Tricondensed ring derivative inhibitor as well as preparation method and application thereof

Abstract

The invention relates to a tricondensed ring derivative inhibitor, and a preparation method and application thereof. In particular, the invention relates to a tri-fused ring derivative compound, a preparation method thereof, a pharmaceutical composition containing the compound, and an application of the compound in treating cancers.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of drug synthesis, and particularly relates to a tricyclic derivative inhibitor and a preparation method and application thereof. BACKGROUND

[0002] Protein arginine methyltransferases (PRMTs) are divided into three major categories: Type I, II, and III, based on catalytic activity and product type. Type I includes PRMT1 / 2 / 3 / 4 / 6 / 8, which catalyzes the formation of asymmetric dimethylarginine (ADMA) from the substrate; Type II includes PRMT5 / 9, which catalyzes the formation of symmetric dimethylarginine (SDMA) from the substrate; and Type III includes only PRMT7, which is responsible for catalyzing the formation of monomethylarginine (MMA) from the substrate. PRMT5 uses S-adenosyl-L-methionine (SAM) as a methyl donor to transfer a methyl group to DNA, RNA, histone, and other substrates, resulting in the symmetric dimethylation of arginine residues in the substrate to form SDMA, which regulates multiple key cellular processes, including transcription, translation, and DNA repair, to maintain cellular homeostasis. PRMT5 is also involved in regulating tumor cell growth and survival pathways and promotes tumorigenesis and progression. Elevated expression of PRMT5 has been shown to be associated with poor prognosis in various cancers, making it a highly potential epigenetic target.

[0003] Methylthioadenosine phosphorylase (MTAP) catalyzes the formation of methionine from methylthioadenosine (MTA), which is essential for maintaining normal cell function. Deletion mutations in the MTAP gene cause accumulation of MTA in cells, which competes with SAM, the substrate of PRMT5, resulting in decreased PRMT5 activity and the formation of a large amount of PRMT5-MTA complex. Deletion of the MTAP gene increases the dependence of tumors on PRMT5, and inhibition of PRMT5 in MTAP-deficient tumors can have a "synthetic lethal" effect. PARP inhibitors based on the "synthetic lethal" theory have achieved great success in the field of precision therapy in tumors. The MTAP gene is adjacent to the most common tumor suppressor gene CDKN2A in human cancers and is often co-deleted with CDKN2A. This co-deletion accounts for 10-15% of all cancers, mainly in non-small cell lung cancer (12-20%), glioma (53%), pancreatic cancer (30%), and DLBCL (20%), and has a huge market prospect.

[0004] Currently, there is no PRMT5 inhibitor on the market, and early PRMT5 inhibitors are all non-selective substrate SAM competitive inhibitors, with serious blood toxicity and small safety window in clinical practice. The first generation of PRMT5 inhibitors GSK-3326595, JNJ-64619178 and PF-06939999 have poor clinical progress. The new generation of PRMT5 inhibitors targeting PRMT5-MTA complex is only effective for tumors with MTAP deletion and MTA enrichment, has high selectivity for MTAP wild type, reduces blood toxicity from the mechanism, and is verified in preclinical studies, which is expected to greatly improve the safety window.

[0005] The present patent relates to a new PRMT5-MTA selective inhibitor, which is only active for MTAP deletion cells and has weak inhibition for MTAP wild type cells, which can avoid the blood toxicity and other side effects of non-selective PRMT5 inhibitors for MTAP wild type in clinical practice. The highly selective PRMT5-MTA inhibitor can be used as a new PRMT5-MTA inhibitor for the treatment of various tumors, cancers and other diseases. SUMMARY

[0006] The purpose of the present application is to provide a compound represented by general formula (I-B) or a pharmaceutically acceptable salt thereof, wherein the compound represented by general formula (I-B) has the following structure:

[0007]

[0008] M1 is selected from -N- or -CR a -;

[0009] M2 is selected from -N- or -CR b -; preferably -CR b -;

[0010] M3 is selected from N or C; preferably N;

[0011] M4 is selected from N or C;

[0012] M5 is selected from -N- or -C=;

[0013] M6 is selected from -N- or -C=;

[0014] M7 is selected from -N- or -CH-;

[0015] Ring A is selected from C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;

[0016] Ring B is selected from C 3-20 cycloalkyl, 3-20 membered heterocyclyl, C 6-20 aryl or 5-20 membered heteroaryl; preferably C3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl;

[0017] L1is selected from a bond, -(CR aa R bb ) m2 -, -(CR aa R bb ) m2 C(O)-, -(CR aa R bb ) m2 NR cc C(O), -(CR aa R bb ) m2 S(O) m1 - or -(CR aa R bb ) m2 NR cc -;

[0018] L2is selected from a bond, -(CR aa R bb ) m2 -, -(CR aa R bb ) m2 C(O)-, -(CR aa R bb ) m2 NR cc C(O), -(CR aa R bb ) m2 S(O) m1 - or -(CR aa R bb ) m2 NR cc -;

[0019] or, R1and L2are linked to form a 3-10 membered heterocyclyl, optionally substituted with 1, 2, 3, 4, 5, or 6 R 1a ; or optionally, the 3-10 membered heterocyclyl is further linked to Ring B to form a ring, wherein the newly created ring is selected from C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;

[0020] or, R1and L1are linked to form a 3-10 membered heterocyclyl, optionally substituted with 1, 2, 3, 4, 5, or 6 R 1b ;

[0021] R1is 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 halogenated alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, -(CR cc R dd ) n1 -C 3-12 cycloalkyl, -(CR cc R dd ) n1 -3-12 membered heterocyclyl, -(CR cc R dd ) n1 -C 6-12 aryl, -(CR cc R dd ) n1 -5-12 membered heteroaryl, -SF5, -OR e , -NR e R f , -C(O)R e , -C(O)OR e , -C(O)NR e R f , -N=S(O)R e R f , -S(O)R e (=NR f ) or -P(O)R e R f , said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 halogenated alkyl, 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, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuterated alkyl, C 1-6 halogenated alkyl, C 1-6alkyl, C 1-6 haloalkyl, 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, -SF5, -OR gg , -NR gg R hh , -C(O)R gg , -S(O)R gg , -S(O)2R gg , -C(O)OR gg , -C(O)NR gg R hh , -N=S(O)R gg R hh , -S(O)R gg (=NR hh ) or -P(O)R gg R hh and =CR gg R hh are preferably substituted with one or more of 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, haloC 1-6 alkoxy, C 1-6 hydroxyalkyl, -(CR cc R dd ) n1 -C 3-12 cycloalkyl, -(CR cc R dd ) n1 -3-12 membered heterocyclyl, -(CR cc R dd ) n1 -C 6-12 aryl, -(CR cc R dd ) n1 -5-12 membered heteroaryl, -SF5, -OR e , -NR e R f , -C(O)R e , -C(O)OR e , -C(O)NR e R f , -N=S(O)R e Rf -S(O)R e (=NR f ) or -P(O)R e R f , said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, haloC 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 one or more substituents as described above; 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuteroalkyl, 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, optionally substituted with one or more substituents as described above; gg R hh R

[0022] or R1and R a , R b , or R c are linked to form a C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, and 5-12 membered heteroaryl, optionally further substituted with one or more substituents as described above; 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuteroalkyl, 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, optionally substituted with one or more substituents as described above;

[0023] R2is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3- to 12-membered heterocyclyl, C6-12 aryl, 5- to 12-membered heteroaryl, -(CH2) n2 OR ee , -(CH2) n2 NR ee R ff , -(CH2) n2 C(O)R ee , -(CH2) n2 C(O)NR ee R ff , -(CH2) n2 P(O)R ee R ff or =CR ee R ff , said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, haloC 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 and 5- to 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, thioxo, C 1-6 deuteroalkyl, 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 6-12substituted with one or more substituents selected from the group consisting of deuterium, halogen, amino, hydroxyl, cyano, nitro, C1-6alkyl,

[0024] or R2and R c linking to form a C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, 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 substituted with one or more substituents selected from the group consisting of deuterium, halogen, amino, hydroxyl, cyano, nitro, C

[0025] or R2and L1or R2and R1linking to form a C 3-12 cycloalkyl or 3-12 membered heterocyclyl, optionally further substituted with deuterium, halogen, amino, hydroxyl, 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 substituted with one or more substituents selected from the group consisting of deuterium, halogen, amino, hydroxyl, cyano, nitro, C; preferably forming a C 3-8 cycloalkyl or 3-8 membered heterocyclyl, optionally further substituted with 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 6-10substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0026] R3 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 Halogenated alkyl, 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 heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, -SF5, -OR g 、-NR g R h 、-C(O)R g 、-C(O)OR g 、-C(O)NR g R h 、-N=S(O)R g R h 、-S(O)R g (=NR h ),-P(O)R g R h or =R g R h , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, 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 heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, 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 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, substituted or unsubstituted C3-12 cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclyl, substituted or unsubstituted C 6-12 aryl, substituted or unsubstituted 5-12 membered heteroaryl, and =CR e R f substituted by one or more substituents selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C

[0027] or any two R3are linked to form a 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, thioxo, C 1-6 deuteroalkyl, 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, optionally further substituted by deuterium, halogen, amino, hydroxyl, cyano, nitro, C

[0028] R 1a selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, -SF5, -(CH2) n1 -C 3-12 cycloalkyl, -(CH2) n3 -3-12 membered heterocyclyl, -(CH2) n3 -C 6-12 aryl, -(CH2) n3 -5-12 membered heteroaryl, -(CH2) n3 OR g , -(CH2) n3 NR g Rh, -(CH2) n3 C(O)R g , -(CH2) n3 C(O)OR g、-(CH2) n3 C(O)NR g Rh, -(CH2) n3 N=S(O)R g R h 、-(CH2) n3 S(O)R g (=NR h ), -(CH2) n3 P(O)R g R h or =R g R h , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, 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 heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, 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 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl;

[0029] Or any two R 1a Linked to its adjacent atoms to form C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, 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 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl;

[0030] R 1b selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, -SF5, -(CH2) n1 -C 3-12 cycloalkyl, -(CH2) n3 -3-12 membered heterocyclyl, -(CH2) n3 -C 6-12 aryl, -(CH2) n3 -5-12 membered heteroaryl, -(CH2) n3 OR g , -(CH2) n3 NR g R h , -(CH2) n3 C(O)R g , -(CH2) n3 C(O)OR g , -(CH2) n3 C(O)NR g Rh, -(CH2) n3 N=S(O)R g R h , -(CH2) n3 S(O)R g (=NR h ), -(CH2) n3 P(O)R g R h or =R g R h , the amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, haloC 1-6alkyl, 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 further substituted by deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuteroalkyl, 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, optionally substituted by one or more substituents selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, C

[0031] or any two R 1b together with the atom to which they are attached form a 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, thioxo, C 1-6 deuteroalkyl, 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, optionally substituted by one or more substituents selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, C

[0032] R a , R b , R c , R e and R f 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, thioxo, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, C1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3- to 12-membered heterocyclyl, C6-12 aryl, 5- to 12-membered heteroaryl, -(CH2) n2 OR ee , -(CH2) n2 NR ee R ff , -(CH2) n2 C(O)R ee , -(CH2) n2 C(O)OR ee , -(CH2) n2 C(O)NR ee R ff , -(CH2) n2 N=S(O)R ee R ff , -(CH2) n2 S(O)R ee (=NR ff ) or -(CH2) n2 P(O)R ee R ff , said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo-substituted 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 and 5- to 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, thioxo, C 1-6 deuteroalkyl, 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 and =CR gg R hh one or more substituents;

[0033] or R a with R b linking 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, thioxo, C 1-6 deuteroalkyl, 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, optionally further substituted by deuterium, halogen, amino, hydroxyl, cyano, nitro, C

[0034] R g and R h 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 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, haloC 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 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, haloC 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 further substituted by deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6deuteroalkyl, 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, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C

[0035] R aa , R bb , R cc and R dd are each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, haloC 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 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, haloC 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, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuteroalkyl, 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 6-12substituted with one or more substituents independently selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C1-C6alkyl,

[0036] R ee and R ff are each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C1-C6alkyl, 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, -C(O)-C 1-6 alkyl, C 3-12 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-12 aryl or 5- to 12-membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, haloC 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 and 5- to 12-membered heteroaryl, optionally substituted with one or more substituents independently selected from the group consisting of deuterium, halogen, amino, hydroxyl, cyano, nitro, C1-C6alkyl, 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuteroalkyl, 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, said amino, C

[0037] R gg and R hh are each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C1-C6alkyl, 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6haloalkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, -C(O)-C 1-6 alkyl, C 3-12 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-12 aryl or 5- to 12-membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, haloC 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 and 5- to 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, thioxo, C 1-6 deuteroalkyl, 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 one or more substituents of aryl and 5- to 12-membered heteroaryl;

[0038] x is selected from 0, 1, 2, 3, 4, 5 or 6;

[0039] y is selected from 0, 1, 2, 3, 4, 5 or 6;

[0040] m1 is selected from 0, 1 or 2;

[0041] m2 is selected from 0, 1 or 2;

[0042] n1 is selected from 0, 1, 2, 3 or 4;

[0043] n2 is selected from 0, 1, 2, 3 or 4; and

[0044] n3 is selected from 0, 1, 2, 3 or 4.

[0045] In certain embodiments of the application, the is selected from

[0046] In certain embodiments of the application, ring A is selected from a 3-8 membered heterocyclyl or a 5-10 membered heteroaryl; preferably a 5 membered heterocyclyl, a 6 membered heterocyclyl, a 5 membered heteroaryl or a 6 membered heteroaryl; more preferably

[0047] In certain embodiments of the application, selected from

[0048] Y1is selected from N, NH, C(O), CH, CH2, or O;

[0049] Y2is selected from N, NH, C(O), CH, CH2, or O;

[0050] Y3is selected from N, NH, C(O), CH, CH2, or O;

[0051] Y4is selected from P(O)H, S(O)2, N, NH, C(O), CH, CH2, or O;

[0052] Y5is selected from P(O)H, S(O)2, N, NH, C(O), CH, CH2, or O;

[0053] Y6is selected from P(O)H, S(O)2, N, NH, C(O), CH, CH2, or O;

[0054] Preferably, selected from

[0055] In certain embodiments of the application, the compound of Formula (I-B) or a pharmaceutically acceptable salt thereof is further represented by Formula (II-A), (II-B), or (II-C):

[0056]

[0057] 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, thioxo, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C3-12 cycloalkyl, 3- to 12-membered heterocyclyl, C6-12 aryl, 5- to 12-membered heteroaryl, -(CH2) n2 OR ee , -(CH2) n2 NR ee R ff , -(CH2) n2 C(O)R ee , -(CH2) n2 C(O)NR ee R ff , -(CH2) n2 P(O)R ee R ff or =CR ee R ff , said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3- to 12-membered heterocyclyl, C6-12 aryl, and 5- to 12-membered heteroaryl, optionally substituted with one or more substituents selected from the group consisting of deuterium, halogen, amino, hydroxyl, cyano, nitro, C 6-12 alkyl, C 1-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 2-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 1-6 cycloalkyl, 3- to 12-membered heterocyclyl, C6-12 aryl, and 5- to 12-membered heteroaryl, optionally substituted with one or more substituents selected from the group consisting of deuterium, halogen, amino, hydroxyl, cyano, nitro, C 3-12 alkyl, C 6-12 alkenyl, C 2c alkynyl, oxo, thioxo, C 2d deuteroalkyl, C 1-6 haloalkyl, C 2-6 alkoxy, C 2-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 1-6 cycloalkyl, 3- to 12-membered heterocyclyl, C6-12 aryl, and 5- to 12-membered heteroaryl, optionally substituted with one or more substituents selected from the group consisting of deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C

[0058] R 2c and R 2d are each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6alkyl, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3- to 12-membered heterocyclyl, C6-12 aryl, 5- to 12-membered heteroaryl, -(CH2) n2 OR ee , -(CH2) n2 NR ee R ff , -(CH2) n2 C(O)R ee , -(CH2) n2 C(O)NR ee R ff , -(CH2) n2 P(O)R ee R ff or =CR ee R ff , said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, haloC 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 and 5- to 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, thioxo, C 1-6 deuteroalkyl, 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, optionally substituted with one or more substituents selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, C

[0059] R 2e is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C1-6 alkoxy, haloC 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3- to 12-membered heterocyclyl, C6-12 aryl, 5- to 12-membered heteroaryl, -(CH2) n2 OR ee , -(CH2) n2 NR ee R ff , -(CH2) n2 C(O)R ee , -(CH2) n2 C(O)NR ee R ff , -(CH2) n2 P(O)R ee R ff or =CR ee R ff , the amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, haloC 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 and 5- to 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, thioxo, C 1-6 deuteroalkyl, 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, optionally substituted with one or more substituents selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, C

[0060] R4is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6haloalkyl, C 1-6 alkoxy, haloC 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 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, haloC 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 deutero, halo, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuteroalkyl, 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 one or more substituents of aryl and 5-12 membered heteroaryl;

[0061] or R1 and R4 are linked to form a 3-10 membered heterocyclyl, said 3-10 membered heterocyclyl optionally substituted with deutero, halo, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuteroalkyl, 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 one or more substituents of aryl and 5-12 membered heteroaryl;

[0062] z is selected from 0, 1, 2, 3, or 4;

[0063] Ring B, L2, R1, R3, R a , R b , R c , and y are as defined in any of the above embodiments.

[0064] In certain embodiments of the application, Ring B is selected from 3-10 membered heterocyclyl and phenyl or 3-10 membered heterocyclyl and 5-6 membered heteroaryl; preferably

[0065] In certain embodiments of the application, Ring B is selected from 6-20 membered tricyclic heterocyclyl; preferably 6-16 membered tricyclic spiroheterocyclyl or 6-16 membered tricyclic fused heterocyclyl; more preferably

[0066]

[0067] In certain embodiments of the application, R1is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 halogenated alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy, C 1-3 hydroxyalkyl, -(CR cc R dd ) n1 -C 3-8 cycloalkyl, -(CR cc R dd ) n1 -3-8 membered heterocyclyl, -(CR cc R dd ) n1 -C 6-10 aryl, -(CR cc R dd ) n1 -5-10 membered heteroaryl, -SF5, -OR e , -NR e R f , -C(O)R e , -C(O)OR e , -C(O)NR e R f , -N=S(O)R e R f , -S(O)R e (=NR f) or -P(O)R e R f , said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, haloC 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, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuteroalkyl, 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, -SF5, -OR gg , -NR gg R hh , -C(O)R gg , -S(O)R gg , -S(O)2R gg , -C(O)OR gg , -C(O)NR gg Rhh, -N=S(O)R gg Rhh, -S(O)R gg (=NRhh) or -P(O)R gg R hh and =CR gg R hh one or more substituents;

[0068] Preferably, R1is selected from methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, methylamino, dimethylamino,

[0069] In certain embodiments of the application, R3is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4alkenyl, C 2-4 alkynyl, oxo, thioxo, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, 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, -SF5, -OR g , -NR g R h , -C(O)R g , -C(O)OR g , -C(O)NR g R h , -N=S(O)R g R h , -S(O)R g (=NR h ), -P(O)R g R h or =R g R h , said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, haloC 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 deutero, halo, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, substituted or unsubstituted C 3-12 cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclyl, substituted or unsubstituted C 6-12 aryl, substituted or unsubstituted 5-12 membered heteroaryl and =CR e R fsubstituted by one or more substituents selected from the group consisting of

[0070] substituted by one or more substituents selected from the group consisting of 3-12 cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclyl, substituted or unsubstituted C 6-12 aryl and substituted or unsubstituted 5-12 membered heteroaryl represent C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl can be optionally deuterium, halogen, 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, haloC 1-3 alkoxy, 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, -SF5, -OR a1 , -NR a1 R b1 , -C(O)R a1 , -C(O)OR a1 , -C(O)NR a1 R b1 , -N=S(O)R a1 R b1 , -S(O)R a1 (=NR b1 ), -P(O)R a1 R b1 and =R a1 R b1 substituted by one or more substituents selected from the group consisting of

[0071] R a1 and R b1 are each independently selected from the group consisting of hydrogen, deuterium, halogen, 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, haloC 1-3 alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10aryl, 5-10 membered heteroaryl, -(CH2) n2 OR ee -(CH2) n2 NR ee R ff -(CH2) n2 C(O)R ee -(CH2) n2 C(O)OR ee -(CH2) n2 C(O)NR ee Rff, -(CH2) n2 N=S(O)R ee Rff, -(CH2) n2 S(O)R ee (=NR ff ) or -(CH2) n2 P(O)R ee R ff , said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, haloC 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, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuteroalkyl, 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 and =CR gg R hh of one or more substituents.

[0072] In certain embodiments of the application, R a is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -(CH2) n2 OR ee 、-(CH2) n2 NR ee R ff 、-(CH2) n2 C(O)R ee 、-(CH2) n2 C(O)OR ee 、-(CH2) n2 C(O)NR ee Rff, -(CH2) n2 N=S(O)R ee Rff, -(CH2) n2 S(O)R ee (=NR ff ) or -(CH2) n2 P(O)R ee R ff , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, 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 heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, 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 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12Aryl, 5-12 membered heteroaryl and =CR gg R hh is substituted by one or more substituents.

[0073] In certain embodiments of the present invention, R b Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -(CH2) n2 OR ee 、-(CH2) n2 NR ee R ff 、-(CH2) n2 C(O)R ee 、-(CH2) n2 C(O)OR ee 、-(CH2) n2 C(O)NR ee Rff, -(CH2) n2 N=S(O)R ee Rff, -(CH2) n2 S(O)R ee (=NR ff ) or -(CH2) n2 P(O)R ee R ff , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, 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 heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6alkynyl, oxo, thioxo, C 1-6 deuteroalkyl, 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, and =CR gg R hh substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl, ethynyl, propynyl, deutero- methyl, deutero-ethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, deutero- methoxy, difluoromethoxy, trifluoromethoxy,

[0074] R b is selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl, ethynyl, propynyl, deutero-methyl, deutero-ethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, deutero-methoxy, difluoromethoxy, trifluoromethoxy,

[0075] R c is selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, halo C 1-3 alkoxy, 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) n2 OR ee , -(CH2) n2 NR ee R ff , -(CH2) n2 C(O)R ee , -(CH2) n2 C(O)OR ee , -(CH2) n2 C(O)NR ee Rff, -(CH2) n2 N=S(O)R ee Rff, -(CH2) n2 S(O)R ee (=NR ff ) or -(CH2) n2 P(O)Ree R ff , said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, haloC 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, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuteroalkyl, 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 and =CR gg R hh one or more substituents.

[0076] The present application further relates to a pharmaceutical composition comprising a therapeutically effective amount of any of the compounds of Formula (I-B) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0077] The present application further relates to the use of any of the compounds of Formula (I-B) or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described, for the manufacture of a PRMT5 inhibitor medicament; preferably for the manufacture of a PRMT5-MTA inhibitor medicament.

[0078] The present application further relates to the use of a compound of Formula (I-B) 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 a MTAP gene deletion associated cancer.

[0079] The present application further relates to the use of a compound of Formula (I-B) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a method for the treatment of a cancer, wherein the cancer is selected from a MTAP gene deletion associated cancer.

[0080] The present application also relates to a method for treating, preventing and / or treating-preparing treatment of cancer, comprising administering to a patient a therapeutically effective dose of a compound represented by general formula (I-B) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0081] In some embodiments of the present application, the pharmaceutical composition comprises the compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in an amount of 0.1% to 95%, preferably 90%, 85%, 80%, 75%, 70%, 60%, 50% by weight of the free base.

[0082] In some embodiments of the present application, the compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, can be administered by any convenient method, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, intrathecal or transdermal administration, and a pharmaceutical composition adjusted accordingly.

[0083] In some embodiments of the present application, the pharmaceutical composition is selected from tablets, capsules, liquid preparations or injections, preferably further comprising a filler, optionally further comprising a disintegrant, or further comprising one or more of a glidant or a lubricant.

[0084] The present application also provides a method for treating a disease condition using the compound or pharmaceutical composition of the present application, which includes but is not limited to a condition associated with MTAP gene deletion.

[0085] The present application also relates to a method for treating cancer in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of the present application or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof.

[0086] In some embodiments, the present method relates to the treatment of conditions 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 pleomorphic sarcoma, diffuse large B-cell lymphoma, leukemia, gastric adenocarcinoma, myxofibrosarcoma, cholangiocarcinoma, brain cancer, stomach cancer, kidney cancer, endometrial cancer, ovarian tumor, prostate cancer, lymphoma, non-Hodgkin's lymphoma, urinary tract cancer, soft tissue cancer, pleural cancer, colorectal cancer, or cholangiocarcinoma.

[0087] In some embodiments, the lung cancer is selected from non-small cell lung cancer, lung squamous carcinoma or lung adenocarcinoma; the esophageal cancer is selected from esophageal squamous cell carcinoma or esophageal adenocarcinoma.

[0088] Detailed description of the invention

[0089] Unless otherwise indicated, herein, all technical and scientific terms have the same meaning as those one of ordinary skill in the art would attribute to such terms, and in particular, the terms used in the specification and claims have their plain and ordinary meaning unless stated otherwise.

[0090] The term "alkyl" refers to straight- chain or branched-chain saturated aliphatic hydrocarbon groups, which alkyl groups can be optionally substituted with one or more substituents. In particular embodiments, alkyl refers to straight- chain saturated aliphatic hydrocarbon groups 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 branched-chain saturated aliphatic hydrocarbon groups 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 ) carbon atoms. As used herein, straight- chain C 1-6 alkyl and branched-chain C 3-6 alkyl groups are also referred to as "lower alkyl." For example, C 1-6 alkyl refers to linear saturated monovalent hydrocarbon groups having 1 to 6 carbon atoms or branched-chain saturated monovalent hydrocarbon groups having 3 to 6 carbon atoms. In one embodiment, the C 1-6An alkyl group contains 1 to 6 (e.g., 1, 2, 3, 4, 5, 6) carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-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, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-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, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof, and the like. In one embodiment, the alkyl group is an optionally substituted alkyl group as described elsewhere herein.

[0091] The term "alkylene" refers to an alkyl group having one hydrogen atom further replaced by a bond, wherein the definition of "alkyl" is as previously described. Non-limiting examples of "alkylene" include methylene (-CH2-), ethylene (-(CH2)2-), propylene (-(CH2)3-), or butylene (-(CH2)4-). In one embodiment, the alkylene is an optionally substituted alkyl group as described elsewhere herein.

[0092] The term "alkenyl" refers to a straight-chain or branched-chain unsaturated aliphatic hydrocarbon group containing at least one carbon-carbon double bond and the carbon-carbon double bond can be located in any position of the alkenyl group, which can be optionally substituted with one or more substituents. In particular embodiments, the alkenyl group is a straight-chain unsaturated hydrocarbon group having 2 to 20 (e.g., 2 to 15, 2 to 12, 2 to 10, 2 to 8, 2 to 6, or 2 to 4) carbon atoms, or a branched-chain unsaturated hydrocarbon group having 3 to 20 (e.g., 3 to 15, 3 to 12, 3 to 10, 3 to 8, 3 to 6, or 3 to 4) carbon atoms. 2-20 2-15 2-12 2-10 2-8 2-6 2-4 3-20 , 3 to 15 (e.g., 3 to 12, 3 to 10, 3 to 8, 3 to 6, or 3 to 4) carbon atoms.​​​​​​​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. Unless otherwise specified, the term "alkenyl" as used herein includes both straight-chain and branched alkenyl groups. 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. 2-6 Alkenyl groups contain 2 to 6 (e.g., 2, 3, 4, 5, 6) carbon atoms. Non-limiting examples of alkenyl groups include: One 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 described elsewhere herein.

[0093] The term "alkynyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group containing at least one carbon-carbon triple bond, which may be located at any position within the alkynyl group, and which may be optionally substituted with one or more substituents. In a particular embodiment, the alkynyl group is a 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 ) carbon atoms, or a straight-chain unsaturated hydrocarbon group 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 Unless otherwise indicated, the term "alkynyl" as used herein includes both straight-chain and branched alkynyl groups. 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. 2-6 Alkynyl groups contain 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.

[0094] The term "cycloalkyl" refers to saturated or partially unsaturated aliphatic monocyclic, polycyclic (two and more) cyclic groups, which can be optionally substituted with one or more substituents. In particular embodiments, the cycloalkyl ring comprises 3 to 20 (C 3-20 ), 3 to 14 (C 3-14 ), 3 to 12 (C 3-12 ), 3 to 8 (C 3-8 ), or 3 to 6 (C 3-6 ) carbon atoms; in one embodiment, the cycloalkyl ring comprises 6 to 14 (C 6-14 ) or 7 to 10 (C 7-10 ) carbon atoms; which can 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, or cyclooctyl, and the like; polycyclic cycloalkyl groups include spirocycloalkyl, fused cycloalkyl, and bridged cycloalkyl groups, in one embodiment. In one embodiment, the cycloalkyl is an optionally substituted cycloalkyl as described elsewhere herein or a cycloalkyl optionally fused to a heterocyclyl, aryl, or heteroaryl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, and the like.

[0095] The term "spirocycloalkyl" refers to aliphatic polycyclic groups that share one carbon atom (termed a spiro atom) between the rings, which can contain one or more double bonds, but does not have a fully conjugated pi-electron system in any of the rings. In particular embodiments, the spirocycloalkyl 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. Spirocycloalkyl groups are classified as mono-, bi-, or polycycloalkyl groups, in one embodiment as mono- and bi-cycloalkyl groups, depending on the number of spiro atoms shared between the rings. In one embodiment, the spirocycloalkyl is a 4-membered / 4-membered, 3-membered / 5-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered spirocycloalkyl. In one embodiment, the spirocycloalkyl is an optionally substituted spirocycloalkyl as described elsewhere herein. Non-limiting examples of spirocycloalkyl groups include:

[0096]

[0097] 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 other rings in the system, where one or more rings can contain one or more double bonds, but no ring has a fully conjugated system of π electrons. In particular embodiments, a fused ring alkyl contains 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. Depending on the number of rings comprising the fused ring alkyl, it can be a bicyclic, tricyclic, tetracyclic, or polycyclic fused ring alkyl, in one embodiment a bicyclic or tricyclic, and in a further embodiment a 3 / 5, 4 / 5, 5 / 5, or 5 / 6 bicyclic alkyl. In one embodiment, the fused ring alkyl is an optionally substituted fused ring alkyl as described elsewhere herein or a fused ring alkyl optionally fused with a heterocyclyl, aryl, or heteroaryl. Non-limiting examples of fused ring alkyl groups include:

[0098]

[0099] The term "bridged ring alkyl" refers to an all-carbon polycyclic group in which any two rings share two non-adjacent carbon atoms, which can contain one or more double bonds, but no ring has a fully conjugated system of π electrons. In particular embodiments, a bridged ring alkyl contains 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. Depending on the number of rings comprising the bridged ring alkyl, it can be a bicyclic, tricyclic, tetracyclic, or polycyclic bridged ring alkyl, preferably a bicyclic or tricyclic. In one embodiment, the bridged ring alkyl is an optionally substituted bridged ring alkyl as described elsewhere herein. Non-limiting examples of bridged ring alkyl groups include:

[0100]

[0101] The term "heterocyclyl" refers to saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon groups in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus, or sulfur, wherein the nitrogen, phosphorus, or sulfur atoms can be optionally oxidized, the nitrogen atoms can be optionally quaternized, the ring carbon atoms can be optionally substituted with oxygen, but not including -0-0-, -0-S- ring moieties, the remaining ring atoms are carbon, which can contain one or more double bonds, but do not have a fully conjugated pi-electron system. In particular embodiments, the heterocyclyl group comprises 3 to 20, 3 to 14, 3 to 12, 3 to 8, or 3 to 6 ring atoms, of which 1 to 4 are heteroatoms; in one embodiment, the heterocyclyl group comprises 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 group comprises 3 to 8 (e.g., 3, 4, 5, 6, 7, 8) ring atoms. Non-limiting examples of monocyclic heterocyclyl groups include tetrahydropyrrolyl, azetidinyl, oxetanyl, oxanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and pyranyl, among others. Polycyclic heterocyclyl groups include spiroheterocyclyl, fused heterocyclyl, and bridged heterocyclyl groups. In one embodiment, the heterocyclyl group is an optionally substituted heterocyclyl group described elsewhere herein, or further annelated with other cycloalkyl, heterocyclyl, aryl, and heteroaryl groups through any two or more atoms on the ring.

[0102] The term "spiroheterocyclyl" refers to polycyclic heterocyclic groups that share one atom (referred to as the spiro atom) between the rings, in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus, or sulfur, the remaining ring atoms are carbon, which can contain one or more double bonds, and no ring has a fully conjugated pi-electron system. In particular embodiments, the spiroheterocyclyl group comprises 5 to 20 or 6 to 14 ring atoms; in one embodiment, 7 to 11 (e.g., 7, 8, 9, 10, 11) ring atoms; the spiroheterocyclyl groups are classified as mono-, bi-, or polyspiroheterocyclyl groups depending on the number of spiro atoms shared between the rings; mono- and bi-spiroheterocyclyl groups are preferred; in one embodiment, the spiroheterocyclyl group is a 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospiroheterocyclyl group; in one embodiment, the spiroheterocyclyl group is an optionally substituted spiroheterocyclyl group described elsewhere herein; non-limiting examples of spiroheterocyclyl groups include:

[0103]

[0104]

[0105] The term "fused heterocyclyl" refers to a polycyclic heterocyclic radical in which each ring in the system shares an adjacent pair of atoms with other rings in the system, one or more rings can contain one or more double bonds, but no ring has a fully conjugated pi-electron system, wherein 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 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, tetracyclic, or polycyclic fused heterocyclyl depending on the number of rings comprising the ring system; preferably bicyclic or tricyclic; in one embodiment, 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclyl; in one embodiment, the fused heterocyclyl is optionally substituted as described elsewhere herein, or can be fused to a cycloalkyl, heterocyclyl, aryl, or heteroaryl; non-limiting examples of fused heterocyclyl include:

[0106]

[0107] The term "bridged heterocyclyl" refers to a polycyclic heterocyclic radical in which any two rings share two non-adjacent atoms, which can contain one or more double bonds, but no ring has a fully conjugated pi-electron system, wherein 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 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, tetracyclic, or polycyclic bridged heterocyclyl depending on the number of rings comprising the ring system; preferably bicyclic, tricyclic, or tetracyclic; in one embodiment, bicyclic or tricyclic; in one embodiment, the bridged heterocyclyl is optionally substituted as described elsewhere herein; non-limiting examples of bridged heterocyclyl include:

[0108]

[0109] The term "tricyclic heterocyclyl" refers to a heterocyclyl in which the number of rings comprising the ring system is three, wherein the tricyclic heterocyclyl can be a fused, spiro, or bridged ring system, in one embodiment, the tricyclic heterocyclyl is a heterocyclyl in which at least one of the three rings in the system is a heterocyclyl, and the other two rings can be cycloalkyl, heterocyclyl, aryl, or heteroaryl, the definitions of which are described above, non-limiting examples of which are preferably the following tricyclic heterocyclyls:

[0110]

[0111] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic ring (that is, rings which share adjacent pairs of carbon atoms) radical that has a conjugated pi-electron system and which can be optionally substituted. In particular embodiments, aryl groups contain from 6 to 20, 6 to 14, 6 to 12, or 6 to 10 ring atoms; in one embodiment, aryl can further refer to a bicyclic, tricyclic, or tetracyclic ring system in which at least one ring is aromatic, the other rings can be saturated, partially unsaturated, carbocyclic, or heterocyclic rings comprising one or more heteroatoms independently selected from O, S, and N; in one embodiment, the aryl group is selected from benzo5-10heteroaryl, benzo3-10cycloalkyl, or benzo3-10heterocyclyl. In one embodiment, the aryl group is selected from benzo5-6heteroaryl, benzo3-6cycloalkyl, or benzo3-6heterocyclyl, wherein the heterocyclyl is a heterocyclic group containing 1-3 nitrogen atoms, oxygen atoms, or sulfur atoms. Non-limiting examples include phenyl, naphthyl, fluorenyl, azulenyl, anthracenyl, phenanthrenyl, pyrenyl, biphenyl, terphenyl, dihydronaphthyl, indenyl, tetrahydronaphthyl (tetrahydroanthracenyl),

[0112] The term "arylene" refers to a divalent aryl radical formed by the further substitution of one hydrogen atom of aryl, wherein arylene is optionally substituted or unsubstituted, and aryl is as defined above.

[0113] The term "heteroaryl" refers to an optionally substituted monocyclic, polycyclic group or ring system comprising at least one aromatic ring having one or more heteroatoms independently selected from O, S, and N. In particular embodiments, the heteroaryl group comprises 5 to 20, 5 to 14, 5 to 12, or 5 to 10 ring atoms, of which 1 to 4 are heteroatoms; in one embodiment, the heteroaryl group comprises 5 or 6 ring atoms; in particular embodiments, the heteroaryl group can further refer to a bicyclic, tricyclic, or tetracyclic ring system, wherein at least one ring is an aromatic ring having one or more heteroatoms independently selected from O, S, and N, and the other rings can be saturated, partially unsaturated carbocyclic rings or rings comprising one or more heteroatoms independently selected from O, S, and N. In one embodiment, the heteroaryl group is selected from heteroaryl and 6-10 membered aryl, heteroaryl and 3-10 membered cycloalkyl, or heteroaryl and 3-10 membered heterocyclyl; in a further embodiment, the heteroaryl group is selected from 5- or 6-membered heteroaryl and 6-10 membered aryl, 5- or 6-membered heteroaryl and 3-6 membered cycloalkyl, 5- or 6-membered heteroaryl and 3-6 membered heterocyclyl, wherein the heterocyclyl is a heterocyclyl comprising 1-3 nitrogen atoms, oxygen atoms, or sulfur atoms. Non-limiting examples include furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, triazolyl, benzofuranyl, benzimidazolyl, benzisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiophenyl, benzothiophenyl, benzothiophenyl, benzotriazolyl, imidazopyridinyl, imidazothiazolyl, indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothiophenyl, isoindolyl, isoquinolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridinyl, pyrrolopyridinyl, quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidinyl, thienopyridinyl, acridinyl, benzoindolyl, carbazolyl, biphenofuranyl, phenanthrolinyl, phenanthridinyl, phenarsenazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl,

[0114] The term "heteroaryl" refers to an optionally substituted monocyclic, polycyclic group or ring system comprising at least one aromatic ring having one or more heteroatoms independently selected from O, S, and N. In particular embodiments, the heteroaryl group comprises 5 to 20, 5 to 14, 5 to 12, or 5 to 10 ring atoms, of which 1 to 4 are heteroatoms; in one embodiment, the heteroaryl group comprises 5 or 6 ring atoms; in particular embodiments, the heteroaryl group can further refer to a bicyclic, tricyclic, or tetracyclic ring system, wherein at least one ring is an aromatic ring having one or more heteroatoms independently selected from O, S, and N, and the other rings can be saturated, partially unsaturated carbocyclic rings or rings comprising one or more heteroatoms independently selected from O, S, and N. In one embodiment, the heteroaryl group is selected from heteroaryl and 6-10 membered aryl, heteroaryl and 3-10 membered cycloalkyl, or heteroaryl and 3-10 membered heterocyclyl; in a further embodiment, the heteroaryl group is selected from 5- or 6-membered heteroaryl and 6-10 membered aryl, 5- or 6-membered heteroaryl and 3-6 membered cycloalkyl, 5- or 6-membered heteroaryl and 3-6 membered heterocyclyl, wherein the heterocyclyl is a heterocyclyl comprising 1-3 nitrogen atoms, oxygen atoms, or sulfur atoms. Non-limiting examples include furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, triazolyl, benzofuranyl, benzimidazolyl, benzisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiophenyl, benzothiophenyl, benzothiophenyl, benzotriazolyl, imidazopyridinyl, imidazothiazolyl, indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothiophenyl, isoindolyl, isoquinolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridinyl, pyrrolopyridinyl, quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidinyl, thienopyridinyl, acridinyl, benzoindolyl, carbazolyl, biphenofuranyl, phenanthrolinyl, phenanthridinyl, phenarsenazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl,

[0115] The term "heteroalkyl" refers to stable straight-chain or branched-chain, or cyclic alkyl hydrocarbon groups, or combinations thereof, consisting of the stated number of carbon atoms and one or more (in one embodiment, one to three) heteroatoms selected from O, N, Si, and S, and wherein the nitrogen and sulfur atoms can optionally be oxidized and the nitrogen heteroatom can optionally be quaternized. In one embodiment, the heteroatoms O, N, and S can be placed at any interior position of the heteroalkyl group. In one embodiment, the heteroatom Si can be placed at any position of the heteroalkyl group, including the position at which the alkyl group is attached to the remainder of the molecule. Non-limiting examples 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(CH3)-CH3. Up to two heteroatoms may

[0116] The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl or cycloalkyl are as previously described. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propyloxy, butyloxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, or cyclohexyloxy. In one embodiment, the alkoxy group is an optionally substituted alkoxy group as described elsewhere herein.

[0117] The term "alkylacyl" refers to -C(O)-alkyl, wherein alkyl is as previously described.

[0118] The term "haloalkyl" refers to an alkyl group as previously described substituted by one or more halogens. Non-limiting examples of haloalkyl groups include trifluoromethyl, -CH2CF3,

[0119] The term "haloalkoxy" refers to an alkoxy group as previously described substituted by one or more halogens.

[0120] The term "hydroxyalkyl" refers to an alkyl group as previously described substituted by a hydroxyl group.

[0121] The term "alkylthio" refers to -S-(alkyl) and -S-(unsubstituted cycloalkyl), where alkyl or cycloalkyl are as previously described. Non-limiting examples of alkylthio include methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, or cyclohexylthio. In one embodiment, the alkylthio is an optionally substituted alkylthio as described elsewhere herein.

[0122] The term "haloalkylthio" refers to an alkylthio group as previously described substituted with one or more halogen.

[0123] The term "alkenylcarbonyl" refers to -C(O)-(alkenyl), where alkenyl is as previously described. Non-limiting examples of alkenylcarbonyl include ethenylcarbonyl, propenylcarbonyl, or butenylcarbonyl. In one embodiment, the alkenylcarbonyl is an optionally substituted alkenylcarbonyl as described elsewhere herein.

[0124] The term "aminocarbonyl" refers to NH2-C(O)-.

[0125] The term "alkylaminocarbonyl" refers to an aminocarbonyl (NH2-C(O)-) having one or both hydrogens replaced with alkyl, where alkyl is as previously described.

[0126] The term "alkylamino" refers to an amino group having one or both hydrogens replaced with alkyl, where alkyl is as previously described.

[0127] The term "carbonyl" refers to the -C(O)-, -(CO)-, or -C(=O)- group. All notations are used interchangeably throughout the specification.

[0128] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0129] The term "oxo" or "keto" refers to =O.

[0130] The term "hydrogen" includes protium ( 1 ), deuterium ( 2 ), tritium ( 3 ), and / or mixtures thereof. In particular embodiments, one or more positions an atom in a compound that is occupied by hydrogen can be enriched in deuterium and / or tritium. Such isotopically enriched analogs can be prepared by using appropriate isotopically enriched starting materials available from commercial sources or by known literature procedures.

[0131] The alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, arylene, heteroaryl, heteroarylene, heteroalkyl, alkoxy, alkylthio, hydroxyalkyl, alkenylcarbonyl, aminocarbonyl, alkylaminocarbonyl, alkylamino, alkylacyl groups can be substituted or unsubstituted, in one embodiment, the substituents are selected from one or more of the following: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, alkylacyl, halogen, thiol, hydroxyl, nitro, cyano, azido, oximyl, phosphato, oxo, thioxo, carboxyl, carboxylate, cycloalkyl, heterocyclyl, aryl, heteroaryl, heterocycloalkoxy, cycloalkylthio, or heterocycloalkylthio.

[0132] The phrases "X is selected from A, B, or C," "X is selected from A, B, and C," "X is A, B, or C," "X is A, B, and C," and the like are used interchangeably and mean that X can be any one of A, B, or C, or any two of A, B, or C, or all three of A, B, or C.

[0133] "Optional" or "optionally" means that the subsequently described event or circumstance can or can not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "heterocyclyl optionally substituted with alkyl" means that alkyl can or can not be present, and that the description includes instances where the heterocyclyl group is substituted with alkyl and instances where the heterocyclyl group is not substituted with alkyl.

[0134] In various portions of the application, connecting substituents are described. When the structure clearly requires a connecting group, the Markush variable recited for that group should be understood to be a connecting group. For example, if the structure requires a connecting group and the Markush group definition recited for that variable recites "alkyl" or "aryl," it should be understood that the "alkyl" or "aryl" represents, respectively, a connected alkylene group or arylene group.

[0135] "Substituted" means that any one or more hydrogen atoms on a given atom is replaced with a substituent, as long as the valency of the given atom is not exceeded and the resulting compound is stable. In one embodiment, when the substituent is oxo (i.e., =0), it means that two hydrogen atoms are replaced. The term "optionally substituted" means that the group can or can not be substituted, and unless otherwise specified, the kind and number of substituents that can be present can be any chemically possible combination of substituents. It goes without saying that the substituents are only in their possible chemical positions, which can be determined (experimentally or theoretically) by one skilled in the art without undue effort, as to whether or not substitution is possible. For example, an amino or hydroxyl group with a free hydrogen can not be stable when bound to a carbon atom with an unsaturation (e.g., olefinic). The substituents can be selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, oxo, thioxo, deuterated alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0136] The indefinite articles "a" and "an," as well as the definite article "the," unless otherwise specified, include the plural as well as the singular.

[0137] "Pharmaceutical composition" means a mixture of one or more of the compounds described herein or a physiologically / pharmaceutically acceptable salt or prodrug thereof with other chemical components, such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of the active ingredient to an organism.

[0138] "Pharmaceutically acceptable salt" refers to those salts of the compounds of the present application which are safe and effective for use in mammals and possess the desired biological activity.

[0139] "Stereoisomer" encompasses all enantiomeric / diastereomeric / stereoisomerically pure and enantiomeric / diastereomeric / stereoisomerically enriched compounds of the present application.

[0140] "stereoisomerically pure" refers to a composition comprising one stereoisomer of a compound and substantially no other stereoisomer of the compound. For example, a stereoisomerically pure composition of a compound having one chiral center will have substantially no opposite enantiomer of the compound. A stereoisomerically pure composition of a compound having two chiral centers will have substantially no other diastereomer of the compound. Typically, a stereoisomerically pure compound comprises greater 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, greater 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, greater 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, greater 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 greater than about 99% by mass of one stereoisomer of the compound and less than about 1% by mass of the other stereoisomer of the compound.

[0141] "stereoisomerically enriched" refers to a composition comprising greater than about 55% by mass of one stereoisomer of a compound, greater than about 60% by mass of one stereoisomer of a compound, greater than about 70% by mass of one stereoisomer of a compound, or greater than about 80% by mass of one stereoisomer of a compound.

[0142] "enantiomerically pure" refers to a stereoisomerically pure composition of a compound having one chiral center. Similarly, the term "enantiomerically enriched" refers to a stereoisomerically enriched composition of a compound having one chiral center.

[0143] "optically active" and "enantiomerically active" refer to a molecular composition 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 by mass of the desired enantiomer or diastereomer and about 5% or less of the less preferred enantiomer or diastereomer of the total racemate.

[0144] In describing an optically active compound, the prefixes R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The (+) and (-) are used to denote the optical rotation of the compound, i.e., the direction in which a plane of polarized light is rotated by the optically active compound. The (-) prefix indicates that the compound is levorotatory, i.e., the compound rotates the plane of polarized light to the left or counterclockwise. The (+) prefix indicates that the compound is dextrorotatory, i.e., the compound rotates the plane of polarized light to the right or clockwise. However, the symbols (+) and (-) have no relation to the absolute configuration of the molecule R and S.

[0145] The compounds of the present application include all "stereoisomers", "stereoisomerically pure", "stereoisomerically enriched", "enantiomerically pure", "optically active", "enantiomerically active" and "optical isomers" thereof. DETAILED DESCRIPTION

[0146] The present application is further described in connection with the following examples, which are not intended to limit the scope of the application.

[0147] Examples

[0148] The structure of the compounds of the present application is determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). NMR shifts (δ) are given in 10 -6 (ppm) units. NMR is measured by a Bruker AVANCE-400 NMR spectrometer, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD) as the solvent, and tetramethylsilane (TMS) as the internal standard.

[0149] MS is measured by a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).

[0150] HPLC is measured by an Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C 18 150 x 4.6 mm chromatographic column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C 18 150 x 4.6 mm chromatographic column).

[0151] The average inhibition rate of kinase and IC 50 values are measured by a NovoStar microplate reader (Germany BMG company).

[0152] Thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the specification of silica gel plate used in thin layer chromatography (TLC) is 0.15mm-0.2mm, the specification of product used in thin layer chromatography separation and purification is 0.4mm-0.5mm.

[0153] Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as carrier.

[0154] Known starting materials of the present application can be synthesized according to methods known in the art or purchased from ABCR GmbH&Co.KG, Acros Organics, Aldrich Chemical Company, AccelaChemBio Inc, Daejung Chemicals Ltd, etc.

[0155] Unless otherwise specified in the examples, the reaction can be carried out under argon atmosphere or nitrogen atmosphere.

[0156] Argon atmosphere or nitrogen atmosphere refers to that the reaction bottle is connected with an argon or nitrogen balloon with a volume of about 1L.

[0157] Hydrogen atmosphere refers to that the reaction bottle is connected with a hydrogen balloon with a volume of about 1L.

[0158] Pressurized hydrogenation reaction uses Parr 3916EKX type hydrogenation instrument and Qinglan QL-500 type hydrogen generator or HC2-SS type hydrogenation instrument.

[0159] Hydrogenation reaction is generally vacuumed, filled with hydrogen, and the operation is repeated for 3 times.

[0160] Microwave reaction uses CEM Discover-S 908860 type microwave reactor.

[0161] Unless otherwise specified in the examples, the solution refers to aqueous solution.

[0162] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20℃-30℃.

[0163] The reaction progress in the examples is monitored by thin layer chromatography (TLC), and the system of developing agent used in the reaction is as follows: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether and ethyl acetate system, D: acetone, and the volume ratio of solvent is adjusted according to the polarity of the compound.

[0164] The eluent system for column chromatography and the developing solvent system for thin-layer chromatography used to purify the compound include: A: n-hexane and ethyl acetate system, B: n-hexane and tetrahydrofuran system. The volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.

[0165] The compounds in the embodiments of the present invention are prepared by referring to the following example preparation steps:

[0166] Example 1

[0167] N-(1-(4-amino-1-methyl-1H-pyrazolo[4,3-c]quinolin-8-yl)-2,2,2-trifluoroethyl)-N-methyl-4-(trifluoromethyl)benzamide

[0168]

[0169] Step 1: Dissolve 1-(4-bromophenyl)-2,2,2-trifluoroethane-1-amine 1a (700 mg, 2.76 mmol), 4-(trifluoromethyl)benzoic acid (629 mg, 3.31 mmol), (7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.56 g, 4.13 mmol) and diisopropylethylamine (1.07 g, 8.27 mmol) in 10 mL of dimethylformamide and allow the reaction to stir at room temperature for 2 hours. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL x 2). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent System A to give N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-(trifluoromethyl)benzamide 1b (850 mg) in a yield of 72.4%.

[0170] MSm / z(ESI):426[M+1]

[0171] Step 2: Disperse N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-(trifluoromethyl)benzamide 1b (850 mg, 1.99 mmol) and cesium carbonate (975 mg, 3 mmol) in 10 mL of dimethylformamide. Add iodomethane (849 mg, 5.98 mmol) dropwise and stir the reaction at room temperature for 1 hour. The reaction mixture was poured into 50 mL of ethyl acetate, washed with saturated sodium chloride solution (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent System A to afford N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methyl-4-(trifluoromethyl)benzamide 1c (790 mg) in a 90.0% yield.

[0172] MS m / z (ESI): 440 [M+1]

[0173] Third Step: Dissolve N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methyl-4- (trifluoromethyl)benzamide 1c (790 mg, 1.79 mmol), tert-butyl carbamate (315 mg, 2.69 mmol) and tris(dibenzylideneacetone) palladium (164 mg, 0.18 mmol), 4,5- bis(diphenylphosphino)-9,9-dimethylxanthene (208 mg, 0.36 mmol) and cesium carbonate (585 mg, 1.79 mmol) in 10 mL of dioxane, let the reaction stir at 100 °C for 16 hours under nitrogen atmosphere. Concentrate the reaction under reduced pressure, purify the residue with silica gel column chromatography with eluent system A to get (N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methyl-4- (trifluoromethyl)benzamide) tert-butyl carbamate 1d (600 mg), yield: 70.1%.

[0174] MS m / z (ESI): 440 [M+1]

[0175] Fourth Step: Dissolve (N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methyl-4- (trifluoromethyl)benzamide) tert-butyl carbamate 1d (600 mg, 1.26 mmol) in 1 mL of trifluoroacetic acid and 5 mL of dichloromethane, let the reaction stir at room temperature for 1 hour. Add saturated sodium bicarbonate solution (50 mL) to the reaction, extract with dichloromethane (50 mL x 2), take the organic phase after extraction, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure to get the title product N-(1-(4-aminophenyl)-2,2,2-trifluoroethyl)-N-methyl-4- (trifluoromethyl)benzamide 1e (330 mg), yield: 69.6%.

[0176] MS m / z (ESI): 440 [M+1]

[0177] Fifth Step: Dissolve N-(1-(4-aminophenyl)-2,2,2-trifluoroethyl)-N-methyl-4- (trifluoromethyl)benzamide 1e (100 mg, 0.27 mmol) in 3 mL of dichloromethane, add N- bromosuccinimide (50 mg, 0.28 mmol) under ice bath, let the reaction stir at ice bath for 1 hour. Concentrate the reaction under reduced pressure, purify the residue with silica gel column chromatography with eluent system A to get N-(1-(4-amino-3-bromophenyl)-2,2,2- trifluoroethyl)-N-methyl-4-(trifluoromethyl)benzamide 1f (101 mg), yield: 83.5%.

[0178] MS m / z (ESI): 455 [M+1]

[0179] Step 6: N-(l-(4-amino-3-bromo-phenyl)-2,2,2-trifluoro-ethyl)-N-methyl-4- (trifluoromethyl)benzamide If (90 mg, 0.20 mmol), bis(pinacolato)diboron (315 mg, 2.69 mmol), DPPF palladium dichloride (14 mg, 0.02 mmol) and potassium pivalate (56 mg, 0.40 mmol) were dispersed in 3 mL of 2-methyltetrahydrofuran and the reaction was allowed to stir at 80 °C under nitrogen for 16 hours. The reaction was poured into 30 mL of ethyl acetate and washed with saturated sodium chloride solution (30 mL x 2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give (2-amino-5-(2,2,2-trifluoro-l-(N-methyl-4- (trifluoromethyl)benzamido)ethyl)phenyl)boronic acid Ig (81 mg) in 96.2% yield.

[0180] MS m / z (ESI): 421 [M+1]

[0181] Step 7: (2-amino-5-(2,2,2-trifluoro-l-(N-methyl-4-(trifluoromethyl)benzamido) ethyl)phenyl)boronic acid Ig (81 mg, 0.19 mmol), 5-bromo-l-methyl-pyrazole-4- carbonitrile (34 mg, 0.18 mmol), tetrakis(triphenylphosphine)palladium (22 mg, 0.02 mmol) and sodium carbonate (41 mg, 0.39 mmol) were dispersed in 4 mL of dioxane and 1 mL of water and the reaction was allowed to stir at 105 °C under nitrogen for 16 hours. The reaction was poured into 30 mL of ethyl acetate and washed with saturated sodium chloride solution (30 mL x 2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system C to give N-(l-(4-amino-l-methyl-lH-pyrazolo[4,3-c]quinolin-8-yl)-2,2,2- trifluoro-ethyl)-N-methyl-4-(trifluoromethyl)benzamide 1 (17 mg) in 18.3% yield.

[0182] 1 H NMR (400 MHz, DMSO) δ 8.40 (s, 1H), 8.27 (s, 1H), 7.87 (d, 2H), 7.73 (d, 2H), 7.67 (d, 1H), 7.63 - 7.58 (m, 1H), 7.15 (s, 2H), 6.85 (s, 1H), 4.41 (s, 3H), 1.24 (s, 3H).

[0183] MS m / z (ESI): 482 [M+1]

[0184] The following examples were prepared according to Example 11:

[0185]

[0186] Example 11

[0187]

[0188] First step: 3,4-diaminobenzoic acid methyl ester 11a (2 g, 12.04 mmol) was dissolved in ethanol (50 mL), ethyl glyoxylate (50% in toluene) (5.04 M, 2.8 mL) was added, the reaction system was replaced with nitrogen three times, and was heated to 90 °C and stirred for 3 h. After cooling to room temperature, it was filtered, the filter residue was washed with a small amount of ethyl acetate, and was rotary dried to obtain a mixture of 2-carbonyl-1,2-dihydroquinoxaline-6-carboxylic acid methyl ester 11b-1 and 3-carbonyl-3,4-dihydroquinoxaline-6-carboxylic acid methyl ester 11b-2 (1.80 g), yield: 73.2%.

[0189] MS m / z (ESI): 205 [M+1]

[0190] Second step: The mixture of 2-carbonyl-1,2-dihydroquinoxaline-6-carboxylic acid methyl ester 11b-1 and 3-carbonyl-3,4-dihydroquinoxaline-6-carboxylic acid methyl ester 11b-2 (1.6 g, 7.84 mmol) was dissolved in N,N dimethylformamide (20 mL), p-methylbenzenesulfonylmethyl isocyanide (1.91 g, 9.80 mmol) and potassium carbonate (2.17 g, 15.67 mmol) were added, and the system was heated to 180 °C in a microwave reactor for 10 min. After cooling to room temperature, it was quenched with water, extracted with ethyl acetate (100 mL x 3), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the residue was concentrated. The obtained residue was purified by silica gel column chromatography with eluent system C to obtain a mixture of 4-carbonyl-4,5-dihydroimidazo[1,5-a]quinoxaline-8-carboxylic acid methyl ester 1c-1 and 4-carbonyl-4,5-dihydroimidazo[1,5-a]quinoxaline-7-carboxylic acid methyl ester 11c-2 (0.30 g), yield: 31.5%.

[0191] MS m / z (ESI): 244 [M+1]

[0192] Step 3: A mixture of 4-carbonyl-4,5-dihydroimidazo[l,5-a]quinoxaline-8-carboxylic acid methyl ester lie-1 and 4-carbonyl-4,5-dihydroimidazo[l,5-a]quinoxaline-7-carboxylic acid methyl ester lie-2 (300 mg, 1.23 mmol) was dissolved in phosphorus oxychloride (189 mg, 1.23 mmol, 5 mL), and the reaction system was heated to 130 °C for 2 h with stirring under nitrogen. The system was cooled to room temperature, concentrated, and the residue was poured into saturated sodium carbonate to quench, extracted with ethyl acetate (50 mL x 3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a mixture of 4-chloroimidazo[l,5-a]quinoxaline-8-carboxylic acid methyl ester lid-1 and 4-chloro-4,5-dihydroimidazo[l,5-a]quinoxaline-7-carboxylic acid methyl ester lid-2 (0.25 g, crude).

[0193] MS m / z (ESI): 262 [M+1]

[0194] Step 4: A mixture of 4-chloroimidazo[l,5-a]quinoxaline-8-carboxylic acid methyl ester lid-1 and 4-chloro-4,5-dihydroimidazo[l,5-a]quinoxaline-7-carboxylic acid methyl ester lid-2 (0.20 g, 0.76 mmol) and potassium carbonate (317 mg, 2.29 mmol) was dissolved in N,N-dimethylformamide (5 mL), and 4-methoxybenzylamine (210 mg, 1.53 mmol, 0.2 mL) was added. The reaction system was heated to 120 °C for 1.5 h in a microwave reactor. After cooling to room temperature, the mixture was filtered, concentrated, quenched with water, extracted with ethyl acetate (50 mL x 3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography with eluent system A to give a mixture of 4-((4-methoxybenzyl)amino)imidazo[l,5-a]quinoxaline-8-carboxylic acid methyl ester le-1 and 4-((4-methoxybenzyl)amino)-4,5-dihydroimidazo[l,5-a]quinoxaline-7-carboxylic acid methyl ester lie-2 (0.15 g) in 54.2% yield.

[0195] MS m / z (ESI): 363 [M+1]

[0196] Step 5: A mixture of methyl 4-((4-methoxybenzyl)amino)imidazo[l,5-a]quinoxaline-8- carboxylate lie-1 and methyl 4-((4-methoxybenzyl)amino)-4,5-dihydroimidazo[l,5-a] quinoxaline-7-carboxylate lie-2 (0.22 g, 0.61 mmol) and lithium hydroxide monohydrate (29 mg, 1.21 mmol) were dissolved in tetrahydrofuran (2 mL), methanol (2 mL) and water (2 mL), the reaction system was heated to 50 °C and stirred for 2 hours. The reaction was cooled to room temperature, concentrated, adjusted to pH 5-6 with 2M hydrochloric acid, filtered, the filter residue was washed with a small amount of water and petroleum ether, and the filter residue was dried to obtain a mixture of 4-((4-methoxybenzyl)amino)imidazo[l,5-a]quinoxaline-8-carboxylic acid 11f-1 and 4-((4-methoxybenzyl)amino)-4,5-dihydroimidazo[l,5-a]quinoxaline-7-carboxylic acid 11f-2 (0.11 g, crude).

[0197] MS m / z (ESI): 349 [M+1]

[0198] Step 6: A mixture of 4-((4-methoxybenzyl)amino)imidazo[l,5-a]quinoxaline-8-carboxylic acid 11f-1 and 4-((4-methoxybenzyl)amino)-4,5-dihydroimidazo[l,5-a]quinoxaline-7-carboxylic acid 11f-2 (108 mg, 0.31 mmol), 3-(4-(trifluoromethyl)phenyl)morpholine (60 mg, 0.26 mmol, obtained by a known method “Chemical Science, 2019, vol. 10, #41, p. 9591-9596”), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (117.48 mg, 311.40 pmol) were dissolved in N,N dimethylformamide (6 mL), N,N-diisopropylethylamine (134 mg, 1.04 mmol, 0.18 mL) was added, the reaction system was replaced with nitrogen three times, and stirred at 25 °C for 12 hours. The reaction was quenched with water, extracted with ethyl acetate (30 mL x 3), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography with eluent system C to obtain (4-((4-methoxybenzyl)amino)imidazo[l,5-a]quinoxalin-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone 11h-1 (15 mg), yield: 10.3%; (4-((4-methoxybenzyl)amino)imidazo[l,5-a]quinoxalin-7-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone 11h-2 (40 mg), yield: 27.5%.

[0199] MS m / z (ESI): 562 [M+1]

[0200] Step 7: (4-((4-methoxybenzyl)amino)imidazo[l,5-a]quinoxalin-8-yl)(3-(4- (trifluoromethyl)phenyl)morpholino)methanone 11h-1 (15 mg, 27 pmol) was dissolved in trifluoroacetic acid (3 mL), and the reaction system was heated to 80 °C for 12 h under nitrogen. After cooling to room temperature, it was concentrated. The residue was purified by silica gel column chromatography with eluent system C to obtain (4-((4-methoxybenzyl)amino)imidazo[l,5-a]quinoxalin-7-yl)(3-(4- (trifluoromethyl)phenyl)morpholino)methanone 11-1 (5 mg), yield: 50.7%.

[0201] MS m / z (ESI): 442 [M + 1]

[0202] 1 H NMR (400 MHz, DMSO) d 9.11 (s, 1H), 8.23 (d, 1H), 7.84 (s, 1H), 7.76-7.56 (m, 4H), 7.45-7.28 (m, 4H), 5.54 (s, 1H), 4.43 (d, 1H), 3.87 (d, 1H), 3.79-3.48 (m, 3H).

[0203] Step 8: (4-((4-methoxybenzyl)amino)imidazo[l,5-a]quinoxalin-7-yl)(3-(4- (trifluoromethyl)phenyl)morpholino)methanone 11h-2 (40 mg, 71 pmol) was obtained by the synthetic method of Example 1, Step 8 to obtain (4-aminoimidazo[l,5-a]quinoxalin-7-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone 2 (24 mg), yield: 76%; (4-((4-methoxybenzyl)amino)imidazo[l,5-a]quinoxalin-7-yl)(3-(4- (trifluoromethyl)phenyl)morpholino)methanone 11-2 (24 mg), yield: 76.2%.

[0204] MS m / z (ESI): 442 [M + 1]

[0205] 1 H NMR (400 MHz, DMSO) d 9.12 (s, 1H), 8.22 (d, 1H), 7.91 (s, 1H), 7.79 (d, 2H), 7.42 (d, 3H), 7.30 (d, 1H), 5.70 (s, 1H), 4.49 (s, 1H), 3.93 (dd, 1H), 3.80 (d, 1H), 3.60 (t, 2H), 3.18 (s, 1H).

[0206] The following examples were prepared according to Example 11:

[0207]

[0208]

[0209]

[0210]

[0211] The following examples were prepared according to Example 1

[0212]

[0213]

[0214] Biological test evaluation

[0215] The following examples are further described in conjunction with the test examples to explain the present application, but these examples are not meant to limit the scope of the present application.

[0216] Test Example 1, Determination of the inhibitory effect of the compounds of the present application on the proliferation activity of HCT116 and MTAP Knockout HCT116 cells

[0217] 1.1 Purpose of the experiment: The purpose of this test example is to measure the inhibitory effect of the compounds on the proliferation activity of HCT116 wild type and HCT116 MTAP knockout cells.

[0218] 1.2 Experimental instruments:

[0219] Centrifuge (Eppendorf 5810R)

[0220] Microplate reader (BioTek Synergy H1 or PerkinElmer Envision),

[0221] Pipettor (Eppendorf or Rainin)

[0222] 1.3 Experimental reagents:

[0223] HCT116 and MTAP Knockout HCT116 cells were purchased from Nanjing Kebai;

[0224] Cell Titer-Glo was purchased from Promega Company, item number G7573;

[0225] McCoy's A was purchased from Gibco, item number 12330031;

[0226] FBS was purchased from Gibco, item number 10091148;

[0227] PBS was purchased from Gibco, item number 10010023;

[0228] Trypsin was purchased from Gibco, item number 25200056;

[0229] Cell culture plates were purchased from Corning, item number 3610

[0230] 1.4 Experimental method:

[0231] When HCT116 and MTAP Knockout HCT116 cells were cultured to a suitable cell density using McCoy's 5A medium containing 10% FBS, the cells were collected, adjusted to a suitable cell concentration using complete medium, and the cell suspension was plated in a 96-well plate at 90 μL per well and incubated overnight at 37°C in a 5% CO2 incubator. DMSO and medium were used to prepare compound solutions of different concentrations, and a vehicle control was set up. The compound solutions were added to the 96-well plate at 10 μL per well, and the plate was incubated at 37°C in a 5% CO2 incubator for 72-240 hours. Then CellTiter-Glo solution was added, mixed well, and incubated in the dark for 10-30 minutes. The plate was read using a Synergy H1 or Envision microplate reader.

[0232] 1.5 Experimental data processing method:

[0233] The inhibition rate was calculated using the luminescence signal value, and the concentration and inhibition rate were subjected to non-linear regression curve fitting using Graphpad Prism software to obtain IC 50 values.

[0234] 1.6 Experimental conclusion:

[0235] The compounds of the present application showed a biological activity of about 0.1 nM to 100 nM (IC 50 ) in the HCT116 MTAP knockout cell proliferation activity inhibition test; preferably a biological activity of 0.1 nM to 50 nM (IC 50 ); more preferably a biological activity of 0.1 nM to 20 nM (IC 50 ); and most preferably a biological activity of 0.1 nM to 10 nM (IC 50 ).

[0236] In some embodiments, the IC 50 of the compounds of the present application for HCT116 cell proliferation activity is greater than the IC 50 of the compounds of the present application for HCT116 MTAP knockout cell proliferation activity.about 20 fold; preferably greater than about 50 fold; more preferably greater than about 70 fold; still more preferably greater than about 100 fold.

[0237] II. Mouse Pharmacokinetic Determination

[0238] 1. Purpose of Study:

[0239] To study the pharmacokinetic behavior of the compound in mice (plasma) after oral administration.

[0240] 2. Experimental Design

[0241] 2.1 Test Drug:

[0242] The compound of the present application was self-prepared.

[0243] 2.2 Test Animals:

[0244] Balb / c mice, male, purchased from Shanghai Jiesijie Experimental Animal Co., Ltd., Animal Production License No. (SCXK (Shanghai) 2013-0006N0.311620400001794).

[0245] 2.3 Drug Preparation:

[0246] Oral drug preparation: 0.5% CMC-Na (1% Tween 80)

[0247] Take 5g hydroxyethyl cellulose (HEC, CMC-Na, viscosity: 800-1200Cps), dissolve in 1000mL pure water, add 10g Tween80. Mix evenly to form a clear solution.

[0248] Take 4mg of the compound of the example, dissolve in the solution, shake well, cell crusher for 1min, ultrasonic for 10min, get suspension solution, concentration is 3mg / mL.

[0249] Intravenous drug preparation: 5% DMSO + 10% Solutol HS15 + 85% PBS

[0250] Take the compound of the example, add 5% DMSO according to the total volume ratio of administration, vortex, ultrasonic for 2min, make it completely dissolved; then add 10% Solutol HS15, vortex, ultrasonic for 2min, make it completely dissolved; finally add 85% PBS, vortex, ultrasonic for 5min, pass through 0.22um filter membrane, get colorless transparent clear solution, concentration is 0.2mg / mL.

[0251] 2.4 Administration:

[0252] Three male Balb / c mice were fasted overnight and PO-administered at a dose of 30 mg / kg in a dosing volume of 10 mL / kg.

[0253] Three male Balb / C mice were fasted overnight and administered IV at a dose of 1 mg / kg in a volume of 5 mL / kg.

[0254] 2.5 Sample collection:

[0255] At 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration, 0.04 mL of blood was collected from the orbital cavity, placed in an EDTA-2K tube, centrifuged at 6000 rpm at 4°C for 6 min to separate the plasma, and stored at -20°C; food was consumed 4 h after administration.

[0256] 3. Measurement results:

[0257] The final determination results were obtained using the LCMS / MS method, which showed that the example compound had a higher oral exposure.

Claims

1. A compound of Formula (I-B) or a pharmaceutically acceptable salt thereof: M1is selected from -N- or -CR a -; M2is selected from -N- or -CR b -; preferably -CR b -; M3 is selected from N or C; preferably N; M4 is selected from N or C; M5 is selected from -N- or -C=; M6 is selected from -N- or -C=; M7 is selected from -N- or -CH-; Ring A is selected from C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl; Ring B is selected from C 3-20 cycloalkyl, 3-20 membered heterocyclyl, C 6-20 aryl or 5-20 membered heteroaryl; preferably C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl; L1is selected from a bond, -(CR aa R bb ) m2 -, aa R bb ) m2 C(O)-, -(CR aa R bb ) m2 NR cc C(O), -(CR aa R bb ) m2 S(O) m1 - or -(CR aa R bb ) m2 NR cc -; L2is selected from a bond, -(CR aa R bb ) m2 -, aa R bb ) m2 C(O)-, -(CR aa R bb ) m2 NR cc C(O), -(CR aa R bb ) m2 S(O) m1 - or -(CR aa R bb ) m2 NR cc -; or R1and L2are linked to form a 3-10 membered heterocyclyl group, which is optionally substituted with 1, 2, 3, 4, 5, or 6 R 1a substituted; or optionally, the 3-10 membered heterocyclyl group is further linked to ring B to form a ring, wherein the newly created ring is selected from C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl; or R1and L1are linked to form a 3-10 membered heterocyclyl group, which is optionally substituted by 1, 2, 3, 4, 5, or 6 R 1b substituted; R1is 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 halogenated alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, -(CR cc R dd ) n1 -C 3-12 cycloalkyl, -(CR cc R dd ) n1 -3-12 membered heterocyclyl, -(CR cc R dd ) n1 -C 6-12 aryl, -(CR cc R dd ) n1 -5-12 membered heteroaryl, -SF5, -OR e , -NR e R f , -C(O)R e , -C(O)OR e , -C(O)NR e R f , -N=S(O)R e R f , -S(O)R e (=NR f ) or -P(O)R e R f , said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 halogenated alkyl, 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, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuterated alkyl, C 1-6 halogenated alkyl, C 1-6 alkyl, C 1-6 haloalkyl, 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, -SF5, -OR gg , -NR gg R hh , -C(O)R gg , -S(O)R gg , -S(O)2R gg , -C(O)OR gg , -C(O)NR gg R hh , -N=S(O)R gg R hh , -S(O)R gg (=NR hh ) or -P(O)R gg R hh and =CR gg R hh are preferably substituted with one or more of 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, haloC 1-6 alkoxy, C 1-6 hydroxyalkyl, -(CR cc R dd ) n1 -C 3-12 cycloalkyl, -(CR cc R dd ) n1 -3-12 membered heterocyclyl, -(CR cc R dd ) n1 -C 6-12 aryl, -(CR cc R dd ) n1 -5-12 membered heteroaryl, -SF5, -OR e , -NR e R f , -C(O)R e , -C(O)OR e , -C(O)NR e R f , -N=S(O)R e R f -S(O)R e (=NR f ) or -P(O)R e R f , said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, haloC 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, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuteroalkyl, 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, and =CR gg R hh ; Or R1 and R a 、R b or R c Link Form C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, 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 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl; R2 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 Halogenated alkyl, 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, C6-12 aryl, 5-12 membered heteroaryl, -(CH2) n2 OR ee 、-(CH2) n2 NR ee R ff 、-(CH2) n2 C(O)R ee 、-(CH2) n2 C(O)NR ee R ff 、-(CH2) n2 P(O)R ee R ff or =CR ee R ff , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, 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 heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, 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 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl; or R2and R c linkage forms 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, thioxo, C 1-6 deuteroalkyl, 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 one or more substituents of aryl and 5-12 membered heteroaryl; or R2and L1are linked to form C 3-12 cycloalkyl or 3-12 membered heterocyclyl, optionally further substituted by deuterium, halogen, amino, hydroxyl, 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 one or more substituents of aryl and 5-12 membered heteroaryl; preferably C 3-8 cycloalkyl or 3-8 membered heterocyclyl, optionally further substituted by 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 one or more substituents of aryl and 5-10 membered heteroaryl; R3is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, haloC 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, hydroxyl, cyano, nitro, C g alkyl, C g R h , -C(O)R g , -C(O)OR g , -C(O)NR g R h , -N=S(O)R g R h , -S(O)R g (=NR h ), -P(O)R g R h or =R g R h , said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, haloC 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, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, substituted or unsubstituted C 3-12 cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclyl, substituted or unsubstituted C 6-12 aryl, substituted or unsubstituted 5-12 membered heteroaryl, and =CR e R f one or more substituents selected from the group consisting of or any two R3are linked to form a C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, 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 one or more substituents of aryl and 5-12 membered heteroaryl; R 1a selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, -SF5, -(CH2) n1 -C 3-12 cycloalkyl, -(CH2) n3 -3-12 membered heterocyclyl, -(CH2) n3 -C 6-12 aryl, -(CH2) n3 -5-12 membered heteroaryl, -(CH2) n3 OR g , -(CH2) n3 NR g R h , -(CH2) n3 C(O)R g , -(CH2) n3 C(O)OR g , -(CH2) n3 C(O)NR g R h , -(CH2) n3 N=S(O)R g R h , -(CH2) n3 S(O)R g (=NR h ), -(CH2) n3 P(O)R g R h or =R g R h , the amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, haloC 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, hydroxyl, 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 one or more substituents of aryl and 5-12 membered heteroaryl; or any two R 1a with its adjacent atoms 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, 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 one or more substituents of aryl and 5-12 membered heteroaryl; R 1b selected from hydrogen, deuterium, halogen, amino, hydroxyl, 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, haloC 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, -SF5, -(CH2) n1 -C 3-12 cycloalkyl, -(CH2) n3 -3-12 membered heterocyclyl, -(CH2) n3 -C 6-12 aryl, -(CH2) n3 -5-12 membered heteroaryl, -(CH2) n3 OR g , -(CH2) n3 NR g R h , -(CH2) n3 C(O)R g , -(CH2) n3 C(O)OR g , -(CH2) n3 C(O)NR g R h , -(CH2) n3 N=S(O)R g R h , -(CH2) n3 S(O)R g (=NR h ), -(CH2) n3 P(O)R g R h or =R g R h , 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, haloC 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, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuteroalkyl, 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 one or more substituents of aryl and 5-12 membered heteroaryl; or any two R 1b with its adjacent atoms forms a C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, 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, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C R a 、R b 、R c 、R e and R f 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 Halogenated alkyl, 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, C6-12 aryl, 5-12 membered heteroaryl, -(CH2) n2 OR ee 、-(CH2) n2 NR ee R ff 、-(CH2) n2 C(O)R ee 、-(CH2) n2 C(O)OR ee 、-(CH2) n2 C(O)NR ee R ff 、-(CH2) n2 N=S(O)R ee R ff 、-(CH2) n2 S(O)R ee (=NR ff ) or -(CH2) n2 P(O)R ee R ff , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, 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 heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuteroalkyl, 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, and =CR gg R hh one or more substituents selected from the group consisting of or R a with R b linkage 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, thioxo, C 1-6 deuteroalkyl, 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, optionally further substituted by deuterium, halogen, amino, hydroxyl, cyano, nitro, C R g and R h each independently 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 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl, -C(O)-C 1-6 alkyl, C 3-12 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-12 aryl and 5- to 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, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl, C 3-12 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-12 aryl and 5- to 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, thioxo, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl, C 3-12 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-12 aryl and 5- to 12-membered heteroaryl, optionally substituted with one or more substituents selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, C R aa 、R bb 、R cc and R dd 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 Halogenated alkyl, 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 heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, 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 heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, 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 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl; R ee and R ff 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 Halogenated alkyl, 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 heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, 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 heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, 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 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl; R gg and R hh 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 Halogenated alkyl, 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 heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, 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 heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, 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 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by one or more substituents of aryl and 5-12 membered heteroaryl; x is selected from 0, 1, 2, 3, 4, 5 or 6; y is selected from 0, 1, 2, 3, 4, 5 or 6; 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; and n3 is selected from 0, 1, 2, 3 or 4.

2. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein The selected from Ring A is selected from a 3-8 membered heterocyclyl or a 5-10 membered heteroaryl; preferably a 5 membered heterocyclyl, 6 membered heterocyclyl, 5 membered heteroaryl or 6 membered heteroaryl; more preferably 3. The compound of any one of claims 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: selected from Y1 is selected from N, NH, C(O), CH, CH2 or O; Y2 is selected from N, NH, C(O), CH, CH2 or O; Y3 is selected from N, NH, C(O), CH, CH2 or O; Y4 is selected from P(O)H, S(O)2, N, NH, C(O), CH, CH2 or O; Y5 is selected from P(O)H, S(O)2, N, NH, C(O), CH, CH2 or O; Y6 is selected from P(O)H, S(O)2, N, NH, C(O), CH, CH2 or O; Preferably, selected from 4. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein further is a compound of Formula (II-A), (II-B) or (II-C) or a pharmaceutically acceptable salt thereof: 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 Halogenated alkyl, 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, C6-12 aryl, 5-12 membered heteroaryl, -(CH2) n2 OR ee 、-(CH2) n2 NR ee R ff 、-(CH2) n2 C(O)R ee 、-(CH2) n2 C(O)NR ee R ff 、-(CH2) n2 P(O)R ee R ff or =CR ee R ff , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, 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 heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, 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 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted with one or more substituents selected from the group consisting of halo, -OH, -CN, -NO2, -NH2, -SF5, -C(O)N(H)R', - R 2c and R 2d 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 Halogenated alkyl, 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, C6-12 aryl, 5-12 membered heteroaryl, -(CH2) n2 OR ee 、-(CH2) n2 NR ee R ff 、-(CH2) n2 C(O)R ee 、-(CH2) n2 C(O)NR ee R ff 、-(CH2) n2 P(O)R ee R ff or =CR ee R ff , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, 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 heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, 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 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted with one or more substituents selected from the group consisting of halo, -CN, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl R 2e 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 Halogenated alkyl, 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, C6-12 aryl, 5-12 membered heteroaryl, -(CH2) n2 OR ee 、-(CH2) n2 NR ee R ff 、-(CH2) n2 C(O)R ee 、-(CH2) n2 C(O)NR ee R ff 、-(CH2) n2 P(O)R ee R ff or =CR ee R ff , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, 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 heterocyclic group, C 6-12 Aryl and 5-12 membered heteroaryl, optionally deuterated, halogenated, 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 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted with one or more substituents selected from the group consisting of halo, -OH, -CN, -NO2, -NH2, -SF5, -C(O)N(H)R', - R4is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, -C(O)-C 1-6 alkyl, C 3-12 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-12 aryl or 5- to 12-membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, haloC 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 and 5- to 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, thioxo, C 1-6 deuteroalkyl, 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, optionally substituted with one or more substituents selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, C or R1and R4are linked to form a 3-10 membered heterocyclyl group, which is optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuteroalkyl, 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; z is selected from 0, 1, 2, 3 or 4; Rings B, L2, R1, R3, R a , R b , R c and y are as defined in claim 1.

5. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein Ring B is selected from 3-10 membered heterocyclyl and phenyl or 3-10 membered heterocyclyl and 5-6 membered heteroaryl; preferably or, ring B is selected from 6-20 membered tricyclic heterocyclyl; preferably 6-16 membered tricyclic spiro heterocyclyl or 6-16 membered tricyclic fused heterocyclyl; more preferably 6. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein R1is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 1-3 hydroxyalkyl, -(CR cc R dd ) n1 -C 3-8 cycloalkyl, -(CR cc R dd ) n1 -3-8 membered heterocyclyl, -(CR cc R dd ) n1 -C 6-10 aryl, -(CR cc R dd ) n1 -5-10 membered heteroaryl, -SF5, -OR e , -NR e R f , -C(O)R e , -C(O)OR e , -C(O)NR e R f , -N=S(O)R e R f , -S(O)R e (=NR f ) or -P(O)R e R f , said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, haloC 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, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuteroalkyl, 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, -SF5, -OR gg , -NR gg R hh , -C(O)R gg , -S(O)R gg , -S(O)2R gg , -C(O)OR gg , -C(O)NR gg R hh , -N=S(O)R gg R hh , -S(O)R gg (=NR hh ) or -P(O)R gg R hh and =CR gg R hh one or more substituents; Preferably, R1is selected from methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, methylamino, dimethylamino, R3is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thioxo, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl and 5-12 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C g , -NR g R h , -C(O)R g , -C(O)OR g , -C(O)NR g R h , -N=S(O)R g R h , -S(O)R g (=NR h ), -P(O)R g R h or =R g R h , said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, haloC 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, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, substituted or unsubstituted C 3-12 cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclyl, substituted or unsubstituted C 6-12 aryl, substituted or unsubstituted 5-12 membered heteroaryl and =CR e R f is substituted by one or more substituents; substituted or unsubstituted C 3-12 cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclyl, substituted or unsubstituted C 6-12 aryl and substituted or unsubstituted 5-12 membered heteroaryl represent C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl can be optionally substituted with one or more substituents selected from deuterium, halo, 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, haloC 1-3 alkoxy, 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, -SF5, -OR a1 , -NR a1 R b1 , -C(O)R a1 , -C(O)OR a1 , -C(O)NR a1 R b1 , -N=S(O)R a1 R b1 , -S(O)R a1 (=NR b1 ), -P(O)R a1 R b1 and =R a1 R b1 substituted; R a1 and R b1 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, 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) n2 OR ee , -(CH2) n2 NR ee R ff , -(CH2) n2 C(O)R ee , -(CH2) n2 C(O)OR ee , -(CH2) n2 C(O)NR ee R ff , -(CH2) n2 N=S(O)R ee R ff , -(CH2) n2 S(O)R ee (=NR ff ) or -(CH2) n2 P(O)R ee R ff , said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, haloC 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, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuteroalkyl, 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, and =CR gg R hh one or more substituents selected from the group consisting of R a selected from hydrogen, deuterium, halogen, 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, haloC 1-3 alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl, 3- to 8-membered heterocyclyl, C 6-10 aryl, 5- to 10-membered heteroaryl, -(CH2) n2 OR ee , -(CH2) n2 NR ee R ff , -(CH2) n2 C(O)R ee , -(CH2) n2 C(O)OR ee , -(CH2) n2 C(O)NR ee R ff , -(CH2) n2 N=S(O)R ee R ff , -(CH2) n2 S(O)R ee (=NR ff ) or -(CH2) n2 P(O)R ee R ff , 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, haloC 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 and 5- to 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, 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, and =CR gg R hh one or more substituents in R R b selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 halogenated alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy, 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) n2 OR ee , -(CH2) n2 NR ee R ff , -(CH2) n2 C(O)R ee , -(CH2) n2 C(O)OR ee , -(CH2) n2 C(O)NR ee R ff , -(CH2) n2 N=S(O)R ee R ff , -(CH2) n2 S(O)R ee (=NR ff ) or -(CH2) n2 P(O)R ee R ff , said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 halogenated alkyl, 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, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thioxo, C 1-6 deuterated alkyl, C 1-6 halogenated alkyl, 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, and =CR gg R hh one or more substituents selected from the group consisting of R is selected from hydrogen, deuterium, fluoro, chloro, cyano, methyl, ethyl, ethynyl, propynyl, deuterated methyl, deuterated ethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, deuterated methoxy, difluoromethoxy, trifluoromethoxy, b R is selected from hydrogen, deuterium, fluoro, chloro, cyano, methyl, ethyl, ethynyl, propynyl, deuterated methyl, deuterated ethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, deuterated methoxy, difluoromethoxy, trifluoromethoxy, R c selected from hydrogen, deuterium, halogen, 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, haloC 1-3 alkoxy, 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) n2 OR ee , -(CH2) n2 NR ee R ff , -(CH2) n2 C(O)R ee , -(CH2) n2 C(O)OR ee , -(CH2) n2 C(O)NR ee R ff , -(CH2) n2 N=S(O)R ee R ff , -(CH2) n2 S(O)R ee (=NR ff ) or -(CH2) n2 P(O)R ee R ff , 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, haloC 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, hydroxyl, 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 haloalkyl, C 1-6 haloalkyl, C 1-6 haloalkyl, C 3-12 haloalkyl, C 6-12 haloalkyl, C gg R hh one or more substituents selected from the group consisting of 7. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein selected from the following compounds:

8. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1-7, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

9. Use of a compound of any one of claims 1-7, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 8, in the manufacture of a medicament for PRMT5 inhibitor; preferably for PRMT5-MTA inhibitor.

10. Use of a compound of any one of claims 1-7, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 8, in the manufacture of a medicament for treating cancer; wherein the cancer is a MTAP gene deletion associated cancer; 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, stomach cancer, kidney cancer, endometrial cancer, ovarian tumor, prostate cancer, diffuse large B-cell lymphoma, non-Hodgkin 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; the esophageal cancer is selected from esophageal squamous cell carcinoma or esophageal adenocarcinoma.

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