxoethyl) carbamate 150i (5.9 g,11.73 mmol) was dissolved in toluene (32 mL), warmed to 90 ℃, acOH (8 mL) and hydrazine hydrate (2.07 g,35.19mmol,2.01mL,85% purity) were added, and after the addition, the system warmed to 105 ℃ for 1 hour. The system changed from transparent to precipitate, cooled to room temperature, filtered, the filter cake was washed with a small amount of ethanol, and dried to give 150j (3.1 g) of tert-butyl 5- (benzyloxy) -7-chloro-4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl carbamate in 63.5% yield.
MS m/z(ESI):416[M+1]
Tenth step
4- (Aminomethyl) -6-chloro-8-hydroxyphthalazin-1 (2H) -one
Tert-butyl 5- (benzyloxy) -7-chloro-4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl carbamate 150j (1 g,2.40 mmol) was dissolved in acetic acid (5 mL) and concentrated hydrochloric acid (1 mL), nitrogen was purged three times, and the system was reacted at 80 ℃ for 1 hour. The reaction was cooled to room temperature and concentrated to give 4- (aminomethyl) -6-chloro-8-hydroxyphthalazin-1 (2H) -one 150k (0.60 g).
MS m/z(ESI):226[M+1]
Eleventh step
(7-Chloro-5-hydroxy-4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl carbamic acid tert-butyl ester
150K (0.6 g,2.66 mmol) of 4- (aminomethyl) -6-chloro-8-hydroxyphthalazin-1 (2H) -one and sodium bicarbonate (670.17 mg,7.98 mmol) were dissolved in water (10 mL) and methanol (10 mL), nitrogen was purged three times, and di-tert-butyl dicarbonate (870.54 mg,3.99mmol,0.92 mL) was added and the system reacted at 25℃for 16 hours. The reaction was precipitated as a large amount of solid, concentrated, filtered, washed with a small amount of water and ethyl acetate, and the residue was spin-dried to give 150l (0.64 g) of (7-chloro-5-hydroxy-4-oxo-3, 4-dihydro-phthalazin-1-yl) methylcarbamic acid tert-butyl ester in 73.4% yield. MS m/z (ESI) 326[ M+1]
Twelfth step
1- (((Tert-Butoxycarbonyl) amino) methyl) -7-chloro-4-oxo-3, 4-dihydro-5-ylphthalic acid triflate
150L (500 mg,1.53 mmol) of tert-butyl (7-chloro-5-hydroxy-4-oxo-3, 4-dihydro-phthalazin-1-yl) methylcarbamate (tert-butyl) was dissolved in tetrahydrofuran (10 mL), N-diisopropylethylamine (793.50 mg,6.14mmol,1.1 mL) and N, N-phenyl-bistrifluoromethane-sulphonimide (1.37 g,3.84 mmol) were added, nitrogen was exchanged three times, and the reaction was stirred at 75℃for 16 hours. Cooled to room temperature, quenched with water, extracted with ethyl acetate (50 ml x 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography with eluent system B to give 1- (((tert-butoxycarbonyl) amino) methyl) -7-chloro-4-oxo-3, 4-dihydro-5-ylphthalic acid trifluoromethanesulfonate 150m (450 mg) in a yield of 64.0%.
MS m/z(ESI):458[M+1]
Thirteenth step
(7-Chloro-5-cyano-4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl carbamic acid tert-butyl ester
1- (((T-Butoxycarbonyl) amino) methyl) -7-chloro-4-oxo-3, 4-dihydro-5-ylphthalic acid trifluoromethane sulfonate 150m (0.17 g,0.37 mmol) was dissolved in N, N-dimethylformamide (3 mL), nitrogen was purged three times, zinc hydride (26 mg,0.22 mmol) and tetrakis triphenylphosphine palladium (64 mg, 56. Mu. Mol) were added, and the reaction system was heated to 100℃in a microwave reactor to react for 1.5 hours. Cooled to room temperature, quenched with water, extracted with ethyl acetate (50 ml x 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using eluent system B to give (7-chloro-5-cyano-4-oxo-3, 4-dihydro-phthalazin-1-yl) methylcarbamic acid tert-butyl ester 150n (50 mg) in 40.2% yield.
MS m/z(ESI):335[M+1]
Fourteenth step
(4- ((Tert-Butoxycarbonyl) amino) methyl) -8-cyano-1-oxo-1, 2-dihydro-phthalic acid-6-yl) boronic acid
Tert-butyl (7-chloro-5-cyano-4-oxo-3, 4-dihydro-phthalazin-1-yl) methylcarbamate 150n (50 mg, 149.36. Mu. Mol), pinacol biborate (56.89 mg, 224.04. Mu. Mol), 2-dicyclohexylphosphine-2 ',4',6 '-triisopropylbiphenyl (14 mg, 30. Mu. Mol) and potassium acetate (44 mg,0.45 mmol) were dissolved in 1' 4-dioxane (3 mL), nitrogen was exchanged three times, and tris (dibenzylideneacetone) palladium (14 mg, 15. Mu. Mol) was added and the reaction system was stirred at 100℃for 2 hours. Cooled to room temperature, filtered and concentrated to give 4- ((t-butoxycarbonyl) amino) methyl) -8-cyano-1-oxo-1, 2-dihydro-phthalic acid-6-yl) boronic acid 150o (0.11 g, crude).
MS m/z(ESI):345[M+1]
Fifteenth step (5-cyano-7- (5- (2-cyano-3-cyclopropyloxy-6-fluoro-5- (prop-1-yn-1-yl) phenyl) -1-methyl-1H-pyrazole-4-
Phenyl) -4-oxo-3, 4-dihydro-phthalazin-1-yl methyl) carbamic acid tert-butyl ester
4- ((Tert-Butoxycarbonyl) amino) methyl) -8-cyano-1-oxo-1, 2-dihydrophthalate-6-yl) boronic acid 150o (108 mg, 141. Mu. Mol,45% purity), 6- (cyclopropoxy) -3-fluoro-2- (4-iodo-2-methyl-pyrazol-3-yl) -4-prop-1-ynyl-benzonitrile 150p (35 mg, 83. Mu. Mol) and sodium bicarbonate (21 mg,0.25 mmol) were dissolved in water (2 mL) and 1 '4-dioxane (10 mL), nitrogen was exchanged three times, 1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (7 mg, 8. Mu. Mol) and the system was heated to 80℃in a microwave reactor for reaction for 1.5 hours. Cooled to room temperature, quenched with water, extracted with ethyl acetate (30 ml×3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using eluent system A to give (7-chloro-5-cyano-4-oxo-3, 4-dihydro-phthalazin-1-yl) methylcarbamic acid tert-butyl ester 150q (30 mg), yield: 60.8%.
MS m/z(ESI):594[M+1]
Sixteenth step
1- (Aminomethyl) -7- (5- (2-cyano-3-cyclopropyloxy-6-fluoro-5- (prop-1-yn-1-yl) phenyl) -1-methyl-1H-pyrazol-4-yl) -4-carbonyl-3, 4-dihydro-phthalazine-5-carbonitrile
(7-Chloro-5-cyano-4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl carbamic acid tert-butyl ester 150q (30 mg, 51. Mu. Mol) was dissolved in dioxane hydrochloride solution (4M, 4 mL) and the system was reacted at 25℃for 1 hour. Concentrated, and the residue was purified by silica gel column chromatography with eluent system a to give 1- (aminomethyl) -7- (5- (2-cyano-3-cyclopropyloxy-6-fluoro-5- (prop-1-yn-1-yl) phenyl) -1-methyl-1H-pyrazol-4-yl) -4-carbonyl-3, 4-dihydro-phthalazine-5-carbonitrile 150 (11 mg) in 44.1% yield.
MS m/z(ESI):494[M+1]
1H NMR(400MHz,DMSO)δ12.80(s,1H),8.42(s,1H),8.29(d,1H),8.21(d,1H),7.89(s,1H),7.82(d,1H),4.17(td,1H),3.76(d,5H),2.19(s,3H),0.90(dd,2H),0.82–0.73(m,2H).
EXAMPLE 150 chiral isomer preparation
P1: ((5-cyano-7- (5- (2-cyano-3-cyclopropyloxy-6-fluoro-5- (prop-1-yn-1-yl) phenyl) -1-methyl-1H-pyrazol-4-yl) -4-carbonyl-3, 4-dihydro-phthalazin-1-yl) methyl) carbamic acid tert-butyl ester
P2: ((5-cyano-7- (5- (2-cyano-3-cyclopropyloxy-6-fluoro-5- (prop-1-yn-1-yl) phenyl) -1-methyl-1H-pyrazol-4-yl) -4-carbonyl-3, 4-dihydro-phthalazin-1-yl) methyl) carbamic acid tert-butyl ester
First step chiral isomer preparation
The compound ((5-cyano-7- (5- (2-cyano-3-cyclopropyloxy-6-fluoro-5- (prop-1-yn-1-yl) phenyl) -1-methyl-1H-pyrazol-4-yl) -4-carbonyl-3, 4-dihydro-phthalazin-1-yl) methyl) carbamic acid tert-butyl ester 1 (130 mg,0.22 mmol) was resolved by Chiral-HPLC to give 150q-P1 (m) - ((5-cyano-7- (5- (2-cyano-3-cyclopropyloxy-6-fluoro-5- (prop-1-yn-1-yl) phenyl) -1-methyl-1H-pyrazol-4-yl) -4-carbonyl-3, 4-dihydro-phthalazin-1-yl) methyl) carbamic acid tert-butyl ester (57 mg), yield 43.8%, 150q-P2 (P) - ((5-cyano-7- (5- (2-cyano-3-cyclopropyloxy-6-fluoro-5- (prop-1-yn-1-yl) phenyl) -1-methyl-1H-pyrazol-4-yl) -4-carbonyl-3, 4-dihydro-phthalazin-1-yl) methyl) carbamic acid tert-butyl ester (51 mg), yield 39.2%.
150Q-P1 (m) - ((5-cyano-7- (5- (2-cyano-3-cyclopropyloxy-6-fluoro-5- (prop-1-yn-1-yl) phenyl) -1-methyl-1H-pyrazol-4-yl) -4-carbonyl-3, 4-dihydro-phthalazin-1-yl) methyl) carbamic acid tert-butyl ester
MS m/z(ESI):594[M+1]
151 Q-P2- (P) - ((5-cyano-7- (5- (2-cyano-3-cyclopropyloxy-6-fluoro-5- (prop-1-yn-1-yl) phenyl) -1-methyl-1H-pyrazol-4-yl) -4-carbonyl-3, 4-dihydro-phthalazin-1-yl) methyl) carbamic acid tert-butyl ester
MS m/z(ESI):594[M+1]
Second step
150-P1- (m) -1- (aminomethyl) -7- (5- (2-cyano-3-cyclopropyloxy-6-fluoro-5- (prop-1-yn-1-yl) phenyl) -1-methyl-1H-pyrazol-4-yl) -4-carbonyl-3, 4-dihydro-phthalazine-5-carbonitrile
150-P2- (P) -1- (aminomethyl) -7- (5- (2-cyano-3-cyclopropyloxy-6-fluoro-5- (prop-1-yn-1-yl) phenyl) -1-methyl-1H-pyrazol-4-yl) -4-carbonyl-3, 4-dihydro-phthalazine-5-carbonitrile
150Q-P1 (M) - ((5-cyano-7- (5- (2-cyano-3-cyclopropyloxy-6-fluoro-5- (prop-1-yn-1-yl) phenyl) -1-methyl-1H-pyrazol-4-yl) -4-carbonyl-3, 4-dihydropyrazin-1-yl) methyl) carbamic acid tert-butyl ester (57 mg,0.096 mmol), and 150q-P2 (P) - ((5-cyano-7- (5- (2-cyano-3-cyclopropyloxy-6-fluoro-5- (prop-1-yn-1-yl) phenyl) -1-methyl-1H-pyrazol-4-yl) -4-carbonyl-3, 4-dihydropyrazin-1-yl) methyl) carbamic acid tert-butyl ester (51 mg,0.086 mmol) were dissolved in 2M methanolic hydrochloride (10 mL), respectively, and stirred at room temperature for 2H. At the end of the reaction, the solution was concentrated to dryness and the resulting residue was purified by C-18 column chromatography, respectively, using eluent system C to give the title product 150-P1 (m) -1- (aminomethyl) -7- (5- (2-cyano-3-cyclopropyloxy-6-fluoro-5- (prop-1-yn-1-yl) phenyl) -1-methyl-1H-pyrazol-4-yl) -4-carbonyl-3, 4-dihydropyrazine-5-carbonitrile (21.6 mg) and 150q-P2 (P) -1- (aminomethyl) -7- (5- (2-cyano-3-cyclopropyloxy-6-fluoro-5- (prop-1-yn-1-yl) phenyl) -1-methyl-1H-pyrazol-4-yl) -4-carbonyl-3, 4-dihydropyrazine-5-carbonitrile (20.6 mg) in 45.6% and 48.5% yields, respectively.
150-P1- (m) -1- (aminomethyl) -7- (5- (2-cyano-3-cyclopropyloxy-6-fluoro-5- (prop-1-yn-1-yl) phenyl) -1-methyl-1H-pyrazol-4-yl) -4-carbonyl-3, 4-dihydro-phthalazine-5-carbonitrile
MS m/z(ESI):494[M+1]
1H NMR(400MHz,DMSO)δ12.90(s,1H),8.43(s,1H),8.21(s,1H),7.90(d,1H),7.82(d,1H),4.18(dt,1H),3.88(s,2H),3.78(s,3H),2.19(s,3H),0.90(dd,2H),0.84–0.73(m,2H).
150-P2- (P) -1- (aminomethyl) -7- (5- (2-cyano-3-cyclopropyloxy-6-fluoro-5- (prop-1-yn-1-yl) phenyl) -1-methyl-1H-pyrazol-4-yl) -4-carbonyl-3, 4-dihydro-phthalazine-5-carbonitrile
MS m/z(ESI):494[M+1]
1H NMR(400MHz,DMSO)δ12.89(s,1H),8.43(s,1H),8.22(d,1H),7.90(d,1H),7.82(d,1H),4.18(tt,1H),3.85(s,2H),3.78(s,3H),2.19(s,3H),0.94–0.84(m,2H),0.85–0.73(m,2H).
Example 160
2- (4- (4-Aminomethyl-8- (3- (difluoromethylene) azetidin-1-yl) -1-oxo-1, 2-dihydro-phthalazin-6-yl) -1-methyl-1H-pyrazol-5-yl) -4-chloro-6-cyclopropyloxy-3-fluoro-cyanobenzene
First step
Bis (tert-butyl) carbamate 160a (960 mg,2.00mmol, synthesized using well-known method "patent WO 2023098439"), tris (dibenzylideneacetone) dipalladium (183mg, 0.2 mmol), 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl (95 mg,0.2 mmol) and cesium carbonate (98 mg,0.3 mmol) were dissolved in 10mL dioxane and reacted at 100 ℃ with stirring for 12 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system a to give ((7-bromo-5- (3- (difluoromethylene) azetidin-1-yl) -4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) carbamic acid tert-butyl ester 160b (556 mg), yield: 60.8%.
The synthesis of the sixth to eighth steps of reference example 1 gave the title product 2- (4- (4-aminomethyl-8- (3- (difluoromethylene) azetidin-1-yl) -1-oxo-1, 2-dihydropyrazin-6-yl) -1-methyl-1H-pyrazol-5-yl) -4-chloro-6-cyclopropyloxy-3-fluorocyanobenzene 160 (65 mg) in 9.4% yield by means of ((7-bromo-5- (3- (difluoromethylene) azetidin-1-yl) -4-oxo-3, 4-dihydropyrazin-1-yl) methyl) carbamic acid tert-butyl ester 160b (556 mg).
MS m/z(ESI):568[M+1]
Example 169
2- [4- [4- (Aminomethyl) -1-oxo-2H-phthalazin-6-yl ] ] -2- (2-methoxyethyl) pyrazol-3-yl ] -4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile
First step
2- (5-Bromopyrazol-1-yl) ethanol
Compound 5-bromo-1H-pyrazole 169a (2 g,13.61 mmol) and 2-bromoethanol (3.15 g,25.17 mmol) were dissolved in ethanol (30 mL), followed by the addition of potassium iodide (3.39 g,20.41 mmol), potassium hydroxide (1.53 g,27.23 mmol). The reaction was stirred at 100℃for 12 hours, the reaction solution was filtered, the cake was rinsed with ethanol (50 mL), the filtrate was concentrated under reduced pressure, water (60 mL) was added to the concentrated residue, extracted with ethyl acetate (60 mL. Times.3), the organic phases were combined, washed with saturated brine (60 mL. Times.3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system C to give 2- (5-bromopyrazol-1-yl) ethanol 169b (1.3 g) in 50.0% yield.
MS m/z(ESI):191[M+1]
1H NMR(400MHz,DMSO)δ7.54(d,1H),6.41(d,1H),4.91(t,1H),4.16(t,2H),3.72(q,2H).
Second step
5-Bromo-1- (2-methoxyethyl) pyrazole
Compound 2- (5-bromopyrazol-1-yl) ethanol 169b (1 g,5.23 mmol) was dissolved in DMF (20 mL), the reaction system was cooled to 0deg.C, sodium hydride (319 mg,10.47mmol,60% purity) was added, stirring was carried out at 0deg.C for 20 minutes, methyl iodide (2.23 g,15.70 mmol) was added, the reaction was stirred at 25deg.C for 2 hours, water (60 mL) was added to the reaction solution, extraction was carried out with ethyl acetate (60 mL. Times.3), the organic phases were combined, washed with saturated brine (60 mL. Times.3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system C to give 5-bromo-1- (2-methoxyethyl) pyrazole 169C (810 mg) in 75.5% yield.
MS m/z(ESI):205[M+1]
Third step
[2- (2-Methoxyethyl) pyrazol-3-yl ] boronic acid
The compound 5-bromo-1- (2-methoxyethyl) pyrazole 169C (500 mg,2.44 mmol) was dissolved in 1 '4-dioxane (10 mL), pinacol biborate (929 mg,3.66 mmol), potassium acetate (178 mg,7.32 mmol) were sequentially added, the reaction system was replaced with nitrogen for 3 times, and nitrogen protection was applied, and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (177 mg, 244. Mu. Mol) was rapidly added, the reaction was stirred at 100℃for 2 hours, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give the product [2- (2-methoxyethyl) pyrazol-3-yl ] boronic acid 169d (320 mg), yield: 76.7%.
MS m/z(ESI):171[M+1]
The synthesis of the third to sixth steps of reference example 9 was carried out by [2- (2-methoxyethyl) pyrazol-3-yl ] boronic acid 169d (320 mg,1.87 mmol) to give the title product 2- [4- [4- (aminomethyl) -1-oxo-2H-phthalazin-6-yl ] ] -2- (2-methoxyethyl) pyrazol-3-yl ] -4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile (40 mg), yield: 4.2%.
MS m/z(ESI):509[M+1]
1H NMR(400MHz,DMSO)δ12.22(s,1H),8.24(s,1H),8.18(dd,1H),7.94(d,1H),7.75-7.64(m,2H),4.24–4.10(m,3H),3.80(d,2H),3.68–3.59(m,2H),3.10(s,3H),1.64(s,2H),0.91(dddd,2H),0.81(dddt,2H).
Example 170
4- (Aminomethyl) -6- (5- (benzo [ c ] [1,2,5] oxadiazol-5-yl) -1-methyl-1H-pyrazol-4-yl) phthalazin-1 (2H) -one
First step
5- (1-Methyl-1H-pyrazol-5-yl) benzo [ c ] [1,2,5] oxadiazole
5-Bromobenzo [ C ] [1,2,5] oxadiazole 170a (250 mg,1.26 mmol), 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (288 mg,1.38 mmol), potassium phosphate (400 mg,1.88 mmol) and 1, 1-bis (diphenylphosphine) bis-iron palladium dichloride (91 mg,0.13 mmol) were dispersed in a mixed solvent of 4mL dioxane and 2mL water, and the reaction was stirred at 100℃for 1.5H. The reaction solution was poured into 50mL of water to quench, extracted with ethyl acetate (50 mL. Times.2), the organic phases were combined, washed with saturated sodium chloride solution (50 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 5- (1-methyl-1H-pyrazol-5-yl) benzo [ c ] [1,2,5] oxadiazol 170B (250 mg), yield: 99.4%. MS m/z (ESI) 201[ M+1]
Second step
5- (4-Bromo-1-methyl-1H-pyrazol-5-yl) benzo [ c ] [1,2,5] oxadiazole
5- (1-Methyl-1H-pyrazol-5-yl) benzo [ c ] [1,2,5] oxadiazole 170b (250 mg,1.25 mmol) and N-bromosuccinimide (248 mg,1.40 mmol) were dissolved in 5mL dichloromethane and reacted at room temperature with stirring for 0.5H. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 5- (4-bromo-1-methyl-1H-pyrazol-5-yl) benzo [ c ] [1,2,5] oxadiazole 170c (201 mg), yield: 56.9%.
MS m/z(ESI):279[M+1]
Third step
5- (1-Methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-5-yl) benzo [ c ] [1,2,5] oxadiazole
5- (4-Bromo-1-methyl-1H-pyrazol-5-yl) benzo [ C ] [1,2,5] oxadiazole 170C (80 mg,0.29 mmol), pinacol biborate (73 mg,0.29 mmol), potassium acetate (42 mg,0.42 mmol) and 1, 1-bis (diphenylphosphino) ferrocene palladium dichloride (21 mg,0.03 mmol) were dissolved in 3mL dioxane and reacted at 100℃with stirring for 3H. The reaction solution was poured into 50mL of water to quench, extracted with ethyl acetate (50 mL. Times.2), the organic phases were combined, washed with saturated sodium chloride solution (50 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 5- (1-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-5-yl) benzo [ c ] [1,2,5] oxadiazole 170d (22 mg), yield: 23.5%.
MS m/z(ESI):327.1[M+1]
Fourth step
4- (Tert-butylcarbamoylmethyl) -6- (5- (benzo [ c ] [1,2,5] oxadiazol-5-yl) -1-methyl-1H-pyrazol-4-yl) phthalazin-1 (2H) -one
4- (Tert-butylcarbamoylmethyl) -6-bromophthalazin-1 (2H) -one (16 mg,0.05mmol, obtained by synthesis of well known methods WO 2022192745), 5- (1-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-5-yl) benzo [ C ] [1,2,5] oxadiazole 170d (15 mg,0.05 mmol), potassium phosphate (15 mg,0.08 mmol) and 1, 1-bis (diphenylphosphine) ferrocene palladium dichloride (3 mg, 0.04 mmol) were dissolved in 1mL dioxane and 0.5mL water and reacted with stirring at 100℃for 3H. The reaction solution was poured into 20mL of water to quench, extracted with ethyl acetate (20 mL. Times.2), the organic phases were combined, washed with saturated sodium chloride solution (20 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 4- (tert-butylcarbamoylmethyl) -6- (5- (benzo [ c ] [1,2,5] oxadiazol-5-yl) -1-methyl-1H-pyrazol-4-yl) phthalazin-1 (2H) -one 170e (18 mg), yield: 76.0%.
MS m/z(ESI):474[M+1]
Fifth step
4- (Aminomethyl) -6- (5- (benzo [ c ] [1,2,5] oxadiazol-5-yl) -1-methyl-1H-pyrazol-4-yl) phthalazine-1 (2H) propanoic acid
Ketone compounds
4- (Tert-butylcarbamoylmethyl) -6- (5- (benzo [ c ] [1,2,5] oxadiazol-5-yl) -1-methyl-1H-pyrazol-4-yl) phthalazin-1 (2H) -one 170e (18 mg,0.04 mmol) was dissolved in 1mL of dioxane and 0.5mL of 4M dioxane hydrochloride, and the reaction was stirred at room temperature for 1H. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system a to give the title product 4- (aminomethyl) -6- (5- (benzo [ c ] [1,2,5] oxadiazol-5-yl) -1-methyl-1H-pyrazol-4-yl) phthalazin-1 (2H) -one 170 (9 mg) in 63.4% yield.
MS m/z(ESI):374[M+1]
1H NMR(400MHz,DMSO)δ12.87(s,1H),8.40(s,2H),8.22(s,1H),8.16(d,1H),8.10(d,1H),7.89(s,1H),7.60(d,2H),7.41(d,1H),4.32(s,2H),3.90(s,3H).
Biological test evaluation
The invention is further illustrated below in conjunction with test examples, which are not meant to limit the scope of the invention.
Test example 1 determination of the inhibitory Effect of the Compounds of the invention on the cell proliferation Activity of HCT116 and MTAP Knockout HCT116
1.1 Experimental purposes the purpose of this test example was to measure the inhibition of the proliferation activity of compounds against HCT116 wild type and HCT116MTAP knockout cells.
1.2 Laboratory apparatus:
centrifuge (Eppendorf 5810R), microplate reader (BioTek Synergy H1 or PERKINELMER ENVISION), pipettor (Eppendorf or Rainin).
1.3 Experimental reagents:
HCT116 and MTAP Knockout HCT cells were purchased from Nanjac, bai, CELL TITER-Glo from Promega corporation under the designation G7573, mcCoy' 5A from Gibco under the designation 12330031, FBS from Gibco under the designation 10091148, PBS from Gibco under the designation 10010023, pancreatin from Gibco under the designation 25200056, and cell culture plates from Corning corporation under the designation 3610.
1.4 Experimental method:
When HCT116 and MTAP Knockout HCT a medium containing 10% fbs was used to culture HCT116 and MTAP Knockout HCT a cells to a suitable cell density, cells were collected, cells were adjusted to a suitable cell concentration using complete medium, cell suspensions were plated in 96 well plates, 90 μl per well, placed in 37 ℃ and 5% CO 2 incubator for overnight, compound solutions of different concentrations were prepared using DMSO and medium, vehicle controls were set, compound solutions were added to 96 well plates, 10 μl per well was placed in 37 ℃ and 5% CO 2 incubator for 72-240 hours, cellTiter-Glo solution was added, shaking and mixing were performed well, and reading was performed with a Synergy H1 or Envision enzyme marker.
1.5 Experimental data processing method:
The inhibition rate was calculated using the luminescence signal values, and the concentration and inhibition rate were fitted to a nonlinear regression curve using GRAPHPAD PRISM software, resulting in IC 50 values as shown in table 1.
Compounds of table 1 have inhibitory activity against HCT116 and MTAP Knockout HCT cell proliferation
1.6 Experimental conclusion:
The compound of the invention has obvious proliferation inhibition activity on MTAP-deleted tumor cells and has high selectivity on wild type cells.
Test example 2, balb/C mouse pharmacokinetic assay
2.1 Study purposes:
The pharmacokinetic behavior of the compounds in plasma in mice was studied orally at a dose of 30mg/kg using Balb/C mice as the test animals.
2.2 Test protocol
2.2.1 Test drug:
Compounds of the invention
2.2.2 Test animals:
Balb/C mice (3/example), male, shanghai Jieshijie laboratory animal Co., ltd., animal production license number (SCXK (Shanghai) 2013-0006N0.311620400001794).
2.2.3 Dosing:
Balb/C mice were 3, male, p.o. after one night fasted, at a dose of 30mg/kg and a dosing volume of 10mL/kg.
2.2.4 Sample collection:
mice were bled with 0.1mL of blood using the orbit at 0, 0.5, 1, 2,4, 6, 8 and 24 hours, placed in EDTA-K 2 tubes, centrifuged at 6000rpm at 4 ℃ for 6min to separate plasma, and stored at-80 ℃.
2.2.5 Sample treatment:
1) And adding 160uL of acetonitrile into 40uL of the plasma sample for precipitation, mixing, and centrifuging at 3500 Xg for 5-20 minutes.
2) The concentration of the test compound was analyzed by LC/MS/MS by taking 100uL of the supernatant solution after the treatment.
2.2.6 Liquid phase analysis:
Liquid phase conditions Shimadzu LC-20AD pump
Mass spectrometry conditions AB Sciex API 4000 Mass spectrometer
Chromatographic column phenomenex Gemiu um C18.times.4.6 mm
Mobile phase A solution is 0.1% formic acid aqueous solution, B solution is acetonitrile
Flow Rate 0.8mL/min
Elution time 0-4.0 minutes, eluent as follows:
2.3 test results
The pharmacokinetic parameters were calculated using WinNonlin 8.2 and the results are shown in the following table:
TABLE 2 pharmacokinetic parameters of intravenous administration of Compounds in mice
TABLE 3 pharmacokinetic parameters of oral administration of Compounds in mice
2.4 Conclusion of experiments
The compounds of the present invention have good blood plasma parameters in mice, and the compounds exhibit high oral exposure and high bioavailability.

Claims (10)

1.一种通式(I)所示的化合物、其立体异构体或其药学上可接受盐：1. A compound represented by general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof: L1选自键、-(CRaRb)n1-、-(CRaRb)n1O(CRaRb)n2-、-(CRaRb)n1S(CRaRb)n2-、-(CRaRb)n1NRc(CRaRb)n2-、-(CRaRb)n1C(O)(CRaRb)n2-、-(CRaRb)n1S(O)m2(CRaRb)n2-、-(CRaRb)n1C(O)NRc(CRaRb)n2-、-(CRaRb)n1NRcC(O)(CRaRb)n2-、-(CRaRb)n1-C3-12环烷基-(CRaRb)n2-、-(CRaRb)n1-3-12元杂环基-(CRaRb)n2-、-(CRaRb)n1-C6-12芳基-(CRaRb)n2-或-(CRaRb)n1-5-12元杂芳基-(CRaRb)n2-，所述的C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、-(CH2)n3-取代或未取代的C3-12环烷基、-(CH2)n3-取代或未取代的3-12元杂环基、-(CH2)n3-取代或未取代的C6-12芳基和-(CH2)n3-取代或未取代的5-12元杂芳基中的一个或多个取代基所取代；优选键、-(CRaRb)n1-、-(CRaRb)n1O(CRaRb)n2-、-(CRaRb)n1S(CRaRb)n2-、-(CRaRb)n1NRc(CRaRb)n2-、-(CRaRb)n1C(O)(CRaRb)n2-、-(CRaRb)n1S(O)m2(CRaRb)n2-、-(CRaRb)n1C(O)NRc(CRaRb)n2-、-(CRaRb)n1NRcC(O)(CRaRb)n2-、-(CRaRb)n1-C3-8环烷基-(CRaRb)n2-、-(CRaRb)n1-3-8元杂环基-(CRaRb)n2-、-(CRaRb)n1-C6-10芳基-(CRaRb)n2-或-(CRaRb)n1-5-10元杂芳基-(CRaRb)n2-，所述的C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、-(CH2)n3-取代或未取代的C3-8环烷基、-(CH2)n3-取代或未取代的3-8元杂环基、-(CH2)n3-取代或未取代的C6-10芳基和-(CH2)n3-取代或未取代的5-10元杂芳基中的一个或多个取代基所取代；L 1 is selected from bonds, -(CR a R b ) n1 -, -(CR a R b ) n1 O(CR a R b ) n2 -, -(CR a R b ) n1 S(CR a R b ) n2 -, -(CR a R b ) n1 NR c (CR a R b ) n2 -, -(CR a R b ) n1 C(O)(CR a R b ) n2 -, -(CR a R b ) n1 S(O) m2 (CR a R b ) n2 -, -(CR a R b ) n1 C(O)NR c (CR a R b ) n2 -, -(CR a R b ) n1 NR c C(O)(CR a R b ) n2 -, -(CR a R b ) n1 -C 3-12 cycloalkyl-(CR a R b ) n2 -, -(CR a R b ) n1 -3-12 membered heterocyclyl-( KR b ) n2- , -( CRaRb ) n1 - C6-12 aryl- ( CRaRb ) n2- , or -( CRaRb ) n1-5-12 membered heteroaryl-( CRa R b ) n2 -, the C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally substituted by deuterium, halogen, amino, Hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, -(CH 2 ) n3 -substituted or unsubstituted C 3-12 cycloalkyl, -(CH 2 ) n3 -substituted or unsubstituted 3-12 membered heterocyclic group, -(CH 2 ) n3 -substituted or unsubstituted C 6-12 aryl group and -(CH 2 ) n3 -substituted or unsubstituted 5-12 membered The heteroaryl group is substituted by one or more substituents; preferably a bond, -(CR a R b ) n1 -, -(CR a R b ) n1 O(CR a R b ) n2 -, -(CR a R b ) n1 S(CR a R b ) n2 -、-(CR a R b ) n1 NR c (CR a R b ) n2 -、-(CR a R b ) n1 C(O)(CR a R b ) n2 -、-(CR a R b ) n1 S(O) m2 (CR a R b ) n2 -、-(CR a R b ) n1 C(O)NR c (CR a R b ) n2 -、-( CR a R b ) n1 NR c C(O)(CR a R b ) n2 -, -(CR a R b ) n1 -C 3-8 cycloalkyl-(CR a R b ) n2 -, -(CR a R b ) n1 -3- 8-membered heterocyclic group -(CR a R b ) n2 -, -(CR a R b ) n1 -C 6-10 aryl group -(CR a R b ) n2 - or -(CR a R b ) n1 -5 -10-membered heteroaryl-(CR a R b ) n2 -, the C 3-8 cycloalkyl, 3-8-membered heterocyclic group, C 6-10 aryl and 5-10-membered heteroaryl, Optionally deuterated, halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1- 3 deuterated alkyl, C 1-3 haloalkyl, C C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, -(CH 2 ) n3 -substituted or unsubstituted C 3-8 cycloalkyl, -(CH 2 ) n3 -substituted or unsubstituted 3-8 membered heterocyclic group, -(CH 2 ) n3 -substituted or unsubstituted C 6-10 aryl group and -(CH 2 ) n3 -substituted substituted by one or more substituents of a substituted or unsubstituted 5-10 membered heteroaryl; R1a、R1b、R1c和R1e各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、-(CH2)n4-C3-12环烷基、-(CH2)n4-3-12元杂环基、-(CH2)n4-C6-12芳基、-(CH2)n4-5-12元杂芳基、-(CH2)n4ORd、-(CH2)n4NRdRe、-(CH2)n4C(O)Rd、-(CH2)n4C(O)NRdRe或-(CH2)n4P(O)RdRe，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基中的一个或多个取代基所取代；优选氢、氘、氟、氯、溴、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、-(CH2)n4-C3-8环烷基、-(CH2)n4-3-8元杂环基、-(CH2)n4-C6-10芳基、-(CH2)n4-5-10元杂芳基、-(CH2)n4ORd、-(CH2)n4NRdRe、-(CH2)n4C(O)Rd、-(CH2)n4C(O)NRdRe或-(CH2)n4P(O)RdRe，所述的氨基、C1-3烷基、C2-6烯基、C2-6炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代基所取代；R 1a , R 1b , R 1c and R 1e are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, -(CH 2 ) n4 -C 3-12 cycloalkyl, -(CH 2 ) n4 -3-12 membered heterocyclyl, -(CH 2 ) n4 -C 6-12 aryl, -(CH 2 ) n4 -5-12 membered heteroaryl, -(CH 2 ) n4 OR d , -(CH 2 ) n4 NR d Re , -(CH 2 ) n4 n4 C(O)R d , -(CH 2 ) n4 C(O)NR d R e or -(CH 2 ) n4 P(O)R d R e , the amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 The alkyl radicals are substituted with one or more substituents selected from the group consisting of C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, -(CH 2 ) n4 -C 3-8 cycloalkyl, -(CH 2 ) n4 -3-8 membered heterocyclyl, -(CH 2 ) n4 -C the amino , C 1-3 alkyl , C 2-6 alkenyl , C 2-6 alkynyl , C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy , C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano , C 3-8 cycloalkyl , 3-8 membered heterocyclyl , C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted with one or more substituents selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl , 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl; R1d选自氢、氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、-(CH2)n4-C3-12环烷基、-(CH2)n4-3-12元杂环基、-(CH2)n4-C6-12芳基、-(CH2)n4-5-12元杂芳基、-(CH2)n4ORd、-(CH2)n4NRdRe、-(CH2)n4C(O)Rd、-(CH2)n4S(O)m3Rd、-(CH2)n4N＝S(O)m3RdRe、-(CH2)n4N＝S(O)m3Rd、-(CH2)n4C(O)NRdRe或-(CH2)n4P(O)RdRe，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基中的一个或多个取代基所取代；优选氢、氘、氟、氯、溴、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、-(CH2)n4-C3-8环烷基、-(CH2)n4-3-8元杂环基、-(CH2)n4-C6-10芳基、-(CH2)n4-5-10元杂芳基、-(CH2)n4ORd、-(CH2)n4NRdRe、-(CH2)n4C(O)Rd、-(CH2)n4C(O)NRdRe或-(CH2)n4P(O)RdRe，所述的氨基、C1-3烷基、C2-6烯基、C2-6炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代基所取代；R 1d is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, -(CH 2 ) n4 -C 3-12 cycloalkyl, -(CH 2 ) n4 -3-12 membered heterocyclyl, -(CH 2 ) n4 -C 6-12 aryl, -(CH 2 ) n4 -5-12 membered heteroaryl, -(CH 2 ) n4 OR d , -(CH 2 ) n4 NR d R e , -(CH 2 ) n4 C(O)R d , -(CH 2 ) n4 S (O) m3Rd , -( CH2 ) n4N = S (O) m3RdRe , -(CH2) n4N =S(O) m3Rd , -( CH2 ) n4C (O) NRdRe or -( CH2 ) n4P (O) RdRe , the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 alkyl substituted with cyano , C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl and 5-12 membered heteroaryl, optionally substituted with deuterium, halogen, amino , hydroxyl, cyano, nitro, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 alkyl substituted with cyano, C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl and 5-12 membered heteroaryl The alkyl radicals are substituted with one or more substituents selected from C 2-6 alkenyl, C 2-6 alkynyl, oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl; preferably hydrogen , deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, -(CH 2 ) n4 -C -(CH 2 ) n4 -3-8 membered cycloalkyl, -(CH 2 ) n4 -3-8 membered heterocyclyl, -(CH 2 ) n4 -C 6-10 aryl, -(CH 2 ) n4 -5-10 membered heteroaryl, -(CH 2 ) n4 OR d , -(CH 2 ) n4 NR d R e , -(CH 2 ) n4 C(O)R d , -(CH 2 ) n4 C(O)NR d R e or -(CH 2 ) n4 P(O)R d R e , the amino, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted with one or more substituents selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy , C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl; 或者R1d和R1e与其相邻的原子、R1c和R1d与其相邻的原子、R1b和R1c与其相邻的原子或R1a和R1b与其相邻的原子链接形成C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基，任选进一步被氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基中的一个或多个取代基所取代；优选形成C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基，任选进一步被氘、卤素、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代基所取代；or R 1d and R 1e and the adjacent atoms, R 1c and R 1d and the adjacent atoms, R 1b and R 1c and the adjacent atoms, or R 1a and R 1b and the adjacent atoms are linked to form a C 3-12 cycloalkyl, a 3-12 membered heterocyclyl, a C 6-12 aryl and a 5-12 membered heteroaryl, which is optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano, C 1-6 alkyl , C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl. The alkyl radicals are substituted with one or more substituents selected from C 6-12 aryl and 5-12 membered heteroaryl; preferably forming C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally further substituted with one or more substituents selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl; R2选自氢、氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基、5-12元杂芳基、-(CH2)n4ORd、-(CH2)n4NRdRe、-(CH2)n4C(O)Rd、-(CH2)n4C(O)NRdRe或-(CH2)n4P(O)RdRe，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基中的一个或多个取代基所取代；优选氢、氘、氟、氯、溴、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)n4ORd、-(CH2)n4NRdRe、-(CH2)n4C(O)Rd、-(CH2)n4C(O)NRdRe或-(CH2)n4P(O)RdRe，所述的氨基、C1-3烷基、C2-6烯基、C2-6炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代基所取代； R2 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, oxo, thio, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 alkyl substituted with cyano, C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl, 5-12 membered heteroaryl, -(CH2)n4ORd, -(CH2)n4NRdRe, -(CH2)n4C(O)Rd, -( CH2 ) n4C( O )NRdRe or -( CH2 ) n4P ( O ) RdRe , wherein the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, oxo, thio, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy , halogenated C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 alkyl substituted with cyano, C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl, 5-12 membered heteroaryl, -( CH2 ) n4ORd , -(CH2)n4NRdRe, -( CH2 )n4C(O)Rd, -(CH2)n4C(O) NRdRe or -( CH2 ) n4P (O) RdRe . C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C The alkylene group may be substituted with one or more substituents selected from C 6-12 aryl and 5-12 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy , C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -(CH 2 ) n4 OR d , -(CH 2 ) n4 NR d R e , -(CH 2 ) n4 C(O)R d , -(CH 2 ) n4 C(O)NR d R e or -(CH 2 ) n4 P ( O) RdRe , the amino, C1-3 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkyl, C1-3 alkyl substituted with cyano, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl and 5-10 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, oxo, thio, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkyl, C1-3 alkyl substituted with cyano, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl and 5-10 membered heteroaryl substituted by one or more substituents selected from 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl; Ra、Rb、Rc、Rd和Re各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、-C(O)-C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基、5-12元杂芳基、＝N-O-Raa和＝RaaRbb中的一个或多个取代基所取代；优选氢、氘、氟、氯、溴、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、-C(O)-C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基，所述的氨基、C1-3烷基、C2-6烯基、C2-6炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代基所取代； Ra , Rb , Rc , Rd and Re are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 alkyl substituted with cyano, -C(O) -C1-6 alkyl, C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl or 5-12 membered heteroaryl, wherein the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, C C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally substituted with one or more substituents of deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl, =NOR aa and =R aa R bb; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl, =NOR aa and =R aa R bb ; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy , C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, -C(O)-C 1-3 alkyl, C 3-8 cycloalkyl , 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, the amino, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted with one or more substituents selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl , 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl; 或者Rd和Re与其相邻的原子链接形成C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基，任选进一步被氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基、5-12元杂芳基、＝N-O-Raa和＝RaaRbb中的一个或多个取代基所取代；优选形成C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基，任选进一步被氘、卤素、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、＝N-O-Raa和＝RaaRbb中的一个或多个取代基所取代；or R d and Re are linked with adjacent atoms to form C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally further substituted by deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy , C 1-6 haloalkoxy , C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl, =NOR aa and = RaaRbb ; preferably C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C C 6-10 aryl and 5-10 membered heteroaryl, optionally further substituted with one or more substituents of deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy , C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl , 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, =NOR aa and =R aa R bb ; Raa和Rbb各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、-C(O)-C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基中的一个或多个取代基所取代；优选氢、氘、氟、氯、溴、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、-C(O)-C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基，所述的氨基、C1-3烷基、C2-6烯基、C2-6炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代基所取代； Raa and Rbb are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 alkyl substituted with cyano, -C(O) -C1-6 alkyl, C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl or 5-12 membered heteroaryl, wherein the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 alkyl substituted with cyano, -C( O ) -C1-6 alkyl, C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl or 5-12 membered heteroaryl The invention also comprises a C 3-12 cycloalkyl, a 3-12 membered heterocyclyl, a C 6-12 aryl and a 5-12 membered heteroaryl, which are optionally substituted by one or more substituents of deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, a 3-12 membered heterocyclyl, a C 6-12 aryl and a 5-12 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, -C(O)-C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, the amino, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C The alkyl radical is substituted with one or more of C 2-4 alkynyl, oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl; m1选自0、1或2；m1 is selected from 0, 1 or 2; m2选自0、1或2；m2 is selected from 0, 1 or 2; n1选自0、1、2、3或4；n1 is selected from 0, 1, 2, 3 or 4; n2选自0、1、2、3或4；n2 is selected from 0, 1, 2, 3 or 4; n3选自0、1、2、3或4；n3 is selected from 0, 1, 2, 3 or 4; n4选自0、1、2、3或4；n4 is selected from 0, 1, 2, 3 or 4; m3选自0、1或2；且m3 is selected from 0, 1 or 2; and x选自0、1、2、3或4。x is selected from 0, 1, 2, 3 or 4. 2.根据权利要求1所述的通式所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，L1选自-(CRaRb)NRc-、-NRc(CRaRb)-、-C(O)NRc-、-NRcC(O)-、5-10元杂芳基、-(CRaRb)-5-10元杂芳基或5-10元杂芳基-(CRaRb)-，所述的5-10元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、取代或未取代的C3-8环烷基、取代或未取代的3-8元杂环基、取代或未取代的C6-10芳基和取代或未取代的5-10元杂芳基中的一个或多个取代基所取代；2. The compound of the general formula according to claim 1, its stereoisomer or pharmaceutically acceptable salt thereof, characterized in that L1 is selected from -( CRaRb ) NRc- , -NRc(CRaRb)-, -C (O) NRc- , -NRcC ( O )-, 5-10 membered heteroaryl, -( CRaRb ) -5-10 membered heteroaryl or 5-10 membered heteroaryl-( CRaRb ) -, wherein the 5-10 membered heteroaryl is optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, oxo, thio, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkyl, cyano substituted C1-3 alkyl, substituted or unsubstituted C substituted by one or more substituents selected from 3-8 membered cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted C 6-10 aryl and substituted or unsubstituted 5-10 membered heteroaryl; Ra、Rb和Rc如上述任一权利要求所定义。 Ra , Rb and Rc are as defined in any of the preceding claims. 3.根据权利要求1或2所述的化合物、其立体异构体或其药学上可接受盐，其特征在于所述化合物进一步如通式(II)所示：3. The compound according to claim 1 or 2, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that the compound is further represented by general formula (II): 环A选自 Ring A is selected from R3选自氢、氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、-(CH2)n5-C3-12环烷基、-(CH2)n5-3-12元杂环基、-(CH2)n5-C6-12芳基、-(CH2)n5-5-12元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基中的一个或多个取代基所取代；优选氢、氘、卤素、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、-(CH2)n5-C3-8环烷基、-(CH2)n5-3-8元杂环基、-(CH2)n5-C6-10芳基或-(CH2)n5-5-10元杂芳基，所述的氨基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代基所取代； R3 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, oxo, thio, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 alkyl substituted with cyano, -( CH2 ) n5 - C3-12 cycloalkyl, -( CH2 ) n5-3-12 membered heterocyclyl, -( CH2 ) n5 - C6-12 aryl, -( CH2 ) n5-5-12 membered heteroaryl, wherein the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally substituted with one or more substituents selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl; preferably hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl; preferably hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, -(CH 2 ) n5 -C 3-8 cycloalkyl, -(CH 2 ) n5 -3-8 membered heterocyclyl, -(CH 2 ) n5 -C 6-10 aryl or -(CH 2 ) n5 -5-10 membered heteroaryl, the amino, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl , C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted with one or more substituents selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy , C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl; n5选自0、1、2、3或4；n5 is selected from 0, 1, 2, 3 or 4; R1a、R1b、R1c、R1d、R1e、R2和x如上述任意权利要求所述。R 1a , R 1b , R 1c , R 1d , R 1e , R 2 and x are as described in any of the preceding claims. 4.根据权利要求1所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，进一步如通式(VI)所示：4. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that it is further represented by general formula (VI): R1a、R1b、R1c和R1e各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、-(CH2)n4-C3-12环烷基、-(CH2)n4-3-12元杂环基、-(CH2)n4-C6-12芳基、-(CH2)n4-5-12元杂芳基、-(CH2)n4ORd、-(CH2)n4NRdRe、-(CH2)n4C(O)Rd、-(CH2)n4C(O)NRdRe或-(CH2)n4P(O)RdRe，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基中的一个或多个取代基所取代；优选氢、氘、氟、氯、溴、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、-(CH2)n4-C3-8环烷基、-(CH2)n4-3-8元杂环基、-(CH2)n4-C6-10芳基、-(CH2)n4-5-10元杂芳基、-(CH2)n4ORd、-(CH2)n4NRdRe、-(CH2)n4C(O)Rd、-(CH2)n4C(O)NRdRe或-(CH2)n4P(O)RdRe，所述的氨基、C1-3烷基、C2-6烯基、C2-6炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代基所取代；R 1a , R 1b , R 1c and R 1e are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, -(CH 2 ) n4 -C 3-12 cycloalkyl, -(CH 2 ) n4 -3-12 membered heterocyclyl, -(CH 2 ) n4 -C 6-12 aryl, -(CH 2 ) n4 -5-12 membered heteroaryl, -(CH 2 ) n4 OR d , -(CH 2 ) n4 NR d Re , -(CH 2 ) n4 n4 C(O)R d , -(CH 2 ) n4 C(O)NR d R e or -(CH 2 ) n4 P(O)R d R e , the amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 The alkyl radicals are substituted with one or more substituents selected from the group consisting of C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, -(CH 2 ) n4 -C 3-8 cycloalkyl, -(CH 2 ) n4 -3-8 membered heterocyclyl, -(CH 2 ) n4 -C the amino , C 1-3 alkyl , C 2-6 alkenyl , C 2-6 alkynyl , C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy , C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano , C 3-8 cycloalkyl , 3-8 membered heterocyclyl , C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted with one or more substituents selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl , 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl; R1d选自氢、氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、-(CH2)n4-C3-12环烷基、-(CH2)n4-3-12元杂环基、-(CH2)n4-C6-12芳基、-(CH2)n4-5-12元杂芳基、-(CH2)n4ORd、-(CH2)n4NRdRe、-(CH2)n4C(O)Rd、-(CH2)n4S(O)m3Rd、-(CH2)n4N＝S(O)m3RdRe、-(CH2)n4N＝S(O)m3Rd、-(CH2)n4C(O)NRdRe或-(CH2)n4P(O)RdRe，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基中的一个或多个取代基所取代；优选氢、氘、氟、氯、溴、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、-(CH2)n4-C3-8环烷基、-(CH2)n4-3-8元杂环基、-(CH2)n4-C6-10芳基、-(CH2)n4-5-10元杂芳基、-(CH2)n4ORd、-(CH2)n4NRdRe、-(CH2)n4C(O)Rd、-(CH2)n4C(O)NRdRe或-(CH2)n4P(O)RdRe，所述的氨基、C1-3烷基、C2-6烯基、C2-6炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代基所取代；R 1d is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, -(CH 2 ) n4 -C 3-12 cycloalkyl, -(CH 2 ) n4 -3-12 membered heterocyclyl, -(CH 2 ) n4 -C 6-12 aryl, -(CH 2 ) n4 -5-12 membered heteroaryl, -(CH 2 ) n4 OR d , -(CH 2 ) n4 NR d R e , -(CH 2 ) n4 C(O)R d , -(CH 2 ) n4 S (O) m3Rd , -( CH2 ) n4N = S (O) m3RdRe , -(CH2) n4N =S(O) m3Rd , -( CH2 ) n4C (O) NRdRe or -( CH2 ) n4P (O) RdRe , the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 alkyl substituted with cyano , C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl and 5-12 membered heteroaryl, optionally substituted with deuterium, halogen, amino , hydroxyl, cyano, nitro, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 alkyl substituted with cyano, C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl and 5-12 membered heteroaryl The alkyl radicals are substituted with one or more substituents selected from C 2-6 alkenyl, C 2-6 alkynyl, oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl; preferably hydrogen , deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, -(CH 2 ) n4 -C -(CH 2 ) n4 -3-8 membered cycloalkyl, -(CH 2 ) n4 -3-8 membered heterocyclyl, -(CH 2 ) n4 -C 6-10 aryl, -(CH 2 ) n4 -5-10 membered heteroaryl, -(CH 2 ) n4 OR d , -(CH 2 ) n4 NR d R e , -(CH 2 ) n4 C(O)R d , -(CH 2 ) n4 C(O)NR d R e or -(CH 2 ) n4 P(O)R d R e , the amino, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted with one or more substituents selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy , C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl; 或者R1d和R1e与其相邻的原子、R1c和R1d与其相邻的原子、R1b和R1c与其相邻的原子或R1a和R1b与其相邻的原子链接形成C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基，任选进一步被氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基中的一个或多个取代基所取代；优选形成C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基，任选进一步被氘、卤素、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代基所取代；or R 1d and R 1e and the adjacent atoms, R 1c and R 1d and the adjacent atoms, R 1b and R 1c and the adjacent atoms, or R 1a and R 1b and the adjacent atoms are linked to form a C 3-12 cycloalkyl, a 3-12 membered heterocyclyl, a C 6-12 aryl and a 5-12 membered heteroaryl, which is optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano, C 1-6 alkyl , C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl. The alkyl radicals are substituted with one or more substituents selected from C 6-12 aryl and 5-12 membered heteroaryl; preferably forming C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally further substituted with one or more substituents selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl; R2a和R2b各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、-(CH2)n7C3-12环烷基、-(CH2)n73-12元杂环基、-(CH2)n7C6-12芳基、-(CH2)n75-12元杂芳基、-(CH2)n7ORm、-(CH2)n7NRmRn、-(CH2)n7C(O)Rm、-(CH2)n7C(O)NRmRn或-(CH2)n7P(O)RmRn，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基中的一个或多个取代基所取代；优选氢、氘、氟、氯、溴、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、-(CH2)n7C3-8环烷基、-(CH2)n73-8元杂环基、-(CH2)n7C6-10芳基、-(CH2)n75-10元杂芳基、-(CH2)n7ORm、-(CH2)n7NRmRn、-(CH2)n7C(O)Rm、-(CH2)n7C(O)NRmRn或-(CH2)n7P(O)RmRn，所述的氨基、C1-3烷基、C2-6烯基、C2-6炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代基所取代；R 2a and R 2b are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano , -(CH 2 ) n7 C 3-12 cycloalkyl, -(CH 2 ) n7 3-12 membered heterocyclyl, -(CH 2 ) n7 C 6-12 aryl, -(CH 2 ) n7 5-12 membered heteroaryl, -(CH 2 ) n7 OR m , -(CH 2 ) n7 NR m R n , -(CH 2 ) n7 C(O)R m , -(CH 2 wherein the amino, C 1-6 alkyl , C 2-6 alkenyl, C 2-6 alkynyl , C 1-6 deuterated alkyl , C 1-6 haloalkyl , C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano , C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl are optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl , oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy , C The alkyl group may be substituted with one or more substituents selected from C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, -(CH 2 ) n7 C 3-8 cycloalkyl, -(CH 2 ) n7 3-8 membered heterocyclyl, -(CH 2 ) n7 C 6-10 aryl, -(CH 2 ) n7 5-10 membered heteroaryl, -(CH 2 ) n7 wherein the amino , C 1-3 alkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 1-3 deuterated alkyl , C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl are selected from the group consisting of: -(CH 2 ) n7 OR m , -(CH 2 ) n7 NR m R n , -(CH 2 ) n7 C(O) R m , -(CH 2 ) n7 C(O)NR m R n or -(CH 2 ) n7 P(O)R m R n , wherein the amino, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl , C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl are selected from the group consisting of: -(CH 2 ) n7 OR m , -(CH 2 ) n7 NR m R n , -(CH 2 ) n7 C(O)R m , -(CH 2 ) n7 C(O)NR m R n or -(CH 2 ) n7 P(O)R m R n The alkyl radical is substituted with one or more of C 2-4 alkynyl, oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl; R3a选自氢、氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、-(CH2)n8-C3-12环烷基、-(CH2)n8-3-12元杂环基、-(CH2)n8-C6-12芳基、-(CH2)n8-5-12元杂芳基、-(CH2)n8ORp、-(CH2)n8NRpRq、-(CH2)n8C(O)Rp、-(CH2)n8C(O)NRpRq或-(CH2)n8P(O)RpRq，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基中的一个或多个取代基所取代；优选氢、氘、氟、氯、溴、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、-(CH2)n8-C3-8环烷基、-(CH2)n8-3-8元杂环基、-(CH2)n8-C6-10芳基、-(CH2)n8-5-10元杂芳基、-(CH2)n8ORp、-(CH2)n8NRpRq、-(CH2)n8C(O)Rp、-(CH2)n8C(O)NRpRq或-(CH2)n8P(O)RpRq，所述的氨基、C1-3烷基、C2-6烯基、C2-6炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代基所取代；R 3a is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, -(CH 2 ) n8 -C 3-12 cycloalkyl, -(CH 2 ) n8 -3-12 membered heterocyclyl, -(CH 2 ) n8 -C 6-12 aryl, -(CH 2 ) n8 -5-12 membered heteroaryl, -(CH 2 ) n8 OR p , -(CH 2 ) n8 NR p R q , -(CH 2 ) n8 C(O)R p , -(CH 2 ) n8 C(O) NRpRq or - ( CH2 ) n8P (O ) RpRq , the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 alkyl substituted with cyano, C3-12 cycloalkyl , 3-12 membered heterocyclyl, C6-12 aryl and 5-12 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, oxo, thio, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C The alkyl group may be substituted with one or more substituents selected from C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, -(CH 2 ) n8 -C 3-8 cycloalkyl, -(CH 2 ) n8 -3-8 membered heterocyclyl, -(CH 2 ) n8 -C 6-10 aryl, -(CH 2 ) n8 -5-10 membered heteroaryl, -(CH 2 ) n8 OR p , -(CH 2 ) n8 NR p R q , -(CH 2 ) n8 C(O)R p , -(CH 2 ) n8 C(O)NR p R q or -(CH 2 ) n8 P(O)R p R q , the amino, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C The alkyl radical is substituted with one or more of C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy , C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl; R3b和R3c选自氢、氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、-(CH2)n8-C3-12环烷基、-(CH2)n8-3-12元杂环基、-(CH2)n8-C6-12芳基、-(CH2)n8-5-12元杂芳基、-(CH2)n8ORp、-(CH2)n8NRpRq、-(CH2)n8C(O)Rp、-(CH2)n8C(O)NRpRq或-(CH2)n8P(O)RpRq，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基中的一个或多个取代基所取代；优选氢、氘、氟、氯、溴、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、-(CH2)n8-C3-8环烷基、-(CH2)n8-3-8元杂环基、-(CH2)n8-C6-10芳基、-(CH2)n8-5-10元杂芳基、-(CH2)n8ORp、-(CH2)n8NRpRq、-(CH2)n8C(O)Rp、-(CH2)n8C(O)NRpRq或-(CH2)n8P(O)RpRq，所述的氨基、C1-3烷基、C2-6烯基、C2-6炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代基所取代；R 3b and R 3c are selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl , oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, -(CH 2 ) n8 -C 3-12 cycloalkyl, -(CH 2 ) n8 -3-12 membered heterocyclyl, -(CH 2 ) n8 -C 6-12 aryl, -(CH 2 ) n8 -5-12 membered heteroaryl, -(CH 2 ) n8 OR p , -(CH 2 ) n8 NR p R q , -(CH 2 ) n8 C(O)R p , -(CH 2 wherein the amino , C 1-6 alkyl , C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl , C 1-6 haloalkyl , C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano , C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl are optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl , oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy , C The alkyl group may be substituted with one or more substituents selected from C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, -(CH 2 ) n8 -C 3-8 cycloalkyl, -(CH 2 ) n8 -3-8 membered heterocyclyl, -(CH 2 ) n8 -C 6-10 aryl, -(CH 2 ) n8 -5-10 membered heteroaryl, -(CH 2 ) n8 OR p , -(CH 2 ) n8 NR p R q , -(CH 2 ) n8 C(O)R p , -(CH 2 ) n8 C(O)NR p R q or -(CH 2 ) n8 P(O)R p R q , the amino, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C The alkyl radical is substituted with one or more of C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy , C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl; Rd、Re、Rm、Rn、Rp和Rq各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、-C(O)-C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基、5-12元杂芳基、＝N-O-Raa和＝RaaRbb中的一个或多个取代基所取代；优选氢、氘、氟、氯、溴、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、-C(O)-C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基，所述的氨基、C1-3烷基、C2-6烯基、C2-6炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代基所取代；R d , Re , R m , R n , R p and R q are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, -C(O)-C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, wherein the amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy , C C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally substituted with one or more substituents of deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl, =NOR aa and =R aa R bb; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl, =NOR aa and =R aa R bb ; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy , C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, -C(O)-C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, the amino, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted with one or more substituents selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl , 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl; 或者Rd和Re与其相邻的原子链接形成C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基，任选进一步被氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基、5-12元杂芳基、＝N-O-Raa和＝RaaRbb中的一个或多个取代基所取代；优选形成C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基，任选进一步被氘、卤素、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、＝N-O-Raa和＝RaaRbb中的一个或多个取代基所取代；or R d and Re are linked with adjacent atoms to form C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally further substituted by deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy , C 1-6 haloalkoxy , C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl, =NOR aa and = RaaRbb ; preferably C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C C 6-10 aryl and 5-10 membered heteroaryl, optionally further substituted with one or more substituents of deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy , C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl , 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, =NOR aa and =R aa R bb ; 或者Rp和Rq与其相邻的原子链接形成C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基，任选进一步被氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基、5-12元杂芳基、＝N-O-Raa和＝RaaRbb中的一个或多个取代基所取代；优选形成C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基，任选进一步被氘、卤素、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、＝N-O-Raa和＝RaaRbb中的一个或多个取代基所取代；or R p and R q are linked with adjacent atoms to form C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally further substituted by deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl, =NOR aa and =R aa R bb; preferably forming C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 2-6 alkynyl, oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl, = NOR aa and =R aa R bb ; C 6-10 aryl and 5-10 membered heteroaryl, optionally further substituted with one or more substituents of deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy , C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl , 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, =NOR aa and =R aa R bb ; Raa和Rbb各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、-C(O)-C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基中的一个或多个取代基所取代；优选氢、氘、氟、氯、溴、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、-C(O)-C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基，所述的氨基、C1-3烷基、C2-6烯基、C2-6炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代基所取代； Raa and Rbb are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 alkyl substituted with cyano, -C(O) -C1-6 alkyl, C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl or 5-12 membered heteroaryl, wherein the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 alkyl substituted with cyano, -C(O) -C1-6 alkyl, C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl or 5-12 membered heteroaryl The invention also comprises a C 3-12 cycloalkyl, a 3-12 membered heterocyclyl, a C 6-12 aryl and a 5-12 membered heteroaryl, which are optionally substituted by one or more substituents of deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, a 3-12 membered heterocyclyl, a C 6-12 aryl and a 5-12 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, -C(O)-C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, the amino, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C The alkyl radical is substituted with one or more of C 2-4 alkynyl, oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl; n4选自0、1、2、3或4；n4 is selected from 0, 1, 2, 3 or 4; n7选自0、1、2、3或4；且n7 is selected from 0, 1, 2, 3 or 4; and n8选自0、1、2、3或4；n8 is selected from 0, 1, 2, 3 or 4; m3选自0、1或2。m3 is selected from 0, 1 or 2. 5.根据权利要求1所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，进一步如通式(VIII)所示：5. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that it is further represented by general formula (VIII): 环F选自5-12元杂环基或5-12元杂芳基；优选5-6元单环杂环基、5-10元螺杂环基、7-10元稠杂环基或7-10元桥杂环基；Ring F is selected from 5-12 membered heterocyclyl or 5-12 membered heteroaryl; preferably 5-6 membered monocyclic heterocyclyl, 5-10 membered spiro heterocyclyl, 7-10 membered fused heterocyclyl or 7-10 membered bridged heterocyclyl; R1a、R1b、R1c和R1e各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、-(CH2)n4-C3-12环烷基、-(CH2)n4-3-12元杂环基、-(CH2)n4-C6-12芳基、-(CH2)n4-5-12元杂芳基、-(CH2)n4ORd、-(CH2)n4NRdRe、-(CH2)n4C(O)Rd、-(CH2)n4C(O)NRdRe或-(CH2)n4P(O)RdRe，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基中的一个或多个取代基所取代；优选氢、氘、氟、氯、溴、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、-(CH2)n4-C3-8环烷基、-(CH2)n4-3-8元杂环基、-(CH2)n4-C6-10芳基、-(CH2)n4-5-10元杂芳基、-(CH2)n4ORd、-(CH2)n4NRdRe、-(CH2)n4C(O)Rd、-(CH2)n4C(O)NRdRe或-(CH2)n4P(O)RdRe，所述的氨基、C1-3烷基、C2-6烯基、C2-6炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代基所取代；R 1a , R 1b , R 1c and R 1e are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, -(CH 2 ) n4 -C 3-12 cycloalkyl, -(CH 2 ) n4 -3-12 membered heterocyclyl, -(CH 2 ) n4 -C 6-12 aryl, -(CH 2 ) n4 -5-12 membered heteroaryl, -(CH 2 ) n4 OR d , -(CH 2 ) n4 NR d Re , -(CH 2 ) n4 n4 C(O)R d , -(CH 2 ) n4 C(O)NR d R e or -(CH 2 ) n4 P(O)R d R e , the amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 The alkyl radicals are substituted with one or more substituents selected from the group consisting of C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, -(CH 2 ) n4 -C 3-8 cycloalkyl, -(CH 2 ) n4 -3-8 membered heterocyclyl, -(CH 2 ) n4 -C the amino , C 1-3 alkyl , C 2-6 alkenyl , C 2-6 alkynyl , C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy , C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano , C 3-8 cycloalkyl , 3-8 membered heterocyclyl , C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted with one or more substituents selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl , 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl; R2a和R2b各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、-(CH2)n7C3-12环烷基、-(CH2)n73-12元杂环基、-(CH2)n7C6-12芳基、-(CH2)n75-12元杂芳基、-(CH2)n7ORm、-(CH2)n7NRmRn、-(CH2)n7C(O)Rm、-(CH2)n7C(O)NRmRn或-(CH2)n7P(O)RmRn，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基中的一个或多个取代基所取代；优选氢、氘、氟、氯、溴、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、-(CH2)n7C3-8环烷基、-(CH2)n73-8元杂环基、-(CH2)n7C6-10芳基、-(CH2)n75-10元杂芳基、-(CH2)n7ORm、-(CH2)n7NRmRn、-(CH2)n7C(O)Rm、-(CH2)n7C(O)NRmRn或-(CH2)n7P(O)RmRn，所述的氨基、C1-3烷基、C2-6烯基、C2-6炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代基所取代；更优选甲基或环丙基；R 2a and R 2b are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano , -(CH 2 ) n7 C 3-12 cycloalkyl, -(CH 2 ) n7 3-12 membered heterocyclyl, -(CH 2 ) n7 C 6-12 aryl, -(CH 2 ) n7 5-12 membered heteroaryl, -(CH 2 ) n7 OR m , -(CH 2 ) n7 NR m R n , -(CH 2 ) n7 C(O)R m , -(CH 2 wherein the amino, C 1-6 alkyl , C 2-6 alkenyl, C 2-6 alkynyl , C 1-6 deuterated alkyl , C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano , C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl are optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl , oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy , C The alkyl group may be substituted with one or more substituents selected from C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, -(CH 2 ) n7 C 3-8 cycloalkyl, -(CH 2 ) n7 3-8 membered heterocyclyl, -(CH 2 ) n7 C 6-10 aryl, -(CH 2 ) n7 5-10 membered heteroaryl, -(CH 2 ) n7 wherein the amino , C 1-3 alkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 1-3 deuterated alkyl , C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl are selected from the group consisting of: -(CH 2 ) n7 OR m , -(CH 2 ) n7 NR m R n , -(CH 2 ) n7 C(O) R m , -(CH 2 ) n7 C(O)NR m R n or -(CH 2 ) n7 P(O)R m R n , wherein the amino, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl are selected from the group consisting of: -(CH 2 ) n7 OR m , -(CH 2 ) n7 NR m R n , -(CH 2 ) n7 C(O)R m , -(CH 2 ) n7 C(O)NR m R n or -(CH 2 ) n7 P(O)R m R n The alkyl group is substituted with one or more of C 2-4 alkynyl, oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl; more preferably methyl or cyclopropyl; R3a选自氢、氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、-(CH2)n8-C3-12环烷基、-(CH2)n8-3-12元杂环基、-(CH2)n8-C6-12芳基、-(CH2)n8-5-12元杂芳基、-(CH2)n8ORp、-(CH2)n8NRpRq、-(CH2)n8C(O)Rp、-(CH2)n8C(O)NRpRq或-(CH2)n8P(O)RpRq，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基中的一个或多个取代基所取代；优选氢、氘、氟、氯、溴、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、-(CH2)n8-C3-8环烷基、-(CH2)n8-3-8元杂环基、-(CH2)n8-C6-10芳基、-(CH2)n8-5-10元杂芳基、-(CH2)n8ORp、-(CH2)n8NRpRq、-(CH2)n8C(O)Rp、-(CH2)n8C(O)NRpRq或-(CH2)n8P(O)RpRq，所述的氨基、C1-3烷基、C2-6烯基、C2-6炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代基所取代；更优选-CH2NH2、-CH2NHCH3、-CH2NHCH2CH3、-CH2OH、-C(O)NH2、 R 3a is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, -(CH 2 ) n8 -C 3-12 cycloalkyl, -(CH 2 ) n8 -3-12 membered heterocyclyl, -(CH 2 ) n8 -C 6-12 aryl, -(CH 2 ) n8 -5-12 membered heteroaryl, -(CH 2 ) n8 OR p , -(CH 2 ) n8 NR p R q , -(CH 2 ) n8 C(O)R p , -(CH 2 ) n8 C(O) NRpRq or - ( CH2 ) n8P (O ) RpRq , the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 alkyl substituted with cyano, C3-12 cycloalkyl , 3-12 membered heterocyclyl, C6-12 aryl and 5-12 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, oxo, thio, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C The alkyl group may be substituted with one or more substituents selected from C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, -(CH 2 ) n8 -C 3-8 cycloalkyl, -(CH 2 ) n8 -3-8 membered heterocyclyl, -(CH 2 ) n8 -C 6-10 aryl, -(CH 2 ) n8 -5-10 membered heteroaryl, -(CH 2 ) n8 OR p , -(CH 2 ) n8 NR p R q , -(CH 2 ) n8 C(O)R p , -(CH 2 ) n8 C(O)NR p R q or -(CH 2 ) n8 P(O)R p R q , the amino, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C The alkylene group is preferably substituted with one or more substituents selected from -CH2NH2, -CH2NHCH3 , -CH2NHCH2CH3, -CH2OH, -C ( O ) NH2, -CH2NHCH3 , -CH2OH , -C( O ) NH2, -CH2NHCH3 , -CH2OH , -C (O ) NH2 , -CH2NHCH3, -CH2NHCH2 ... R3b和R3c选自氢、氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、-(CH2)n8-C3-12环烷基、-(CH2)n8-3-12元杂环基、-(CH2)n8-C6-12芳基、-(CH2)n8-5-12元杂芳基、-(CH2)n8ORp、-(CH2)n8NRpRq、-(CH2)n8C(O)Rp、-(CH2)n8C(O)NRpRq或-(CH2)n8P(O)RpRq，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基中的一个或多个取代基所取代；优选氢、氘、氟、氯、溴、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、-(CH2)n8-C3-8环烷基、-(CH2)n8-3-8元杂环基、-(CH2)n8-C6-10芳基、-(CH2)n8-5-10元杂芳基、-(CH2)n8ORp、-(CH2)n8NRpRq、-(CH2)n8C(O)Rp、-(CH2)n8C(O)NRpRq或-(CH2)n8P(O)RpRq，所述的氨基、C1-3烷基、C2-6烯基、C2-6炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代基所取代；R 3b and R 3c are selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl , oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, -(CH 2 ) n8 -C 3-12 cycloalkyl, -(CH 2 ) n8 -3-12 membered heterocyclyl, -(CH 2 ) n8 -C 6-12 aryl, -(CH 2 ) n8 -5-12 membered heteroaryl, -(CH 2 ) n8 OR p , -(CH 2 ) n8 NR p R q , -(CH 2 ) n8 C(O)R p , -(CH 2 wherein the amino , C 1-6 alkyl , C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl , C 1-6 haloalkyl , C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano , C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl are optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl , oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy , C The alkyl group may be substituted with one or more substituents selected from C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, -(CH 2 ) n8 -C 3-8 cycloalkyl, -(CH 2 ) n8 -3-8 membered heterocyclyl, -(CH 2 ) n8 -C 6-10 aryl, -(CH 2 ) n8 -5-10 membered heteroaryl, -(CH 2 ) n8 OR p , -(CH 2 ) n8 NR p R q , -(CH 2 ) n8 C(O)R p , -(CH 2 ) n8 C(O)NR p R q or -(CH 2 ) n8 P(O)R p R q , the amino, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C The alkyl radical is substituted with one or more of C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy , C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl; R9选自氢、氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、-C(O)-C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基、5-12元杂芳基、-COORaa、＝N-O-Raa或＝RaaRbb，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基中的一个或多个取代基所取代；优选氢、氘、氟、氯、溴、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、-C(O)-C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、＝N-O-Raa或＝RaaRbb，所述的氨基、C1-3烷基、C2-6烯基、C2-6炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代基所取代； R is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, -C(O)-C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl, -COOR aa , =NOR aa or =R aa R bb , wherein the amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy , C C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally substituted with one or more substituents selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl , 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl , C 1-3 alkyl substituted with cyano, -C(O)-C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, =NOR aa or =R aa R bb , the amino, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted with one or more substituents selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl , 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl; Rd、Re、Rm、Rn、Rp和Rq各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、-C(O)-C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基中的一个或多个取代基所取代；优选氢、氘、氟、氯、溴、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、-C(O)-C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基，所述的氨基、C1-3烷基、C2-6烯基、C2-6炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代基所取代；R d , Re , R m , R n , R p and R q are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, -C(O)-C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, wherein the amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy , C C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally substituted with one or more substituents selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl , 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl , C 1-3 alkyl substituted with cyano, -C(O)-C 1-3 alkyl , C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, the amino, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted with one or more substituents selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl , 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl; 或者Rp和Rq与其相邻的原子链接形成C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基，任选进一步被氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基、5-12元杂芳基、＝N-O-Raa和＝RaaRbb中的一个或多个取代基所取代；优选形成C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基，任选进一步被氘、卤素、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、＝N-O-Raa和＝RaaRbb中的一个或多个取代基所取代；or R p and R q are linked with adjacent atoms to form C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally further substituted by deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl, =NOR aa and =R aa R bb; preferably forming C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 2-6 alkynyl, oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl, = NOR aa and =R aa R bb ; C 6-10 aryl and 5-10 membered heteroaryl, optionally further substituted with one or more substituents of deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy , C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl , 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, =NOR aa and =R aa R bb ; Raa和Rbb各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、-C(O)-C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基中的一个或多个取代基所取代；优选氢、氘、氟、氯、溴、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、-C(O)-C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基，所述的氨基、C1-3烷基、C2-6烯基、C2-6炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代基所取代； Raa and Rbb are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 alkyl substituted with cyano, -C(O) -C1-6 alkyl, C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl or 5-12 membered heteroaryl, wherein the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 alkyl substituted with cyano, -C(O) -C1-6 alkyl, C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl or 5-12 membered heteroaryl The invention also comprises a C 3-12 cycloalkyl, a 3-12 membered heterocyclyl, a C 6-12 aryl and a 5-12 membered heteroaryl, which are optionally substituted by one or more substituents of deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, a 3-12 membered heterocyclyl, a C 6-12 aryl and a 5-12 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, -C(O)-C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, the amino, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C The alkyl radical is substituted with one or more of C 2-4 alkynyl, oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl; n4选自0、1、2、3或4；n4 is selected from 0, 1, 2, 3 or 4; n7选自0、1、2、3或4；且n7 is selected from 0, 1, 2, 3 or 4; and n8选自0、1、2、3或4；n8 is selected from 0, 1, 2, 3 or 4; m3选自0、1或2。m3 is selected from 0, 1 or 2. 6.根据权利要求1-5任一项所述的化合物、其立体异构体或其药学上可接受的盐，其特征在于，所述化合物结构如下：6. The compound according to any one of claims 1 to 5, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that the compound has the following structure: 7.一种药用组合物，其包括治疗有效剂量的权利要求1-6任一所示的化合物、其立体异构体或其药学上可接受的盐以及一种或多种药学上可接受的载体、稀释剂或赋形剂。7. A pharmaceutical composition comprising a therapeutically effective dose of a compound as claimed in any one of claims 1 to 6, a stereoisomer thereof or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, diluents or excipients. 8.根据权利要求1-6任一所示的化合物、其立体异构体或其药学上可接受的盐，或权利要求7所述的药物组合物在制备PRMT5抑制剂药物中的应用。8. Use of the compound according to any one of claims 1 to 6, its stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 7 in the preparation of a PRMT5 inhibitor drug. 9.根据权利要求1-6任一所示的化合物、其立体异构体或其药学上可接受的盐，或权利要求7所述的药物组合物在制备治疗癌症中的应用；其中所述癌症是MTAP相关癌症。9. Use of the compound according to any one of claims 1 to 6, its stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 7 in the preparation of a treatment for cancer; wherein the cancer is MTAP-related cancer. 10.根据权利要求9所述的应用，其特征在于，所述癌症选自肺癌、肝细胞癌、乳腺癌、皮肤癌、膀胱癌、肝癌、胰腺癌、头颈癌、胶质瘤、胶质母细胞瘤、食管癌、胰腺癌、间皮瘤、黑色素瘤、星形细胞瘤、未分化的多形性肉瘤、白血病、胃腺癌、粘液纤维肉瘤、胆管肉瘤、脑癌、胃癌、肾癌、子宫内膜癌、卵巢瘤、前列腺癌、弥漫性大B细胞淋巴瘤、非霍奇金淋巴瘤、尿路癌、软组织癌、胸膜癌、大肠癌、结直肠癌或胆管癌；所述肺癌选自非小细胞肺癌、肺鳞癌或肺腺癌；所述食管癌选自食管鳞状细胞癌或食管腺癌。10. The use according to claim 9, characterized in that the cancer is selected from lung cancer, hepatocellular carcinoma, breast cancer, skin cancer, bladder cancer, liver cancer, pancreatic cancer, head and neck cancer, glioma, glioblastoma, esophageal cancer, pancreatic cancer, mesothelioma, melanoma, astrocytoma, undifferentiated pleomorphic sarcoma, leukemia, gastric adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, brain cancer, gastric cancer, kidney cancer, endometrial cancer, ovarian tumor, prostate cancer, diffuse large B-cell lymphoma, non-Hodgkin's lymphoma, urinary tract cancer, soft tissue cancer, pleural cancer, colorectal cancer, colorectal cancer or bile duct cancer; the lung cancer is selected from non-small cell lung cancer, squamous cell lung carcinoma or lung adenocarcinoma; the esophageal cancer is selected from esophageal squamous cell carcinoma or esophageal adenocarcinoma.
CN202410865246.9A 2023-06-29 2024-06-28 Polycyclic derivative inhibitor, preparation method and application thereof Pending CN119219608A (en)

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WO2025113499A1 (en) * 2023-11-28 2025-06-05 正大天晴药业集团股份有限公司 Compound containing heterocyclic dihydrophthalazine

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025113499A1 (en) * 2023-11-28 2025-06-05 正大天晴药业集团股份有限公司 Compound containing heterocyclic dihydrophthalazine

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