Compound having KRAS inhibitory activity and pharmaceutical use thereof

Abstract

The present application relates to a compound having KRAS inhibitory activity and a pharmaceutical use thereof. In particular, the present application relates to a KRAS inhibitor having the structure of formula (I), a pharmaceutical composition containing the KRAS inhibitor, a use thereof as a KRAS inhibitor, and a use thereof in the treatment and / or prevention of KRAS-related cancers or tumors. Substituents in formula (I) are the same as those defined in the description.

Description

A compound with KRAS inhibitory activity and its pharmaceutical use TECHNICAL FIELD

[0001] The present application belongs to the field of drug synthesis, and particularly relates to a compound with KRAS inhibitory activity and its pharmaceutical use. BACKGROUND

[0002] The RAS gene family includes HRAS, KRAS and NRAS, which are frequently mutated as oncogenes in tumors. Mutations in RAS proteins occur in 20-30% of human tumors. Abnormally activated RAS proteins lead to malignant phenotypes of tumor cells, including dysregulation of cell growth and programmed cell death, increased invasiveness and neovascularization. Due to the high affinity of RAS for GTP / GDP and the lack of a clear drug binding pocket, the development of drugs targeting RAS proteins has been a long-standing problem.

[0003] Under physiological conditions, RAS proteins act as molecular switches, which exhibit dynamic balance between the inactivated GDP-bound state and the activated GTP-bound state. On the one hand, under the stimulation of exogenous growth factors (such as EGFR, FGFR, etc.), RAS proteins are converted from the inactivated GDP-bound form to the activated GTP-bound form through the catalysis of guanine nucleotide exchange factors (GEFs), thereby binding to downstream effector proteins and activating downstream signaling pathways. On the other hand, RAS returns to the inactivated GDP-bound form through the intrinsic GTPase activity of RAS proteins and the catalytic action of GTPase-activating proteins (GAPs).

[0004] Missense mutations of RAS proteins often lead to abnormal activation of RAS, in which mutations at amino acid positions 12 (G12), 13 (G13) and 61 (Q61) are the most common. These mutations disrupt the original dynamic balance of GDP / GTP binding state of RAS, causing RAS proteins to be more in the activated GTP-bound state, thereby leading to persistent activation of RAS downstream signaling pathways.

[0005] In human tumors, KRAS mutations are the most common subtype of RAS family mutations. Studies have found that KRAS mutations are found in about 71% of pancreatic cancer, about 35% of small intestine cancer, about 35% of colorectal cancer, about 26% of biliary tract cancer, about 17% of endometrial cancer and about 19% of lung cancer. Among them, G12D / G12V / G12C / G13D mutations are the most common types of KRAS mutations in pancreatic cancer, lung cancer and colorectal cancer. In addition, recent studies suggest that targeting KRAS WT may also bring certain therapeutic benefits in KRAS wild-type (KRAS WT) dependent tumors.

[0006] However, due to the lack of a clear drug binding pocket in the KRAS protein, the development of KRAS inhibitors has always been challenging. Recent studies have found a previously undiscovered drug binding pocket in the mutant KRAS G12C protein in the GDP-bound state. Based on these new findings, covalent binding inhibitors targeting KRAS G12C have become a hot spot in the development of KRAS inhibitors and have made some clinical progress. However, in addition to the G12C mutation, targeting other activating mutations of KRAS is still urgent, including KRAS G12D / G12V / G13D mutations. On the other hand, it was found that KRAS G12C inhibitors may have a certain probability of developing resistance after use, and may restore the abnormal activation of KRAS through KRAS G12D / G12R / G12V / G12W / G13D mutations.

[0007] Therefore, it is necessary to continue to develop safe and effective pan-KRAS inhibitors to treat more KRAS mutant / KRAS-dependent tumor patients, and to overcome the resistance of KRAS G12C inhibitors. SUMMARY

[0008] The purpose of the present application is to provide a compound having KRAS inhibitory activity and its pharmaceutical application. The series of compounds of the present application have strong inhibitory effect on KRAS, and can be widely used in the preparation of drugs for treating and / or preventing KRAS-related cancer or tumor, so as to develop a new generation of KRAS inhibitors.

[0009] The first aspect of the present application provides a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

[0010] wherein, is a single bond or a double bond, when is a double bond, R4 and R7 are absent;

[0011] X1 is CR8 or N; X2 is CR9 or N; X3 is CR 10 or N;

[0012] X4 is N or CR 11 ;

[0013] Ring A is C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, or the C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, or the C 6-10 aryl or 5-10 membered heteroaryl, C 3-12cycloalkyl or 3-12 membered heterocyclyl;

[0014] m is 0, 1, 2, 3, 4, or 5; each R1is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C1-6alkyl, 1-10 C1-6alkyl, C2-6alkenyl, 2-10 C2-6alkynyl, C3-6cycloalkyl, 2-10 C3-6cycloalkyl, 3-6 membered heterocyclyl, 3-12 aryl, 5-6 membered heteroaryl, -C1-6alkyl-aryl, 6-10 C1-6alkyl, C2-6alkenyl, 0-8 C2-6alkynyl, C3-6cycloalkyl, 0-8 C3-6cycloalkyl, 3-6 membered heterocyclyl, 12 aryl, 5-6 membered heteroaryl, -C1-6alkyl-aryl, 13 C1-6alkyl, C2-6alkenyl, 0-8 C2-6alkynyl, C3-6cycloalkyl, 13 C3-6cycloalkyl, 3-6 membered heterocyclyl, 14 aryl, 5-6 membered heteroaryl, -C1-6alkyl-aryl, 0-8 C1-6alkyl, C2-6alkenyl, 13 C2-6alkynyl, C3-6cycloalkyl, 14 C3-6cycloalkyl, 3-6 membered heterocyclyl, 0-8 aryl, 5-6 membered heteroaryl, -C1-6alkyl-aryl, 15 C1-6alkyl, C2-6alkenyl, 0-8 C2-6alkynyl, C3-6cycloalkyl, r C3-6cycloalkyl, 3-6 membered heterocyclyl, 15 aryl, 5-6 membered heteroaryl, -C1-6alkyl-aryl, 0-8 C1-6alkyl, C2-6alkenyl, 16 C2-6alkynyl, C3-6cycloalkyl, 0-8 C3-6cycloalkyl, 3-6 membered heterocyclyl, 16 aryl, 5-6 membered heteroaryl, -C1-6alkyl-aryl, 0-8 C1-6alkyl, C2-6alkenyl, 16 C2-6alkynyl, C3-6cycloalkyl, 0-8 C3-6cycloalkyl, 3-6 membered heterocyclyl, 17 aryl, 5-6 membered heteroaryl, -C1-6alkyl-aryl, 0-8 C1-6alkyl, C2-6alkenyl, 17 C2-6alkynyl, C3-6cycloalkyl, 0-8 C3-6cycloalkyl, 3-6 membered heterocyclyl, 17 aryl, 5-6 membered heteroaryl, -C1-6alkyl-aryl, 0-8 C1-6alkyl, C2-6alkenyl, 17 C2-6alkynyl, C3-6cycloalkyl, 0-8 C3-6cycloalkyl, 3-6 membered heterocyclyl, 18 aryl, 5-6 membered heteroaryl, -C1-6alkyl-aryl, 19 C1-6alkyl, C2-6alkenyl, 0-8 C2-6alkynyl, C3-6cycloalkyl, 18 C3-6cycloalkyl, 3-6 membered heterocyclyl, 17 aryl, 5-6 membered heteroaryl, -C1-6alkyl-aryl, 0-8 C1-6alkyl, C2-6alkenyl, 18 C2-6alkynyl, C3-6cycloalkyl, 19 C3-6cycloalkyl, 3-6 membered heterocyclyl, 17 aryl, 5-6 membered heteroaryl, -C1-6alkyl-aryl, 0-8 C1-6alkyl, C2-6alkenyl, 18 C2-6alkynyl, C3-6cycloalkyl, 19 C3-6cycloalkyl, 3-6 membered heterocyclyl, 0-8 aryl, 5-6 membered heteroaryl, -C1-6alkyl-aryl, 18 C1-6alkyl, C2-6alkenyl, 17 C2-6alkynyl, C3-6cycloalkyl,, or, when m > 2, two adjacent R1together with the moieties to which they are directly attached form a C 3-12 Cycloalkyl or 3-12 membered heterocyclyl, each of which is independently and optionally further substituted by one or more, preferably 1, 2, 3 or 4, more preferably 1 or 2, substituents independently selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halogen-substituted C 1-10 Alkyl, deuterium-substituted C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, =0, =S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=N-R 12 )R 13 , -C 0-8 Alkyl-N=S(O)R 13 R 14 , -C 0-8 Alkyl-N=SR 13 R 14 , -C 0-8 Alkyl-O-S(O)2R 15 , -C 0-8 Alkyl-S(O) r R 15 , -C 0-8 Alkyl-O-R 16 , -C 0-8 Alkyl-C(O)OR 16 , -C 0-8 Alkyl-C(O)SR 16 , -C 0-8 Alkyl-S-C(O)R 17 , -C 0-8 Alkyl-C(O)R 17 , -C 0-8 Alkyl-O-C(O)R 17 , -C 0-8 Alkyl-P(O)(R 17 )2, -C 0-8 Alkyl-NR 18 R 19 , -C 0-8 Alkyl-C(=NR 18 )R 17 , -C 0-8 Alkyl-N(R 18 )-C(=NR 19 )R 17 , -C 0-8 Alkyl-C(O)NR 18 R19 and -C 0-8 alkyl-N(R 18 )-C(O)R 17 substituted by one or more substituents selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C

[0015] R2is selected from the group consisting of hydrogen, halogen, -(L) s -O-(L) s -R 2a , -(L) s -NR 2b R 2c , -(L) s -O-(L) s -NR 2b R 2c , C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, independently optionally further substituted by one or more substituents selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C s -O-(L) s -R 2a , -(L) s -NR 2b R 2c , -(L) s -O-(L) s -NR 2b R 2c , C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, independently optionally further substituted by one or more substituents selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, halogen-substituted C 1-10 alkyl, deuterium-substituted C 1-10 alkyl, C 1-10 alkylene, halogen-substituted C 1-10 alkylene, deuterium-substituted C 1-10 alkylene, C 2-10 alkenylene, C 2-10 alkynylene, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, =0, =S, -C 0-8 alkyl-SF5, -C 0-8 alkyl-S(O)(=N-R 12 )R 13 , -C 0-8 alkyl-N=S(O)R 13 R 14 , -C 0-8 alkyl-N=SR 13 R 14 , -C 0-8 alkyl-O-S(O)2R15 -C 0-8 Alkyl-S(O) r R 15 -C 0-8 Alkyl-OR 16 -C 0-8 Alkyl-C(O)OR 16 -C 0-8 Alkyl-C(O)SR 16 -C 0-8 Alkyl-SC(O)R 17 -C 0-8 Alkyl-C(O)R 17 -C 0-8 Alkyl-OC(O)R 17 -C 0-8 Alkyl-P(O)(R) 17 )2、-C 0-8 Alkyl-NR 18 R 19 -C 0-8 Alkyl-C (=NR) 18 )R 17 -C 0-8 Alkyl-N(R) 18 )-C(=NR 19 )R 17 -C 0-8 Alkyl-C(O)NR 18 R 19 and -C 0-8 Alkyl-N(R) 18 )-C(O)R 17 The substituents are replaced;

[0016] Each s is independently 0, 1, 2, or 3; each L is independently selected from C. 1-10 Alkylene, C 3-12 Cycloalkylene or 3-12 membered heterocyclic alkylene groups, the above C 1-10 Alkylene, C 3-12 The cycloalkyl or 3-12-membered heterocyclic group is independently and optionally further selected from one or more of deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, =O, =S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR) 12)R 13 -C 0-8 Alkyl-N=S(O)R 13 R 14 -C 0-8 Alkyl-N=SR 13 R 14 -C 0-8 Alkyl-OS(O)2R 15 -C 0-8 Alkyl-S(O) r R 15 -C 0-8 Alkyl-OR 16 -C 0-8 Alkyl-C(O)OR 16 -C 0-8 Alkyl-C(O)SR 16 -C 0-8 Alkyl-SC(O)R 17 -C 0-8 Alkyl-C(O)R 17 -C 0-8 Alkyl-OC(O)R 17 -C 0-8 Alkyl-P(O)(R) 17 )2、-C 0-8 Alkyl-NR 18 R 19 -C 0-8 Alkyl-C (=NR) 18 )R 17 -C 0-8 Alkyl-N(R) 18 )-C(=NR 19 )R 17 -C 0-8 Alkyl-C(O)NR 18 R 19 and -C 0-8 Alkyl-N(R) 18 )-C(O)R 17 The substituents are replaced;

[0017] R 2a Selected from hydrogen, deuterium, and C 1-10 Alkyl, C 2-10 Alkenyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, wherein the above groups are optionally further divided by one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 1-10alkylene, halogen-substituted C 1-10 alkylene, deuterium-substituted C 1-10 alkylene, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-10 aryl, 5- to 10-membered heteroaryl, =0, =S, -C 0-8 alkyl-SF5, -C 0-8 alkyl-S(O)(=N-R 12 )R 13 , -C 0-8 alkyl-N=S(O)R 13 R 14 , -C 0-8 alkyl-N=SR 13 R 14 , -C 0-8 alkyl-O-S(O)2R 15 , -C 0-8 alkyl-S(O) r R 15 , -C 0-8 alkyl-O-R 16 , -C 0-8 alkyl-C(O)OR 16 , -C 0-8 alkyl-C(O)SR 16 , -C 0-8 alkyl-S-C(O)R 17 , -C 0-8 alkyl-C(O)R 17 , -C 0-8 alkyl-O-C(O)R 17 , -C 0-8 alkyl-P(O)(R 17 )2, -C 0-8 alkyl-NR 18 R 19 , -C 0-8 alkyl-C(=NR 18 )R 17 , -C 0-8 alkyl-N(R 18 )-C(=NR 19 )R 17 , -C 0-8 alkyl-C(O)NR 18 R 19 and -C 0-8 alkyl-N(R 18 )-C(O)R 17 ;

[0018] each R2b and each R 2c is independently selected from hydrogen, deuterium, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -C 0-8 alkyl-S(O)2R 15 , -C 0-8 alkyl-C(O)OR 16 , -C 0-8 alkyl-C(O)SR 16 , -C 0-8 alkyl-C(O)R 17 , -C 0-8 alkyl-C(=NR 18 )R 17 and -C 0-8 alkyl-C(O)NR 18 R 19 , the aforementioned groups being independently and optionally further substituted by one or more substituents selected from deuterium, halogen, hydroxyl, =O, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halosubstituted C 1-10 alkyl, deuterium- substituted C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C 6-10 aryl, C 6-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, amino, mono C 1-10 alkylamino, di C 1-10 alkylamino and C 1-10 alkanoyl;

[0019] or, R 2b and R 2c together with the nitrogen atom to which they are directly attached form a 4-10 membered heterocyclyl or 5-10 membered heteroaryl, said 4-10 membered heterocyclyl or 5-10 membered heteroaryl being optionally further substituted by one or more substituents selected from deuterium, halogen, hydroxyl, =O, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halosubstituted C 1-10 alkyl, deuterium- substituted C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl, C 3-12cycloalkoxy, 3- to 12-membered heterocyclyl, 3- to 12-membered heterocyclyloxy, C 6-10 aryl, C 6-10 aryloxy, 5- to 10-membered heteroaryl, 5- to 10-membered heteroaryloxy, amino, mono C 1- 10 alkylamino, di C 1-10 alkylamino and C 1-10 alkanoyl, substituted by one or more substituents selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C

[0020] R3is selected from the group consisting of hydrogen, deuterium, hydroxyl, cyano, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-10 aryl, 5- to 10-membered heteroaryl, -S(O)2R 15 , -C(O)OR 16 , -C(O)SR 16 , -C(O)R 17 , -C(=NR 18 )R 17 and -C(O)NR 18 R 19 , the aforementioned groups being independently optionally further substituted by one or more substituents selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3- 12 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-10 aryl, 5- to 10-membered heteroaryl, -C 0-8 alkyl-SF5, -C 0-8 alkyl-S(O)(=N-R 12 )R 13 , -C 0-8 alkyl-N=S(O)R 13 R 14 , -C 0-8 alkyl-N=SR 13 R 14 , -C 0-8 alkyl-O-S(O)2R 15 , -C 0-8 alkyl-S(O) r R 15 , -C 0-8 alkyl-O-R 16 , -C 0-8 alkyl-C(O)OR 16 , -C 0-8 alkyl-C(O)SR 16 , -C0-8 alkyl-S-C(O)R 17 , -C 0-8 alkyl-C(O)R 17 , -C 0-8 alkyl-O-C(O)R 17 , -C 0-8 alkyl-P(O)(R 17 )2, -C 0-8 alkyl-NR 18 R 19 , -C 0-8 alkyl-C(=NR 18 )R 17 , -C 0-8 alkyl-N(R 18 )-C(=NR 19 )R 17 , -C 0-8 alkyl-C(O)NR 18 R 19 , and -C 0-8 alkyl-N(R 18 )-C(O)R 17 , the aforementioned groups are independently optionally further substituted by one or more substituents selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, halosubstituted C 1-10 alkyl, deuterium- substituted C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, =O, =S, -C 0-8 alkyl-SF5, -C 0- 8alkyl-S(O)(=N-R 12 )R 13 , -C 0-8 alkyl-N=S(O)R 13 R 14 , -C 0-8 alkyl-N=SR 13 R 14 , -C 0-8 alkyl-O-S(O)2R 15 , -C 0-8 alkyl-S(O) r R 15 , -C 0-8 alkyl-O-R 16 , -C 0-8 alkyl-C(O)OR 16 , -C 0-8 alkyl-C(O)SR16 -C(O)R 0-8 alkyl-S-C(O)R 17 -C(O)OR 0-8 alkyl-C(O)R 17 -C(O)SR 0-8 alkyl-O-C(O)R 17 -C(O)N(R 0- )2, -C 17 alkyl-P(O)(R 0-8 )2, -C 18 alkyl-N(R 19 )2, -C 0-8 alkyl-C(=NR 18 )R 17 , -C 0-8 alkyl-N(R 18 )-C(=NR 19 )R 17 , -C 0-8 alkyl-C(O)NR 18 R 19 , and -C 0-8 alkyl-N(R 18 )-C(O)R 17 ;

[0021] R4and R5are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2- 10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -C 0-8 alkyl-SF5, -C 0-8 alkyl-S(O)(=N-R 12 )R 13 , -C 0-8 alkyl-N=S(O)R 13 R 14 , -C 0-8 alkyl-N=SR 13 R 14 , -C 0-8 alkyl-O-S(O)2R 15 , -C 0-8 alkyl-S(O) r R 15 , -C 0-8 alkyl-O-R 16 , -C 0-8 alkyl-C(O)OR 16 , -C 0-8 alkyl-C(O)SR16 , -C 0-8 alkyl-S-C(O)R 17 , -C 0-8 alkyl-C(O)R 17 , -C 0- 8alkyl-O-C(O)R 17 , -C 0-8 alkyl-P(O)(R 17 )2, -C 0-8 alkyl-NR 18 R 19 , -C 0-8 alkyl-C(=NR 18 )R 17 , -C 0-8 alkyl-N(R 18 )-C(=NR 19 )R 17 , -C 0-8 alkyl-C(O)NR 18 R 19 , and -C 0-8 alkyl-N(R 18 )-C(O)R 17 , or R4and R5together with the carbon atom to which they are directly attached form a C(O), C 3-12 cycloalkyl, or 3-12 membered heterocyclyl, each of which is independently optionally further substituted with one or more substituents independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, halosubstituted C 1-10 alkyl, deuterium- substituted C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, =O, =S, -C 0-8 alkyl-SF5, -C 0-8 alkyl-S(O)(=N-R 12 )R 13 , -C 0-8 alkyl-N=S(O)R 13 R 14 , -C 0-8 alkyl-N=SR 13 R 14 , -C 0-8 alkyl-O-S(O)2R 15 , -C 0-8 alkyl-S(O) r R 15 , -C 0-8 alkyl-O-R 16 , -C0-8 alkyl-C(O)OR 16 , -C 0- 8alkyl-C(O)SR 16 , -C 0-8 alkyl-S-C(O)R 17 , -C 0-8 alkyl-C(O)R 17 , -C 0-8 alkyl-O-C(O)R 17 , -C 0-8 alkyl-P(O)(R 17 )2, -C 0-8 alkyl-NR 18 R 19 , -C 0-8 alkyl-C(=NR 18 )R 17 , -C 0-8 alkyl-N(R 18 )-C(=NR 19 )R 17 , -C 0-8 alkyl-C(O)NR 18 R 19 , and -C 0-8 alkyl-N(R 18 )-C(O)R 17 ;

[0022] R6and R7are each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2- 10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -C 0-8 alkyl-SF5, -C 0-8 alkyl-S(O)(=N-R 12 )R 13 , -C 0-8 alkyl-N=S(O)R 13 R 14 , -C 0-8 alkyl-N=SR 13 R 14 , -C 0-8 alkyl-O-S(O)2R 15 , -C 0-8 alkyl-S(O) r R 15 , -C 0-8 alkyl-O-R 16 , -C0-8 alkyl-C(O)OR 16 , -C 0-8 alkyl-C(O)SR 16 , -C 0-8 alkyl-S-C(O)R 17 , -C 0-8 alkyl-C(O)R 17 , -C 0- 8alkyl-O-C(O)R 17 , -C 0-8 alkyl-P(O)(R 17 )2, -C 0-8 alkyl-NR 18 R 19 , -C 0-8 alkyl-C(=NR 18 )R 17 , -C 0-8 alkyl-N(R 18 )-C(=NR 19 )R 17 , -C 0-8 alkyl-C(O)NR 18 R 19 and -C 0-8 alkyl-N(R 18 )-C(O)R 17 , or R6and R7together with the carbon atom to which they are directly attached form a C(O), C 3-12 cycloalkyl or 3-12 membered heterocyclyl, each of the above groups being independently optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, halosubstituted C 1-10 alkyl, deuterium- substituted C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, =O, =S, -C 0-8 alkyl-SF5, -C 0-8 alkyl-S(O)(=N-R 12 )R 13 , -C 0-8 alkyl-N=S(O)R 13 R 14 , -C 0-8 alkyl-N=SR 13 R 14 , -C 0-8 alkyl-O-S(O)2R 15 , -C 0-8 alkyl-S(O)r R 15 -C 0-8 Alkyl-OR 16 -C 0-8 Alkyl-C(O)OR 16 -C 0- 8alkyl-C(O)SR 16 -C 0-8 Alkyl-SC(O)R 17 -C 0-8 Alkyl-C(O)R 17 -C 0-8 Alkyl-OC(O)R 17 -C 0-8 Alkyl-P(O)(R) 17 )2、-C 0-8 Alkyl-NR 18 R 19 -C 0-8 Alkyl-C (=NR) 18 )R 17 -C 0-8 Alkyl-N(R) 18 )-C(=NR 19 )R 17 -C 0-8 Alkyl-C(O)NR 18 R 19 and -C 0-8 Alkyl-N(R) 18 )-C(O)R 17 The substituents are replaced;

[0023] Alternatively, R5 and R6 together with their directly connected parts form a C 3-12 Cycloalkyl or 3-12 membered heterocyclic groups, wherein the above groups are independently and optionally further selected from one or more of deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, =O, =S, -C 0-8 Alkyl-SF5, -C 0- 8alkyl-S(O)(=NR) 12 )R 13 -C 0-8 Alkyl-N=S(O)R 13 R 14 -C 0-8 Alkyl-N=SR13 R 14 、-C 0-8 alkyl-O-S(O)2R 15 、-C 0-8 alkyl-S(O) r R 15 、-C 0-8 alkyl-O-R 16 、-C 0-8 alkyl-C(O)OR 16 、-C 0-8 alkyl-C(O)SR 16 、-C 0-8 alkyl-S-C(O)R 17 、-C 0-8 alkyl-C(O)R 17 、-C 0-8 alkyl-O-C(O)R 17 、-C 0- 8alkyl-P(O)(R 17 )2、-C 0-8 alkyl-NR 18 R 19 、-C 0-8 alkyl-C(=NR 18 )R 17 、-C 0-8 alkyl-N(R 18 )-C(=NR 19 )R 17 、-C 0-8 alkyl-C(O)NR 18 R 19 and -C 0-8 alkyl-N(R 18 )-C(O)R 17 , R4and R7are as previously defined;

[0024] R8, R9, R 10 and R 11 are each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azido, C 1- 10 alkyl, halogen-substituted C 1-10 alkyl, deuterium-substituted C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -C 0-8 alkyl-SF5, -C 0-8 alkyl-S(O)(=N-R 12 )R 13-C 0-8 alkyl-N=S(O)R 13 R 14 -C 0-8 alkyl-N=SR 13 R 14 -C 0-8 alkyl-O-S(O)2R 15 -C 0-8 alkyl-S(O) r R 15 -C 0-8 alkyl-O-R 16 -C 0-8 alkyl-C(O)OR 16 -C 0-8 alkyl-C(O)SR 16 -C 0-8 alkyl-S-C(O)R 17 -C 0-8 alkyl-C(O)R 17 -C 0-8 alkyl-O-C(O)R 17 -C 0-8 alkyl-P(O)(R 17 )2 0-8 -C 18 alkyl-NR 19 R 0-8 -C 18 alkyl-C(=NR 17 )R 0-8 -C 18 alkyl-N(R 19 )-C(=NR 17 )R 0-8 -C 18 alkyl-C(O)NR 19 R 0-8 -C 18 alkyl-N(R 17 )-C(O)R 12 ;

[0025] each R 1-10 is independently selected from hydrogen, deuterium, C 2-10 alkyl, C 2-10 alkenyl, C 3-10 alkynyl, C 6-10 cycloalkyl, 3-10 membered heterocyclyl, C 0-8 aryl, 5-10 membered heteroaryl, -C r alkyl-S(O) 15 R 0-8 -C 16 alkyl-C(O)OR 0-8 ;alkyl-C(O)R 17 and -C 0-8 alkyl-C(O)NR 18 R 19 , the aforementioned groups are optionally further substituted by one or more substituents selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2- 10 alkynyl, halogen-substituted C 1-10 alkyl, deuterium-substituted C 1-10 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6- 10 aryl and 5-10 membered heteroaryl, or, R 0-8 and R r alkyl-S(O) 15 R 0-8 , -C 16 alkyl-O-R 0-8 , -C 16 alkyl-C(O)OR 0-8 , -C 17 alkyl-C(O)R 0-8 , -C 17 alkyl-O-C(O)R 0-8 , -C 18 alkyl-NR 19 R 0-8 , -C 18 alkyl-C(=NR 17 )R 0-8 , -C 18 alkyl-N(R 19 )-C(=NR 17 )R 0-8 , -C 18 alkyl-C(O)NR 19 R 0-8 and -C 18 alkyl-N(R 17 )-C(O)R 13 ;

[0026] each R 14 and each R 1-10 is independently selected from the group consisting of hydrogen, deuterium, hydroxyl, C 2-10 alkyl, C 2-10 alkenyl, C 3-10 alkynyl, C 6-10 cycloalkyl, 3-10 membered heterocyclyl, C 13 aryl and 5-10 membered heteroaryl, or, R 14Together with the sulfur atom directly attached thereto, a 3-10 membered heterocyclic group is formed, which may be further selected by one or more elements selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -C 0-8 Alkyl-S(O) r R 15 -C 0-8 Alkyl-OR 16 -C 0-8 Alkyl-C(O)OR 16 -C 0-8 Alkyl-C(O)R 17 -C 0-8 Alkyl-OC(O)R 17 -C 0-8 Alkyl-NR 18 R 19 -C 0-8 Alkyl-C (=NR) 18 )R 17 -C 0-8 Alkyl-N(R) 18 )-C(=NR 19 )R 17 -C 0-8 Alkyl-C(O)NR 18 R 19 and -C 0-8 Alkyl-N(R) 18 )-C(O)R 17 The substituents are replaced;

[0027] Each R 15 Independently selected from hydrogen, deuterium, hydroxyl, C 1-10 Alkyl, C 2-10 Alkenyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 quinone heteroaryl and -NR 18 R 19 The aforementioned groups are independently and optionally further selected by one or more radicals chosen from deuterium, halogen, hydroxyl, nitro, cyano, =O, C 1-10 Alkyl, C 1-10 Alkoxy, C 3-12 cycloalkyl, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group, C 6-10aryl, C 6-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, and -NR 18 R 19 is optionally substituted with one or more substituents selected from the group consisting of deuterium, halogen, hydroxyl, =0, cyano, C

[0028] each R 16 is independently selected from the group consisting of hydrogen, deuterium, C 1-10 alkyl, C 2-10 alkenyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl, which are independently optionally further substituted with one or more substituents selected from the group consisting of deuterium, halogen, hydroxyl, =0, cyano, C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C 6-10 aryl, C 6-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, and -NR 18 R 19 is optionally substituted with one or more substituents selected from the group consisting of deuterium, halogen, hydroxyl, =0, cyano, C

[0029] each R 17 is independently selected from the group consisting of hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C 6-10 aryl, C 6-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, and -NR 18 R 19 is optionally substituted with one or more substituents selected from the group consisting of deuterium, halogen, hydroxyl, =0, cyano, C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C 6-10 aryl, C 6-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, and -NR 18 R 19 is optionally substituted with one or more substituents selected from the group consisting of deuterium, halogen, hydroxyl, =0, cyano, C

[0030] each R 18 and each R 19 is each independently selected from the group consisting of hydrogen, deuterium, hydroxyl, C1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropanesulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, and C 1-10 Alkyl group, wherein the above groups are independently and optionally further divided by one or more radicals selected from deuterium, halogen, hydroxyl, =O, C. 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 1-10 Alkoxy, C 3-12 cycloalkyl, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group, C 6-10 Aryl, C 6-10 Aryloxy, 5-10 heteroaryl, 5-10 heteroaryloxy, amino, mono-C 1-10 Alkylamino, diC 1-10 Alkylamino and C 1-10 The alkyl acyl group is replaced by a substituent;

[0031] Or, R 18 and R 19 Together with the nitrogen atom directly attached thereto, a 4-10 membered heterocyclic group or a 5-10 membered heteroaryl group is formed, wherein the 4-10 membered heterocyclic group or the 5-10 membered heteroaryl group is optionally further surrounded by one or more elements selected from deuterium, halogen, hydroxyl, =O, C. 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 1-10 Alkoxy, C 3-12 cycloalkyl, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group, C 6-10 Aryl, C 6-10 Aryloxy, 5-10 heteroaryl, 5-10 heteroaryloxy, amino, mono-C 1- 10 Alkylamino, diC 1-10 Alkylamino and C 1-10 The alkyl acyl group is substituted by a substituent; and

[0032] Each r is independently 0, 1, or 2.

[0033] As a preferred embodiment, in the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, X4is N or CR 11 ;

[0034] Ring A is C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;

[0035] m is 0, 1, 2, 3, 4, or 5; each R1is independently selected from hydrogen, deuterium, halogen, cyano, C 1- 4alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -C 0-4 alkyl-SF5, -C 0-4 alkyl-S(O)(=N-R 12 )R 13 , -C 0-4 alkyl-N=S(O)R 13 R 14 , -C 0-4 alkyl-N=SR 13 R 14 , -C 0-4 alkyl-O-S(O)2R 15 , -C 0-4 alkyl-S(O) r R 15 , -C 0-4 alkyl-O-R 16 , -C 0- 4alkyl-C(O)OR 16 , -C 0-4 alkyl-C(O)SR 16 , -C 0-4 alkyl-S-C(O)R 17 , -C 0-4 alkyl-C(O)R 17 , -C 0-4 alkyl-O-C(O)R 17 , -C 0-4 alkyl-P(O)(R 17 )2, -C 0-4 alkyl-NR 18 R 19 , -C 0-4 alkyl-C(=NR 18 )R 17 , -C 0-4 alkyl-N(R 18 )-C(=NR 19 )R17 , -C 0-4 alkyl-C(O)NR 18 R 19 and -C 0-4 alkyl-N(R 18 )-C(O)R 17 , or, when m > 2, two adjacent R1together with the moieties to which they are directly attached form a C 3-8 cycloalkyl or 3-8 membered heterocyclyl, each of the above groups being independently optionally further substituted by one or more substituents independently selected from the group consisting of deuterium, halogen, cyano, C 1-4 alkyl, halosubstituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, =O, =S, -C 0-4 alkyl-SF5, -C 0-4 alkyl-S(O)(=N-R 12 )R 13 , -C 0-4 alkyl-N=S(O)R 13 R 14 , -C 0-4 alkyl-N=SR 13 R 14 , -C 0-4 alkyl-O-S(O)2R 15 , -C 0-4 alkyl-S(O) r R 15 , -C 0-4 alkyl-O-R 16 , -C 0-4 alkyl-C(O)OR 16 , -C 0-4 alkyl-C(O)SR 16 , -C 0-4 alkyl-S-C(O)R 17 , -C 0-4 alkyl-C(O)R 17 , -C 0- 4alkyl-O-C(O)R 17 , -C 0-4 alkyl-P(O)(R 17 )2, -C 0-4 alkyl-NR 18 R 19 , -C 0-4 alkyl-C(=NR 18 )R 17 , -C0-4 alkyl-N(R 18 )-C(=NR 19 )R 17 , -C 0-4 alkyl-C(O)NR 18 R 19 , and -C 0-4 alkyl-N(R 18 )-C(O)R 17 ;

[0036] R2is selected from hydrogen, halogen, -(L) s -O-(L) s -R 2a , -(L) s -NR 2b R 2c , -(L) s -O-(L) s -NR 2b R 2c , C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, and 5-8 membered heteroaryl, said -(L) s -O-(L) s -R 2a , -(L) s -NR 2b R 2c , -(L) s -O-(L) s -NR 2b R 2c , C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, or 5-8 membered heteroaryl are each independently optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, C 1-4 alkyl, halosubstituted C 1-4 alkyl, deuterium- substituted C 1-4 alkyl, C 1-4 alkylene, halosubstituted C 1-4 alkylene, deuterium- substituted C 1-4 alkylene, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, =O, =S, -C 0-4 alkyl-SF5, -C 0-4 alkyl-S(O)(=N-R 12 )R 13 , -C 0-4 alkyl-N=S(O)R 13R 14 , -C 0-4 alkyl-N=SR 13 R 14 , -C 0-4 alkyl-O-S(O)2R 15 , -C 0-4 alkyl-S(O) r R 15 , -C 0-4 alkyl-O-R 16 , -C 0-4 alkyl-C(O)OR 16 , -C 0-4 alkyl-C(O)SR 16 , -C 0-4 alkyl-S-C(O)R 17 , -C 0-4 alkyl-C(O)R 17 , -C 0- 4alkyl-O-C(O)R 17 , -C 0-4 alkyl-P(O)(R 17 )2, -C 0-4 alkyl-NR 18 R 19 , -C 0-4 alkyl-C(=NR 18 )R 17 , -C 0-4 alkyl-N(R 18 )-C(=NR 19 )R 17 , -C 0-4 alkyl-C(O)NR 18 R 19 , and -C 0-4 alkyl-N(R 18 )-C(O)R 17 ;

[0037] each s is independently 0, 1, 2, or 3;

[0038] each L is independently selected from C 1-4 alkylene, C 3-6 cycloalkylene, or 3-6 membered heterocyclylene, wherein the C 1- 4alkylene, C 3-6 cycloalkylene, or 3-6 membered heterocyclylene is independently optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, C 1-4 alkyl, halosubstituted C 1-4 alkyl, deuterium- substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, =0, =S, -C 0-4 alkyl-SF5, -C 0-4 alkyl-S(O)(=N-R 12 )R 13 , -C 0-4 alkyl-N=S(O)R 13 R 14 , -C 0-4 alkyl-N=SR 13 R 14 , -C 0-4 alkyl-O-S(O)2R 15 , -C 0-4 alkyl-S(O) r R 15 , -C 0-4 alkyl-O-R 16 , -C 0-4 alkyl-C(O)OR 16 , -C 0- 4alkyl-C(O)SR 16 , -C 0-4 alkyl-S-C(O)R 17 , -C 0-4 alkyl-C(O)R 17 , -C 0-4 alkyl-O-C(O)R 17 , -C 0-4 alkyl-P(O)(R 17 )2, -C 0-4 alkyl-NR 18 R 19 , -C 0-4 alkyl-C(=NR 18 )R 17 , -C 0-4 alkyl-N(R 18 )-C(=NR 19 )R 17 , -C 0-4 alkyl-C(O)NR 18 R 19 and -C 0-4 alkyl-N(R 18 )-C(O)R 17 ;

[0039] R 2a is selected from the group consisting of hydrogen, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl, 3-10 membered heterocyclyl, C 6-8aryl and 5-8 membered heteroaryl, which are optionally further substituted by one or more, identical or different, deuterium, halogen, cyano, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 1-4 alkylene, halogen-substituted C 1-4 alkylene, deuterium-substituted C 1-4 alkylene, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, =0, =S, -C 0-4 alkyl-SF5, -C 0-4 alkyl-S(O)(=N-R 12 )R 13 , -C 0-4 alkyl-N=S(O)R 13 R 14 , -C 0-4 alkyl-N=SR 13 R 14 , -C 0-4 alkyl-O-S(O)2R 15 , -C 0-4 alkyl-S(O) r R 15 , -C 0-4 alkyl-O-R 16 , -C 0-4 alkyl-C(O)OR 16 , -C 0-4 alkyl-C(O)SR 16 , -C 0-4 alkyl-S-C(O)R 17 , -C 0-4 alkyl-C(O)R 17 , -C 0-4 alkyl-O-C(O)R 17 , -C 0-4 alkyl-P(O)(R 17 )2, -C 0-4 alkyl-NR 18 R 19 , -C 0-4 alkyl-C(=NR 18 )R 17 , -C 0-4 alkyl-N(R 18 )-C(=NR 19 )R 17 , -C 0-4 alkyl-C(O)NR 18 R19 and -C 0-4 alkyl-N(R 18 )-C(O)R 17 substituted by one or more substituents selected from the group consisting of deuterium, halogen, hydroxyl, =O, C

[0040] each R 2b and each R 2c is each independently selected from the group consisting of hydrogen, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -C 0-4 alkyl-S(O)2R 15 , -C 0- 4alkyl-C(O)OR 16 , -C 0-4 alkyl-C(O)SR 16 , -C 0-4 alkyl-C(O)R 17 , -C 0-4 alkyl-C(=NR 18 )R 17 and -C 0-4 alkyl-C(O)NR 18 R 19 , the aforementioned groups being independently optionally further substituted by one or more substituents selected from the group consisting of deuterium, halogen, hydroxyl, =O, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halosubstituted C 1-4 alkyl, deuterium- substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C 6- 8aryl, C 6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, amino, mono C 1-4 alkylamino, di C 1-4 alkylamino and C 1-4 alkanoyl;

[0041] Alternatively, R 2b and R 2c together with the nitrogen atom to which they are directly attached form a 4-6 membered heterocyclyl or 5-8 membered heteroaryl, said 4-6 membered heterocyclyl or 5-8 membered heteroaryl being optionally further substituted by one or more substituents selected from the group consisting of deuterium, halogen, hydroxyl, =O, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl;alkynyl, halo-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C 6- 8aryl, C 6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, amino, mono C 1-4 alkylamino, di C 1-4 alkylamino and C 1-4 substituted by one or more substituents selected from the group consisting of alkyl, C

[0042] R3is selected from the group consisting of hydrogen, deuterium, hydroxyl, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -S(O)2R 15 , -C(O)OR 16 , -C(O)SR 16 , -C(O)R 17 , -C(=NR 18 )R 17 and -C(O)NR 18 R 19 , the aforementioned groups being independently optionally further substituted by one or more substituents selected from the group consisting of deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -C 0-4 alkyl-SF5, -C 0-4 alkyl-S(O)(=N-R 12 )R 13 , -C 0- 4alkyl-N=S(O)R 13 R 14 , -C 0-4 alkyl-N=SR 13 R 14 , -C 0-4 alkyl-O-S(O)2R 15 , -C 0-4 alkyl-S(O) r R 15 , -C 0-4 alkyl-O-R 16 , -C 0-4 alkyl-C(O)OR16 -C 0-4 Alkyl-C(O)SR 16 -C 0-4 Alkyl-SC(O)R 17 -C 0-4 Alkyl-C(O)R 17 -C 0-4 Alkyl-OC(O)R 17 -C 0-4 Alkyl-P(O)(R) 17 )2、-C 0-4 Alkyl-NR 18 R 19 -C 0-4 Alkyl-C (=NR) 18 )R 17 -C 0-4 Alkyl-N(R) 18 )-C(=NR 19 )R 17 -C 0-4 Alkyl-C(O)NR 18 R 19 and -C 0-4 Alkyl-N(R) 18 )-C(O)R 17 The substituents are replaced by one or more groups selected from deuterium, halogen, cyano, C. 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1- 4-alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-8 Aryl, 5-8 heteroaryl, =O, =S, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O)(=NR) 12 )R 13 -C 0-4 Alkyl-N=S(O)R 13 R 14 -C 0-4 Alkyl-N=SR 13 R 14 -C 0-4 Alkyl-OS(O)2R 15 -C 0-4 Alkyl-S(O) r R 15 -C 0-4 Alkyl-OR 16 -C 0-4 Alkyl-C(O)OR16 -C 0-4 Alkyl-C(O)SR 16 -C 0-4 Alkyl-SC(O)R 17 -C 0-4 Alkyl-C(O)R 17 -C 0-4 Alkyl-OC(O)R 17 -C 0-4 Alkyl-P(O)(R) 17 )2、-C 0-4 Alkyl-NR 18 R 19 -C 0-4 Alkyl-C (=NR) 18 )R 17 -C 0-4 Alkyl-N(R) 18 )-C(=NR 19 )R 17 -C 0-4 Alkyl-C(O)NR 18 R 19 and -C 0-4 Alkyl-N(R) 18 )-C(O)R 17 The substituents are replaced;

[0043] R4 and R5 are each independently selected from hydrogen, deuterium, halogen, cyano, and C. 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-8 Aryl, 5-8 quinone heteroaryl, -C 0-4 Alkyl-SF5, -C 0- 4-alkyl-S(O)(=NR) 12 )R 13 -C 0-4 Alkyl-N=S(O)R 13 R 14 -C 0-4 Alkyl-N=SR 13 R 14 -C 0-4 Alkyl-OS(O)2R 15 -C 0-4 Alkyl-S(O) r R 15 -C 0-4 Alkyl-OR 16 -C 0-4 Alkyl-C(O)OR 16 -C 0-4alkyl-C(O)SR 16 , -C 0-4 alkyl-S-C(O)R 17 , -C 0-4 alkyl-C(O)R 17 , -C 0-4 alkyl-O-C(O)R 17 , -C 0- 4alkyl-P(O)(R 17 )2, -C 0-4 alkyl-NR 18 R 19 , -C 0-4 alkyl-C(=NR 18 )R 17 , -C 0-4 alkyl-N(R 18 )-C(=NR 19 )R 17 , -C 0-4 alkyl-C(O)NR 18 R 19 , and -C 0-4 alkyl-N(R 18 )-C(O)R 17 , or R4and R5together with the carbon atom to which they are directly attached form a C(O), C 3-6 cycloalkyl, or 3-6 membered heterocyclyl, each of which is independently optionally further substituted with one or more substituents independently selected from deuterium, halogen, cyano, C 1-4 alkyl, halosubstituted C 1-4 alkyl, deuterium- substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, =O, =S, -C 0-4 alkyl-SF5, -C 0-4 alkyl-S(O)(=N-R 12 )R 13 , -C 0-4 alkyl-N=S(O)R 13 R 14 , -C 0-4 alkyl-N=SR 13 R 14 , -C 0-4 alkyl-O-S(O)2R 15 , -C 0-4 alkyl-S(O) r R 15 , -C 0-4 alkyl-O-R 16 , -C0-4 alkyl-C(O)OR 16 , -C 0-4 alkyl-C(O)SR 16 , -C 0-4 alkyl-S-C(O)R 17 , -C 0-4 alkyl-C(O)R 17 , -C 0-4 alkyl-O-C(O)R 17 , -C 0-4 alkyl-P(O)(R 17 )2, -C 0-4 alkyl-NR 18 R 19 , -C 0-4 alkyl-C(=NR 18 )R 17 , -C 0-4 alkyl-N(R 18 )-C(=NR 19 )R 17 , -C 0-4 alkyl-C(O)NR 18 R 19 , and -C 0-4 alkyl-N(R 18 )-C(O)R 17 ;

[0044] R6and R7are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -C 0-4 alkyl-SF5, -C 0-4 alkyl-S(O)(=N-R 12 )R 13 , -C 0-4 alkyl-N=S(O)R 13 R 14 , -C 0-4 alkyl-N=SR 13 R 14 , -C 0-4 alkyl-O-S(O)2R 15 , -C 0-4 alkyl-S(O) r R 15 , -C 0-4 alkyl-O-R 16 , -C 0-4 alkyl-C(O)OR16 -C(O)R 0-4 -C(O)SR 16 -C(O)OR 0-4 -C(O)NRR 17 -C(O)N(R 0-4 )-C(O)R 17 -C(O)N(R 0-4 )-C(O)OR 17 -C(O)N(R 0- )-C(O)SR 17 -C(O)N(R 0-4 )-C(O)NRR 18 -C(O)N(R 19 )-C(O)N(R 0-4 )-C(O)R 18 -C(O)N(R 17 )-C(O)OR 0-4 -C(O)N(R 18 )-C(O)SR 19 -C(O)N(R 17 )-C(O)NRR 0-4 -C(O)N(R 18 )-C(O)N(R 19 )-C(O)R 0-4 -C(O)N(R 18 )-C(O)OR 17 -C(O)N(R 3-6 )-C(O)SR 1-4 -C(O)N(R 1-4 )-C(O)NRR 1-4 -C(O)N(R 2-4 )-C(O)N(R 2-4 )-C(O)R 3-6 -C(O)N(R 6-8 )-C(O)OR 0-4 -C(O)N(R 0-4 )-C(O)SR 12 -C(O)N(R 13 )-C(O)NRR 0-4 -C(O)N(R 13 )-C(O)N(R 14 )-C(O)R 0-4 -C(O)N(R 13 )-C(O)OR 14 -C(O)N(R 0-4 )-C(O)SR 15 -C(O)N(R 0-4 )-C(O)NRR r -C(O)N(R 15 )-C(O)N(R 0-4 -C(O)N(Ralkyl-O-R 16 , -C 0-4 alkyl-C(O)OR 16 , -C 0-4 alkyl-C(O)SR 16 , -C 0-4 alkyl-S-C(O)R 17 , -C 0-4 alkyl-C(O)R 17 , -C 0-4 alkyl-O-C(O)R 17 , -C 0-4 alkyl-P(O)(R 17 )2, -C 0-4 alkyl-NR 18 R 19 , -C 0-4 alkyl-C(=NR 18 )R 17 , -C 0-4 alkyl-N(R 18 )-C(=NR 19 )R 17 , -C 0-4 alkyl-C(O)NR 18 R 19 , and -C 0-4 alkyl-N(R 18 )-C(O)R 17 ;

[0045] or R5and R6together with the moiety to which they are directly attached form a C 3-6 cycloalkyl or 3-6 membered heterocyclyl, each of which is independently optionally further substituted with one or more substituents selected from the group consisting of deuterium, halogen, cyano, C 1-4 alkyl, halosubstituted C 1-4 alkyl, deuterium- substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, =O, =S, -C 0-4 alkyl-SF5, -C 0-4 alkyl-S(O)(=N-R 12 )R 13 , -C 0-4 alkyl-N=S(O)R 13 R 14 , -C 0-4 alkyl-N=SR 13 R 14 , -C 0-4 alkyl-O-S(O)2R15 -C 0-4 Alkyl-S(O) r R 15 -C 0-4 Alkyl-OR 16 -C 0-4 Alkyl-C(O)OR 16 -C 0-4 Alkyl-C(O)SR 16 -C 0-4 Alkyl-SC(O)R 17 -C 0-4 Alkyl-C(O)R 17 -C 0-4 Alkyl-OC(O)R 17 -C 0-4 Alkyl-P(O)(R) 17 )2、-C 0-4 Alkyl-NR 18 R 19 -C 0-4 Alkyl-C (=NR) 18 )R 17 -C 0-4 Alkyl-N(R) 18 )-C(=NR 19 )R 17 -C 0-4 Alkyl-C(O)NR 18 R 19 and -C 0-4 Alkyl-N(R) 18 )-C(O)R 17 The substituents are replaced by R4 and R7 as defined above;

[0046] R8, R9, R 10 and R 11 Each is independently selected from hydrogen, deuterium, halogen, cyano, and C. 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-8 Aryl, 5-8 quinone heteroaryl, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O)(=NR) 12 )R 13 -C 0-4 Alkyl-N=S(O)R 13 R 14 -C 0-4 Alkyl-N=SR13 R 14 , -C 0-4 alkyl-O-S(O)2R 15 , -C 0-4 alkyl-S(O) r R 15 , -C 0-4 alkyl-O-R 16 , -C 0-4 alkyl-C(O)OR 16 , -C 0-4 alkyl-C(O)SR 16 , -C 0-4 alkyl-S-C(O)R 17 , -C 0-4 alkyl-C(O)R 17 , -C 0-4 alkyl-O-C(O)R 17 , -C 0-4 alkyl-P(O)(R 17 )2, -C 0-4 alkyl-NR 18 R 19 , -C 0-4 alkyl-C(=NR 18 )R 17 , -C 0-4 alkyl-N(R 18 )-C(=NR 19 )R 17 , -C 0-4 alkyl-C(O)NR 18 R 19 , and -C 0-4 alkyl-N(R 18 )-C(O)R 17 ;

[0047] wherein R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 and r are as defined for the compound of formula (I).

[0048] As a preferred option, in the compound of formula (I), in the stereoisomer thereof, or in the pharmaceutically acceptable salt thereof, each R 12 is each independently selected from hydrogen, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8Aryl, 5-8 quinone heteroaryl, -C 0-4 Alkyl-S(O) r R 15 -C 0-4 Alkyl-C(O)OR 16 -C 0-4 Alkyl-C(O)R 17 and -C 0-4 Alkyl-C(O)NR 18 R 19 The above-mentioned groups may optionally be further divided by one or more groups selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-8 Aryl, 5-8 quinone heteroaryl, -C 0-4 Alkyl-S(O) r R 15 -C 0-4 Alkyl-OR 16 -C 0-4 Alkyl-C(O)OR 16 -C 0-4 Alkyl-C(O)R 17 -C 0-4 Alkyl-OC(O)R 17 -C 0-4 Alkyl-NR 18 R 19 -C 0-4 Alkyl-C (=NR) 18 )R 17 -C 0-4 Alkyl-N(R) 18 )-C(=NR 19 )R 17 -C 0-4 Alkyl-C(O)NR 18 R 19 and -C 0-4 Alkyl-N(R) 18 )-C(O)R 17 The substituents are replaced;

[0049] Each R 13 and each R 14 Each is independently selected from hydrogen, deuterium, hydroxyl, and C. 1-4 Alkyl, C 2-4 Alkenyl, C 2- 4-chain ynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C6-8 aryl and 5-8 membered heteroaryl, or, R 13 and R 14 together with the sulfur atom to which they are directly attached form a 3-6 membered heterocyclyl, which is optionally further substituted by one or more substituents selected from the group consisting of deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -C 0-4 alkyl-S(O) r R 15 , -C 0-4 alkyl-O-R 16 , -C 0-4 alkyl-C(O)OR 16 , -C 0-4 alkyl-C(O)R 17 , -C 0-4 alkyl-O-C(O)R 17 , -C 0-4 alkyl-NR 18 R 19 , -C 0-4 alkyl-C(=NR 18 )R 17 , -C 0-4 alkyl-N(R 18 )-C(=NR 19 )R 17 , -C 0-4 alkyl-C(O)NR 18 R 19 and -C 0-4 alkyl-N(R 18 )-C(O)R 17 ;

[0050] each R 15 is independently selected from the group consisting of hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl and -NR 18 R 19 , which are independently optionally further substituted by one or more substituents selected from the group consisting of deuterium, halogen, hydroxyl, nitro, cyano, =O, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6cycloalkoxy, 3- to 6-membered heterocyclyl, 3- to 6-membered heterocyclyloxy, C 6-8 aryl, C 6-8 aryloxy, 5- to 8-membered heteroaryl, 5- to 8-membered heteroaryloxy, and -NR 18 R 19 , are optionally substituted by one or more substituents independently selected from the group consisting of deuterium, halogen, hydroxyl, =0, cyano, C

[0051] each R 16 is independently selected from the group consisting of hydrogen, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, C 6-8 aryl and 5- to 8-membered heteroaryl, said groups being independently and optionally further substituted by one or more substituents independently selected from the group consisting of deuterium, halogen, hydroxyl, =0, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3- to 6-membered heterocyclyl, 3- to 6-membered heterocyclyloxy, C 6-8 aryl, C 6-8 aryloxy, 5- to 8-membered heteroaryl, 5- to 8-membered heteroaryloxy, and -NR 18 R 19 , are optionally substituted by one or more substituents independently selected from the group consisting of deuterium, halogen, hydroxyl, =0, cyano, C

[0052] each R 17 is independently selected from the group consisting of hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3- to 6-membered heterocyclyl, 3- to 6-membered heterocyclyloxy, C 6-8 aryl, C 6-8 aryloxy, 5- to 8-membered heteroaryl, 5- to 8-membered heteroaryloxy, and -NR 18 R 19 , are optionally substituted by one or more substituents independently selected from the group consisting of deuterium, halogen, hydroxyl, =0, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3- 6cycloalkoxy, 3- to 6-membered heterocyclyl, 3- to 6-membered heterocyclyloxy, C 6-8 aryl, C 6-8 aryloxy, 5- to 8-membered heteroaryl, 5- to 8-membered heteroaryloxy, and -NR 18 R 19 , are optionally substituted by one or more substituents independently selected from the group consisting of deuterium, halogen, hydroxyl, =0, cyano, C

[0053] each R 18 and each R 19each independently selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 2-4 alkenyl, C 2- 4alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, sulfinyl, sulfonyl, methylsulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, and C 1-4 alkanoyl, the aforementioned groups being independently optionally further substituted by one or more substituents selected from the group consisting of deuterium, halogen, hydroxyl, =0, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C 6- 8aryl, C 6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, amino, mono-C 1-4 alkylamino, di-C 1-4 alkylamino, and C 1-4 alkanoyl, the substituents of which are optionally substituted by one or more substituents selected from the group consisting of deuterium, halogen, hydroxyl, =0, C

[0054] or, R 18 and R 19 form, together with the nitrogen atom to which they are directly attached, a 4-6 membered heterocyclyl or 5-8 membered heteroaryl, said 4-6 membered heterocyclyl or 5-8 membered heteroaryl being optionally further substituted by one or more substituents selected from the group consisting of deuterium, halogen, hydroxyl, =0, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C 6- 8aryl, C 6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, amino, mono-C 1-4 alkylamino, di-C 1-4 alkylamino, and C 1-4 alkanoyl, the substituents of which are optionally substituted by one or more substituents selected from the group consisting of deuterium, halogen, hydroxyl, =0, C

[0055] each r is independently 0, 1 or 2.

[0056] As a further preferred aspect, in the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, X1is N, X2is N, and X3is CR 10 or N; or, X1is N, X2is CR9, and X3is CR 10 or N; or, X1is CR8, X2is N, and X3is CR 10 or N; or, X1is CR8, X2is CR9, and X3is CR 10 or N; wherein R8, R9, and R 10 are as defined for the compound of formula (I).

[0057] As a further preferred aspect, in the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, the compound of formula (I) is a compound of formula (II):

[0058] wherein, is a single or double bond, and when is a double bond, R4and R7are absent;

[0059] X3is CR 10 or N;

[0060] Ring A is C 6-10 aryl or 5-10 membered heteroaryl;

[0061] m is 0, 1, 2, 3, 4, or 5; each R1is independently selected from hydrogen, deuterium, halogen, cyano, C 1- 4alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -SF5, -S(O)(=N-R 12 )R 13 , -N=S(O)R 13 R 14 , -N=SR 13 R 14 , -O-S(O)2R 15 , -S(O) r R 15 , -O-R 16 , -C(O)OR 16 , -C(O)SR 16 , -S-C(O)R 17 , -C(O)R 17 , -O-C(O)R 17 , -P(O)(R 17 )2, -NR 18 R19 , -C(=NR 18 )R 17 , -N(R 18 )-C(=NR 19 )R 17 , -C(O)NR 18 R 19 , and -N(R 18 )-C(O)R 17 , or, when m > 2, two adjacent R1groups together with the atoms to which they are directly attached form a C 3-8 cycloalkyl or 3-8 membered heterocyclyl, each of which is independently further optionally substituted with one or more substituents selected from deuterium, halogen, cyano, C 1-4 alkyl, halosubstituted C 1-4 alkyl, deuterium- substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3- 6cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, =O, =S, -SF5, -S(O)(=N-R 12 )R 13 , -N=S(O)R 13 R 14 , -N=SR 13 R 14 , -O-S(O)2R 15 , -S(O) r R 15 , -O-R 16 , -C(O)OR 16 , -C(O)SR 16 , -S-C(O)R 17 , -C(O)R 17 , -O-C(O)R 17 , -P(O)(R 17 )2, -NR 18 R 19 , -C(=NR 18 )R 17 , -N(R 18 )-C(=NR 19 )R 17 , -C(O)NR 18 R 19 , and -N(R 18 )-C(O)R 17 ;

[0062] R2is each independently selected from hydrogen, halogen, -(L) s -O-(L) s-R 2a -(L) s -NR 2b R 2c -(L) s -O-(L) s -NR 2b R 2c C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-8 Aryl and 5-8 membered heteroaryl groups, the above-(L) s -O-(L) s -R 2a -(L) s -NR 2b R 2c -(L) s -O-(L) s -NR 2b R 2c C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-8 aryl or 5-8 heteroaryl groups are independently and optionally further selected by one or more groups selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 1-4 Alkylene, halogenated C 1-4 Alkylene, deuterated C 1-4 Alkylene, C 2-4 Alkenyl, C 2-4 Alkyne group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-8 Aryl, 5-8 heteroaryl, =O, =S, -SF5, -S(O)(=NR) 12 )R 13 -N=S(O)R 13 R 14 -N=SR 13 R 14 -OS(O)2R 15 -S(O) r R 15 -OR 16 -C(O)OR 16 -C(O)SR 16 -SC(O)R 17 -C(O)R 17 -OC(O)R 17 -P(O)(R 17 )2、-NR 18 R 19 -C(=NR) 18)R 17 -N(R) 18 )-C(=NR 19 )R 17 -C(O)NR 18 R 19 and -N(R) 18 )-C(O)R 17 The substituents are replaced;

[0063] Each s is independently 0, 1, 2, or 3;

[0064] Each L is independently selected from C. 1-4 Alkylene, C 3-6 Cycloalkylene or 3-6 membered heterocyclic alkylene groups, the above C 1- 4-alkylene, C 3-6 The cycloalkyl or 3-6 membered heterocyclic group is independently and optionally further selected from one or more of deuterium, halogen, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-8 Aryl, 5-8 heteroaryl, =O, =S, -SF5, -S(O)(=NR) 12 )R 13 -N=S(O)R 13 R 14 -N=SR 13 R 14 -OS(O)2R 15 -S(O) r R 15 -OR 16 -C(O)OR 16 -C(O)SR 16 -SC(O)R 17 -C(O)R 17 -OC(O)R 17 -P(O)(R 17 )2、-NR 18 R 19 -C(=NR) 18 )R 17 -N(R) 18 )-C(=NR 19 )R 17 -C(O)NR 18 R 19 and -N(R) 18 )-C(O)R 17The substituents are replaced;

[0065] R 2a Selected from hydrogen, deuterium, and C 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-8 aryl and 5-8 heteroaryl groups, wherein the above groups are optionally further divided by one or more groups selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 1-4 Alkylene, halogenated C 1-4 Alkylene, deuterated C 1-4 Alkylene, C 2-4 Alkenyl, C 2-4 Alkyne group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-8 Aryl, 5-8 heteroaryl, =O, =S, -SF5, -S(O)(=NR) 12 )R 13 -N=S(O)R 13 R 14 -N=SR 13 R 14 -OS(O)2R 15 -S(O) r R 15 -OR 16 -C(O)OR 16 -C(O)SR 16 -SC(O)R 17 -C(O)R 17 -OC(O)R 17 -P(O)(R 17 )2、-NR 18 R 19 -C(=NR) 18 )R 17 -N(R) 18 )-C(=NR 19 )R 17 -C(O)NR 18 R 19 and -N(R) 18 )-C(O)R 17 The substituents are replaced;

[0066] Each R 2b and each R 2c Each is independently selected from hydrogen, deuterium, and C. 1-4 Alkyl, C 2-4 Alkenyl, C2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -S(O)2R 15 , -C(O)OR 16 , -C(O)SR 16 , -C(O)R 17 , -C(=NR 18 )R 17 and -C(O)NR 18 R 19 , said groups being independently and optionally further substituted by one or more substituents selected from the group consisting of deuterium, halogen, hydroxyl, =O, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C 6-8 aryl, C 6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, amino, mono C 1-4 alkylamino, di C 1-4 alkylamino and C 1-4 alkanoyl;

[0067] or, R 2b and R 2c form, together with the nitrogen atom to which they are directly attached, a 4-6 membered heterocyclyl or 5-8 membered heteroaryl, said 4-6 membered heterocyclyl or 5-8 membered heteroaryl being optionally further substituted by one or more substituents selected from the group consisting of deuterium, halogen, hydroxyl, =O, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C 6- aryl, C 6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, amino, mono C 1-4 alkylamino, di C 1-4 alkylamino and C 1-4 alkanoyl;

[0068] R3is selected from C 1-4 alkyl, C2-4 Alkenyl, C 2-4 Alkyne group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-8 Aryl, 5-8 quinone heteroaryl, -C(O)OR 16 -C(O)R 17 and -C(O)NR 18 R 19 The aforementioned groups are independently and optionally further selected by one or more radicals selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-8 Aryl, 5-8 heteroaryl, -SF5, -S(O)(=NR 12 )R 13 -N=S(O)R 13 R 14 -N=SR 13 R 14 -OS(O)2R 15 -S(O) r R 15 -OR 16 -C(O)OR 16 -C(O)SR 16 -SC(O)R 17 -C(O)R 17 -OC(O)R 17 -P(O)(R 17 )2、-NR 18 R 19 -C(=NR) 18 )R 17 -N(R) 18 )-C(=NR 19 )R 17 -C(O)NR 18 R 19 and -N(R) 18 )-C(O)R 17 The substituents are replaced by one or more groups selected from deuterium, halogen, cyano, C. 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-8 Aryl, 5-8 heteroaryl, -SF5, -S(O)(=NR12 )R 13 -N=S(O)R 13 R 14 -N=SR 13 R 14 -OS(O)2R 15 -S(O) r R 15 -C 0-1 Alkyl-OR 16 -C(O)OR 16 -C(O)SR 16 -SC(O)R 17 -C(O)R 17 -OC(O)R 17 -P(O)(R 17 )2、-C 0-1 Alkyl-NR 18 R 19 -C(=NR) 18 )R 17 -N(R) 18 )-C(=NR 19 )R 17 -C(O)NR 18 R 19 and -N(R) 18 )-C(O)R 17 The substituents are replaced;

[0069] R4 and R5 are each independently selected from hydrogen, deuterium, halogen, cyano, and C. 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-8 Aryl, 5-8 heteroaryl, -SF5, -S(O)(=NR 12 )R 13 -N=S(O)R 13 R 14 -N=SR 13 R 14 -OS(O)2R 15 -S(O) r R 15 -OR 16 -C(O)OR 16 -C(O)SR 16 -SC(O)R 17 -C(O)R 17, -O-C(O)R 17 , -P(O)(R 17 )2, -NR 18 R 19 , -C(=NR 18 )R 17 , -N(R 18 )-C(=NR 19 )R 17 , -C(O)NR 18 R 19 , and -N(R 18 )-C(O)R 17 ;

[0070] R6and R7are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halo-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -SF5, -S(O)(=N-R 12 )R 13 , -N=S(O)R 13 R 14 , -N=SR 13 R 14 , -O-S(O)2R 15 , -S(O) r R 15 , -O-R 16 , -C(O)OR 16 , -C(O)SR 16 , -S-C(O)R 17 , -C(O)R 17 , -O-C(O)R 17 , -P(O)(R 17 )2, -NR 18 R 19 , -C(=NR 18 )R 17 , -N(R 18 )-C(=NR 19 )R 17 , -C(O)NR 18 R 19 , and -N(R 18 )-C(O)R 17 ;

[0071] or, R5and R6together with the moieties to which they are directly attached form a C 3-6Cycloalkyl or 3-6 membered heterocyclic groups, wherein the above groups are independently and optionally further selected by one or more radicals selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-8 Aryl, 5-8 heteroaryl, =O, =S, -SF5, -S(O)(=NR) 12 )R 13 -N=S(O)R 13 R 14 -N=SR 13 R 14 -OS(O)2R 15 -S(O) r R 15 -OR 16 -C(O)OR 16 -C(O)SR 16 -SC(O)R 17 -C(O)R 17 -OC(O)R 17 -P(O)(R 17 )2、-NR 18 R 19 -C(=NR) 18 )R 17 -N(R) 18 )-C(=NR 19 )R 17 -C(O)NR 18 R 19 and -N(R) 18 )-C(O)R 17 The substituents are replaced by R4 and R7 as defined above;

[0072] R 10 Selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-8 Aryl, 5-8 heteroaryl, -SF5, -S(O)(=NR 12 )R 13 -N=S(O)R 13 R 14 -N=SR13 R 14 , -O-S(O)2R 15 , -S(O) r R 15 , -O-R 16 , -C(O)OR 16 , -C(O)SR 16 , -S-C(O)R 17 , -C(O)R 17 , -O-C(O)R 17 , -P(O)(R 17 )2, -NR 18 R 19 , -C(=NR 18 )R 17 , -N(R 18 )-C(=NR 19 )R 17 , -C(O)NR 18 R 19 , and -N(R 18 )-C(O)R 17 ;

[0073] wherein R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , and r are as defined for the compound of formula (I).

[0074] As a still further preferred aspect, the compound of formula (I), stereoisomer or pharmaceutically acceptable salt thereof is a compound of formula (IIIa), (IIIb) or (IIIc):

[0075] wherein, is a single or double bond;

[0076] Z1is O, S or NH; Z2is CR 1a or N; Z3is CR 1b or N; Z4is CR 1c or N; Z5is CR 1d or N; Z6is CR 1e or N; Z7is CR 1f or N; Z8is CR 1g or N; Z9is CR 1h or N;

[0077] m1is 0, 1, 2, 3, 4 or 5; m2is 0, 1 or 2;

[0078] each R1is independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -SF5, -S(O) r R 15 , -O-R 16 , -C(O)OR 16 , -C(O)R 17 , -O-C(O)R 17 , and -NR 18 R 19 ;

[0079] R 1a , R 1b , R 1c , R 1d , R 1e , R 1f , R 1g , and R 1h are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3- 6cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -SF5, -S(O) r R 15 , -O-R 16 , -C(O)OR 16 , -C(O)R 17 , -O-C(O)R 17 , and -NR 18 R 19 ;

[0080] each R2is independently selected from hydrogen, halogen, 3-6 membered heterocyclyl, -(L) s -O-(L) s -R 2a , -(L) s -NR 2b R 2c , or -(L) s -O-(L) s -NR 2b R2c the above 3-6 membered heterocyclyl, -(L) s -O-(L) s -R 2a , -(L) s -NR 2b R 2c or -(L) s -O-(L) s -NR 2b R 2c is independently optionally further substituted by one or more substituents selected from the group consisting of deuterium, halogen, cyano, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 1-4 alkylene, halogen-substituted C 1-4 alkylene, deuterium-substituted C 1-4 alkylene, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, =0, =S, -SF5, -O-R 16 and -NR 18 R 19 ;

[0081] each s is independently 0, 1, 2 or 3;

[0082] each L is independently selected from C 1-4 alkylene, C 3-6 cycloalkylene or 3-6 membered heterocyclylalkylene, said C 1- 4alkylene, C 3-6 cycloalkylene or 3-6 membered heterocyclylalkylene is independently optionally further substituted by one or more substituents selected from the group consisting of deuterium, halogen, cyano, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, =0, =S, -SF5, -O-R 16 and -NR 18 R 19 ;

[0083] each R 2a is independently selected from hydrogen, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 3-6cycloalkyl, 3-10 membered heterocyclyl, C 6-8 aryl and 5-8 membered heteroaryl, which are optionally further substituted by one or more substituents independently selected from the group consisting of deuterium, halogen, cyano, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 1-4 alkylene, halogen-substituted C 1- alkylene, deuterium-substituted C 1-4 alkylene, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, =0, =S, -SF5, -O-R 16 and -NR 18 R 19 substituted by one or more substituents independently selected from the group consisting of deuterium, halogen, cyano, C

[0084] each R 2b and each R 2c is independently selected from the group consisting of hydrogen, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl and C 1-4 alkanoyl, which are independently optionally further substituted by one or more substituents independently selected from the group consisting of deuterium, halogen, hydroxyl, =0, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C 6-8 aryl, C 6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, amino, mono-C 1-4 alkylamino, di-C 1-4 alkylamino and C 1-4 alkanoyl, which are substituted by one or more substituents independently selected from the group consisting of deuterium, halogen, hydroxyl, =0, C

[0085] or, R 2b and R 2ctogether with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl or 5-8 membered heteroaryl, which is optionally further substituted by one or more substituents selected from the group consisting of deuterium, halogen, hydroxyl, =0, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C 6- 8aryl, C 6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, amino, mono 1-4 alkylamino, di 1-4 alkylamino and C 1-4 alkanoyl, which is optionally further substituted by one or more substituents selected from the group consisting of deuterium, halogen, hydroxyl, =0, C

[0086] each R3is independently selected from the group consisting of C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl, which are independently optionally further substituted by one or more substituents selected from the group consisting of deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -SF5, -O-S(O)2R 15 , -S(O) r R 15 , -O-R 16 , -C(O)OR 16 , -C(O)R 17 , -O-C(O)R 17 , -NR 18 R 19 , -C(O)NR 18 R 19 and -N(R 18 )-C(O)R 17 , which are independently optionally further substituted by one or more substituents selected from the group consisting of deuterium, halogen, cyano, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6C3-6cycloalkyl, 3-6 membered heterocyclyl, -O-R 6-8 aryl, 5-8 membered heteroaryl, -SF5, -S(O)(=N-R 12 )R 13 , -N=S(O)R 13 R 14 , -N=SR 13 R 14 , -O-S(O)2R 15 , -S(O) r R 15 , -C 0-1 alkyl-O-R 16 , -C(O)OR 16 , -C(O)SR 16 , -S-C(O)R 17 , -C(O)R 17 , -O-C(O)R 17 , -P(O)(R 17 )2, -C 0-1 alkyl-NR 18 R 19 , -C(=NR 18 )R 17 , -N(R 18 )-C(=NR 19 )R 17 , -C(O)NR 18 R 19 and -N(R 18 )-C(O)R 17 ;

[0087] each R5is independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, -O-R 16 and -NR 18 R 19 ;

[0088] each R6is independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, -O-R 16 and -NR 18R 19 ;

[0089] Alternatively, R5and R6together with the moiety to which they are directly attached form a C 3-6 cycloalkyl or 3-6 membered heterocyclyl, each of which is independently optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, C 1-4 alkyl, halosubstituted C 1-4 alkyl, deuterium- substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, =0, -0-R 16 , -C(O)OR 16 , -C(O)R 17 , -O-C(O)R 17 , -NR 18 R 19 , -C(O)NR 18 R 19 and -N(R 18 )-C(O)R 17 ;

[0090] each R 10 is independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halosubstituted C 1-4 alkyl, deuterium- substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -SF5, -O-R 16 and -NR 18 R 19 ;

[0091] wherein R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 and r are as defined for the compound of formula (I).

[0092] As a still further preferred aspect, the compound of formula (I), stereoisomer or pharmaceutically acceptable salt thereof is a compound of formula (IVa1), (IVb1) or (IVc1):

[0093] wherein Z1is O, S or NH; Z2is CR 1a or N; Z3is CR 1b or N; Z4is CR 1c or N; Z5is CR 1d or N; Z6is CR 1e or N; Z7is CR 1f or N; Z8is CR 1g or N; Z9is CR 1h or N;

[0094] R 1a , R 1b , R 1c , R 1d , R 1e , R 1f , R 1g and R 1h are each independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, methyl, ethyl, n-propyl, i-propyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, ethenyl, allyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, oxetanyl, azetanyl, amino, methylamino and dimethylamino;

[0095] In the compound of formula (IVa1), formula (IVb1) or formula (IVc1), R1, R2, R3, R5, R6, R 10 , m1and m2are as defined in the compound of formula (I).

[0096] As a still further preferred aspect, in the compound of formula (I), stereoisomer thereof or pharmaceutically acceptable salt thereof, the compound of formula (I) is a compound of formula (IVa2), formula (IVb2) or formula (IVc2):

[0097] wherein Z1is O, S or NH; Z2is CR 1a or N; Z3is CR 1b or N; Z4is CR 1c or N; Z5is CR 1d or N; Z6is CR 1e or N; Z7is CR 1f or N; Z8is CR 1g or N; Z9is CR 1h or N;

[0098] R 1a , R 1b , R 1c , R 1d , R 1e , R 1f , R1g and R 1h each independently is selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, methyl, ethyl, n-propyl, i-propyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, ethenyl, allyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, oxetanyl, azetanyl, amino, methylamino and dimethylamino;

[0099] In the compound of formula (IVa2), (IVb2) or (IVc2), R1, R2, R3, R5, R6, R 10 m1and m2are as defined for the compound of formula (I).

[0100] As a further preferred aspect, in the compound of formula (I), in the stereoisomer thereof or in the pharmaceutically acceptable salt thereof, each R1is independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, methyl, ethyl, n-propyl, i-propyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, ethenyl, allyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, oxetanyl, azetanyl, amino, methylamino and dimethylamino.

[0101] As a further preferred aspect, in the compound of formula (I), in the stereoisomer thereof or in the pharmaceutically acceptable salt thereof, R 10 each independently is selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, methyl, ethyl, n-propyl, i-propyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, ethenyl, allyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, oxetanyl, azetanyl, amino, methylamino and dimethylamino.

[0102] As a further preferred aspect, in the compound of formula (I), in the stereoisomer thereof or in the pharmaceutically acceptable salt thereof, R5is independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl, n-propyl, i-propyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, ethenyl, allyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, oxetanyl, azetanyl, amino, methylamino and dimethylamino.

[0103] R6is selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl, n-propyl, i-propyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, ethenyl, allyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, oxetanyl, azetanyl, amino, methylamino and dimethylamino.

[0104] As a still further preferred embodiment, in the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, R3is selected from C 1-4 alkyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl, each of which is independently and optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -O-R 16 , -C(O)OR 16 , -C(O)R 17 , -O-C(O)R 17 , -NR 18 R 19 , -C(O)NR 18 R 19 and -N(R 18 )-C(O)R 17 , each of which is independently and optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, C 1-4 alkyl, halosubstituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -S(O) r R 15 , -C 0-1 alkyl-O-R 16 , -C(O)OR 16 , -C(O)R 17 , -O-C(O)R 17 , -P(O)(R 17 )2, -C 0-1 alkyl-NR 18 R 19 , -C(O)NR 18 R 19 and -N(R 18 )-C(O)R 17 ;

[0105] wherein R 15 , R 16 , R 17 , R 18 , R 19 and r are as defined for the compound of formula (I).

[0106] As yet a further preferred embodiment, in the compound of formula (I), stereoisomer thereof, or pharmaceutically acceptable salt thereof, R3is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, and isobutyl, each of which is independently optionally further substituted with one or more substituents selected from the group consisting of deuterium, halogen, cyano, hydroxyl, methyl, ethyl, propyl, isopropyl, ethenyl, allyl, propargyl, cyclopropyl, cyclobutyl, oxacyclopropyl, azacyclopropyl, oxacyclobutyl, azacyclobutyl, morpholinyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, imidazolyl, oxazolyl, thiazolyl, quinolinyl, indolyl, and isoquinolinyl, each of which is independently optionally further substituted with one or more substituents selected from the group consisting of deuterium, halogen, cyano, amino, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, -C 0-1 alkyl-O-R 16a and -C 0-1 alkyl-NR 18a R 19a ;

[0107] R 16a is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, and dideuteromethyl;

[0108] R 18a and R 19a are each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, and dideuteromethyl.

[0109] As a further preferred embodiment, in the compound of formula (I), stereoisomer thereof, or pharmaceutically acceptable salt thereof, R2is selected from the group consisting of 3-6 membered heterocyclyl, -(L) s -O-(L) s -R 2a or -(L) s -NR 2b R 2c , the 3-6 membered heterocyclyl, -(L) s -O-(L) s -R 2a or -(L) s -NR 2b R 2c is independently optionally further substituted with one or more substituents selected from the group consisting of deuterium, halogen, cyano, hydroxyl, C 1-4 alkyl, C 1-4alkyl, halo-substituted C 1-4 alkyl, halo-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 1-4 alkylene, halo-substituted C 1-4 alkylene, deuterium-substituted C 1-4 alkylene, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3- to 6-membered heterocyclyl, 3- to 6-membered heterocyclyloxy, =0, =S, -SF5, amino, mono-C 1-4 alkylamino and di-C 1-4 substituted by one or more substituents selected from the group consisting of deuterium, halogen, cyano, hydroxyl, C

[0110] each s is independently 0, 1, 2 or 3;

[0111] each L is independently selected from C 1-4 alkylene, C 3-6 cycloalkylene or 3- to 6-membered heterocyclylene, the C 1- 4alkylene, C 3-6 cycloalkylene or 3- to 6-membered heterocyclylene is independently optionally further substituted by one or more substituents selected from the group consisting of deuterium, halogen, cyano, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, halo-substituted C 1-4 alkyl, halo-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, C 3- 6cycloalkoxy, 3- to 6-membered heterocyclyl, 3- to 6-membered heterocyclyloxy, =0, =S, -SF5, amino, mono-C 1-4 alkylamino and di-C 1-4 substituted by one or more substituents selected from the group consisting of deuterium, halogen, cyano, hydroxyl, C

[0112] R 2a is selected from the group consisting of hydrogen, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl, amino, methylamino, dimethylamino, the above groups are optionally further substituted by one or more substituents selected from the group consisting of deuterium, halogen, cyano, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, halo-substituted C 1-4alkyl, halogen-substituted C 1-4 alkoxy, deuterium-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkoxy, C 1-4 alkylene, halogen-substituted C 1-4 alkylene, deuterium-substituted C 1-4 alkylene, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3- to 6-membered heterocyclyl, 3- to 6-membered heterocyclyloxy, =0, =S, -SF5, amino, mono-C 1-4 alkylamino and di-C 1-4 substituted by one or more substituents selected from the group consisting of deuterium, halogen, hydroxyl, =0, C

[0113] each R 2b and each R 2c is each independently selected from the group consisting of hydrogen, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl and 3- to 6-membered heterocyclyl, said radicals being independently optionally further substituted by one or more substituents selected from the group consisting of deuterium, halogen, hydroxyl, =0, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3- to 6-membered heterocyclyl, 3- to 6-membered heterocyclyloxy, C 6-8 aryl, 5- to 8-membered heteroaryl, amino, mono-C 1-4 alkylamino, di-C 1-4 alkylamino and C 1-4 substituted by one or more substituents selected from the group consisting of deuterium, halogen, hydroxyl, =0, C

[0114] or, R 2b and R 2c form, together with the nitrogen atom to which they are directly attached, a 4- to 6-membered heterocyclyl or a 5- to 8-membered heteroaryl, said 4- to 6-membered heterocyclyl or 5- to 8-membered heteroaryl being optionally further substituted by one or more substituents selected from the group consisting of deuterium, halogen, hydroxyl, =0, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C 6- 8aryl, 5-8 membered heteroaryl, amino, mono C 1-4 alkylamino, di C 1-4 alkylamino and C 1-4 substituted by one or more substituents selected from the group consisting of deuterium, halogen, cyano, hydroxyl, methyl, ethyl, isopropyl, vinyl, allyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, amino, methylamino, dimethylamino,

[0115] each s is independently 0, 1, 2 or 3.

[0116] As a further preferred option, in the compound of formula (I), stereoisomer thereof, or pharmaceutically acceptable salt thereof, R2is selected from

[0117] each R 2a is each independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, isopropyl, vinyl, allyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, amino, methylamino, dimethylamino, said groups are optionally further substituted by one or more substituents selected from the group consisting of deuterium, halogen, cyano, hydroxyl, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, methylene, monofluoromethylene, difluoromethylene, vinyl, ethynyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, =0, =S, -SF5, amino, methylamino and dimethylamino;

[0118] R 2a1 and R 2a2 is each independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, hydroxyl, methyl, ethyl, isopropyl, vinyl, allyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, amino, methylamino and dimethylamino;

[0119] R 2a3 and R 2a4 is each independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, hydroxyl, methyl, ethyl, isopropyl, vinyl, allyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, amino, methylamino and dimethylamino;

[0120] R 2b is selected from the group consisting of hydrogen, deuterium, methyl, ethyl, isopropyl, vinyl, allyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl and azetidinyl;

[0121] R 2c1selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, phenyl, pyridyl, or pyrimidinyl, which is optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, hydroxyl, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, C1-6alkylene, C1-6alkenylene, C1-6alkynylene, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, =0, =S, -SF5, amino, methylamino, and dimethylamino; 1-4 alkylene, halogen-substituted C 1-4 alkylene, deuterium-substituted C 1-4 alkylene, vinyl, ethynyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, =0, =S, -SF5, amino, methylamino, and dimethylamino;

[0122] each R 2d is independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, isopropyl, vinyl, allyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, amino, methylamino, and dimethylamino;

[0123] each R 2e is independently selected from hydrogen, deuterium, methyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, ethyl, isopropyl, vinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, or azetidinyl.

[0124] As a further preferred aspect, the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is a compound of formula (Va1-1), formula (Va1-2), formula (Vb1), or formula (Vc1):

[0125] wherein,

[0126] In the compounds of formula (Va1-1) and formula (Va1-2), each R 1i , each R 1j , and each R 1k is independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, vinyl, allyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, amino, methylamino, and dimethylamino;

[0127] In the compounds of formula (Vb1), R 1a , R 1b , R 1c , R 1d , and R 1eeach independently is selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, ethenyl, allyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, amino, methylamino, and dimethylamino;

[0128] In the compound of formula (Vc1), R 1f , R 1g , and R 1h each independently is selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, ethenyl, allyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, amino, methylamino, and dimethylamino;

[0129] R 1L , and R 1m each independently is selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, ethenyl, allyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, amino, methylamino, and dimethylamino;

[0130] In the compound of formula (Va1-1), formula (Vb1), or formula (Vc1), each R 2a1 , and each R 2a2 each independently is selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, hydroxyl, methyl, ethyl, isopropyl, ethenyl, allyl, propynyl, cyclopropyl, amino, methylamino, and dimethylamino;

[0131] In the compound of formula (Va1-1), formula (Vb1), or formula (Vc1), each R 2a5 , and each R 2a6 each independently is selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, methylene, monofluoromethylene, difluoromethylene, ethenyl, ethynyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, =0, =S, -SF5, amino, methylamino, and dimethylamino;

[0132] In the compound of formula (Va1-2), R 2a8 , and R 2a9each independently is selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, methylene, monofluoromethylene, difluoromethylene, ethenyl, ethynyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, amino, methylamino, and dimethylamino;

[0133] each R 3a each independently is selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, methylene, monofluoromethylene, difluoromethylene, ethenyl, ethynyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, amino, methylamino, and dimethylamino;

[0134] each R 3b each independently is selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, methylene, monofluoromethylene, difluoromethylene, ethenyl, ethynyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, amino, methylamino, and dimethylamino;

[0135] each R5is independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, amino, methylamino, and dimethylamino;

[0136] each R6is independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, amino, methylamino, and dimethylamino.

[0137] As a further preferred aspect, the compound of formula (I), stereoisomer thereof, or pharmaceutically acceptable salt thereof is a compound of formula (Va2-1), (Va2-2), (Vb2), or (Vc2):

[0138] wherein,

[0139] In the compounds of formula (Va2-1) and (Va2-2), each R 1i , each R 1j , and each R 1k is independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, ethenyl, allyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, amino, methylamino, and dimethylamino;

[0140] In the compound of formula (Vb2), R 1a , R 1b , R 1c , R 1d and R 1e are each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, ethenyl, allyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, amino, methylamino and dimethylamino;

[0141] In the compound of formula (Vc2), R 1f , R 1g and R 1h are each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, ethenyl, allyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, amino, methylamino and dimethylamino;

[0142] R 1L and R 1m are each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, ethenyl, allyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, amino, methylamino and dimethylamino;

[0143] each R 2a1 and each R 2a2 are each independently selected from hydrogen, deuterium, fluorine, chlorine, hydroxyl, methyl, ethyl, isopropyl, ethenyl, allyl, propynyl, cyclopropyl, amino, methylamino and dimethylamino;

[0144] In the compound of formula (Va2-1), formula (Vb2) or formula (Vc2), each R 2a5 and each R 2a6 are each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, methylene, monofluoromethylene, difluoromethylene, ethenyl, ethynyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, =0, =S, -SF5, amino, methylamino and dimethylamino;

[0145] In the compound of formula (Va2-2), R 2a7 is selected from the group consisting of hydrogen, deuterium, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, and azetidinyl;

[0146] R 2a8 and R 2a9 are each independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, methylene, monofluoromethylene, difluoromethylene, ethenyl, ethynyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, amino, methylamino, and dimethylamino;

[0147] each R 3a is independently selected from the group consisting of hydrogen, methyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, ethyl, propyl, isopropyl, butyl, isobutyl, and cyclopropyl;

[0148] each R 3b is independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, cyano, amino, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, morpholinyl, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, -CH2-OH, -CH2-NH2, amino, methylamino, and dimethylamino.

[0149] As the most preferred aspect, the compound of formula (I), stereoisomer thereof, or pharmaceutically acceptable salt thereof includes, but is not limited to, the following compounds:

[0150] The second aspect of the present application provides a pharmaceutical composition comprising the compound of formula (I), stereoisomer thereof, or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0151] The present application also relates to the use of the compound of formula (I), stereoisomer thereof, or pharmaceutically acceptable salt thereof for the preparation of a medicament for treating a tumor associated with KRAS.

[0152] As a preferred option, the tumor associated with KRAS is a tumor associated with wild-type KRAS, KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D, or KRAS Q61H.

[0153] As a further preferred option, the tumor is a cancer.

[0154] As a further preferred option, the tumor is an adenoma, a lymphoma, a mesothelioma, a lung cancer, an esophageal cancer, a gastric cancer, a pancreatic cancer, a liver cancer, a cholangiocarcinoma, a gallbladder cancer, a cancer of the ampulla, a small intestinal cancer, a large intestinal cancer, a kidney cancer, a testicular cancer, a hematological cancer, a hemangioma, a myeloma, a chondroma, a cancer of the skull, a brain cancer, a glioma, a uterine cancer, a vulvar cancer, a vaginal cancer, a cancer of the fallopian tube, a bladder cancer, a urethral cancer, a prostate cancer, an adrenal adenoma, a sarcoma, a myxoma, a rhabdomyoma, a fibroma, a lipoma, a bronchial cancer, a Hodgkin's disease, a malignant melanoma, a basal cell carcinoma, a squamous cell carcinoma, a chondrodysplasia, a psoriasis, or a neuroblastoma.

[0155] The present application also relates to a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of a tumor associated with wild-type KRAS, KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D, or KRAS Q61H.

[0156] The present application also relates to a method of treating a tumor associated with KRAS, comprising administering to a patient in need thereof a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0157] As a preferred option, the tumor is an adenoma, a lymphoma, a mesothelioma, a lung cancer, an esophageal cancer, a gastric cancer, a pancreatic cancer, a liver cancer, a cholangiocarcinoma, a gallbladder cancer, a cancer of the ampulla, a small intestinal cancer, a large intestinal cancer, a kidney cancer, a testicular cancer, a hematological cancer, a hemangioma, a myeloma, a chondroma, a cancer of the skull, a brain cancer, a glioma, a uterine cancer, a vulvar cancer, a vaginal cancer, a cancer of the fallopian tube, a bladder cancer, a urethral cancer, a prostate cancer, an adrenal adenoma, a sarcoma, a myxoma, a rhabdomyoma, a fibroma, a lipoma, a bronchial cancer, a Hodgkin's disease, a malignant melanoma, a basal cell carcinoma, a squamous cell carcinoma, a chondrodysplasia, a psoriasis, or a neuroblastoma. DETAILED DESCRIPTION

[0158] The inventors of the present application have made extensive and in-depth research, and for the first time developed a KRAS inhibitor with the structure of formula (I). The series of compounds of the present application can be widely used in the preparation of drugs for treating and / or preventing KRAS-related cancers or tumors, and are expected to develop into a new generation of KRAS inhibitors. On this basis, the present application is completed.

[0159] Detailed description: Unless otherwise stated or specifically stated, the following terms used in the specification and claims have the following meanings.

[0160] "Alkyl" refers to straight-chain or branched-chain saturated aliphatic hydrocarbon groups, preferably including straight-chain alkyl and branched-chain alkyl groups of 1 to 10 or 1 to 6 carbon atoms or 1 to 4 carbon atoms, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 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, or various branched-chain isomers thereof, and the like. "C 1-21 "Alkyl" refers to straight-chain alkyl and branched-chain alkyl groups including 1 to 21 carbon atoms, "C 1-10 "Alkyl" refers to straight-chain alkyl and branched-chain alkyl groups including 1 to 10 carbon atoms, "C 1-4 "Alkyl" refers to straight-chain alkyl and branched-chain alkyl groups including 1 to 4 carbon atoms, "C 0-8 "Alkyl" refers to straight-chain alkyl and branched-chain alkyl groups including 0 to 8 carbon atoms, "C 0-4 "Alkyl" refers to straight-chain alkyl and branched-chain alkyl groups including 0 to 4 carbon atoms, "C 0-1 "Alkyl" refers to straight-chain alkyl groups including 0 or 1 carbon atom, "C0alkyl" refers to a bond, "C1alkyl" refers to a methyl group.

[0161] Alkyl can be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more (preferably 1, 2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6haloalkenyl, C2-6alkynyl, C2-6haloalkynyl, C3-6cycloalkyl, 3- to 12-membered heterocyclyl, aryl, 5- to 10-membered heteroaryl, =0, =S, -OR, -O- 1- 10 Alkyl, halogen-substituted C 1-10 Alkyl, deuterium-substituted C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, =0, =S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=N-R 12 )R 13 , -C 0-8 Alkyl-N=S(O)R 13 R 14 , -C 0-8 Alkyl-N=SR 13 R 14 , -C 0-8 Alkyl-O-S(O)2R 15 , -C 0-8 Alkyl-S(O) r R 15 , -C 0-8 Alkyl-O-R 16 , -C 0-8 Alkyl-C(O)OR 16 , -C 0-8 Alkyl-C(O)SR 16 , -C 0-8 Alkyl-S-C(O)R 17 , -C 0-8 Alkyl-C(O)R 17 , -C 0-8 Alkyl-O-C(O)R 17 , -C 0- 8Alkyl-P(O)(R 17 )2, -C 0-8 Alkyl-NR 18 R 19 , -C 0-8 Alkyl-C(=NR 18 )R 17 , -C 0-8 Alkyl-N(R 18 )-C(=NR 19 )R 17 , -C 0-8 Alkyl-C(O)NR 18 R 19 and -C0-8 alkyl-N(R 18 )-C(O)R 17 substituted by a substituent selected from the group consisting of:

[0162] "Alkylene" refers to a radical of the formula "-R-" or of the formula "=R" wherein "R" is "alkyl" as defined above. When "alkylene" is attached to the same atom, it refers to a radical of the formula "=R", preferably including straight chain alkylene groups of 1 to 10 or 1 to 6 carbon atoms or 1 to 4 carbon atoms and branched chain alkylene groups, including but not limited to methylene (=CH2), ethylene (=CHCH3), hexylene (=CH(CH2)4CH3), and the like. For example, in the following compound:

[0163] The boxed arrow indicates a methylene group within the boxed line.

[0164] When "alkylene" is attached to different atoms, it refers to a radical of the formula "-R-", preferably including straight chain alkylene groups of 1 to 10 or 1 to 6 carbon atoms or 1 to 4 carbon atoms and branched chain alkylene groups, including but not limited to methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), isopropylene (-CH(CH3)CH2-), hexylene (-CH2(CH2)4CH2-), and the like.

[0165] Alkylene can be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1- 10 alkyl, halosubstituted C 1-10 alkyl, deuterium-substituted C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, =O, =S, -C 0-8 alkyl-SF5, -C 0-8 alkyl-S(O)(=N-R 12 )R 13 , -C 0-8 alkyl-N=S(O)R 13 R 14 , -C 0-8 alkyl-N=SR 13 R 14 , -C 0-8 alkyl-O-S(O)2R 15 , -C 0-8 alkyl-S(O) r R15 -C 0-8 Alkyl-OR 16 -C 0-8 Alkyl-C(O)OR 16 -C 0-8 Alkyl-C(O)SR 16 -C 0-8 Alkyl-SC(O)R 17 -C 0-8 Alkyl-C(O)R 17 -C 0-8 Alkyl-OC(O)R 17 -C 0- 8alkyl-P(O)(R) 17 )2、-C 0-8 Alkyl-NR 18 R 19 -C 0-8 Alkyl-C (=NR) 18 )R 17 -C 0-8 Alkyl-N(R) 18 )-C(=NR 19 )R 17 -C 0-8 Alkyl-C(O)NR 18 R 19 and -C 0-8 Alkyl-N(R) 18 )-C(O)R 17 The substituents are replaced by the substituents.

[0166] "Cycloalkyl" or "carbocyclic" refers to a substituent in a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon. A partially unsaturated cyclic hydrocarbon is one that may contain one or more (preferably 1, 2, or 3) double bonds, but none of the rings has a fully conjugated π-electron system. Cycloalkyl groups are classified as monocyclic or polycyclic, and preferably include 3 to 12, 3 to 8, or 3 to 6 carbon atoms. For example, "C..." 3-12 "Cycloalkyl" refers to a cycloalkyl group consisting of 3 to 12 carbon atoms, "C 3-10 "Cycloalkyl" refers to a cycloalkyl group consisting of 3 to 10 carbon atoms, "C 3-8 "Cycloalkyl" refers to a cycloalkyl group consisting of 3 to 8 carbon atoms, "C 3-6 "Cycloalkyl" refers to a cycloalkyl group comprising 3 to 6 carbon atoms, wherein:

[0167] Monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptanetrienyl, and cyclooctyl.

[0168] Polycyclic cycloalkyl groups include spirocyclic, fused, and bridged cycloalkyl groups. "Spirocycloalkyl" refers to polycyclic groups in which single rings share a carbon atom (referred to as a spiro atom) between rings, which can contain one or more (preferably 1, 2, or 3) double bonds, but no ring has a fully conjugated pi-electron system. Spirocycloalkyl groups include, but are not limited to:

[0169] "Fused cycloalkyl" refers to all-carbon polycyclic groups in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, in which one or more rings can contain one or more (preferably 1, 2, or 3) double bonds, but no ring has a fully conjugated pi-electron system. Fused cycloalkyl groups can be divided into bicyclic, tricyclic, tetracyclic, or polycyclic, depending on the number of rings comprising the group, and include, but are not limited to:

[0170] "Bridged cycloalkyl" refers to all-carbon polycyclic groups in which any two rings share two non-adjacent carbon atoms, which can contain one or more (preferably 1, 2, or 3) double bonds, but no ring has a fully conjugated pi-electron system. Bridged cycloalkyl groups can be divided into bicyclic, tricyclic, tetracyclic, or polycyclic, depending on the number of rings comprising the group, and include, but are not limited to:

[0171] The cycloalkyl rings can be fused to aryl, heteroaryl, or heterocycloalkyl rings, where the ring attached to the parent structure is cycloalkyl, including, but not limited to, indanyl, tetrahydronaphthyl, benzocycloheptyl, and the like.

[0172] When "cycloalkyl" is attached to two different groups, it is referred to as "cycloalkylene," and includes, but is not limited to:

[0173] Cycloalkyl or cycloalkylene groups can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3, or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, halosubstituted C 1-10 alkyl, deuterium-substituted C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, =0, =S, -C 0-8 alkyl-SF5, -C 0-8 alkyl-S(O)(=N-R 12 )R 13 , -C 0-8alkyl-N=S(O)R 13 R 14 , -C 0-8 alkyl-N=SR 13 R 14 , -C 0-8 alkyl-O-S(O)2R 15 , -C 0-8 alkyl-S(O) r R 15 , -C 0-8 alkyl-O-R 16 , -C 0-8 alkyl-C(O)OR 16 , -C 0-8 alkyl-C(O)SR 16 , -C 0-8 alkyl-S-C(O)R 17 , -C 0-8 alkyl-C(O)R 17 , -C 0-8 alkyl-O-C(O)R 17 , -C 0-8 alkyl-P(O)(R 17 )2, -C 0-8 alkyl-NR 18 R 19 , -C 0-8 alkyl-C(=NR 18 )R 17 , -C 0-8 alkyl-N(R 18 )-C(=NR 19 )R 17 , -C 0-8 alkyl-C(O)NR 18 R 19 , and -C 0-8 alkyl-N(R 18 )-C(O)R 17 .

[0174] "Heteroaryl" or "heteroaromatic" means a monocyclic or polycyclic ring system containing one or more (preferably 1, 2, 3, or 4) rings, wherein one or more (preferably 1, 2, 3, or 4) ring atoms are selected from N, O, N+O, or S(O) rring members are carbon. Preferred are heterocyclyl groups comprising 3 to 12 or 3 to 8 or 3 to 6 ring members, for example, "3-6 membered heterocyclyl" means a heterocyclyl group comprising 3 to 6 ring members, "3-8 membered heterocyclyl" means a heterocyclyl group comprising 3 to 8 ring members, "4-8 membered heterocyclyl" means a heterocyclyl group comprising 4 to 8 ring members, "4-10 membered heterocyclyl" means a heterocyclyl group comprising 4 to 10 ring members, "5-8 membered heterocyclyl" means a heterocyclyl group comprising 5 to 8 ring members, "3-12 membered heterocyclyl" means a heterocyclyl group comprising 3 to 12 ring members.

[0175] Monocyclic heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, oxetanyl, tetrahydrofuranyl and the like.

[0176] Polycyclic heterocyclyl groups include spiro, fused and bridged ring heterocyclyl groups. "Spiroheterocyclyl" means a polycyclic heterocyclic group in which the rings share one atom (referred to as a spiro atom) between the rings, wherein one or more (preferably 1, 2, 3 or 4) ring atoms are selected from N, O, N-O or S(O) r ring atoms are carbon. These can contain one or more double bonds (preferably 1, 2 or 3), but none of the rings has a fully conjugated pi-electron system. Spiroheterocyclyl groups are classified as mono-, bi- or polyspiroheterocyclyl groups depending on the number of spiro atoms shared between the rings. Spiroheterocyclyl groups include, but are not limited to:

[0177] "Fused heterocyclyl" means a polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, one or more (preferably 1, 2, 3 or 4) rings can contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings has a fully conjugated pi-electron system, wherein one or more (preferably 1, 2, 3 or 4) ring atoms are selected from N, O, N-O or S(O) r ring atoms are carbon. Depending on the number of rings making up the group, fused heterocycloalkyl groups can be bicyclic, tricyclic, tetracyclic or polycyclic. Fused heterocyclyl groups include, but are not limited to:

[0178] "Bridged heterocyclyl" means a polycyclic heterocyclic group in which any two rings share two non-adjacent atoms, these can contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings has a fully conjugated pi-electron system, wherein one or more (preferably 1, 2, 3 or 4) ring atoms are selected from N, O, N-O or S(O) rBridged heterocyclic groups consist of heteroatoms (where r is an integer of 0, 1, or 2) and the remaining ring atoms are carbon. Based on the number of rings, they can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic groups. Bridged heterocyclic groups include, but are not limited to:

[0179] The heterocyclic ring may be fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, including but not limited to:

[0180] When a "heterocyclic alkyl" is attached to different groups, it is called a "heterocyclic alkylene", including but not limited to:

[0181] The heterocyclic or heterocyclic alkyl group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups, independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, =O, =S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR) 12 )R 13 -C 0-8 Alkyl-N=S(O)R 13 R 14 -C 0-8 Alkyl-N=SR 13 R 14 -C 0-8 Alkyl-OS(O)2R 15 -C 0-8 Alkyl-S(O) r R 15 -C 0-8 Alkyl-OR 16 -C 0-8 Alkyl-C(O)OR 16 -C 0-8 Alkyl-C(O)SR 16 -C 0-8 Alkyl-SC(O)R 17 -C 0-8 Alkyl-C(O)R 17 -C 0-8 Alkyl-OC(O)R 17 -C0-8 Alkyl-P(O)(R) 17 )2、-C 0-8 Alkyl-NR 18 R 19 -C 0-8 Alkyl-C (=NR) 18 )R 17 -C 0-8 Alkyl-N(R) 18 )-C(=NR 19 )R 17 -C 0-8 Alkyl-C(O)NR 18 R 19 and -C 0-8 Alkyl-N(R) 18 )-C(O)R 17 The substituents are replaced by the substituents.

[0182] "Aryl" or "aromatic ring" refers to an all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group, a polycyclic (i.e., a ring with adjacent carbon atom pairs) group with a conjugated π-electron system, preferably an all-carbon aryl group containing 6-10 or 6-8 carbons, for example, "C 6-10 "Aryl" refers to a full-carbon aryl group containing 6-10 carbons, including but not limited to phenyl and naphthyl groups. 6-8 "Aryl" refers to a fully carbon-based aryl group containing 6-8 carbons. The aryl ring may be fused to a heteroaryl, heterocyclic, or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, including but not limited to:

[0183] The "aryl" group can be substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups, independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, =O, =S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR) 12 )R 13 -C 0-8 Alkyl-N=S(O)R 13 R 14 -C 0-8 Alkyl-N=SR 13 R14 -C(O)R 0-8 alkyl-O-S(O)2R 15 -C(O)R 0-8 alkyl-S(O) r R 15 -C(O)R 0-8 alkyl-O-R 16 -C(O)R 0-8 alkyl-C(O)OR 16 -C(O)R 0-8 alkyl-C(O)SR 16 -C(O)R 0-8 alkyl-S-C(O)R 17 -C(O)R 0-8 alkyl-C(O)R 17 -C(O)R 0-8 alkyl-O-C(O)R 17 -C(O)R 0-8 alkyl-P(O)(R 17 )2 0-8 alkyl-NR 18 R 19 -C(O)R 0-8 alkyl-C(=NR 18 )R 17 -C(O)R 0-8 alkyl-N(R 18 )-C(=NR 19 )R 17 -C(O)R 0-8 alkyl-C(O)NR 18 R 19 -C(O)R 0-8 alkyl-N(R 18 )-C(O)R 17

[0184] "Heteroaryl" means a heteroaromatic system comprising one or more (preferably 1, 2, 3, or 4) heteroatoms, including N, O, N-O, and S(O)r(where r is an integer 0, 1, 2) heteroatoms, preferably a heteroaromatic system containing 5-10 or 5-8 or 5-6 ring atoms, for example, "5-8 membered heteroaryl" means a heteroaromatic system containing 5-8 ring atoms, "5-10 membered heteroaryl" means a heteroaromatic system containing 5-10 ring atoms, including but not limited to furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like. The heteroaryl ring can be fused to an aryl, heterocyclyl, or cycloalkyl ring, where the ring that is attached to the parent structure is a heteroaryl ring, including but not limited to:

[0185] ​The "heteroaryl" group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups, independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, =O, =S, -C 0-8 Alkyl-SF5, -C 0- 8alkyl-S(O)(=NR) 12 )R 13 -C 0-8 Alkyl-N=S(O)R 13 R 14 -C 0-8 Alkyl-N=SR 13 R 14 -C 0-8 Alkyl-OS(O)2R 15 -C 0-8 Alkyl-S(O) r R 15 -C 0-8 Alkyl-OR 16 -C 0-8 Alkyl-C(O)OR 16 -C 0-8 Alkyl-C(O)SR 16 -C 0-8 Alkyl-SC(O)R 17 -C 0-8 Alkyl-C(O)R 17 -C 0-8 Alkyl-OC(O)R 17 -C 0- 8alkyl-P(O)(R) 17 )2、-C 0-8 Alkyl-NR 18 R 19 -C 0-8 Alkyl-C (=NR) 18 )R 17 -C 0-8 Alkyl-N(R) 18 )-C(=NR 19 )R 17 -C 0-8 Alkyl-C(O)NR 18 R 19 and -C 0-8alkyl-N(R 18 )-C(O)R 17 substituted by one or more (preferably 1, 2, 3, or 4) substituents selected, independently from each other, from deuterium, halogen, cyano, nitro, azido, C

[0186] "alkenyl" means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, preferably a straight-chain or branched alkenyl group containing 2 to 10 or 2 to 4 carbons, for example, "C 2-10 alkenyl" means a straight-chain or branched alkenyl group containing 2 to 10 carbons, "C 2-4 alkenyl" means a straight-chain or branched alkenyl group containing 2 to 4 carbons. Included, but not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, and the like.

[0187] "alkenyl" can be substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3, or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, halogen-substituted C 1-10 alkyl, deuterium-substituted C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-10 aryl, 5- to 10-membered heteroaryl, =O, =S, -C 0-8 alkyl-SF5, -C 0-8 alkyl-S(O)(=N-R 12 )R 13 , -C 0-8 alkyl-N=S(O)R 13 R 14 , -C 0-8 alkyl-N=SR 13 R 14 , -C 0-8 alkyl-O-S(O)2R 15 , -C 0-8 alkyl-S(O) r R 15 , -C 0-8 alkyl-O-R 16 , -C 0-8 alkyl-C(O)OR 16 , -C 0-8 alkyl-C(O)SR 16 , -C 0-8 alkyl-S-C(O)R 17 , -C 0-8 alkyl-C(O)R 17 , -C 0-8 alkyl-O-C(O)R 17 , -C0-8 alkyl-P(O)(R 17 )2, -C 0-8 alkyl-NR 18 R 19 , -C 0-8 alkyl-C(=NR 18 )R 17 , -C 0-8 alkyl-N(R 18 )-C(=NR 19 )R 17 , -C 0-8 alkyl-C(O)NR 18 R 19 , and -C 0-8 alkyl-N(R 18 )-C(O)R 17 .

[0188] "Alkenyl" refers to an alkyl radical as defined above containing at least one carbon-carbon double bond. Preferably, the alkenyl group will be a straight chain or branched chain alkenyl group containing from 2 to 10 or 2 to 4 carbons. "C 2-10 Alkenyl" refers to an alkyl radical as defined above containing at least one carbon-carbon double bond. Preferably, the alkenyl group will be a straight chain or branched chain alkenyl group containing from 2 to 10 or 2 to 4 carbons. "C 2-4 Alkenyl" refers to an alkyl radical as defined above containing at least one carbon-carbon double bond. Preferably, the alkenyl group will be a straight chain or branched chain alkenyl group containing from 2 to 10 or 2 to 4 carbons. "C

[0189] "Alkenyl" can be substituted or unsubstituted, and when substituted, the substituent(s) is preferably one or more (preferably 1, 2, 3, or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, halosubstituted C 1-10 alkyl, deuterium- substituted C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-10 aryl, 5- to 10-membered heteroaryl, =O, =S, -C 0-8 alkyl-SF5, -C 0-8 alkyl-S(O)(=N-R 12 )R 13 , -C 0-8 alkyl-N=S(O)R 13 R 14 , -C 0-8 alkyl-N=SR 13 R 14 , -C 0-8 alkyl-O-S(O)2R 15 , -C0-8 alkyl-S(O) r R 15 , -C 0-8 alkyl-O-R 16 , -C 0-8 alkyl-C(O)OR 16 , -C 0-8 alkyl-C(O)SR 16 , -C 0-8 alkyl-S-C(O)R 17 , -C 0-8 alkyl-C(O)R 17 , -C 0-8 alkyl-O-C(O)R 17 , -C 0-8 alkyl-P(O)(R 17 )2, -C 0-8 alkyl-NR 18 R 19 , -C 0-8 alkyl-C(=NR 18 )R 17 , -C 0-8 alkyl-N(R 18 )-C(=NR 19 )R 17 , -C 0-8 alkyl-C(O)NR 18 R 19 , and -C 0-8 alkyl-N(R 18 )-C(O)R 17 .

[0190] "Alkoxy" means -O-alkyl, wherein alkyl is as defined above, for example, "C 1-10 alkoxy" means an alkyloxy group containing 1 to 10 carbons, "C 1-4 alkoxy" means an alkyloxy group containing 1 to 4 carbons, "C 1-2 alkoxy" means an alkyloxy group containing 1 to 2 carbons, including but not limited to methoxy, ethoxy, propyloxy, butyloxy, and the like.

[0191] "Alkoxy" can be optionally substituted or unsubstituted, and when substituted, the substituents, preferably one or more (preferably 1, 2, 3, or 4) are independently selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, halosubstituted C 1-10 alkyl, deuterium- substituted C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-10aryl, 5-10 membered heteroaryl, =0, =S, -C 0-8 alkyl-SF5, -C 0- 8alkyl-S(O)(=N-R 12 )R 13 , -C 0-8 alkyl-N=S(O)R 13 R 14 , -C 0-8 alkyl-N=SR 13 R 14 , -C 0-8 alkyl-O-S(O)2R 15 , -C 0-8 alkyl-S(O) r R 15 , -C 0-8 alkyl-O-R 16 , -C 0-8 alkyl-C(O)OR 16 , -C 0-8 alkyl-C(O)SR 16 , -C 0-8 alkyl-S-C(O)R 17 , -C 0-8 alkyl-C(O)R 17 , -C 0-8 alkyl-O-C(O)R 17 , -C 0- 8alkyl-P(O)(R 17 )2, -C 0-8 alkyl-NR 18 R 19 , -C 0-8 alkyl-C(=NR 18 )R 17 , -C 0-8 alkyl-N(R 18 )-C(=NR 19 )R 17 , -C 0-8 alkyl-C(O)NR 18 R 19 , and -C 0-8 alkyl-N(R 18 )-C(O)R 17 substituted.

[0192] "Cycloalkoxy" or "cycloalkyloxy" refers to -O-cycloalkyl, wherein cycloalkyl is as defined above, for example, "C 3-12 Cycloalkoxy" refers to cycloalkyloxy groups containing 3 to 12 carbons, "C 3-6 Cycloalkoxy" refers to cycloalkyloxy groups containing 3 to 6 carbons, including, but not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.

[0193] "Cycloalkoxy" or "cycloalkyloxy" can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3, or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6haloalkenyl, C2-6alkynyl, C2-6haloalkynyl, C3-6cycloalkyl, 3- to 8-membered heterocycloalkyl, C1-4alkylamino, C1-4dialkylamino, C1-4alkoxy, C1-4haloalkoxy, C1-4alkylthio, C1-4haloalkylthio, C1-4alkylsulfinyl, C1-4haloalkylsulfinyl, C1-4alkylsulfonyl, C1-4haloalkylsulfonyl, C3-6cycloalkyl, 3- to 6-membered heterocycloalkyl, aryl, 5- to 6-membered heteroaryl, =O, =S, -C1-4alkyl-SF5, -C1-4alkyl-S(O)(=N-R 1-10 alkyl, halo-substituted C 1-10 alkyl, deuterium-substituted C 1-10 alkyl, C 2-10 alkenyl, C 2- 10 alkynyl, C 3-12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, =O, =S, -C 0- 8alkyl-SF5, -C 0-8 alkyl-S(O)(=N-R 12 )R 13 , -C 0-8 alkyl-N=S(O)R 13 R 14 , -C 0-8 alkyl-N=SR 13 R 14 , -C 0-8 alkyl-O-S(O)2R 15 , -C 0-8 alkyl-S(O) r R 15 , -C 0-8 alkyl-O-R 16 , -C 0-8 alkyl-C(O)OR 16 , -C 0-8 alkyl-C(O)SR 16 , -C 0-8 alkyl-S-C(O)R 17 , -C 0-8 alkyl-C(O)R 17 , -C 0- 8alkyl-O-C(O)R 17 , -C 0-8 alkyl-P(O)(R 17 )2, -C 0-8 alkyl-NR 18 R 19 , -C 0-8 alkyl-C(=NR 18 )R 17 , -C 0-8 alkyl-N(R 18 )-C(=NR 19 )R 17 , -C 0-8alkyl-C(O)NR 18 R 19 and -C 0-8 alkyl-N(R 18 )-C(O)R 17 substituted by one or more, preferably 1, 2, 3, or 4, substituents independently selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C

[0194] "Heterocyclyloxy" or "heterocyclyl-oxy" means -O-heterocyclyl, wherein heterocyclyl is as defined above, including, but not limited to, azetidinyloxy, oxetanyloxy, azetidinyl, oxetanyl, azetidinyl, oxetanyl, and the like.

[0195] "Heterocyclyloxy" or "heterocyclyl-oxy" can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3, or 4) groups independently selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, halogen-substituted C 1-10 alkyl, deuterium-substituted C 1-10 alkyl, C 2-10 alkenyl, C 2- 10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, =O, =S, -C 0- 8alkyl-SF5, -C 0-8 alkyl-S(O)(=N-R 12 )R 13 , -C 0-8 alkyl-N=S(O)R 13 R 14 , -C 0-8 alkyl-N=SR 13 R 14 , -C 0-8 alkyl-O-S(O)2R 15 , -C 0-8 alkyl-S(O) r R 15 , -C 0-8 alkyl-O-R 16 , -C 0-8 alkyl-C(O)OR 16 , -C 0-8 alkyl-C(O)SR 16 , -C 0-8 alkyl-S-C(O)R 17 , -C 0-8 alkyl-C(O)R 17 , -C 0- 8alkyl-O-C(O)R 17 , -C 0-8 alkyl-P(O)(R17 )2, -C 0-8 alkyl-NR 18 R 19 , -C 0-8 alkyl-C(=NR 18 )R 17 , -C 0-8 alkyl-N(R 18 )-C(=NR 19 )R 17 , -C 0-8 alkyl-C(O)NR 18 R 19 and -C 0-8 alkyl-N(R 18 )-C(O)R 17 .

[0196] "C 1-10 alkanoyl" means a monovalent radical derived from a C 1-10 alkanoic acid from which the hydroxyl group has been removed, and is also commonly represented as "C 0- 9alkyl-C(O)-", e.g., "C1alkanoyl" means acetyl; "C2alkanoyl" means propionyl; and "C3alkanoyl" means butyryl or isobutyryl.

[0197] "C 0-8 alkyl-S(O)(=N-R 13 )R 14 " means the sulfur atom in -S(O)(=N-R 13 )R 14 is attached to a C 0-8 alkyl group, wherein C 0-8 alkyl is as defined above.

[0198] "C 0-8 alkyl-N=S(O)R 13 R 14 " means the nitrogen atom in -N=S(O)R 13 R 14 is attached to a C 0-8 alkyl group, wherein C 0-8 alkyl is as defined above.

[0199] "C 0-8 alkyl-N=SR 15 R 15 " means the nitrogen atom in -N=SR 0-8 R 0- is attached to a C 0-8 alkyl group, wherein C r alkyl is as defined above.

[0200] "C 0-8 alkyl-O-S(O)2R 15 " means -O-S(O)2R 15 where the oxygen atom is attached to a C 0-8 alkyl group, where C 0- 8alkyl is as defined above.

[0201] "C 0-8 alkyl-S(O) r R 15 " means -S(O) r R 15 where the sulfur atom is attached to a C 0-8 alkyl group, where C 0-8 alkyl is as defined above.

[0202] "C 0-8 alkyl-O-R 16 " means -O-R 16 where the oxygen atom is attached to a C 0-8 alkyl group, where C 0-8 alkyl is as defined above.

[0203] "C 0-8 alkyl-C(O)OR 16 " means -C(O)OR 16 where the carbonyl group is attached to a C 0-8 alkyl group, where C 0-8 alkyl is as defined above.

[0204] "C 0-8 alkyl-C(O)SR 16 " means -C(O)SR 16 where the carbonyl group is attached to a C 0-8 alkyl group, where C 0-8 alkyl is as defined above.

[0205] "C 0-8 alkyl-S-C(O)R 17 " means -S-C(O)R 17 where the sulfur atom is attached to a C 0-8 alkyl group, where C 0-8 alkyl is as defined above.

[0206] "C 0-8 alkyl-C(O)R 17 " means -C(O)R 17 where the carbonyl group is attached to a C 0-8 alkyl group, where C 0-8 alkyl is as defined above.

[0207] "C 0-8alkyl-O-C(O)R 17 "O-C(O)R means the oxygen atom of -O-C(O)R is attached to a C 17 alkyl group, wherein the C 0-8 alkyl group is as defined above. 0-8

[0208] "C 0-8 alkyl-P(O)(R 17 )2" means the phosphorus atom of -P(O)(R 17 )2 is attached to a C 0-8 alkyl group, wherein the C 0-8 alkyl group is as defined above.

[0209] "C 0-8 alkyl-NR 18 R 19 " means the nitrogen atom of -NR 18 R 19 is attached to a C 0-8 alkyl group, wherein the C 0-8 alkyl group is as defined above.

[0210] "C 0-8 alkyl-C(=NR 18 )R 17 " means the carbon atom of -C(=NR 18 )R 17 is attached to a C 0-8 alkyl group, wherein the C 0-8 alkyl group is as defined above.

[0211] "C 0-8 alkyl-N(R 18 )-C(=NR 19 )R 17 " means the nitrogen atom of -N(R 18 )-C(=NR 19 )R 17 is attached to a C 0-8 alkyl group, wherein the C 0-8 alkyl group is as defined above.

[0212] "C 0-8 alkyl-C(O)NR 18 R 19 " means the carbonyl group of -C(O)NR 18 R 19 is attached to a C 0-8 alkyl group, wherein the C 0- 8alkyl group is as defined above.

[0213] "C 0-8 alkyl-N(R 18 )-C(O)R​17 "R" means -N(R 18 )-C(O)R 17 "R" means -N(R 0-8 alkyl, wherein C 0-8 alkyl is as defined above.

[0214] "halo-substituted C 1-10 alkyl" means an alkyl group of 1 to 10 carbons in which the hydrogens on the alkyl are optionally replaced with fluorine, chlorine, bromine, iodine atoms. Included, but not limited to, difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, and the like.

[0215] "halo-substituted C 1-10 alkoxy" means an alkoxy group of 1 to 10 carbons in which the hydrogens on the alkyl are optionally replaced with fluorine, chlorine, bromine, iodine atoms. Included, but not limited to, difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, tribromomethoxy, and the like.

[0216] "deuterium-substituted C 1-10 alkyl" means an alkyl group of 1 to 10 carbons in which the hydrogens on the alkyl are optionally replaced with deuterium atoms. Included, but not limited to, monodeuteromethyl, diduteromethyl, trideuteromethyl, and the like.

[0217] "halogen" means fluorine, chlorine, bromine, or iodine.

[0218] "optionally" or "optionally" means that the subsequently described event or circumstance can or can not occur, and thus the description includes instances where the event or circumstance occurs and instances where it does not, i.e., both substituted and non-substituted instances. For example, "heterocyclyl optionally substituted with alkyl" means that alkyl can or can not be present, and the description includes instances where the heterocyclyl is substituted with alkyl and instances where the heterocyclyl is not substituted with alkyl.

[0219] "substituted" means that one or more "hydrogen atoms" in a group are independently replaced with a corresponding number of substituents. It is understood that substituents are only in their possible chemical locations, consistent with the valency of the theory of chemistry, and one of skill in the art can determine (experimentally or theoretically) the possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with a free hydrogen can not be stable when bound to a carbon atom with an unsaturated bond (such as an alkene).

[0220] "stereoisomer" refers to isomers that differ in the way the atoms are arranged in space. It can be divided into two categories: cis-trans isomer and enantiomer. The stereoisomer caused by the rotation of single bond is called conformational stereo-isomer, sometimes also called rotamer. The stereoisomer caused by the bond length, bond angle, double bond in the molecule, ring, etc. is called configuration stereo-isomer, which can be divided into two categories. The isomer caused by the non-free rotation of single bond of double bond or ring carbon atom is called geometric isomer, also known as cis-trans isomer, which can be divided into Z and E configurations. For example, cis-2-butene and trans-2-butene are a pair of geometric isomers. The stereoisomer with different optical properties caused by the absence of inversion symmetry in the molecule is called optical isomer, which can be divided into R and S configurations. In the present application, "stereoisomer" is understood to include one or more of the above-mentioned enantiomers, configuration isomers and conformational isomers unless otherwise specified.

[0221] "pharmaceutically acceptable salt" in the present application refers to a pharmaceutically acceptable acid addition salt, including inorganic acid salt and organic acid salt, which can be prepared by methods known in the art.

[0222] "pharmaceutical composition" means a mixture containing one or more compounds described herein or physiologically / pharmaceutically acceptable salts or prodrugs thereof and other chemical components, such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate the administration to the organism, facilitate the absorption of the active ingredient and thus exert biological activity.

[0223] "effective amount" in the present application refers to the dose or concentration that can cause minimal pharmacological effect in clinic, also known as minimum effective amount or threshold dose.

[0224] The present application will be further described in detail below in combination with examples, but is not limited to the content of the examples, and the present application is not limited to the examples only.

[0225] The structure of the compounds of the present application is determined by nuclear magnetic resonance (NMR) or / and liquid chromatography-mass spectrometry (LC-MS). The NMR chemical shifts (δ) are given in parts per million (ppm). The NMR measurements are performed on a Bruker AVANCE-400 / 500 NMR spectrometer with deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD or MeOH-d4) and deuterated chloroform (CDCl3) as the solvent and tetramethylsilane (TMS) as the internal standard.

[0226] The LC-MS measurements are performed on an Agilent 6120 mass spectrometer. The HPLC measurements are performed on an Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C18 150 x 4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 x 4.6 mm column).

[0227] The thin layer chromatography silica gel plates are purchased from Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates, and the TLC specifications are 0.15 mm to 0.20 mm, and the thin layer chromatography separation and purification product specifications are 0.4 mm to 0.5 mm. The column chromatography generally uses Yantai Huanghai silica gel 200 to 300 mesh silica gel as the carrier.

[0228] The starting materials in the embodiments of the present application are known and commercially available, or can be synthesized by using or according to the methods known in the art.

[0229] Unless otherwise specified, all the reactions of the present application are carried out under a dry nitrogen or argon atmosphere with continuous magnetic stirring, the solvent is a dry solvent, and the reaction temperature unit is in degrees Celsius (°C).

[0230] I. Preparation of intermediates

[0231] Preparation of intermediate 1-1: 3-(1-aminoethyl)-N,N-di(4-methoxybenzyl)pyridin-2-amine

[0232] First step: synthesis of 1-(2-(di(4-methoxybenzyl)amino)pyridin-3-yl)ethan-1-one

[0233] 1-(2-chloropyridin-3-yl)ethan-1-one (10 g, 64.28 mmol), bis(4-methoxybenzyl)amine (24.81 g, 96.41 mmol) were dissolved in DMF (60 mL), K2CO3(26.65 g, 192.83 mmol) was added at room temperature, heated to 100 °C and stirred overnight. The reaction was complete, after cooling, saturated brine was added to dilute, extracted with ethyl acetate, washed with saturated brine. The organic phase was concentrated, the residue was separated by flash silica gel column chromatography (eluent: EA / PE = 0-10%) to give 1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethan-1-one (14.5 g, yield: 60%). ESI-MS: 377.2 [M+1] + .

[0234] Second step: synthesis of 1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethan-1-one oxime

[0235] 1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethan-1-one (5.0 g, 13.28 mmol) was dissolved in pyridine (25 mL), hydroxylamine hydrochloride (1.38 g, 19.922 mmol) was added at room temperature, heated to 80 °C and stirred for 2 hours. The reaction solution was diluted with saturated brine, extracted with ethyl acetate, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. Filtration, concentration, the residue was separated by flash silica gel column chromatography (eluent: EA / PE = 0-30%) to give 1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethan-1-one oxime (3.65 g, yield: 70%). ESI-MS: 392.2 [M+1] + .

[0236] Third step: synthesis of 3-(1-aminoethyl)-N,N-bis(4-methoxybenzyl)pyridin-2-amine

[0237] Dissolve 1-(2-(di(4-methoxybenzyl)amino)pyridin-3-yl)ethan-1-one oxime (3.20 g, 8.174 mmol) in acetic acid (32 mL), add zinc powder (2.14 g, 32.697 mmol) at room temperature, and stir the reaction at 70 °C for 1 h. Filter the reaction, and wash the filter cake with methanol. Concentrate the filtrate, dilute the residue with dichloromethane, adjust the pH to ~9 with saturated aqueous Na2CO3solution, separate the layers, and extract the aqueous layer with dichloromethane. Concentrate the combined organic layers, and purify the residue by flash chromatography on silica gel (eluting with EA / PE = 10-50%) to give 3-(1-aminoethyl)-N,N-di(4-methoxybenzyl)pyridin-2-amine (1.92 g, 62% yield). ESI-MS: 378.2 [M+1] + .

[0238] Intermediates 1-2 and 1-3 were prepared according to the synthetic procedure of Intermediate 1-1 using the appropriate reagents.

[0239] Intermediate 1-4: Preparation of (R)-3-(1-aminoethyl)-N,N-di(4-methoxybenzyl)pyridin-2-amine

[0240] First Step: Synthesis of 2-(di(4-methoxybenzyl)amino)nicotine aldehyde

[0241] Dissolve 2-chloropyridine-3-carboxaldehyde (29 g, 204.875 mmol) in DMA (250 mL), add bis[(4-methoxyphenyl)methyl]amine (60.63 g, 235.606 mmol) and K2CO3(42.47 g, 307.312 mmol) at room temperature, and stir the reaction at 110 °C for 24 h. Cool the reaction to room temperature, filter, and concentrate the filtrate. Purify the crude product by chromatography on silica gel (eluting with EA / PE = 0-20%) to give 2-(di(4-methoxybenzyl)amino)nicotine aldehyde (30 g, 82.775 mmol, 40.4% yield). MS m / z (ESI): 363.2 [M+1] + .

[0242] Second Step: Synthesis of (S,E)-N-((2-(di(4-methoxybenzyl)amino)pyridin-3-yl)methylene)-2-methylpropane-2-sulfmamide

[0243] To a solution of (S)-N-((R)-1-(2-(di(4-methoxybenzyl)amino)pyridin-3- yl)ethyl)-2-methylpropane-2-sulfmamide (33 g, 68.514 mmol) in CH2CI2(600 mL) was added methylmagnesium chloride (93.927 mL, 281.781 mmol) dropwise at -78 °C. The reaction was continued at -78 °C for 3 h. The reaction was complete, the reaction was poured into ice saturated aqueous ammonium chloride solution (500 mL) and extracted with EtOAc (300 mL) for 3 times. The combined organic layers were washed with saturated brine (500 mL) and dried over anhydrous sodium sulfate. Filtration, concentration gave (S)-N-((R)-1-(2-(di(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)-2- methylpropane-2-sulfmamide (33 g, 68.514 mmol). MS m / z (ESI): 482.2 [M+1] + .

[0244] Third step: Synthesis of (S)-N-((R)-1-(2-(di(4-methoxybenzyl)amino)pyridin-3- yl)ethyl)-2-methylpropane-2-sulfmamide

[0245] To a solution of (S)-N-((R)-1-(2-(di(4-methoxybenzyl)amino)pyridin-3- yl)ethyl)-2-methylpropane-2-sulfmamide (33 g, 68.514 mmol) in CH2CI2(600 mL) was added methylmagnesium chloride (93.927 mL, 281.781 mmol) dropwise at -78 °C. The reaction was continued at -78 °C for 3 h. The reaction was complete, the reaction was poured into ice saturated aqueous ammonium chloride solution (500 mL) and extracted with EtOAc (300 mL) for 3 times. The combined organic layers were washed with saturated brine (500 mL) and dried over anhydrous sodium sulfate. Filtration, concentration gave (S)-N-((R)-1-(2-(di(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)-2- methylpropane-2-sulfmamide (33 g, 68.514 mmol). MS m / z (ESI): 482.2 [M+1] + .

[0246] Fourth step: Synthesis of (R)-3-(1-aminoethyl)-N,N-di(4-methoxybenzyl)pyridin-2- amine

[0247] (S)-N-((R)-1-(2-(di(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)-2- methylpropane-2-sulfmamide (33 g, 68.514 mmol) was dissolved in MeOH (300 mL) and HCl / 1,4-Dioxane solution (30 mL, 120.00 mmol) was added at 0 °C. Stirring was maintained at 0 °C for 4 h. The reaction was complete, the reaction was poured into saturated aqueous NaHC03solution (500 mL) and extracted with EtOAc (300 mL) three times. The combined organic layer was washed with saturated brine (500 mL) and dried over anhydrous sodium sulfate. Filtration and concentration, the crude product was separated by silica gel column chromatography (eluent: MeOH / DCM = 0-6%) to give (R)-3-(1-aminoethyl)-N,N-di(4-methoxybenzyl)pyridin-2-amine (17 g, 45.035 mmol, two-step yield: 63.9%). MS m / z (ESI): 378.2 [M+1] + .

[0248] 1 H NMR (400 MHz, CDC13) δ 8.35 (s, 1H), 7.67 (d, J = 7.62 Hz, 1H), 7.12 (d, J = 8.1 Hz, 4H), 7.04 (dd, J = 7.6, 4.9 Hz, 1H), 6.78 (d, J = 8.1 Hz, 4H), 4.62 (d, J = 6.6 Hz, 1H), 4.13 (d, J = 11.3 Hz, 3H), 3.76 (s, 6H), 1.19 (dd, J = 6.7, 1.5 Hz, 3H).

[0249] Intermediates 1-5~1-8 were prepared according to the synthetic procedure of Intermediate 1-4 by selecting the corresponding reagents.

[0250] Preparation of Intermediate 2-1: 3-(1-(8-chloro-9-fluoro-2-(methylthio)-5,6- dihydro-4H-pyrimido[4,5,6-de][1,6]naphthyridin-4-yl)ethyl)-N,N-di(4- methoxybenzyl)pyridin-2-amine

[0251] First Step: Synthesis of (E)-7-chloro-5-(2-ethoxyvinyl)-8-fluoro-2-(methylthio)pyrido[4,3- d]pyrimidin-4-ol

[0252] To a solution of 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3- d]pyrimidin-4-ol (3.00 g, 10.71 mmol) in DMF (30 mL) was added (E)-2-(2- ethoxyvinyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (2.546 g, 12.85 mmol), Pd(dppf)Cl2(392 mg, 0.536 mmol) and K3PO4(6.82 g, 32.131 mmol) at room temperature. The reaction mixture was stirred at 75 °C for 5 h. The reaction mixture was slowly poured into ice water and adjusted to pH = 5-6 with dilute hydrochloric acid. The mixture was stirred at room temperature for 30 min. The solid was collected by filtration. The filter cake was separated by flash silica gel column chromatography (eluent: EA / DCM = 0-10%). (E)-7-chloro-5-(2-ethoxyvinyl)-8-fluoro-2-(methylthio)pyrido[4,3- d]pyrimidin-4-ol (1800 mg, yield: 45%) was obtained. ESI-MS: 316.0 [M+1] + .

[0253] 1 H NMR (400 MHz, DMSO-d6) δ 12.99 (s, 1H), 7.73 (d, J = 12.2 Hz, 1H), 7.37 (d, J = 12.2 Hz, 1H), 4.02 (q, J = 7.1 Hz, 2H), 2.58 (s, 3H), 1.30 (t, J = 7.0 Hz, 3H).

[0254] Second Step: Synthesis of 2-(7-chloro-8-fluoro-4-hydroxy-2-(methylthio)pyrido[4,3- d]pyrimidin-5-yl)acetaldehyde

[0255] To a solution of (E)-7-chloro-5-(2-ethoxyvinyl)-8-fluoro-2-(methylthio)pyrido[4,3- d]pyrimidin-4-ol (700 mg, 2.217 mmol) in a mixture of dichloromethane (50 mL) and acetonitrile (50 mL) was added hydrochloric acid aqueous solution (2.22 mL, 4.44 mmol, 2N) at room temperature. The reaction mixture was stirred at 50 °C for 1.5 h. After the reaction was completed, NaHCO3(373 mg, 4.44 mmol) was added. The mixture was stirred at room temperature for 5 min. Anhydrous sodium sulfate was added to dry the mixture. The mixture was filtered. The filtrate was directly concentrated to give 2-(7-chloro-8-fluoro-4-hydroxy-2-(methylthio)pyrido[4,3- d]pyrimidin-5-yl)acetaldehyde (600 mg, yield: 94%). ESI-MS: 288.0 [M+1] + .

[0256] Step 3: Synthesis of 5-(2-((1-(2-(di(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)amino)ethyl)-7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol

[0257] To a solution of 2-(7-chloro-8-fluoro-4-hydroxy-2-(methylthio)pyrido[4,3- d]pyrimidin-5-yl)acetaldehyde (300 mg, 1.043 mmol) in dichloromethane (10 mL) was added 3-(1-aminoethyl)-N,N-di(4-methoxybenzyl)pyridin-2-amine (394 mg, 1.043 mmol) and NaBH3CN (176 mg, 5.214 mmol) at room temperature. The mixture was stirred at room temperature overnight. The reaction was complete, quenched with saturated aqueous ammonium chloride solution and extracted with dichloromethane. The organic phase was concentrated and the residue was purified by flash column chromatography on silica gel (eluent: methanol / dichloromethane = 0-5%) to give 5-(2-((1-(2-(di(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)amino)ethyl)-7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (450 mg, yield: 66%). ESI-MS: 649.4 [M+1] + .

[0258] Step 4: Synthesis of 3-(1-(8-chloro-9-fluoro-2-(methylthio)-5,6-dihydro-4H-pyrimido[4,5,6-de][1,6]naphthyridin-4-yl)ethyl)-N,N-di(4-methoxybenzyl)pyridin-2-amine

[0259] To a solution of 5-(2-((1-(2-(di(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)amino)ethyl)-7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (110 mg, 0.169 mmol) in dichloromethane (5 mL) was added DIPEA (109 mg, 0.847 mmol) and BOPCl (129 mg, 0.508 mmol) at room temperature. The mixture was stirred at room temperature overnight. The reaction was complete and directly concentrated. The residue was purified by flash column chromatography on silica gel (eluent: MeOH / CH2Cl20-5%) to give 3-(1-(8-chloro-9-fluoro-2-(methylthio)-5,6-dihydro-4H-pyrimido[4,5,6-de][1,6]naphthyridin-4-yl)ethyl)-N,N-di(4-methoxybenzyl)pyridin-2-amine (88 mg, yield: 81%). ESI-MS: 631.4 [M+1] + .

[0260] Intermediates 2-2 to 2-6 were prepared by selecting appropriate reagents following the same synthesis steps as intermediate 2-1.

[0261] Preparation of Intermediate 2-7: (R)-3-(1-(8-chloro-9-fluoro-2-(methylthio)-4H-pyrimidino[4,5,6-de][1,6]diazanaphthyl-4-yl)ethyl)-N,N-di(4-methoxybenzyl)pyridine-2-amine

[0262] Step 1: Synthesis of (R)-5-(2-((1-(2-(di(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)imino)ethyl)-7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine-4-phenol

[0263] 2-(7-chloro-8-fluoro-4-hydroxy-2-(methylthio)pyrido[4,3-d]pyrimidin-5-yl)acetaldehyde (5.00 g, 11.30 mmol, 65% purity) and (R)-3-(1-aminoethyl)-N,N-di(4-methoxybenzyl)pyridin-2-amine (5.12 g, 13.56 mmol) were dissolved in dichloromethane (50 mL) and stirred at room temperature for 2.5 hours. LC-MS analysis showed that the starting aldehyde had largely reacted. The reaction solution was directly concentrated under reduced pressure to obtain (R,E)-5-(2-((1-(2-(di(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)imino)ethyl)-7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-phenol. The crude product was directly added to the next reaction. ESI-MS: 647.4 [M+1] + .

[0264] Step 2: Synthesis of (R)-3-(1-(8-chloro-9-fluoro-2-(methylthio)-4H-pyrimidino[4,5,6-de][1,6]diazanaphthyl-4-yl)ethyl)-N,N-di(4-methoxybenzyl)pyridine-2-amine

[0265] The crude product (R)-5-(2-((1-(2-(di(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)imino)ethyl)-7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine-4-phenol (calculated as 11.30 mmol) obtained in the previous step was dissolved in anhydrous acetonitrile (300 mL). Under nitrogen protection, DIPEA (15.74 mL, 90.38 mmol) and BOP-Cl (14.38 g, 56.49 mmol) were added sequentially, and the reaction was carried out overnight at room temperature. LC-MS showed that there was residual starting material, so the reaction was heated to 50 °C and carried out overnight. LC-MS showed that the starting material was completely reacted. The mixture was cooled to room temperature, quenched with saturated sodium bicarbonate aqueous solution, and then extracted twice with ethyl acetate (200 mL). The combined organic phases were washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate. The crude product was filtered, concentrated, and separated by rapid silica gel column chromatography (eluent: dichloromethane / methanol = 20:1) to give (R)-3-(1-(8-chloro-9-fluoro-2-(methylthio)-4H-pyrimidino[4,5,6-de][1,6]diazanaphthyl-4-yl)ethyl)-N,N-bis(4-methoxybenzyl)pyridine-2-amine (7.5 g, purity: 70.5%, yield: 74.4%). ESI-MS: 629.4 [M+1] + .

[0266] Intermediates 2-8 to 2-13 were prepared by selecting appropriate reagents following the synthesis steps of intermediate 2-7.

[0267] Preparation of Intermediate 3: N,N-Di(4-methoxybenzyl)-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)-5-(trifluoromethyl)pyridine-2-amine

[0268] Step 1: Synthesis of 4-chloro-N,N-di(4-methoxybenzyl)-6-methylpyridin-2-amine

[0269] 4-Chloro-6-methylpyridin-2-amine (10.0 g, 70.13 mmol) was dissolved in DMF (100 mL), and NaH (7.01 g, 175.33 mmol, 60%) was slowly added under ice-water bath cooling. After reacting at 0 °C for 1 hour, 4-methoxybenzyl chloride (24.16 g, 156.61 mmol) was slowly added dropwise, and the mixture was stirred overnight at room temperature. The reaction was monitored by LCMS until completion. The reaction solution was poured into an ice-water bath, extracted with ethyl acetate, and the organic phase was washed once with saturated brine. The organic phase was dried, filtered, and the filtrate was concentrated. The residue was added to methanol (100 mL), stirred at room temperature for 1 hour, filtered, and the filter cake was dried under vacuum to give 4-chloro-N,N-di(4-methoxybenzyl)-6-methylpyridin-2-amine (13.5 g, yield: 86.4%). ESI-MS: 383.2 [M+1] + .

[0270] Step 2: Synthesis of 4-chloro-5-iodo-N,N-bis(4-methoxybenzyl)-6-methylpyridine-2-amine

[0271] 10.0 g (26.12 mmol) of 4-chloro-N,N-di(4-methoxybenzyl)-6-methylpyridin-2-amine was dissolved in 200 mL of DMF. HOAc (15.0 mL, 261.2 mmol) and NIS (7.05 g, 31.34 mmol) were added at room temperature, and the mixture was stirred for 2 hours at room temperature. The reaction was monitored by LCMS until completion. The reaction mixture was poured into 600 mL of ice water and extracted twice with 200 mL of ethyl acetate. The combined organic phases were washed successively with saturated sodium thiosulfate, saturated sodium bicarbonate solution, and saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was added to 100 mL of methanol, stirred overnight at room temperature, filtered, and the filter cake was dried under vacuum to give 10.6 g (79.8%) of 4-chloro-5-iodo-N,N-di(4-methoxybenzyl)-6-methylpyridin-2-amine. ESI-MS: 509.2 [M+1] + .

[0272] Step 3: Synthesis of 4-chloro-N,N-di(4-methoxybenzyl)-6-methyl-5-(trifluoromethyl)pyridine-2-amine

[0273] 4-Chloro-5-iodo-N,N-di(4-methoxybenzyl)-6-methylpyridin-2-amine (3.60 g, 7.08 mmol) was dissolved in DMA (50 mL), and methyl fluorosulfonyl difluoroacetate (6.80 g, 35.38 mmol) and cuprous iodide (6.74 g, 35.38 mmol) were added at room temperature. The mixture was heated to 100 °C and stirred for 2 hours. The reaction was monitored by LCMS until completion. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic phase was washed successively with 10% ammonia and saturated brine. The organic phase was dried and filtered. The filtrate was concentrated, and the residue was separated by rapid silica gel column chromatography (eluent: EA / PE = 0–10%) to give 4-chloro-N,N-di(4-methoxybenzyl)-6-methyl-5-(trifluoromethyl)pyridin-2-amine (2.92 g, yield: 87.9%). ESI-MS: 451.2 [M+1] + .

[0274] Step 4: Synthesis of N,N-di(4-methoxybenzyl)-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)-5-(trifluoromethyl)pyridine-2-amine

[0275] 4-Chloro-N,N-Di(4-methoxybenzyl)-6-methyl-5-(trifluoromethyl)pyridin-2-amine (1.50 g, 3.33 mmol) and pinacol diboronate (1.69 g, 6.66 mmol) were dissolved in 1,4-dioxane (30 mL). KOAc (979 mg, 9.98 mmol), Cy3P (187 mg, 0.67 mmol) and Pd2(dba)3 (305 mg, 0.33 mmol) were added at room temperature. Nitrogen gas was purged, and the mixture was heated to 110 °C and stirred for 4 hours under nitrogen protection. The reaction was monitored by LCMS until completion. The reaction solution was diluted with saturated brine, extracted with ethyl acetate, and the organic phase was concentrated. The residue was separated by rapid silica gel column chromatography (eluent: EA / PE = 0–10%) to give N,N-di(4-methoxybenzyl)-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)-5-(trifluoromethyl)pyridine-2-amine (900 mg, yield: 49.4%). ESI-MS: 543.4 [M+1] + .

[0276] Intermediate 4: Preparation of tert-butyl (3-cyano-4-(5,5-dimethyl-1,3,2-dioxoborhexane-2-yl)-7-fluorobenzo[b]thiophene-2-yl)carbamate

[0277] Step 1: Synthesis of ethyl (4-bromo-3-cyano-7-fluorobenzo[b]thiophene-2-yl)carbamate

[0278] 2-(6-bromo-2,3-difluorophenyl)acetonitrile (3.8 g, 16.38 mmol) was dissolved in DMF (70 mL), and NaH (980 mg, 24.57 mmol, 60%) was added under ice-water bath cooling. The mixture was stirred at 0 °C for 30 minutes. Then, ethoxycarbonyl isothiocyanate (2.58 g, 19.65 mmol) was added, and the mixture was heated to 100 °C for 18 hours. The reaction was monitored by LC-MS until completion. After cooling to room temperature, the mixture was diluted with ethyl acetate, and the organic phase was separated and washed with saturated brine. The organic phase was dried, filtered, and the filtrate was concentrated. The residue was separated by rapid silica gel column chromatography (eluent: EA / PE = 0–10%) to give ethyl (4-bromo-3-cyano-7-fluorobenzo[b]thiophene-2-yl)carbamate (4.78 g, yield: 85.1%). ESI-MS: 344.4 [M+1] + .

[0279] Step 2: Synthesis of 2-amino-4-bromo-7-fluorobenzo[b]thiophene-3-carboxylon

[0280] Ethyl (4.78 g, 13.93 mmol) of (4-bromo-3-cyano-7-fluorobenzo[b]thiophene-2-yl)carbamate was dissolved in DMSO (19 mL), and NaOH aqueous solution (15.6 mL, 78 mmol, 5 N) was added at 0 °C. After the addition was complete, the mixture was heated to 125 °C and stirred for 18 hours. The reaction was monitored by LCMS until completion. After the reaction was complete, the mixture was diluted with ethyl acetate, the organic phase was separated, and washed with saturated brine. The organic phase was dried, filtered, and the filtrate was concentrated. The residue was separated by rapid silica gel column chromatography (eluent: EA / PE = 0–20%) to give 2-amino-4-bromo-7-fluorobenzo[b]thiophene-3-carboxynitrile (1.91 g, yield: 50.5%). ESI-MS: 272.3 [M+1] + .

[0281] Step 3: Synthesis of tert-butyl (4-bromo-3-cyano-7-fluorobenzo[b]thiophene-2-yl) carbamate

[0282] 2-Amino-4-bromo-7-fluorobenzo[b]thiophene-3-carboxynitrile (1.91 g, 7.04 mmol), DMAP (70 mg, 0.56 mmol), and DIPEA (1.37 g, 10.6 mmol) were dissolved in a mixture of THF (60 mL) and DMF (5 mL). Boc₂O (1.69 g, 7.75 mmol) was added under ice-water bath cooling, and the mixture was stirred at room temperature for 18 hours after the addition was complete. The reaction was monitored by LCMS until completion. After the reaction, the mixture was diluted with ethyl acetate, the organic phase was separated, and washed once with saturated brine. The organic phase was dried, filtered, and the filtrate was concentrated. The residue was separated by rapid silica gel column chromatography (eluent: EA / PE = 0–10%) to give tert-butyl(4-bromo-3-cyano-7-fluorobenzo[b]thiophene-2-yl)carbamate (1.69 g, yield: 64.5%). ESI-MS: 372.3 [M+1] + .

[0283] Step 4: Synthesis of tert-butyl(3-cyano-4-(5,5-dimethyl-1,3,2-dioxoborhexane-2-yl)-7-fluorobenzo[b]thiophene-2-yl)carbamate

[0284] 1.59 g (4.28 mmol), KOAc (1.26 g (12.85 mmol), and bis(neopentylethylene glycol)diboron (3.68 g (16.28 mmol) were dissolved in 1,4-dioxane (40 mL), and DPEPosPdCl2 (230 mg (0.43 mmol)) was added. The mixture was purged with nitrogen three times and heated to 95 °C with stirring for 18 hours. The reaction was monitored by LCMS until completion. After the reaction, the mixture was concentrated, and the residue was separated by rapid silica gel column chromatography (eluent: EA / PE = 0–10%) to give tert-butyl(3-cyano-4-(5,5-dimethyl-1,3,2-dioxoboron-2-yl)-7-fluorobenzo[b]thiophene-2-yl)carbamate (1.08 g, yield: 62.4%). ESI-MS: 405.4 [M+1] + .

[0285] Intermediate 5: Preparation of tert-butyl(3-cyano-4-(5,5-dimethyl-1,3,2-dioxoborhexane-2-yl)benzo[b]thiophene-2-yl)carbamate

[0286] Select the appropriate reagents for preparation, referring to the synthesis steps of intermediate 4.

[0287] Preparation of intermediate 6: tert-butyl(3-cyano-4-(5,5-dimethyl-1,3,2-dioxoborhexane-2-yl)benzofuran-2-yl)carbamate

[0288] Step 1: Synthesis of ethyl 4-bromobenzofuran-2-carboxylate

[0289] 2-Bromo-6-hydroxybenzaldehyde (10 g, 49.746 mmol) and ethyl chloroacetate (6.36 mL, 59.696 mmol) were dissolved in dry DMF (100 mL), and K2CO3 (20.62 g, 149.239 mmol) was added. The mixture was heated to 130 °C and stirred for 4 hours. The reaction was monitored by LCMS until complete. Water (200 mL) was added, and the mixture was extracted three times with EtOAc (200 mL). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was separated by silica gel column chromatography (eluent: EA / PE = 0–3%) to give ethyl 4-bromobenzofuran-2-carboxylate (9 g, yield: 67.2%).

[0290] 1 H NMR (400MHz, DMSO-d6) δ7.80(dt,J=8.4,0.9Hz,1H),7.68–7.54(m,2H),7.49(t,J=8.0Hz,1H),4.38(q,J=7.2Hz,2H),1.36(t,J=7.2Hz,3H).

[0291] Step 2: Synthesis of 4-bromobenzofuran-2-carboxylic acid

[0292] Ethyl 4-bromobenzofuran-2-carboxylic acid (2 g, 7.432 mmol) was dissolved in DMF (10 mL), and 20% sodium hydroxide aqueous solution (2 mL) was added. The mixture was heated to 60 °C for 1 hour. Water (50 mL) was added, and the mixture was extracted three times with EtOAc (50 mL). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 4-bromobenzofuran-2-carboxylic acid (1 g, yield: 55.8%).

[0293] Step 3: Synthesis of tert-butyl(4-bromobenzofuran-2-yl)carbamate

[0294] Under nitrogen protection, 4-bromobenzofuran-2-carboxylic acid (1 g, 4.149 mmol) and triethylamine (1.153 mL, 8.297 mmol) were dissolved in tert-butanol (15 mL), followed by the addition of DPPA (1.166 mL, 5.393 mmol). The mixture was stirred for 10 minutes and then heated to 95 °C for 4 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: EA / PE = 0–10%) to give tert-butyl(4-bromobenzofuran-2-yl)carbamate (1 g, yield: 77.2%).

[0295] 1 H NMR (400MHz, DMSO-d6) δ10.91(s,1H),7.46(d,J=8.0Hz,1H),7.39(d,J=8.0Hz,1H),7.09(t,J=8.0Hz,1H),6.31(s,1H),1.50(s,9H).

[0296] Step 4: Synthesis of tert-butyl (4-bromo-3-cyanobenzofuran-2-yl)carbamate

[0297] 500 mg (1.602 mmol) of tert-butyl(4-bromobenzofuran-2-yl)carbamate was dissolved in 10 mL of anhydrous THF. The mixture was cooled to -70 °C under nitrogen protection. Then, 1.394 mL (16.020 mmol) of chlorosulfonate isocyanate was added, and the mixture was stirred for 1 hour. Then, 0.42 mL of chlorosulfonate is added, and the reaction was continued for another hour. Then, 10 mL of anhydrous DMF was added, and the mixture was stirred for 1 hour. After the reaction was complete, the mixture was quenched with 30 mL of water, extracted three times with EtOAc (30 mL), and the organic phases were combined. The mixture was washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was separated by silica gel column chromatography (eluent: EA / PE = 0–10%) to give 430 mg (1.104 mmol, yield: 68.9%) of tert-butyl(4-bromo-3-cyanobenzofuran-2-yl)carbamate. ESI-MS: 356.0 [M+18+1] + .

[0298] Step 5: Synthesis of tert-butyl(3-cyano-4-(5,5-dimethyl-1,3,2-dioxoborhexane-2-yl)benzofuran-2-yl)carbamate

[0299] tert-butyl (4-bromo-3-cyanobenzofuran-2-yl) carbamate (280 mg, 0.830 mmol) and 2-(5,5-dimethyl-1,3,2-dioxoborhexane-2-yl)-5,5-dimethyl-1,3,2-dioxoborhexane (562.8 mg, 2.491 mmol) were dissolved in 1,4-dioxane (3 mL), and then Pd(DPEPhos)Cl2 (297.1 mg, 0.415 mmol) and KOAc (269 mg, 2.740 mmol) were added. The mixture was heated to 100 °C and stirred for 2 hours under nitrogen protection. The reaction was confirmed to be complete by LCMS. After cooling, water (30 mL) was added, and the mixture was extracted three times with EtOAc (30 mL). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was separated by silica gel column chromatography (eluent: EA / PE = 0–10%) to give tert-butyl(3-cyano-4-(5,5-dimethyl-1,3,2-dioxoborhexane-2-yl)benzofuran-2-yl)carbamate (170 mg, yield: 55.3%). ESI-MS: 320.2 [M-51+1] + .

[0300] Intermediate 7: Preparation of tert-butyl (4-chloro-3-acrylonitrile-7-fluorothieno[3,2-c]pyridin-2-yl)carbamate

[0301] Step 1: Synthesis of 4-(4-chloro-5-fluoropyridin-3-yl)isothiazol

[0302] 3-Bromo-4-chloro-5-fluoropyridine (14 g, 66.5 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)isoxazole (15.6 g, 79.8 mmol) were dissolved in DMSO (100 mL) and water (10 mL). KF (11.6 g, 200 mmol) and Pd(dtbpf)Cl2 (1.30 g, 2.00 mmol) were added under nitrogen protection. The reaction mixture was stirred at 90 °C for 2 hours. After the reaction was complete, the reaction solution was used directly in the next step.

[0303] Step 2: Synthesis of 2-(4-chloro-5-fluoropyridin-3-yl)acetonitrile

[0304] Methanol (50 mL) and water (0.5 mL) were added to the reaction solution from the previous step, followed by KF (11.6 g, 200 mmol). The reaction solution was stirred at 90 °C for 16 hours. The reaction solution was extracted three times with water (200 mL) and ethyl acetate (200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was separated by rapid silica gel column chromatography (eluent: EA / PE = 0–3%) to give 2-(4-chloro-5-fluoropyridin-3-yl)acetonitrile (8.5 g, yield: 90.0%). ESI-MS: 170.8 [M+1] + .

[0305] Step 3: Synthesis of ethyl (3-acrylonitrile-7-fluorothiopheno[3,2-c]pyridin-2-yl)carbamate

[0306] 2-(4-chloro-5-fluoropyridin-3-yl)acetonitrile (7.5 g, 43.9 mmol) was dissolved in DMF (80 mL), followed by the addition of t-BuOK (5.96 mL, 48.4 mmol) and ethoxycarbonyl isothiocyanate (5.70 mL, 48.3 mmol). The mixture was stirred at 25 °C for 15 hours. The reaction solution was filtered, and the filter cake was dried to give ethyl(3-acrylonitrile-7-fluorothieno[3,2-c]pyridin-2-yl)carbamate (11 g, yield: 94.3%), which was used directly in the next step. ESI-MS: 266.0 [M+1] + .

[0307] Step 4: Synthesis of 2-amino-7-fluorothiopheno[3,2-c]pyridine-3-carboxylonitrile

[0308] Ethyl (3-acrylonitrile-7-fluorothieno[3,2-c]pyridin-2-yl)carbamate (5 g, 18.8 mmol) was dissolved in DMSO (32 mL), and then 4N NaOH aqueous solution (33 mL, 132 mmol) was added to the reaction solution. The mixture was heated to 105 °C and stirred for 10 hours. The reaction solution was poured into water (500 mL), filtered, and the filter cake was dried to remove the solvent, yielding 2-amino-7-fluorothieno[3,2-c]pyridin-3-carboxylonitrile (3.60 g, yield: 98.9%), which was used directly in the next step.

[0309] Step 5: Synthesis of tert-butyl (3-acrylonitrile-7-fluorothieno[3,2-c]pyridin-2-yl)carbamate

[0310] 2-Amino-7-fluorothieno[3,2-c]pyridin-3-carboxylonitrile (3.60 g, 18.6 mmol) was dissolved in THF (70 mL), followed by the addition of DIPEA (9.24 mL, 55.9 mmol) and DMAP (0.23 g, 1.86 mmol). Finally, Boc₂O (5.98 mL, 27.9 mmol) was added in portions, and the mixture was heated to 40 °C and stirred for 2 hours. The mixture was then extracted three times with an aqueous citric acid solution (60 mL, 5%) and EtOAc (60 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give tert-butyl(3-acrylonitrile-7-fluorothieno[3,2-c]pyridin-2-yl)carbamate (5 g, yield: 91.5%). ESI-MS: m / z 237.9 [M-56+1] + .

[0311] Step 6: Synthesis of 2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorothiopheno[3,2-c]pyridine 5-oxide

[0312] tert-butyl(3-acrylonitrile-7-fluorothieno[3,2-c]pyridin-2-yl)carbamate (8 g, 27.3 mmol) was dissolved in CH2Cl2 (100 mL), and m-CPBA (7.06 g, 40.9 mmol) was added in portions at room temperature. After the addition was complete, the reaction was continued for 12 hours. After the reaction was complete, water (200 mL) was added, and the mixture was extracted three times with ethyl acetate (200 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was separated by rapid silica gel column chromatography (eluent: EA / PE = 0–10%) to give 2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorothieno[3,2-c]pyridine 5-oxide (6 g, yield: 71.1%). ESI-MS: m / z 253.9 [M-56+1] + .

[0313] Step 7: Synthesis of tert-butyl (4-chloro-3-acrylonitrile-7-fluorothieno[3,2-c]pyridin-2-yl)carbamate

[0314] 2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorothieno[3,2-c]pyridine 5-oxide (6 g, 19.4 mmol) was dissolved in DCE (60 mL), and POCl3 (36.1 mL, 388 mmol) was added under nitrogen protection. After the addition was complete, the mixture was heated to 45 °C for 1 hour, resulting in the precipitation of a large amount of solid. The reaction solution was filtered, and the filter cake was added to a saturated NaHCO3 aqueous solution (100 mL) and extracted three times with dichloromethane (100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was separated by rapid silica gel column chromatography (eluent: EA / PE = 0–10%) to give tert-butyl(4-chloro-3-cyano-7-fluorothieno[3,2-c]pyridin-2-yl)carbamate (2.7 g, yield: 41.6%). ESI-MS: m / z 271.9 [M-100+1] + .

[0315] 1 H NMR (400MHz, DMSO-d6) δ8.33(br s,1H),8.14(s,1H),1.62(s,9H).

[0316] Preparation of Intermediate 8: tert-butyl(5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)naphth-2-yl)carbamate

[0317] Step 1: Synthesis of tert-butyl(5-ethynyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)naphth-2-yl))carbamate

[0318] 500 mg (0.88 mmol) of tert-butyl(6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)-5-((triisopropylsilyl)ethynyl)naphth-2-yl)carbamate was dissolved in DMF (5 mL), and CsF (1.338 g, 8.81 mmol) was added at room temperature. The mixture was heated to 50 °C and stirred for 1 hour. The reaction solution was extracted with EtOAc and saturated NaHCO3 aqueous solution. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give 362 mg (yield: 99%) of tert-butyl(5-ethynyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)naphth-2-yl)carbamate. ESI-MS: 410.2 [MH] - .

[0319] Step 2: Synthesis of tert-butyl (5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)naphth-2-yl)carbamate

[0320] 362 mg (0.87 mmol) of tert-butyl(5-ethynyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)naphth-2-yl) carbamate was dissolved in 20 mL of EtOAc. Pd-C (10%, 60 mg) was added at room temperature, and the mixture was stirred at room temperature for 2 hours under a normal pressure and H2 atmosphere. The reaction solution was filtered through diatomaceous earth, washed with 20 mL of ethyl acetate, and the filtrate was concentrated to give 360 ​​mg (yield: 98%) of tert-butyl(5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)naphth-2-yl) carbamate. ESI-MS: 360.2 [M-56+H] + .

[0321] II. Preparation of Specific Embodiments

[0322] Example 1: Preparation of 3-(1-(8-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-9-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,6-dihydro-4H-pyrimidino[4,5,6-de][1,6]diazanaphthyl-4-yl)ethyl)pyridine-2-amine

[0323] Step 1: Synthesis of 3-(1-(8-chloro-9-fluoro-2-(methanesulfonyl)-5,6-dihydro-4H-pyrimidino[4,5,6-de][1,6]diazanaphthyl-4-yl)ethyl)-N,N-di(4-methoxybenzyl)pyridine-2-amine

[0324] 3-(1-(8-chloro-9-fluoro-2-(methylthio)-5,6-dihydro-4H-pyrimidino[4,5,6-de][1,6]diazanaphthyl-4-yl)ethyl)-N,N-bis(4-methoxybenzyl)pyridine-2-amine (420 mg, 0.665 mmol) was dissolved in dichloromethane (15 mL), and m-CPBA (405 mg, 1.996 mmol) was stirred at room temperature for 2 hours. The reaction solution was diluted with dichloromethane, quenched with a saturated aqueous solution of sodium bicarbonate and sodium thiosulfate, separated, and the organic phase was directly concentrated. The residue was then separated by rapid silica gel column chromatography (eluent: methanol / dichloromethane 0–5%) to give 3-(1-(8-chloro-9-fluoro-2-(methanesulfonyl)-5,6-dihydro-4H-pyrimidino[4,5,6-de][1,6]diazanaphthyl-4-yl)ethyl)-N,N-di(4-methoxybenzyl)pyridine-2-amine (350 mg, yield: 60%). ESI-MS: 663.4 [M+1] + .

[0325] Step 2: Synthesis of 3-(1-(8-chloro-9-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,6-dihydro-4H-pyrimidino[4,5,6-de][1,6]diazanaphthyl-4-yl)ethyl)-N,N-di(4-methoxybenzyl)pyridine-2-amine

[0326] Dissolve ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (82.1 mg, 0.516 mmol) in dry THF (5 mL), add LiHMDS (0.86 mL, 0.86 mmol, 1N) under ice-water bath cooling, stir at 0 °C for 30 minutes, then add a THF (5 mL) solution of 3-(1-(8-chloro-9-fluoro-2-(methanesulfonyl)-5,6-dihydro-4H-pyrimidino[4,5,6-de][1,6]diazanaphthyl-4-yl)ethyl)-N,N-bis(4-methoxybenzyl)pyridine-2-amine (300 mg, 0.344 mmol), and continue stirring at 0 °C for 2 hours. The reaction solution was quenched with saturated brine, extracted with ethyl acetate, and the organic phase was directly concentrated. The residue was separated by reversed-phase column chromatography (eluent: CH3CN / H2O = 0–50%) to give 3-(1-(8-chloro-9-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidone-7a(5H)-yl)methoxy)-5,6-dihydro-4H-pyrimidino[4,5,6-de][1,6]diazanaphthyl-4-yl)ethyl)-N,N-di(4-methoxybenzyl)pyridin-2-amine (181 mg, yield: 71%). ESI-MS: 742.4 [M+1]+ .

[0327] Step 3: Synthesis of 3-(1-(8-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-9-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,6-dihydro-4H-pyrimidino[4,5,6-de][1,6]diazanaphthyl-4-yl)ethyl)-N,N-di(4-methoxybenzyl)pyridine-2-amine

[0328] 3-(1-(8-chloro-9-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,6-dihydro-4H-pyrimidino[4,5,6-de][1,6]diazanaphthyl-4-yl)ethyl)-N,N-bis(4-methoxybenzyl)pyridine-2-amine (15.0 mg, 0.020 mmol) was dissolved in 1,4-dioxane (0.9 mL), and H2O (0.1 mL), CataXium A-Pd-G2 (2.7 mg, 0.004 mmol), and K3PO4 (12.9 mg, 0.061 mmol) were added. The mixture was then microwaved at 100 °C for 1 hour. The reaction solution was extracted with saturated brine and ethyl acetate. The organic phase was directly concentrated, and the residue was separated by reversed-phase column chromatography (eluent: CH3CN / H2O = 0–50%) to give 3-(1-(8-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-9-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrololinazine-7a(5H)-yl)methoxy)-5,6-dihydro-4H-pyrimidino[4,5,6-de][1,6]diazanaphthyl-4-yl)ethyl)-N,N-di(4-methoxybenzyl)pyridine-2-amine (19 mg, yield: 75%). ESI-MS: 901.4 [M+1] + .

[0329] Step 4: Synthesis of 3-(1-(8-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-9-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,6-dihydro-4H-pyrimidino[4,5,6-de][1,6]diazanaphthyl-4-yl)ethyl)pyridine-2-amine

[0330] 3-(1-(8-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-9-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,6-dihydro-4H-pyrimidino[4,5,6-de][1,6]diazanaphthyl-4-yl)ethyl)-N,N-bis(4-methoxybenzyl)pyridine-2-amine (19 mg, 0.015 mmol) was dissolved in TFA (2.0 mL), and methanesulfonic acid (0.2 mL) was added under ice bath cooling. The reaction was carried out at 0 °C for 30 minutes. The reaction solution was poured into ice water, neutralized with saturated sodium bicarbonate solution, extracted with dichloromethane, and the organic phase was concentrated. The residue was then separated by preparative HPLC (eluent: CH3CN / (H2O+10mM NH4HCO3)=25~50%) to give 3-(1-(8-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-9-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidone-7a(5H)-yl)methoxy)-5,6-dihydro-4H-pyrimidino[4,5,6-de][1,6]diazanaphthyl-4-yl)ethyl)pyridin-2-amine (2.6 mg, yield: 26%). ESI-MS: 661.4 [M+1] + .

[0331] 1 H NMR (400MHz, DMSO-d6) δ7.96(d,J=4.8Hz,1H),7.67(d,J=7.4Hz,1H),6.86(d,J=2.2Hz,1H),6 .66(dd,J=7.5,4.8Hz,1H),6.43(d,J=2.3Hz,1H),6.31(s,2H),6.01(q,J=6.8Hz,1H),5.73(s ,2H),5.29(d,J=54.3Hz,1H),4.26–4.04(m,2H),3.77–3.65(m,1H),3.25–3.18(m,1H),3.12– 3.02(m,4H),2.96–2.80(m,2H),2.14–2.00(m,3H),1.88–1.78(m,3H),1.61(d,J=6.9Hz,3H).

[0332] Example 63: Preparation of 3-((R)-1-(8-(3-amino-8-ethynyl-7-fluoronaphthyl-1-yl)-9-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4H-pyrimidino[4,5,6-de][1,6]diazanaphthyl-4-yl)ethyl)pyridine-2-amine

[0333] Step 1: Synthesis of 3-((1R)-1-(8-chloro-9-fluoro-2-(methylthionyl)-4H-pyrimido[4,5,6-de][1,6]diazanaphth-4-yl)ethyl)-N,N-di(4-methoxybenzyl)pyridine-2-amine and (R)-3-(1-(8-chloro-9-fluoro-2-(methanesulfonyl)-4H-pyrimido[4,5,6-de][1,6]diazanaphth-4-yl)ethyl)-N,N-di(4-methoxybenzyl)pyridine-2-amine)

[0334] (R)-3-(1-(8-chloro-9-fluoro-2-(methylthio)-4H-pyrimidino[4,5,6-de][1,6]diazanaphthyl-4-yl)ethyl)-N,N-bis(4-methoxybenzyl)pyridine-2-amine (7.5 g, 70.5% purity, 8.40 mmol) was dissolved in anhydrous dichloromethane (20 mL), cooled to 0 °C, and m-CPBA (3.41 g, 16.81 mmol) was added. After the addition was complete, the mixture was allowed to rise to room temperature and reacted for 1 hour. LC-MS monitoring showed that the reaction was complete. The reaction solution was quenched with saturated sodium sulfite aqueous solution, and then extracted twice with dichloromethane (100 mL). The organic phases were combined, washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. The product was filtered and concentrated, yielding 3-((1R)-1-(8-chloro-9-fluoro-2-(methylthionyl)-4H-pyrimido[4,5,6-de][1,6]diazanaphthyl-4-yl)ethyl)-N,N-di(4-methoxybenzyl)pyridine-2-amine and (R)-3-(1-(8-chloro-9-fluoro-2-(methanesulfonyl)-4H-pyrimido[4,5,6-de][1,6]diazanaphthyl-4-yl)ethyl)-N,N-di(4-methoxybenzyl)pyridine-2-amine. The crude product was directly fed into the next reaction. ESI-MS: 661.4; 645.4 [M+1] + .

[0335] Step 2: Synthesis of (R)-3-(1-(8-chloro-9-fluoro-2-(2,2,2-trifluoroethoxy)-4H-pyrimidino[4,5,6-de][1,6]diazanaphthyl-4-yl)ethyl)-N,N-di(4-methoxybenzyl)pyridine-2-amine

[0336] The crude product from the previous step (8.40 mmol) was dissolved in 10 mL of 2,2,2-trifluoroethanol, and DIPEA (4.39 mL, 25.21 mmol) was added. The mixture was heated to 60 °C for 1 hour. LC-MS showed that the reaction was complete. The reaction solution was directly concentrated under reduced pressure, and the crude product was separated by rapid silica gel column chromatography (eluent: PE / EA = 7:3) to give (R)-3-(1-(8-chloro-9-fluoro-2-(2,2,2-trifluoroethoxy)-4H-pyrimidino[4,5,6-de][1,6]diazanaphthyl-4-yl)ethyl)-N,N-di(4-methoxybenzyl)pyridine-2-amine (4.3 g, purity 78.2%, yield: 58.8%). ESI-MS: 681.3 [M+1] + .

[0337] Step 3: Synthesis of 3-((R)-1-(8-chloro-9-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4H-pyrimidino[4,5,6-de][1,6]diazanaphthyl-4-yl)ethyl)-N,N-di(4-methoxybenzyl)pyridine-2-amine

[0338] (R)-3-(1-(8-chloro-9-fluoro-2-(2,2,2-trifluoroethoxy)-4H-pyrimidino[4,5,6-de][1,6]diazanaphthyl-4-yl)ethyl)-N,N-bis(4-methoxybenzyl)pyridine-2-amine (0.74 g, 0.85 mmol, purity: 78.2%) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (0.20 g, 1.27 mmol) were dissolved in anhydrous THF (15 mL). Sodium tert-amyl alcohol (0.28 g, 2.55 mmol) was added at 0 °C, and the reaction was maintained at a low temperature for 1.5 h. The reaction was monitored by LCMS until complete. The reaction was quenched with saturated ammonium chloride aqueous solution, and then extracted twice with ethyl acetate (40 mL). The organic phases were combined, washed with saturated brine (30 mL), and dried over anhydrous sodium sulfate. The crude product was filtered, concentrated, and separated by rapid silica gel column chromatography (eluent: CH2Cl2 / MeOH = 20:1) to give 3-((R)-1-(8-chloro-9-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4H-pyrimidino[4,5,6-de][1,6]diazanaphthyl-4-yl)ethyl)-N,N-di(4-methoxybenzyl)pyridine-2-amine (0.56 g, yield: 82.0%). ESI-MS: 740.4 [M+1] + .

[0339] Step 4: Synthesis of tert-butyl(4-(4-((R)-1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)-9-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4H-pyrimidino[4,5,6-de][1,6]diazanaphthyl-8-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthyl-2-yl)carbamate

[0340] 3-((R)-1-(8-chloro-9-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4H-pyrimidino[4,5,6-de][1,6]diazanaphthyl-4-yl)ethyl)-N,N-di(4-methoxybenzyl)pyridine-2-amine (0.56 g, 0.70 mmol) and (6-fluoro-4-(4, 4,5,5-Tetramethyl-1,3,2-dioxoboronyl-2-yl)-5-((triisopropylsilyl)ethynyl)naphth-2-yl)tert-butyl carbamate (0.67 g, 1.18 mmol) was dissolved in a mixture of 1,4-dioxane / water (8.0 mL / 0.8 mL), and then K3PO4 (0.52 g, 2.44 mmol) and CataXium A-Pd-G2 (90 mg, 0.14 mmol) were added sequentially. After purging with nitrogen, the mixture was microwaved at 100 °C for 2 hours. The reaction was completed, concentrated, and the crude product was separated by rapid silica gel column chromatography (eluent: CH2Cl2 / MeOH = 20:1) to give tert-butyl(4-(4-((R)-1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)-9-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4H-pyrimidino[4,5,6-de][1,6]diazanaphthyl-8-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthyl-2-yl)carbamate (0.78 g, yield: 95.6%). ESI-MS: 1145.6 [M+1] + .

[0341] Step 5: Synthesis of 3-((R)-1-(8-(3-amino-7-fluoro-8-(((triisopropylsilyl)ethynyl)naphth-1-yl)-9-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4H-pyrimidino[4,5,6-de][1,6]diazanaphth-4-yl)ethyl)pyridine-2-amine

[0342] 0.78 g (0.67 mmol) of tert-butyl(4-(4-((R)-1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)-9-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolinazin-7a(5H)-yl)methoxy)-4H-pyrimidino[4,5,6-de][1,6]diazanaphthyl-8-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthyl-2-yl)carbamate (3 mL) was dissolved in TFA. Methanesulfonic acid (1.0 mL) was added at 0 °C, and the reaction was maintained at 0 °C for 2 hours. LC-MS showed that the reaction was complete. The reaction solution was concentrated and the pH was adjusted to 7–8 with saturated sodium bicarbonate solution. The solution was then extracted twice with ethyl acetate (20 mL). The combined organic phases were washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated to obtain 3-((R)-1-(8-(3-amino-7-fluoro-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-9-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrololinazine-7a(5H)-yl)methoxy)-4H-pyrimidino[4,5,6-de][1,6]diazanaphth-4-yl)ethyl)pyridin-2-amine. The crude product was directly fed into the next reaction. ESI-MS: 805.6 [M+1] + .

[0343] Step 6: Synthesis of 3-((R)-1-(8-(3-amino-8-ethynyl-7-fluoronaphthyl-1-yl)-9-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4H-pyrimidino[4,5,6-de][1,6]diazanaphthyl-4-yl)ethyl)pyridine-2-amine

[0344] The crude product 3-((R)-1-(8-(3-amino-7-fluoro-8-(((triisopropylsilyl)ethynyl)naphth-1-yl)-9-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4H-pyrimidino[4,5,6-de][1,6]diazanaphth-4-yl)ethyl)pyridin-2-amine (based on 0.67 mmol) was dissolved in DMF (4.0 mL), and then CsF (0.51 g, 3.33 mmol) was added. The mixture was heated to 60 °C and reacted for 1 hour. The reaction was monitored by LCMS until it was complete. The reaction solution was concentrated and then separated by reversed-phase column chromatography (eluent: water / acetonitrile / ammonium bicarbonate = 6:4:0.05) to give 3-((R)-1-(8-(3-amino-8-ethynyl-7-fluoronaphthyl-1-yl)-9-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrololinazine-7a(5H)-yl)methoxy)-4H-pyrimidino[4,5,6-de][1,6]diazanaphthyl-4-yl)ethyl)pyridin-2-amine (322.8 mg, yield: 72.3%). ESI-MS: 649.4 [M+1] + .

[0345] 1 H-NMR (400MHz, DMSO-d6) δ8.03–7.95(m,1H),7.82–7.64(m,3H),7.32(t,J=9.0Hz,1H),7.04(d,J=1. 6Hz,1H),7.01(d,J=2.0Hz,1H),6.83–6.76(m,1H),6.74–6.64(m,1H),6.38–6.25(m,1H),5.89(d,J= 6.9Hz,2H),5.61(d,J=2.9Hz,2H),5.31(d,J=54.3Hz,1H),4.14(q,J=10.5Hz,2H),3.87(d,J=44.9Hz ,1H),3.19–3.06(m,2H),3.06–2.99(m,1H),2.88–2.79(m,1H),2.19–1.99(m,3H),1.89–1.72(m,6H).

[0346] Example 64: Preparation of 3-((R)-1-(8-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-9-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4H-pyrimidino[4,5,6-de][1,6]diazanaphthyl-4-yl)ethyl)pyridine-2-amine

[0347] Step 1: Synthesis of 3-((R)-1-(8-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-9-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4H-pyrimidino[4,5,6-de][1,6]diazanaphthyl-4-yl)ethyl)-N,N-di(4-methoxybenzyl)pyridine-2-amine

[0348] 3-((R)-1-(8-chloro-9-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4H-pyrimidino[4,5,6-de][1,6]diazanaphthyl-4-yl)ethyl)-N,N-di(4-methoxybenzyl)pyridine-2-amine (55 mg, 0.70 mmol) and 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)-4-(trifluoromethyl)aniline (29 mg, 0.089 mmol) were dissolved in a 1,4-dioxane / water (2.0 mL / 0.2 mL) mixture, and then K3PO4 (47 mg, 0.22 mmol) and CataXium were added sequentially. A-Pd-G2 (10 mg, 0.015 mmol) was purged with nitrogen and then microwaved at 100 °C for 1 hour. After the reaction was complete, the product was concentrated, and the crude product was separated by rapid silica gel column chromatography (eluent: CH2Cl2 / MeOH / ammonia = 10:1:0.1) to give 3-((R)-1-(8-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-9-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidone-7a(5H)-yl)methoxy)-4H-pyrimidino[4,5,6-de][1,6]diazanaphthyl-4-yl)ethyl)-N,N-di(4-methoxybenzyl)pyridin-2-amine (52 mg, yield: 67.9%). ESI-MS: 899.4 [M+1] + .

[0349] Step 2: Synthesis of 3-((R)-1-(8-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-9-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4H-pyrimidino[4,5,6-de][1,6]diazanaphthyl-4-yl)ethyl)pyridine-2-amine

[0350] 3-((R)-1-(8-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-9-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4H-pyrimidino[4,5,6-de][1,6]diazanaphthyl-4-yl)ethyl)-N,N-di(4-methoxybenzyl)pyridine-2-amine (52 mg, 0.050 mmol) was dissolved in TFA (2 mL), cooled in an ice-water bath, and then MeSO3H (0.2 mL) was added. The reaction was maintained at 0 °C for 1 hour. LC-MS showed that the reaction was complete. The reaction solution was concentrated at low temperature, neutralized with saturated sodium bicarbonate aqueous solution, and then extracted twice with ethyl acetate (20 mL). The combined organic phases were washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. The crude product was filtered and concentrated, and then subjected to preparative column chromatography (eluent: CH3CN / (H2O+10mM NH4HCO3)=10~50%) to obtain 3-((R)-1-(8-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-9-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4H-pyrimidino[4,5,6-de][1,6]diazanaphthyl-4-yl)ethyl)pyridin-2-amine (11.8 mg, yield: 35.1%). ESI-MS: 659.4 [M+1] + .

[0351] 1 HNMR(400MHz,DMSO-d6)δ7.97(d,J=4.8Hz,1H),7.79–7.68(m,1H),7.66(dd,J=7.8,5.3Hz ,1H),6.86(d,J=2.2Hz,1H),6.81(d,J=7.8Hz,1H),6.68(t,J=5.6Hz,1H),6.44(d,J=2.9Hz ,1H),6.35–6.22(m,3H),5.81(d,J=6.5Hz,2H),5.29(d,J=54.3Hz,1H),4.21–4.08(m,2H) ,3.17–3.05(m,2H),3.01(s,1H),2.86–2.80(m,1H),2.21–2.00(m,3H),1.88–1.67(m,6H).

[0352] Example 65: Preparation of 3-((R)-1-(8-(3-amino-8-ethynyl-7-fluoronaphth-1-yl)-2-((R)-3-(dimethylamino)pyrrolidine-1-yl)-9-fluoro-4H-pyrimidino[4,5,6-de][1,6]diazanaphth-4-yl)ethyl)pyridine-2-amine

[0353] Step 1: Synthesis of tert-butyl(R)-(4-(4-(1-(2-(di(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)-9-fluoro-2-(methylthio)-4H-pyrimidino[4,5,6-de][1,6]diazanaphthyl-8-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthyl-2-yl)carbamate

[0354] (R)-3-(1-(8-chloro-9-fluoro-2-(methylthio)-4H-pyrimidino[4,5,6-de][1,6]diazanaphthyl-4-yl)ethyl)-N,N-di(4-methoxybenzyl)pyridine-2-amine (0.33 g, 0.525 mmol) and (6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-5-((triisopropylsilyl)ethynyl)naphthyl-2-yl)tert-butyl carbamate (0.45 g, 0.787 mmol) were dissolved in a 1,4-dioxane / water (5.0 mL / 0.5 mL) mixture, followed by the sequential addition of K3PO4 (0.39 g, 1.836 mmol) and CataXium. A-Pd-G2 (70 mg, 0.105 mmol) was reacted with nitrogen gas purging followed by microwave heating at 100 °C for 2 hours. After complete reaction, the mixture was concentrated and the crude product was separated by silica gel column chromatography (eluent: PE / EA = 3:2) to give tert-butyl(R)-(4-(4-(1-(2-(di(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)-9-fluoro-2-(methylthio)-4H-pyrimidino[4,5,6-de][1,6]diazanaphthyl-8-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthyl-2-yl)carbamate (0.46 g, yield: 84%). ESI-MS: 1034.6 [M+1] + .

[0355] Step 2: Synthesis of tert-butyl(R)-(4-(4-(1-(2-(di(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)-9-fluoro-2-(methanesulfonyl)-4H-pyrimidino[4,5,6-de][1,6]diazanaphthyl-8-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthyl-2-yl)carbamate

[0356] (R)-3-(1-(8-chloro-9-fluoro-2-(methylthio)-4H-pyrimidino[4,5,6-de][1,6]diazanaphthyl-4-yl)ethyl)-N,N-di(4-methoxybenzyl)pyridine-2-amine (0.44 g, 0.425 mmol) was dissolved in CH2Cl2 (20 mL), cooled to 0 °C, and m-CPBA (0.35 g, 1.702 mmol) was added. After the addition was complete, the reaction was carried out at 0 °C for 3 hours. LC-MS showed that the reaction was complete. The reaction was quenched with saturated sodium sulfite aqueous solution, and then extracted twice with CH2Cl2 (100 mL). The organic phases were combined, washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. The product was filtered, concentrated, and the crude product was separated by silica gel column chromatography (eluent: PE / EA = 13:7) to give tert-butyl(R)-(4-(4-(1-(2-(di(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)-9-fluoro-2-(methanesulfonyl)-4H-pyrimidino[4,5,6-de][1,6]diazanaphthyl-8-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthyl-2-yl)carbamate (0.22 g, yield: 49%). ESI-MS: 1066.6 [M+1] + .

[0357] Step 3: Synthesis of tert-butyl(4-(4-((R)-1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)-2-((R)-3-(dimethylamino)pyrrolidone-1-yl)-9-fluoro-4H-pyrimidino[4,5,6-de][1,6]naphthidin-8-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphth-2-yl)carbamate

[0358] tert-Butyl(R)-(4-(4-(1-(2-(di(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)-9-fluoro-2-(methanesulfonyl)-4H-pyrimidino[4,5,6-de][1,6]diazanaphthyl-8-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthyl-2-yl)carbamate (20 mg, 0.019 mmol) and (R)-N,N-dimethylpyrrolidine-3-amine (4 mg, 0.038 mmol) were dissolved in anhydrous 1,4-dioxane (1 mL), and DIPEA (0.015 mL) was added. 0.094 mmol), heated to 100 °C overnight. LC-MS showed the reaction was complete. Concentration yielded tert-butyl(4-(4-((R)-1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)-2-((R)-3-(dimethylamino)pyrrolidine-1-yl)-9-fluoro-4H-pyrimidino[4,5,6-de][1,6]naphthidin-8-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphth-2-yl)carbamate, the crude product of which was used directly in the next reaction. ESI-MS: 1100.6 [M+1] + .

[0359] Step 4: Synthesis of 3-((R)-1-(8-(3-amino-7-fluoro-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-2-((R)-3-(dimethylamino)pyrrolidine-1-yl)-9-fluoro-4H-pyrimidino[4,5,6-de][1,6]diazanaphth-4-yl)ethyl)pyridine-2-amine

[0360] Crude tert-butyl(4-(4-((R)-1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)-2-((R)-3-(dimethylamino)pyrrolidine-1-yl)-9-fluoro-4H-pyrimidino[4,5,6-de][1,6]naphthidin-8-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphth-2-yl)carbamate (based on 0.018 mmol) was dissolved in TFA (1 mL), cooled to 0 °C, and then MeSO3H (0.2 mL) was added. The reaction was maintained at 0 °C for 2 hours. LC-MS showed that the reaction was complete. The reaction solution was dried under nitrogen, neutralized with saturated sodium bicarbonate aqueous solution, and then extracted twice with CH2Cl2 (20 mL). The combined organic phases were washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. The sample was filtered and concentrated to obtain 3-((R)-1-(8-(3-amino-7-fluoro-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-2-((R)-3-(dimethylamino)pyrrolidine-1-yl)-9-fluoro-4H-pyrimidino[4,5,6-de][1,6]diazanaphth-4-yl)ethyl)pyridine-2-amine. The crude product was directly fed into the next reaction step. ESI-MS: 760.6 [M+1] + .

[0361] Step 5: Synthesis of 3-((R)-1-(8-(3-amino-8-ethynyl-7-fluoronaphth-1-yl)-2-((R)-3-(dimethylamino)pyrrolidine-1-yl)-9-fluoro-4H-pyrimidino[4,5,6-de][1,6]diazanaphth-4-yl)ethyl)pyridine-2-amine

[0362] Crude 3-((R)-1-(8-(3-amino-7-fluoro-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-2-((R)-3-(dimethylamino)pyrrolidine-1-yl)-9-fluoro-4H-pyrimidino[4,5,6-de][1,6]diazanaphth-4-yl)ethyl)pyridine-2-amine (calculated as 0.018 mmol) was dissolved in DMF (1.0 mL), CsF (110 mg, 0.726 mmol) was added, and the mixture was heated to 60 °C for 2 hours. LC-MS showed that the reaction was complete. Reversed-phase column chromatography (eluent: water / acetonitrile / ammonium bicarbonate = 6:4:0.05) yielded 3-((R)-1-(8-(3-amino-8-ethynyl-7-fluoronaphth-1-yl)-2-((R)-3-(dimethylamino)pyrrolidine-1-yl)-9-fluoro-4H-pyrimidino[4,5,6-de][1,6]diazanaphth-4-yl)ethyl)pyridin-2-amine (4.1 mg, yield: 36%). ESI-MS: 604.4 [M+1] + .

[0363] 1 H NMR (400MHz, DMSO-d6) δ7.95 (brd, J=6.8Hz, 1H), 7.74 (dd, J=9.2, 6.0Hz, 1H), 7.65–7.60 (m, 1H), 7.31 (t,J=9.1Hz,1H),7.03–6.94(m,2H),6.71–6.55(m,2H),(m,2H),6.43–6.33(m,1H),6.15–5.90(m,2H), 5.57(s,2H),4.16–3.95(m,1H),3.94–3.86(m,1H),3.85–3.74(m,1H),3.50(q,J=10.5Hz,1H),2.76(b rs,1H),2.23(s,3H),2.21(s,3H),2.17(brs,2H),2.00(q,J=7.1Hz,1H),1.75(dd,J=10.3,7.0Hz,4H).

[0364] Examples 2-62 and 66-112 can be prepared by selecting appropriate raw materials and reagents, referring to all or part of the synthesis methods of Examples 1, 63, 64 or Example 65.

[0365] The NMR data of the compounds prepared in the above examples are as follows:

[0366] This invention provides two comparative compounds. The preparation of comparative compounds 1 and 2 can be carried out by selecting the appropriate raw materials and reagents according to all or part of the synthesis method of E21 in patent WO2024104453A1.

[0367] Biological testing evaluation

[0368] I. GMP PNP-KRAS / c-RAF Binding Test

[0369] 1. Detection of biochemical activity of KRAS G12D / c-RAF

[0370] 1.1 Preparation of experimental buffer solutions

[0371] First, prepare a 5X buffer solution (250mM pH 7.4 HEPES, 500mM NaCl, 2.5% TritionX-100). Based on this, prepare a 1X buffer solution (50mM pH 7.4 HEPES, 100mM NaCl, 0.5% TritionX-100, 0.5% BSA).

[0372] 1.2 Compound dilution and preparation

[0373] Dilute the 10 mM stock solution at a ratio of 1:5 nine times consecutively, and then dilute with 1X buffer to prepare a 10X solution containing the compound. Transfer 2 μL of each solution to the corresponding well of a 384-well plate and centrifuge (1000 rpm, 1 min).

[0374] 1.3 Preparation of KRAS and GMPPNP working solutions

[0375] Prepare a 5X KRAS and GMPPNP mixture (50 nM KRAS G12D, 50 μM GMPPNP) using 1X buffer, incubate on ice for 30 minutes, then transfer 4 μL to the corresponding well of a 384-well plate and centrifuge (1000 rpm, 1 min). Incubate at room temperature for 15 minutes.

[0376] 1.4 Preparation of cRAF working solution

[0377] Prepare a 5X cRAF working solution (250 nM cRAF) using 1X buffer, transfer 4 μL to the corresponding well of a 384-well plate, and centrifuge (1000 rpm, 1 min). Then incubate at room temperature for 15 min.

[0378] 1.5 Add test reagents

[0379] Prepare the 2X assay reagent (4x Alphascreen GSH donor beads, 4X Alphalisa NICKEL Acceptor beads) using 1X buffer solution. Transfer 10 μL to the corresponding wells of a 384-well plate and centrifuge (1000 rpm, 1 min). Then incubate at room temperature for 1 hour. Read the values ​​on a SpectraMax Paradigm (MD) microplate reader.

[0380] 2. Biochemical activity assay of KRAS G12V / c-RAF

[0381] 2.1 Preparation of experimental buffer solutions

[0382] First, prepare a 5X buffer solution (250mM pH 7.4 HEPES, 500mM NaCl, 2.5% TritionX-100). Based on this, prepare a 1X buffer solution (50mM pH 7.4 HEPES, 100mM NaCl, 0.5% TritionX-100, 0.5% BSA).

[0383] 2.2 Compound dilution and preparation

[0384] Dilute the 10 mM stock solution at a ratio of 1:5 nine times consecutively, and then dilute with 1X buffer to prepare a 10X solution containing the compound. Transfer 2 μL of each solution to the corresponding well of a 384-well plate and centrifuge (1000 rpm, 1 min).

[0385] 2.3 Preparation of KRAS and GMPPNP working solutions

[0386] Prepare a 5X KRAS and GMPPNP mixture (50 nM KRASG12D, 400 nM GMPPNP) using 1X buffer, pre-incubate on ice for 30 minutes, then transfer 4 μL to the corresponding well of a 384-well plate and centrifuge (1000 rpm, 1 min). Incubate at room temperature for 15 minutes.

[0387] 2.4 Preparation of cRAF working solution

[0388] Prepare a 5X cRAF working solution (250 nM cRAF) using 1X buffer, transfer 4 μL to the corresponding well of a 384-well plate, and centrifuge (1000 rpm, 1 min). Then incubate at room temperature for 15 min.

[0389] 2.5 Add test reagents

[0390] Prepare 2X assay reagent (4X Alphascreen GSH donor beads, 4X Alphalisa NICKEL Acceptor beads) using 1X buffer solution. Transfer 10 μL to the corresponding wells of a 384-well plate and centrifuge (1000 rpm, 1 min). Then incubate at room temperature for 1 hour. Read the values ​​on a SpectraMax Paradigm (MD) microplate reader.

[0391] Table 1: Results of Biological Tests

[0392] II. KRas mutant cells anti-proliferation 2D CTG test

[0393] 1. Experimental steps:

[0394] 1.1 Day 0 Cell Culture and Plating

[0395] Cells in the logarithmic growth phase were harvested and counted using a platelet counter. Cell viability was assessed using the trypan blue exclusion method to ensure it was above 90%. The cell concentration was adjusted to the desired final density, and 90 μL of cell suspension was added to each 96-well plate and incubated overnight at 37°C, 5% CO2, and 95% humidity. Cell density and cell culture status are shown in the figure below.

[0396] 1.2 Baseline readings on day 1

[0397] Add 10 μL of PBS to each well of a T0 plate containing cells. Thaw the CTG reagent and equilibrate the cell plate to room temperature for 30 minutes. Add 50 μL of CTG solution to each well. Shake on a track-mounted shaker for 5 minutes to lyse the cells. Incubate the cell plate at room temperature for 20 minutes to stabilize the fluorescence signal. Read the T0 fluorescence signal value.

[0398] 1.3 Day 1 Compound Treatment

[0399] Nine consecutive dilutions were made from the 10 mM stock solution at a ratio of 1:5. 10X culture medium containing the compound was transferred to the corresponding wells in the 96-well plate. The final peak compound concentration was 10 μM, and the final DMSO concentration was 0.1%. The 96-well plate was incubated at 37°C for 4 days.

[0400] 1.4 Read the signal on day 5

[0401] Cells were added with 50 μL of detection reagent (CTG) per well, and the signal was read in the Envision instrument to calculate the IC50. 50 Value (unit: nM).

[0402] Table 2: Biological Test Results

[0403] Based on the activity data of the compounds in the specific embodiments, the series of compounds of the present invention exhibit strong inhibitory activity against various KRAS mutant cells. Under the same test conditions, the cell inhibitory activity of some of the compound examples is significantly improved compared with that of the comparative compounds.

[0404] III. Pharmacokinetic Evaluation

[0405] 1. Research Objectives

[0406] The purpose of this experiment was to study the in vivo pharmacokinetic behavior of some compounds of the present invention using SD rats as test animals. The administration method was: rats were given a single oral (PO) dose.

[0407] 2. Test Plan

[0408] 2.1 Test Drugs

[0409] The compounds used in this experiment were derived from the compounds in the specific embodiments of this invention and the listed comparative compounds.

[0410] 2.2 Experimental Animals

[0411] Male SD rats (N=3) Original source: Shanghai Jihui Experimental Animal Breeding Co., Ltd.

[0412] 2.3 Drug Preparation and Administration

[0413] The compounds were weighed and dissolved in their respective solvents (PO: 0.5% CMC + 1% Tween + pure water; IV: 20% HP-β-CD in 50mM pH 4.7 Acetate buffer), shaken, and sonicated to prepare suspensions. Three rats were fasted overnight and then administered the suspension orally at a dose of 10 mg / kg (or IV 2 mg / kg).

[0414] 2.4 Sample Collection

[0415] Approximately 90 μL of blood was collected via the submandibular vein at each time point. Heparin sodium was used for anticoagulation. After collection, the samples were placed on ice and centrifuged within 1 hour to separate the plasma (centrifugation conditions: 8000 rpm, 6 minutes, 2-8℃). Blood collection time points were 0, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours. Samples were stored at -20℃.

[0416] Add 160 μL of ice-cold acetonitrile containing internal standard to 40 μL of plasma sample, vortex for 3 minutes, and centrifuge at 11,000 rpm for 5 minutes. Take 100 μL of the supernatant and add it to 100 μL of water, then inject 5 μL into LC / MS / MS for analysis.

[0417] 2.5 Test Results

[0418] Table 3: Results of Rat Pharmacokinetic Experiment

[0419] The pharmacokinetic data of the compounds in the above specific embodiments show that the compounds of this invention, after a single oral dose (10 mpk), are absorbed into rats with very good PK data. Compared with the comparative compounds, the oral AUC of the compounds of this invention is significantly improved, especially the oral AUC of some of the compound examples is at least three times higher, and they also have significantly improved bioavailability.

[0420] The experimental results show that, compared with existing compounds in the prior art, the series of compounds of this invention have significantly improved animal exposure and bioavailability. Through head-to-head comparison of multiple groups of positive compounds, the exposure or bioavailability of some compounds has been improved by about 5-10 times, showing better development prospects and the potential to solve the problem of poor pharmacokinetic properties of positive compounds, which make them unsuitable for oral administration.

[0421] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the above disclosure of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: wherein, is a single or double bond, when R4and R7are absent when the bond is a double bond; X1is CR8or N; X2is CR9or N; X3is CR 10 or N; X4is N or CR 11 ; Cycloalkyl, 3-12 membered heterocyclyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 Aryl or 5-10 membered heteroaryl, or, said C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 Aryl or 5-10 membered heteroaryl, or, said C 6-10 Aryl or 5-10 membered heteroaryl, or, said C 3-12 Cycloalkyl or 3-12 membered heterocyclyl; m is 0, 1, 2, 3, 4, or 5; each R1is independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azido, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6haloalkenyl, C2-C6alkynyl, C2-C6haloalkynyl, C3-C6cycloalkyl, 3- to 12-membered heterocyclyl, C6-C10aryl, 5- to 10-membered heteroaryl, -C1-C6alkyl-6,10-dioxo-6,6a,7,7a-tetrahydrocyclopropa 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-10 aryl, 5- to 10-membered heteroaryl, -C 0-8 alkyl-SF5, -C 0-8 alkyl-S(O)(=N-R 12 )R 13 , -C 0-8 alkyl-N=S(O)R 13 R 14 , -C 0-8 alkyl-N=SR 13 R 14 , -C 0-8 alkyl-O-S(O)2R 15 , -C 0-8 alkyl-S(O) r R 15 , -C 0-8 alkyl-O-R 16 , -C 0-8 alkyl-C(O)OR 16 , -C 0-8 alkyl-C(O)SR 16 , -C 0-8 alkyl-S-C(O)R 17 , -C 0-8 alkyl-C(O)R 17 , -C 0-8 alkyl-O-C(O)R 17 , -C 0-8 alkyl-P(O)(R 17 )2, -C 0-8 alkyl-NR 18 R 19 , -C 0-8 alkyl-C(=NR 18 )R 17 , -C 0-8 alkyl-N(R 18 )-C(=NR 19 )R 17 , -C 0-8 alkyl-C(O)NR 18 R 19 , and -C 0-8 alkyl-N(R 18 )-C(O)R 17 , or, when m > 2, wherein two adjacent R1together with the moiety they are directly attached to form a C6-C10aryl or 5- to 10-membered heteroaryl; 3-12 cycloalkyl or 3-12 membered heterocyclyl, each of which is independently and optionally further substituted by one or more, preferably 1, 2, 3 or 4, more preferably 1 or 2, substituents independently selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C1-6-alkyl, C1-6-alkyl substituted by deuterium, halogen, cyano or 1-10 C1-6-alkyl, halogen-substituted C1-6-alkyl 1-10 C1-6-alkyl, deuterium-substituted C1-6-alkyl 1-10 C1-6-alkyl, C1-6-alkyl substituted by deuterium, halogen, cyano or 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, =0, =S, -C 0-8 alkyl-SF5, -C 0-8 alkyl-S(O)(=N-R 12 )R 13 , -C 0-8 alkyl-N=S(O)R 13 R 14 , -C 0-8 alkyl-N=SR 13 R 14 , -C 0-8 alkyl-O-S(O)2R 15 , -C 0-8 alkyl-S(O) r R 15 , -C 0-8 alkyl-O-R 16 , -C 0-8 alkyl-C(O)OR 16 , -C 0-8 alkyl-C(O)SR 16 , -C 0-8 alkyl-S-C(O)R 17 , -C 0-8 alkyl-C(O)R 17 , -C 0-8 alkyl-O-C(O)R 17 , -C 0-8 alkyl-P(O)(R 17 )2, -C 0-8 alkyl-NR 18 R 19 , -C 0-8 alkyl-C(=NR 18 )R 17 , -C 0-8 alkyl-N(R 18 )-C(=NR 19 )R 17 , -C 0-8 alkyl-C(O)NR 18 R 19 and -C 0-8 alkyl-N(R 18 ) -C(O)R 17 substituted by substituents selected from the group consisting of R2is selected from hydrogen, halogen, -(L) s -O-(L) s -R 2a , -(L) s -NR 2b R 2c , -(L) s -O-(L) s -NR 2b R 2c , C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, each of which is independently and optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, nitro, azido, C s alkyl, halo-substituted C s alkyl, deuterium-substituted C 2a alkyl, C s alkylene, halo-substituted C 2b alkylene, deuterium-substituted C 2c alkylene, C s alkenylene, C s alkynylene, C 2b cycloalkyl, 3-12 membered heterocyclyl, C 2c aryl, or 5-10 membered heteroaryl, =0, =S, -C 3-12 alkyl-SF5, -C 6-10 alkyl-S(O)(=N-R 1-10 )R 1-10 , -C 1-10 alkyl-N=S(O)R 1-10 R 1-10 , -C 1-10 alkyl-N=SR 2-10 R 2-10 , -C 3-12 alkyl-O-S(O)2R 6-10 , -C 0-8 alkyl-S(O) 0-8 R 12 , -C 13 alkyl-O-R 0-8 13 14 0-8 13 14 0-8 15 0-8 r 15 0-8 16 ​​​​​​​​​​​​, -C 0-8 alkyl-C(O)OR 16 , -C 0-8 alkyl-C(O)SR 16 , -C 0-8 alkyl-S-C(O)R 17 , -C 0-8 alkyl-C(O)R 17 , -C 0-8 alkyl-O-C(O)R 17 , -C 0-8 alkyl-P(O)(R 17 )2, -C 0-8 alkyl-NR 18 R 19 , -C 0-8 alkyl-C(=NR 18 )R 17 , -C 0-8 alkyl-N(R 18 )-C(=NR 19 )R 17 , -C 0-8 alkyl-C(O)NR 18 R 19 and -C 0-8 alkyl-N(R 18 )-C(O)R 17 ; each s is independently 0, 1, 2, or 3; each L is independently selected from C 1-10 alkylene, C 3-12 cycloalkylene, or 3-12 membered heterocyclylene is independently and optionally further substituted by one or more substituents independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkylene, C 3-12 cycloalkylene, or 3-12 membered heterocyclylene is independently and optionally further substituted by one or more substituents independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, halogen-substituted C 1-10 alkyl, deuterium-substituted C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, =O, =S, -C 0-8 alkyl-SF5, -C 0-8 alkyl-S(O)(=N-R 12 )R 13 , -C 0-8 alkyl-N=S(O)R 13 R 14 , -C 0-8 alkyl-N=SR 13 R 14 , -C 0-8 alkyl-O-S(O)2R 15 , -C 0-8 alkyl-S(O) r R 15 , -C 0-8 alkyl-O-R 16 , -C 0-8 alkyl-C(O)OR 16 , -C 0-8 alkyl-C(O)SR 16 , -C 0-8 alkyl-S-C(O)R 17 , -C 0-8 alkyl-C(O)R 17 , -C 0-8 alkyl-O-C(O)R 17 , -C 0-8 alkyl-P(O)(R 17 )2, -C 0-8 alkyl-NR 18 R 19 , -C 0-8 alkyl-C(=NR 18 )R 17 , -C 0-8 alkyl-N(R 18 )-C(=NR 19 )R 17 , -C 0-8 alkyl-C(O)NR 18 R 19 and -C 0-8 alkyl-N(R 18 )-C(O)R 17 substituted by one or more substituents independently selected from the group consisting of R 2a selected from hydrogen, deuterium, C 1-10 alkyl, C 2-10 alkenyl, C 3-12 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-10 aryl and 5- to 10-membered heteroaryl, said radicals being optionally further substituted by one or more radicals selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, halogen-substituted C 1-10 alkyl, deuterium-substituted C 1-10 alkyl, C 1-10 alkylene, halogen-substituted C 1-10 alkylene, deuterium-substituted C 1-10 alkylene, C 2-10 alkenylene, C 2-10 alkynylene, C 3-12 cycloalkylene, 3- to 12-membered heterocyclylene, C 6-10 aryl, 5- to 10-membered heteroarylene, =0, =S, -C 0-8 alkyl-SF5, -C 0-8 alkyl-S(O)(=N-R 12 )R 13 , -C 0-8 alkyl-N=S(O)R 13 R 14 , -C 0-8 alkyl-N=SR 13 R 14 , -C 0-8 alkyl-O-S(O)2R 15 , -C 0-8 alkyl-S(O) r R 15 , -C 0-8 alkyl-O-R 16 , -C 0-8 alkyl-C(O)OR 16 , -C 0-8 alkyl-C(O)SR 16 , -C 0-8 alkyl-S-C(O)R 17 , -C 0-8 alkyl-C(O)R 17 , -C 0-8 alkyl-O-C(O)R 17 , -C 0-8 alkyl-P(O)(R 17 )2, -C 0-8 alkyl-NR 18 R 19 , -C 0-8 alkyl-C(=NR 18 )R 17 , -C 0-8 alkyl-N(R 18 )-C(=NR 19 )R 17 , -C 0-8 alkyl-C(O)NR 18 R 19 , and -C 0-8 alkyl-N(R 18 )-C(O)R 17 substituted; each R 2b and each R 2c is independently selected from hydrogen, deuterium, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -C 0-8 alkyl-S(O)2R 15 , -C 0-8 alkyl-C(O)OR 16 , -C 0-8 alkyl-C(O)SR 16 , -C 0-8 alkyl-C(O)R 17 , -C 0-8 alkyl-C(=NR 18 )R 17 , and -C 0-8 alkyl-C(O)NR 18 R 19 , the aforementioned groups being independently and optionally further substituted by one or more substituents selected from deuterium, halogen, hydroxyl, =O, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halosubstituted C 1-10 alkyl, deuterium- substituted C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C 6-10 aryl, C 6-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, amino, mono C 1-10 alkylamino, di C 1-10 alkylamino, and C 1-10 alkanoyl; Or, R 2b and R 2c Together with the nitrogen atom directly attached thereto, a 4-10 membered heterocyclic group or a 5-10 membered heteroaryl group is formed, wherein the 4-10 membered heterocyclic group or the 5-10 membered heteroaryl group is optionally further surrounded by one or more elements selected from deuterium, halogen, hydroxyl, =O, C. 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 1-10 Alkoxy, C 3-12 cycloalkyl, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group, C 6-10 Aryl, C 6-10 Aryloxy, 5-10 heteroaryl, 5-10 heteroaryloxy, amino, mono-C 1- 10 Alkylamino, diC 1-10 Alkylamino and C 1-10 The alkyl acyl group is replaced by a substituent; R3is selected from hydrogen, deuterium, hydroxyl, cyano, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-10 aryl, 5- to 10-membered heteroaryl, -S(O)2R 15 , -C(O)OR 16 , -C(O)SR 16 , -C(O)R 17 , -C(=NR 18 )R 17 , and -C(O)NR 18 R 19 , each of which is independently and optionally further substituted with one or more substituents independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3- 12 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-10 aryl, 5- to 10-membered heteroaryl, -C 0-8 alkyl-SF5, -C 0-8 alkyl-S(O)(=N-R 12 )R 13 , -C 0-8 alkyl-N=S(O)R 13 R 14 , -C 0-8 alkyl-N=SR 13 R 14 , -C 0-8 alkyl-O-S(O)2R 15 , -C 0-8 alkyl-S(O) r R 15 , -C 0-8 alkyl-O-R 16 , -C 0-8 alkyl-C(O)OR 16 , -C 0-8 alkyl-C(O)SR 16 , -C 0-8 alkyl-S-C(O)R 17 , -C 0-8 alkyl-C(O)R 17 , -C 0-8 alkyl-O-C(O)R 17 , -C 0-8 alkyl-P(O)(R 17 )2, -C 0-8 alkyl-NR 18 R 19 -C 0-8 Alkyl-C (=NR) 18 )R 17 -C 0-8 Alkyl-N(R) 18 )-C(=NR 19 )R 17 -C 0-8 Alkyl-C(O)NR 18 R 19 and -C 0-8 Alkyl-N(R) 18 )-C(O)R 17 The substituents are replaced by one or more substituents selected from deuterium, halogen, cyano, nitro, azido, C. 1-10 Alkyl, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, =O, =S, -C 0-8 Alkyl-SF5, -C 0- 8alkyl-S(O)(=NR) 12 )R 13 -C 0-8 Alkyl-N=S(O)R 13 R 14 -C 0-8 Alkyl-N=SR 13 R 14 -C 0-8 Alkyl-OS(O)2R 15 -C 0-8 Alkyl-S(O) r R 15 -C 0-8 Alkyl-OR 16 -C 0-8 Alkyl-C(O)OR 16 -C 0-8 Alkyl-C(O)SR 16 -C 0-8 Alkyl-SC(O)R 17 -C 0-8 Alkyl-C(O)R 17 -C 0-8 Alkyl-OC(O)R 17 -C 0- 8alkyl-P(O)(R 17 )2、-C 0-8 Alkyl-NR 18 R 19 , -C 0-8 alkyl-C(=NR 18 )R 17 , -C 0-8 alkyl-N(R 18 )-C(=NR 19 )R 17 , -C 0-8 alkyl-C(O)NR 18 R 19 , and -C 0-8 alkyl-N(R 18 )-C(O)R 17 ; R4 and R5 are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide, and C. 1-10 Alkyl, C 2- 10 Alkenyl, C 2-10 Alkyne group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR) 12 )R 13 -C 0-8 Alkyl-N=S(O)R 13 R 14 -C 0-8 Alkyl-N=SR 13 R 14 -C 0-8 Alkyl-OS(O)2R 15 -C 0-8 Alkyl-S(O) r R 15 -C 0-8 Alkyl-OR 16 -C 0-8 Alkyl-C(O)OR 16 -C 0-8 Alkyl-C(O)SR 16 -C 0-8 Alkyl-SC(O)R 17 -C 0-8 Alkyl-C(O)R 17 -C 0- 8alkyl-OC(O)R 17 -C 0-8 Alkyl-P(O)(R) 17 )2、-C 0-8 Alkyl-NR 18 R 19 -C 0-8 Alkyl-C (=NR) 18 )R 17 -C 0-8 Alkyl-N(R) 18 )-C(=NR 19 )R 17 -C 0-8 Alkyl-C(O)NR 18 R 19 and -C 0-8 Alkyl-N(R) 18 )-C(O)R 17 Alternatively, R4 and R5 together with the carbon atom directly bonded to them form a C(O), C 3-12 Cycloalkyl or 3-12 membered heterocyclic groups, wherein the above groups are independently and optionally further selected from one or more of deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, =O, =S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR) 12 )R 13 -C 0-8 Alkyl-N=S(O)R 13 R 14 -C 0-8 Alkyl-N=SR 13 R 14 -C 0-8 Alkyl-OS(O)2R 15 -C 0-8 Alkyl-S(O) r R 15 -C 0-8 Alkyl-OR 16 -C 0-8 Alkyl-C(O)OR 16 -C 0- 8alkyl-C(O)SR 16 -C 0-8 Alkyl-SC(O)R 17 -C 0-8 Alkyl-C(O)R 17 -C 0-8 Alkyl-OC(O)R 17 -C 0-8 Alkyl-P(O)(R) 17 )2、-C 0-8 Alkyl-NR 18 R 19 -C 0-8 Alkyl-C (=NR) 18 )R 17 -C 0-8 Alkyl-N(R) 18 )-C(=NR 19 )R 17 -C 0-8 Alkyl-C(O)NR 18 R 19 and -C 0-8 Alkyl-N(R) 18 )-C(O)R 17 substituted by substituents selected from the group consisting of R6 and R7 are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, and C. 1-10 Alkyl, C 2- 10 Alkenyl, C 2-10 Alkyne group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR) 12 )R 13 -C 0-8 Alkyl-N=S(O)R 13 R 14 -C 0-8 Alkyl-N=SR 13 R 14 -C 0-8 Alkyl-OS(O)2R 15 -C 0-8 Alkyl-S(O) r R 15 -C 0-8 Alkyl-OR 16 -C 0-8 Alkyl-C(O)OR 16 -C 0-8 Alkyl-C(O)SR 16 -C 0-8 Alkyl-SC(O)R 17 -C 0-8 Alkyl-C(O)R 17 -C 0- 8alkyl-OC(O)R 17 -C 0-8 Alkyl-P(O)(R) 17 )2、-C 0-8 Alkyl-NR 18 R 19 -C 0-8 Alkyl-C (=NR) 18 )R 17 -C 0-8 Alkyl-N(R) 18 )-C(=NR 19 )R 17 -C 0-8 Alkyl-C(O)NR 18 R 19 and -C 0-8 Alkyl-N(R) 18 )-C(O)R 17 Alternatively, R6 and R7 together with the carbon atom directly bonded to them form a C(O), C 3-12 Cycloalkyl or 3-12 membered heterocyclic groups, wherein the above groups are independently and optionally further selected from one or more of deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, =O, =S, -C 0-8 Alkyl-SF5, -C 0-8 Alkyl-S(O)(=NR) 12 )R 13 -C 0-8 Alkyl-N=S(O)R 13 R 14 -C 0-8 Alkyl-N=SR 13 R 14 -C 0-8 Alkyl-OS(O)2R 15 -C 0-8 Alkyl-S(O) r R 15 -C 0-8 Alkyl-OR 16 -C 0-8 Alkyl-C(O)OR 16 -C 0- 8alkyl-C(O)SR 16 -C 0-8 Alkyl-SC(O)R 17 -C 0-8 Alkyl-C(O)R 17 -C 0-8 Alkyl-OC(O)R 17 -C 0-8 Alkyl-P(O)(R) 17 )2、-C 0-8 Alkyl-NR 18 R 19 -C 0-8 Alkyl-C (=NR) 18 )R 17 -C 0-8 Alkyl-N(R) 18 )-C(=NR 19 )R 17 -C 0-8 Alkyl-C(O)NR 18 R 19 and -C 0-8 Alkyl-N(R) 18 ) -C(O)R 17 substituted by substituents selected from the group consisting of or R5and R6together with the moiety they are directly attached to form a C 3-12 Cycloalkyl or 3-12 membered heterocyclyl, each of the above groups being independently and optionally further substituted by one or more, preferably 1, 2 or 3, more preferably 0, 1 or 2, even more preferably 0 or 1, R substituents, which are the same as or different from one another and are selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halogen-substituted C 1-10 Alkyl, deuterium-substituted C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, =0, =S, -C 0-8 Alkyl-SF5, -C 0- 8Alkyl-S(O)(=N-R 12 )R 13 , -C 0-8 Alkyl-N=S(O)R 13 R 14 , -C 0-8 Alkyl-N=SR 13 R 14 , -C 0-8 Alkyl-O-S(O)2R 15 , -C 0-8 Alkyl-S(O) r R 15 , -C 0-8 Alkyl-O-R 16 , -C 0-8 Alkyl-C(O)OR 16 , -C 0-8 Alkyl-C(O)SR 16 , -C 0-8 Alkyl-S-C(O)R 17 , -C 0-8 Alkyl-C(O)R 17 , -C 0-8 Alkyl-O-C(O)R 17 , -C 0- 8Alkyl-P(O)(R 17 )2, -C 0-8 Alkyl-NR 18 R 19 , -C 0-8 Alkyl-C(=NR 18 )R 17 , -C 0-8 Alkyl-N(R 18 )-C(=NR 19 )R 17 , -C 0-8 Alkyl-C(O)NR 18 R 19 and -C 0-8 alkyl-N(R 18 )-C(O)R 17 substituted by R4and R7as defined previously; R8, R9, R 10 and R 11 are each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azido, C 1- 10 alkyl, halogen-substituted C 1-10 alkyl, deuterium-substituted C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -C 0-8 alkyl-SF5, -C 0-8 alkyl-S(O)(=N-R 12 )R 13 , -C 0-8 alkyl-N=S(O)R 13 R 14 , -C 0-8 alkyl-N=SR 13 R 14 , -C 0-8 alkyl-O-S(O)2R 15 , -C 0-8 alkyl-S(O) r R 15 , -C 0-8 alkyl-O-R 16 , -C 0-8 alkyl-C(O)OR 16 , -C 0-8 alkyl-C(O)SR 16 , -C 0-8 alkyl-S-C(O)R 17 , -C 0-8 alkyl-C(O)R 17 , -C 0-8 alkyl-O-C(O)R 17 , -C 0-8 alkyl-P(O)(R 17 )2, -C 0-8 alkyl-NR 18 R 19 , -C 0-8 alkyl-C(=NR 18 )R 17 , -C 0-8 alkyl-N(R 18 )-C(=NR 19 )R 17 , -C 0-8 alkyl-C(O)NR 18 R 19 , and -C 0-8 alkyl-N(R 18 )-C(O)R 17 ; Each R 12 Each is independently selected from hydrogen, deuterium, and C. 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkyne group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -C 0-8 Alkyl-S(O) r R 15 -C 0-8 Alkyl-C(O)OR 16 -C 0-8 Alkyl-C(O)R 17 and -C 0-8 Alkyl-C(O)NR 18 R 19 The above-mentioned groups may optionally be further divided by one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2- 10 Alkyne group, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6- 10 Aryl, 5-10 heteroaryl, -C 0-8 Alkyl-S(O) r R 15 -C 0-8 Alkyl-OR 16 -C 0-8 Alkyl-C(O)OR 16 -C 0-8 Alkyl-C(O)R 17 -C 0-8 Alkyl-OC(O)R 17 -C 0-8 Alkyl-NR 18 R 19 -C 0-8 Alkyl-C (=NR) 18 )R 17 -C 0-8 Alkyl-N(R) 18 )-C(=NR 19 )R 17 -C 0-8 Alkyl-C(O)NR 18 R 19 and -C 0-8 Alkyl-N(R) 18 )-C(O)R 17 The substituents are replaced; each R 13 and each R 14 is independently selected from the group consisting of hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl, or, R 13 and R 14 together with the sulfur atom to which they are directly attached form a 3-10 membered heterocyclyl, optionally further substituted by one or more substituents independently selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halosubstituted C 1-10 alkyl, deuterium- substituted C 1-10 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -C 0-8 alkyl-S(O) r R 15 , -C 0-8 alkyl-O-R 16 , -C 0-8 alkyl-C(O)OR 16 , -C 0-8 alkyl-C(O)R 17 , -C 0-8 alkyl-O-C(O)R 17 , -C 0-8 alkyl-NR 18 R 19 , -C 0-8 alkyl-C(=NR 18 )R 17 , -C 0-8 alkyl-N(R 18 )-C(=NR 19 )R 17 , -C 0-8 alkyl-C(O)NR 18 R 19 , and -C 0-8 alkyl-N(R 18 )-C(O)R 17 ; Each R 15 Independently selected from hydrogen, deuterium, hydroxyl, C 1-10 Alkyl, C 2-10 Alkenyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 quinone heteroaryl and -NR 18 R 19 The aforementioned groups are independently and optionally further selected by one or more radicals chosen from deuterium, halogen, hydroxyl, nitro, cyano, =O, C 1-10 Alkyl, C 1-10 Alkoxy, C 3-12 cycloalkyl, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group, C 6-10 Aryl, C 6-10 aryloxy groups, 5-10 heteroaryl groups, 5-10 heteroaryloxy groups and -NR 18 R 19 The substituents are replaced; Each R 16 Independently selected from hydrogen, deuterium, and C 1-10 Alkyl, C 2-10 Alkenyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, wherein the above groups are independently and optionally further selected by one or more radicals selected from deuterium, halogen, hydroxyl, =O, cyano, C 1-10 Alkyl, C 1-10 Alkoxy, C 3-12 cycloalkyl, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group, C 6-10 Aryl, C 6-10 aryloxy groups, 5-10 heteroaryl groups, 5-10 heteroaryloxy groups and -NR 18 R 19 The substituents are replaced; Each R 17 Independently selected from hydrogen, deuterium, hydroxyl, C 1-10 Alkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkyne group, C 3-12 cycloalkyl, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group, C 6-10 Aryl, C 6-10 aryloxy groups, 5-10 heteroaryl groups, 5-10 heteroaryloxy groups and -NR 18 R 19 The above-mentioned groups may independently and optionally be further selected by one or more groups selected from deuterium, halogen, hydroxyl, =O, cyano, C 1-10 Alkyl, C 1-10 Alkoxy, C 3-12 cycloalkyl, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group, C 6-10 Aryl, C 6-10 aryloxy groups, 5-10 heteroaryl groups, 5-10 heteroaryloxy groups and -NR 18 R 19 The substituents are replaced; each R 18 and each R 19 is each independently selected from hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, sulfinyl, sulfonyl, methylsulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, and C 1-10 alkanoyl, the aforementioned groups being independently optionally further substituted by one or more substituents selected from deuterium, halogen, hydroxyl, =0, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen-substituted C 1-10 alkyl, deuterium-substituted C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C 6-10 aryl, C 6-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, amino, mono-C 1-10 alkylamino, di-C 1-10 alkylamino, and C 1-10 alkanoyl; or R 18 and R 19 together with the nitrogen atom to which they are directly attached form a 4-10 membered heterocyclyl or 5-10 membered heteroaryl, which is optionally further substituted by one or more substituents selected from deuterium, halogen, hydroxyl, =0, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen-substituted C 1-10 alkyl, deuterium-substituted C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C 6-10 aryl, C 6-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, amino, mono-C 1- 10 dialkylamino, di-C 1-10 alkylamino and C 1-10 alkanoyl; and each r is independently 0, 1, or 2.

2. The compound of formula (I) according to claim 1, its stereoisomers or its pharmaceutically acceptable salts, characterized in that, X4is N or CR 11 ; Ring A is C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl; m is 0, 1, 2, 3, 4, or 5; each R1is independently selected from hydrogen, deuterium, halogen, cyano, C 1- 4alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -C 0-4 alkyl-SF5, -C 0-4 alkyl-S(O)(=N-R 12 )R 13 , -C 0-4 alkyl-N=S(O)R 13 R 14 , -C 0-4 alkyl-N=SR 13 R 14 , -C 0-4 alkyl-O-S(O)2R 15 , -C 0-4 alkyl-S(O) r R 15 , -C 0-4 alkyl-O-R 16 , -C 0- 4alkyl-C(O)OR 16 , -C 0-4 alkyl-C(O)SR 16 , -C 0-4 alkyl-S-C(O)R 17 , -C 0-4 alkyl-C(O)R 17 , -C 0-4 alkyl-O-C(O)R 17 , -C 0-4 alkyl-P(O)(R 17 )2, -C 0-4 alkyl-NR 18 R 19 , -C 0-4 alkyl-C(=NR 18 )R 17 , -C 0-4 alkyl-N(R 18 )-C(=NR 19 )R 17 , -C 0-4 alkyl-C(O)NR 18 R 19 , and -C 0-4 alkyl-N(R 18 )-C(O)R 17 , or, when m > 2, wherein two adjacent R1together with the moiety to which they are directly attached form a C 3-8 Cycloalkyl or 3-8 membered heterocyclic groups, wherein the above groups are independently and optionally further selected by one or more radicals selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-8 Aryl, 5-8 heteroaryl, =O, =S, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O)(=NR) 12 )R 13 -C 0-4 Alkyl-N=S(O)R 13 R 14 -C 0-4 Alkyl-N=SR 13 R 14 -C 0-4 Alkyl-OS(O)2R 15 -C 0-4 Alkyl-S(O) r R 15 -C 0-4 Alkyl-OR 16 -C 0-4 Alkyl-C(O)OR 16 -C 0-4 Alkyl-C(O)SR 16 -C 0-4 Alkyl-SC(O)R 17 -C 0-4 Alkyl-C(O)R 17 -C 0- 4alkyl-OC(O)R 17 -C 0-4 Alkyl-P(O)(R) 17 )2、-C 0-4 Alkyl-NR 18 R 19 -C 0-4 Alkyl-C (=NR) 18 )R 17 -C 0-4 Alkyl-N(R) 18 )-C(=NR 19 )R 17 -C 0-4 Alkyl-C(O)NR 18 R 19 and -C 0-4 Alkyl-N(R) 18 )-C(O)R 17 substituted by one or more substituents selected from the group consisting of R2is selected from hydrogen, halogen, -(L) s -O-(L) s -R 2a , -(L) s -NR 2b R 2c , -(L) s -O-(L) s -NR 2b R 2c , C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, and 5-8 membered heteroaryl, each of which is independently and optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, C s alkyl, -O-(L) s -R 2a , -(L) s -NR 2b R 2c , -(L) s -O-(L) s -NR 2b R 2c , C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, or 5-8 membered heteroaryl, each of which is independently and optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, C 1-4 alkyl, halosubstituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 1-4 alkylene, halosubstituted C 1-4 alkylene, deuterium-substituted C 1-4 alkylene, C 2-4 alkenylene, C 2-4 alkynylene, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, =O, =S, -C 0-4 alkyl-SF5, -C 0-4 alkyl-S(O)(=N-R 12 )R 13 , -C 0-4 alkyl-N=S(O)R 13 R 14 , -C 0-4 alkyl-N=SR 13 R 14 , -C 0-4 alkyl-O-S(O)2R 15 , -C 0-4 alkyl-S(O) r R 15 , -C 0-4 alkyl-O-R 16 , -C 0-4 alkyl-C(O)OR 16 , -C 0-4 alkyl-C(O)SR 16 , -C 0-4 alkyl-S-C(O)R 17 , -C 0-4 alkyl-C(O)R 17 , -C 0- 4alkyl-O-C(O)R 17 , -C 0-4 alkyl-P(O)(R 17 )2, -C 0-4 alkyl-NR 18 R 19 , -C 0-4 alkyl-C(=NR 18 )R 17 , -C 0-4 alkyl-N(R 18 )-C(=NR 19 )R 17 , -C 0-4 alkyl-C(O)NR 18 R 19 and -C 0-4 alkyl-N(R 18 )-C(O)R 17 ; each s is independently 0, 1, 2, or 3; each L is independently selected from C 1-4 alkylene, C 3-6 cycloalkylene, or 3-6 membered heterocycloalkylene, each of which is independently optionally further substituted by one or more substituents independently selected from deuterium, halogen, cyano, C 1-4 alkylene, C 3-6 cycloalkylene, or 3-6 membered heterocycloalkylene, each of which is independently optionally further substituted by one or more substituents independently selected from deuterium, halogen, cyano, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 aryl, 5-8 membered heteroaryl, =O, =S, -C 0-4 alkyl-SF5, -C 0-4 alkyl-S(O)(=N-R 12 )R 13 , -C 0-4 alkyl-N=S(O)R 13 R 14 , -C 0-4 alkyl-N=SR 13 R 14 , -C 0-4 alkyl-O-S(O)2R 15 , -C 0-4 alkyl-S(O) r R 15 , -C 0-4 alkyl-O-R 16 , -C 0-4 alkyl-C(O)OR 16 , -C 0-4 alkyl-C(O)SR 16 , -C 0-4 alkyl-S-C(O)R 17 , -C 0-4 alkyl-C(O)R 17 , -C 0-4 alkyl-O-C(O)R 17 , -C 0-4 alkyl-P(O)(R 17 )2, -C 0-4 alkyl-NR 18 R 19 , -C 0-4 alkyl-C(=NR 18 )R 17 , -C 0-4 alkyl-N(R 18 )-C(=NR 19 )R 17 , -C, -C 0-4 alkyl-C(O)NR 18 R 19 and -C 0-4 alkyl-N(R 18 )-C(O)R 17 substituted by one or more substituents independently selected from the group consisting of R 2a selected from hydrogen, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl, 3-10 membered heterocyclyl, C 6-8 aryl and 5-8 membered heteroaryl, said groups being optionally further substituted by one or more, preferably 1, 2 or 3, more preferably 1 or 2, even more preferably 1, substituents, each independently selected from deuterium, halogen, cyano, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 1-4 alkylene, halogen-substituted C 1-4 alkylene, deuterium-substituted C 1-4 alkylene, C 2-4 alkenylene, C 2-4 alkynylene, C 3-6 cycloalkylene, 3-6 membered heterocyclylene, C 6-8 arylene, 5-8 membered heteroarylene, =0, =S, -C 0-4 alkyl-SF5, -C 0-4 alkyl-S(O)(=N-R 12 )R 13 , -C 0-4 alkyl-N=S(O)R 13 R 14 , -C 0-4 alkyl-N=SR 13 R 14 , -C 0-4 alkyl-O-S(O)2R 15 , -C 0-4 alkyl-S(O) r R 15 , -C 0-4 alkyl-O-R 16 , -C 0-4 alkyl-C(O)OR 16 , -C 0-4 alkyl-C(O)SR 16 , -C 0-4 alkyl-S-C(O)R 17 , -C 0-4 alkyl-C(O)R 17 , -C 0-4 alkyl-O-C(O)R 17 , -C 0-4 alkyl-P(O)(R 17 )2, -C 0-4 alkyl-NR 18 R 19 , -C 0-4 alkyl-C(=NR 18 )R 17 , -C 0-4 alkyl-C(O)N(R 18 )-C(=NR 19 )R 17 , -C 0-4 alkyl-C(O)N(R 18 )R 19 , and -C 0-4 alkyl-N(R 18 )-C(O)R 17 ; each R 2b and each R 2c is independently selected from hydrogen, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -C 0-4 alkyl-S(O)2R 15 , -C 0- 4alkyl-C(O)OR 16 , -C 0-4 alkyl-C(O)SR 16 , -C 0-4 alkyl-C(O)R 17 , -C 0-4 alkyl-C(=NR 18 )R 17 , and -C 0-4 alkyl-C(O)NR 18 R 19 , the aforementioned groups being independently and optionally further substituted by one or more substituents selected from deuterium, halogen, hydroxyl, =O, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halosubstituted C 1-4 alkyl, deuterium- substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C 6- 8aryl, C 6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, amino, mono C 1-4 alkylamino, di C 1-4 alkylamino, and C 1-4 alkanoyl; or R 2b and R 2c together with the nitrogen atom to which they are directly attached form a 4-6 membered heterocyclyl or 5-8 membered heteroaryl, which is optionally further substituted by one or more substituents selected from the group consisting of deuterium, halogen, hydroxyl, =0, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C 6- aryl, C 6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, amino, mono-C 1-4 alkylamino, di-C 1-4 alkylamino and C 1-4 alkanoyl; R3is selected from hydrogen, deuterium, hydroxyl, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -S(O)2R 15 , -C(O)OR 16 , -C(O)SR 16 , -C(O)R 17 , -C(=NR 18 )R 17 , and -C(O)NR 18 R 19 , each of the above groups being independently and optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -C 0-4 alkyl-SF5, -C 0-4 alkyl-S(O)(=N-R 12 )R 13 , -C 0- 4alkyl-N=S(O)R 13 R 14 , -C 0-4 alkyl-N=SR 13 R 14 , -C 0-4 alkyl-O-S(O)2R 15 , -C 0-4 alkyl-S(O) r R 15 , -C 0-4 alkyl-O-R 16 , -C 0-4 alkyl-C(O)OR 16 , -C 0-4 alkyl-C(O)SR 16 , -C 0-4 alkyl-S-C(O)R 17 , -C 0-4 alkyl-C(O)R 17 , -C 0-4 alkyl-O-C(O)R 17 , -C 0-4 alkyl-P(O)(R 17 )2, -C 0-4 alkyl-NR 18 R 19 , -C 0-4 alkyl-C(=NR 18 )R 17 , -C 0-4 alkyl-N(R 18 )-C(=NR 19 )R 17 , -C 0-4 alkyl-C(O)NR 18 R 19 , and -C 0-4 alkyl-N(R 18 )-C(O)R 17 , the aforementioned groups are independently optionally further substituted by one or more substituents selected from the group consisting of deuterium, halogen, cyano, C 1-4 alkyl, halosubstituted C 1-4 alkyl, C 1- 4alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, C 6-8 aryl, 5- to 8-membered heteroaryl, =0, =S, -C 0-4 alkyl-SF5, -C 0-4 alkyl-S(O)(=N-R 12 )R 13 , -C 0-4 alkyl-N=S(O)R 13 R 14 , -C 0-4 alkyl-N=SR 13 R 14 , -C 0-4 alkyl-O-S(O)2R 15 , -C 0-4 alkyl-S(O) r R 15 , -C 0-4 alkyl-O-R 16 , -C 0-4 alkyl-C(O)OR 16 , -C 0-4 alkyl-C(O)SR 16 , -C 0-4 alkyl-S-C(O)R 17 , -C 0-4 alkyl-C(O)R 17 , -C 0-4 alkyl-O-C(O)R 17 , -C 0-4 alkyl-P(O)(R 17 )2, -C 0-4 alkyl-NR 18 R 19 , -C 0-4 alkyl-C(=NR 18 )R 17 , -C 0-4 alkyl-N(R 18 )-C(=NR 19 )R 17 , -C 0-4 alkyl-C(O)NR 18 R 19 , and -C 0-4 alkyl-N(R 18 )-C(O)R 17 ; R4 and R5 are each independently selected from hydrogen, deuterium, halogen, cyano, and C. 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-8 Aryl, 5-8 quinone heteroaryl, -C 0-4 Alkyl-SF5, -C 0- 4-alkyl-S(O)(=NR) 12 )R 13 -C 0-4 Alkyl-N=S(O)R 13 R 14 -C 0-4 Alkyl-N=SR 13 R 14 -C 0-4 Alkyl-OS(O)2R 15 -C 0-4 Alkyl-S(O) r R 15 -C 0-4 Alkyl-OR 16 -C 0-4 Alkyl-C(O)OR 16 -C 0-4 Alkyl-C(O)SR 16 -C 0-4 Alkyl-SC(O)R 17 -C 0-4 Alkyl-C(O)R 17 -C 0-4 Alkyl-OC(O)R 17 -C 0- 4-alkyl-P(O)(R 17 )2、-C 0-4 Alkyl-NR 18 R 19 -C 0-4 Alkyl-C (=NR) 18 )R 17 -C 0-4 Alkyl-N(R) 18 )-C(=NR 19 )R 17 -C 0-4 Alkyl-C(O)NR 18 R 19 and -C 0-4 Alkyl-N(R) 18 )-C(O)R 17 Alternatively, R4 and R5 together with the carbon atom directly bonded to them form a C(O), C 3-6 cycloalkyl or 3-6 membered heterocyclyl, each of the above groups being independently and optionally further substituted by one or more, identical or different, substituents from the group consisting of deuterium, halogen, cyano, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, =0, =S, -C 0-4 alkyl-SF5, -C 0-4 alkyl-S(O)(=N-R 12 )R 13 , -C 0-4 alkyl-N=S(O)R 13 R 14 , -C 0-4 alkyl-N=SR 13 R 14 , -C 0-4 alkyl-O-S(O)2R 15 , -C 0-4 alkyl-S(O) r R 15 , -C 0-4 alkyl-O-R 16 , -C 0-4 alkyl-C(O)OR 16 , -C 0-4 alkyl-C(O)SR 16 , -C 0-4 alkyl-S-C(O)R 17 , -C 0-4 alkyl-C(O)R 17 , -C 0-4 alkyl-O-C(O)R 17 , -C 0-4 alkyl-P(O)(R 17 )2, -C 0-4 alkyl-NR 18 R 19 , -C 0-4 alkyl-C(=NR 18 )R 17 , -C 0-4 alkyl-N(R 18 )-C(=NR 19 )R 17 , -C 0-4 alkyl-C(O)NR 18 R 19 and -C 0-4 alkyl-N(R 18 )-C(O)R 17 substituted by one or more substituents selected from the group consisting of halo, R6 and R7 are each independently selected from hydrogen, deuterium, halogen, cyano, and C. 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-8 Aryl, 5-8 quinone heteroaryl, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O)(=NR) 12 )R 13 -C 0-4 Alkyl-N=S(O)R 13 R 14 -C 0-4 Alkyl-N=SR 13 R 14 -C 0-4 Alkyl-OS(O)2R 15 -C 0-4 Alkyl-S(O) r R 15 -C 0-4 Alkyl-OR 16 -C 0-4 Alkyl-C(O)OR 16 -C 0-4 Alkyl-C(O)SR 16 -C 0-4 Alkyl-SC(O)R 17 -C 0-4 Alkyl-C(O)R 17 -C 0-4 Alkyl-OC(O)R 17 -C 0- 4-alkyl-P(O)(R 17 )2、-C 0-4 Alkyl-NR 18 R 19 -C 0-4 Alkyl-C (=NR) 18 )R 17 -C 0-4 Alkyl-N(R) 18 )-C(=NR 19 )R 17 -C 0-4 Alkyl-C(O)NR 18 R 19 and -C 0-4 Alkyl-N(R) 18 )-C(O)R 17 Alternatively, R6 and R7 together with the carbon atom directly bonded to them form a C(O), C 3-6 cycloalkyl or 3-6 membered heterocyclyl, each of the above groups being independently and optionally further substituted with one or more, preferably 1, 2 or 3, more preferably 1 or 2, even more preferably 1, selected from the group consisting of deuterium, halogen, cyano, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, =0, =S, -C 0-4 alkyl-SF5, -C 0-4 alkyl-S(O)(=N-R 12 )R 13 , -C 0-4 alkyl-N=S(O)R 13 R 14 , -C 0-4 alkyl-N=SR 13 R 14 , -C 0-4 alkyl-O-S(O)2R 15 , -C 0-4 alkyl-S(O) r R 15 , -C 0-4 alkyl-O-R 16 , -C 0-4 alkyl-C(O)OR 16 , -C 0-4 alkyl-C(O)SR 16 , -C 0-4 alkyl-S-C(O)R 17 , -C 0-4 alkyl-C(O)R 17 , -C 0-4 alkyl-O-C(O)R 17 , -C 0-4 alkyl-P(O)(R 17 )2, -C 0-4 alkyl-NR 18 R 19 , -C 0-4 alkyl-C(=NR 18 )R 17 , -C 0-4 alkyl-N(R 18 )-C(=NR 19 )R 17 , -C 0-4 alkyl-C(O)NR 18 R 19 and -C 0-4 alkyl-N(R 18 )-C(O)R 17 substituted by one or more substituents selected from the group consisting of halo, or R5and R6together with the moiety to which they are directly attached form a C 3-6 Cycloalkyl or 3-6 membered heterocyclyl, each of the above groups being independently and optionally further substituted by one or more substituents independently selected from the group consisting of deuterium, halogen, cyano, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, deuterium-substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 6-8 Aryl, 5-8 membered heteroaryl, =0, =S, -C 0-4 Alkyl-SF5, -C 0-4 Alkyl-S(O)(=N-R 12 )R 13 , -C 0-4 Alkyl-N=S(O)R 13 R 14 , -C 0-4 Alkyl-N=SR 13 R 14 , -C 0-4 Alkyl-O-S(O)2R 15 , -C 0-4 Alkyl-S(O) r R 15 , -C 0-4 Alkyl-O-R 16 , -C 0-4 Alkyl-C(O)OR 16 , -C 0-4 Alkyl-C(O)SR 16 , -C 0-4 Alkyl-S-C(O)R 17 , -C 0-4 Alkyl-C(O)R 17 , -C 0-4 Alkyl-O-C(O)R 17 , -C 0-4 Alkyl-P(O)(R 17 )2, -C 0-4 Alkyl-NR 18 R 19 , -C 0-4 Alkyl-C(=NR 18 )R 17 , -C 0-4 Alkyl-N(R 18 )-C(=NR 19 )R 17 , -C 0-4 Alkyl-C(O)NR 18 R 19 and -C 0-4 alkyl-N(R 18 )-C(O)R 17 substituted by R4and R7as previously defined; R8, R9, R 10 and R 11 are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halosubstituted C 1-4 alkyl, deuterium- substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -C 0-4 alkyl-SF5, -C 0-4 alkyl-S(O)(=N-R 12 )R 13 , -C 0-4 alkyl-N=S(O)R 13 R 14 , -C 0-4 alkyl-N=SR 13 R 14 , -C 0-4 alkyl-O-S(O)2R 15 , -C 0-4 alkyl-S(O) r R 15 , -C 0-4 alkyl-O-R 16 , -C 0-4 alkyl-C(O)OR 16 , -C 0-4 alkyl-C(O)SR 16 , -C 0-4 alkyl-S-C(O)R 17 , -C 0-4 alkyl-C(O)R 17 , -C 0-4 alkyl-O-C(O)R 17 , -C 0-4 alkyl-P(O)(R 17 )2, -C 0-4 alkyl-NR 18 R 19 , -C 0-4 alkyl-C(=NR 18 )R 17 , -C 0-4 alkyl-N(R 18 )-C(=NR 19 )R 17 , -C 0-4 alkyl-C(O)NR 18 R 19 and -C 0-4 alkyl-N(R 18 )-C(O)R 17 ； wherein R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 and r are as described in claim 1.

3. The compound of formula (I) according to claim 1, its stereoisomers or its pharmaceutically acceptable salts, characterized in that, each R 12 is independently selected from hydrogen, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -C 0-4 alkyl-S(O) r R 15 , -C 0-4 alkyl-C(O)OR 16 , -C 0-4 alkyl-C(O)R 17 , and -C 0-4 alkyl-C(O)NR 18 R 19 , the aforementioned groups being optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halosubstituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -C 0-4 alkyl-S(O) r R 15 , -C 0-4 alkyl-O-R 16 , -C 0-4 alkyl-C(O)OR 16 , -C 0-4 alkyl-C(O)R 17 , -C 0-4 alkyl-O-C(O)R 17 , -C 0-4 alkyl-NR 18 R 19 , -C 0-4 alkyl-C(=NR 18 )R 17 , -C 0-4 alkyl-N(R 18 )-C(=NR 19 )R 17 , -C 0-4 alkyl-C(O)NR 18 R 19 , and -C 0-4 alkyl-N(R 18 )-C(O)R 17 ; each R 13 and each R 14 is independently selected from the group consisting of hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 2-4 alkenyl, C 2- 4alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, and 5-8 membered heteroaryl, or, R 13 and R 14 together with the sulfur atom to which they are directly attached form a 3-6 membered heterocyclyl, which is optionally further substituted with one or more substituents selected from the group consisting of deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halosubstituted C 1-4 alkyl, deuterium- substituted C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -C 0-4 alkyl-S(O) r R 15 , -C 0-4 alkyl-O-R 16 , -C 0-4 alkyl-C(O)OR 16 , -C 0-4 alkyl-C(O)R 17 , -C 0-4 alkyl-O-C(O)R 17 , -C 0-4 alkyl-NR 18 R 19 , -C 0-4 alkyl-C(=NR 18 )R 17 , -C 0-4 alkyl-N(R 18 )-C(=NR 19 )R 17 , -C 0-4 alkyl-C(O)NR 18 R 19 , and -C 0-4 alkyl-N(R 18 )-C(O)R 17 ; Each R 15 is independently selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic group, C 6-8 aryl, 5- to 8-membered heteroaryl, and -NR 18 R 19 , and the above groups are independently optionally further substituted by one or more substituents selected from deuterium, halogen, hydroxyl, nitro, cyano, =O, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3- to 6-membered heterocyclic group, 3- to 6-membered heterocyclic oxy group, C 6-8 aryl, C 6-8 aryloxy, 5- to 8-membered heteroaryl, 5- to 8-membered heteroaryloxy, and -NR 18 R 19 ; Each R 16 is independently selected from hydrogen, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic group, C 6-8 aryl, and 5- to 8-membered heteroaryl, and the above groups are independently optionally further substituted by one or more substituents selected from deuterium, halogen, hydroxy, =O, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3- to 6-membered heterocyclic group, 3- to 6-membered heterocyclic oxy group, C 6-8 aryl, C 6-8 aryloxy, 5- to 8-membered heteroaryl, 5- to 8-membered heteroaryloxy, and -NR 18 R 19 ; Each R 17 is independently selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3- to 6-membered heterocyclic group, 3- to 6-membered heteroepoxy group, C 6-8 aryl, C 6-8 aryloxy, 5- to 8-membered heteroaryl, 5- to 8-membered heteroaryloxy and -NR 18 R 19 , and the above groups are independently optionally further substituted by one or more substituents selected from deuterium, halogen, hydroxyl, =O, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3- 6 cycloalkoxy, 3- to 6-membered heterocyclic group, 3- to 6-membered heteroepoxy group, C 6-8 aryl, C 6-8 aryloxy, 5- to 8-membered heteroaryl, 5- to 8-membered heteroaryloxy and -NR 18 R 19 ; each R 18 and each R 19 is each independently selected from the group consisting of hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 2-4 alkenyl, C 2- 4alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, sulfinyl, sulfonyl, methylsulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, and C 1-4 alkanoyl, the aforementioned groups being independently optionally further substituted by one or more substituents selected from the group consisting of deuterium, halogen, hydroxyl, =0, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halosubstituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C 6- aryl, C 6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, amino, mono C 1-4 alkylamino, di C 1-4 alkylamino, and C 1-4 alkanoyl; or R 18 and R 19 together with the nitrogen atom to which they are directly attached form a 4-6 membered heterocyclyl or 5-8 membered heteroaryl, which is optionally further substituted by one or more substituents selected from deuterium, halogen, hydroxyl, =0, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C 6- aryl, C 6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, amino, mono-C 1-4 alkylamino, di-C 1-4 alkylamino and C 1-4 alkanoyl; and each r is independently 0, 1, or 2.

4. The compound of formula (I) according to claim 1, its stereoisomers or its pharmaceutically acceptable salts, characterized in that, X1is N, X2is N, X3is CR 10 or N; or, X1is N, X2is CR9, X3is CR 10 or N; or, X1is CR8, X2is N, and X3is CR 10 or N; or, X1is CR8, X2is CR9, X3is CR 10 or N; wherein R8, R9and R 10 As in claim 1.

5. The compound of formula (I) according to claim 1, its stereoisomers or its pharmaceutically acceptable salts, characterized in that, The compound of formula (I) is a compound of formula (II) wherein, is a single or double bond, when R4and R7are absent when the bond is a double bond; X3is CR 10 or N; Ring A is C 6-10 aryl or 5-10 membered heteroaryl; m is 0, 1, 2, 3, 4 or 5; each R1 is independently selected from hydrogen, deuterium, halogen, cyano, C 1- 4-alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl, C 3-6 -cycloalkyl, 3- to 6-membered heterocyclic group, C 6-8 -aryl, 5- to 8-membered heteroaryl, -SF5, -S(O)(=N-R 12 )R 13 , -N=S(O)R 13 R 14 , -N=SR 13 R 14 , -O-S(O)2R 15 , -S(O) r R<00,01950>, -O-R 16 , -C(O)OR 16 , -C(O)SR 16 , -S-C(O)R 17 , -C(O)R 17 , -O-C(O)R 17 , -P(O)(R 17 )2, -NR 18 R 19 , -C(=NR 18 )R 17 , -N(R 18 )-C(=NR 19 )R 17 , -C(O)NR 18 R 19 and -N(R 18 )-C(O)R 17 , or, when m ≥ 2, two adjacent R1s together with the part to which they are directly attached form a C 3-8 -cycloalkyl or 3- to 8-membered heterocyclic group, and the above groups are independently optionally further substituted by one or more selected from deuterium, halogen, cyano, C 1-4 -alkyl, halogen-substituted C 1-4 -alkyl, deuterium-substituted C 1-4 -alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl, C 3- -cycloalkyl, 3- to 6-membered heterocyclic group, C 6-8 -aryl, 5- to 8-membered heteroaryl, =O, =S, -SF5, -S(O)(=N-R 12 )R 13 , -N=S(O)R 13 R<, 14 , -N=SR 13 R 14 , -O-S(O)2R 15 , -S(O) r R 15 , -O-R 16 , -C(O)OR 16 , -C(O)SR 16 , -S-C(O)R 17 , -C(O)R 17 , -O-C(O)R 17 , -P(O)(R 17 )2, -NR 18 R 19 , -C(=NR 18 )R 17 , -N(R 18 )-C(=NR 19 )R 17 , -C(O)NR 18 R 19 and -N(R 18 )-C(O)R 17 ; R2are each independently selected from the group consisting of hydrogen, halogen, -(L) s -O-(L) s -R 2a , -(L) s -NR 2b R 2c , -(L) s -O-(L) s -NR 2b R 2c , C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl and 5-8 membered heteroaryl, -(L) s -O-(L) s -R 2a , -(L) s -NR 2b R 2c , -(L) s -O-(L) s -NR 2b R 2c , C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl or 5-8 membered heteroaryl are each independently optionally further substituted by one or more substituents selected from the group consisting of deuterium, halogen, cyano, C 1-4 alkyl, halosubstituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 1-4 alkylene, halosubstituted C 1-4 alkylene, deuterium-substituted C 1-4 alkylene, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, =0, =S, -SF5, -S(O)(=N-R 12 )R 13 , -N=S(O)R 13 R 14 , -N=SR 13 R 14 , -O-S(O)2R 15 , -S(O) r R 15 , -O-R 16 , -C(O)OR 16 , -C(O)SR 16 , -S-C(O)R 17 , -C(O)R 17 , -O-C(O)R 17 , -P(O)(R 17 )2, -NR 18 R 19 , -C(=NR 18 )R 17 , -N(R 18 )-C(=NR 19 )R 17 , -C(O)NR 18 R 19 , and -N(R 18 )-C(O)R 17 substituted; each s is independently 0, 1, 2, or 3; each L is each independently selected from C 1-4 alkylene, C 3-6 cycloalkylene, or 3-6 membered heterocycloalkylene, each of which is independently optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, C 1-4 alkylene, C 3-6 cycloalkylene, or 3-6 membered heterocycloalkylene, each of which is independently optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 aryl, 5-8 membered heteroaryl, =0, =S, -SF5, -S(O)(=N-R 12 )R 13 , -N=S(O)R 13 R 14 , -N=SR 13 R 14 , -O-S(O)2R 15 , -S(O) r R 15 , -O-R 16 , -C(O)OR 16 , -C(O)SR 16 , -S-C(O)R 17 , -C(O)R 17 , -O-C(O)R 17 , -P(O)(R 17 )2, -NR 18 R 19 , -C(=NR 18 )R 17 , -N(R 18 )-C(=NR 19 )R 17 , -C(O)NR 18 R 19 , and -N(R 18 )-C(O)R 17 ; R 2a selected from hydrogen, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl, 3-10 membered heterocyclyl, C 6-8 aryl and 5-8 membered heteroaryl, which are optionally further substituted by one or more substituents selected from the group consisting of deuterium, halogen, cyano, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 1-4 alkylene, halogen-substituted C 1-4 alkylene, deuterium-substituted C 1-4 alkylene, C 2-4 alkenylene, C 2-4 alkynylene, C 3-6 cycloalkylene, 3-6 membered heterocyclylene, C 6-8 aryl, 5-8 membered heteroarylene, =0, =S, -SF5, -S(O)(=N-R 12 )R 13 , -N=S(O)R 13 R 14 , -N=SR 13 R 14 , -O-S(O)2R 15 , -S(O) r R 15 , -O-R 16 , -C(O)OR 16 , -C(O)SR 16 , -S-C(O)R 17 , -C(O)R 17 , -O-C(O)R 17 , -P(O)(R 17 )2, -NR 18 R 19 , -C(=NR 18 )R 17 , -N(R 18 )-C(=NR 19 )R 17 , -C(O)NR 18 R 19 and -N(R 18 )-C(O)R 17 ; each R 2b and each R 2c is independently selected from hydrogen, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -S(O)2R 15 , -C(O)OR 16 , -C(O)SR 16 , -C(O)R 17 , -C(=NR 18 )R 17 , and -C(O)NR 18 R 19 , the aforementioned groups being independently and optionally further substituted by one or more substituents selected from deuterium, halogen, hydroxyl, =O, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halosubstituted C 1-4 alkyl, deuterosubstituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C 6-8 aryl, C 6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, amino, mono C 1-4 alkylamino, di C 1-4 alkylamino, and C 1-4 alkanoyl; Alternatively, R 2b and R 2c together with the nitrogen atom directly connected thereto form a 4-6 membered heterocyclic group or a 5-8 membered heteroaryl group, and the 4-6 membered heterocyclic group or the 5-8 membered heteroaryl group is optionally further substituted by one or more substituents selected from deuterium, halogen, hydroxy, ═O, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy group, C 6- 8 aryl, C 6-8 aryloxy, 5-8 membered heteroaryl group, 5-8 membered heteroaryloxy group, amino, mono-C 1-4 alkylamino, di-C 1-4 alkylamino and C 1-4 alkanoyl; R3 is selected from C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic group, C 6-8 aryl, 5- to 8-membered heteroaryl, -C(O)OR 16 , -C(O)R 17 and -C(O)NR 18 R 19 , where the above groups are independently optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic group, C 6-8 aryl, 5- to 8-membered heteroaryl, -SF5, -S(O)(=N-R 12 )R 13 , -N=S(O)R 13 R 14 , -N=SR 13 R 14 , -O-S(O)2R 15 , -S(O) r R 15 , -O-R 16 , -C(O)OR 16 , -C(O)SR 16 , -S-C(O)R 17 , -C(O)R 17 , -O-C(O)R 17 , -P(O)(R 17 )2, -NR 18 R 19 , -C(=NR 18 )R 17 , -N(R 18 )-C(=NR 19 )R 17 , -C(O)NR 18 R 19 and -N(R 18 )-C(O)R 17 , and the above groups are independently optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic group, C 6-8 aryl, 5-8 membered heteroaryl, -SF5, -S(O)(=N-R 12 )R 13 , -N=S(O)R 13 R 14 , -N=SR 13 R 14 , -O-S(O)2R 15 , -S(O) r R 15 , -C 0-1 alkyl-O-R 16 , -C(O)OR 16 , -C(O)SR 16 , -S-C(O)R 17 , -C(O)R 17 , -O-C(O)R 17 , -P(O)(R 17 )2, -C 0-1 alkyl-NR 18 R 19 , -C(=NR 18 )R 17 , -N(R 18 )-C(=NR 19 )R 17 , -C(O)NR 18 R 19 and -N(R 18 )-C(O)R 17 ; R4and R5are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -SF5, -S(O)(=N-R 12 )R 13 , -N=S(O)R 13 R 14 , -N=SR 13 R 14 , -O-S(O)2R 15 , -S(O) r R 15 , -O-R 16 , -C(O)OR 16 , -C(O)SR 16 , -S-C(O)R 17 , -C(O)R 17 , -O-C(O)R 17 , -P(O)(R 17 )2, -NR 18 R 19 , -C(=NR 18 )R 17 , -N(R 18 )-C(=NR 19 )R 17 , -C(O)NR 18 R 19 , and -N(R 18 )-C(O)R 17 ; R6and R7are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, C 6-8 aryl, 5- to 8-membered heteroaryl, -SF5, -S(O)(=N-R 12 )R 13 , -N=S(O)R 13 R 14 , -N=SR 13 R 14 , -O-S(O)2R 15 , -S(O) r R 15 , -O-R 16 , -C(O)OR 16 , -C(O)SR 16 , -S-C(O)R 17 , -C(O)R 17 , -O-C(O)R 17 , -P(O)(R 17 )2, -NR 18 R 19 , -C(=NR 18 )R 17 , -N(R 18 )-C(=NR 19 )R 17 , -C(O)NR 18 R 19 , and -N(R 18 )-C(O)R 17 ; or R5and R6together with the moiety to which they are directly attached form a C 3-6 Cycloalkyl or 3-6 membered heterocyclyl, each of the above groups being independently and optionally further substituted by one or more substituents independently selected from the group consisting of deuterium, halogen, cyano, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, deuterium-substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 6-8 Aryl, 5-8 membered heteroaryl, =0, =S, -SF5, -S(O)(=N-R 12 )R 13 , -N=S(O)R 13 R 14 , -N=SR 13 R 14 , -O-S(O)2R 15 , -S(O) r R 15 , -O-R 16 , -C(O)OR 16 , -C(O)SR 16 , -S-C(O)R 17 , -C(O)R 17 , -O-C(O)R 17 , -P(O)(R 17 )2, -NR 18 R 19 , -C(=NR 18 )R 17 , -N(R 18 )-C(=NR 19 )R 17 , -C(O)NR 18 R 19 and -N(R 18 )-C(O)R 17 ; R 10 selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halosubstituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, C 6-8 aryl, 5- to 8-membered heteroaryl, -SF5, -S(O)(=N-R 12 )R 13 , -N=S(O)R 13 R 14 , -N=SR 13 R 14 , -O-S(O)2R 15 , -S(O) r R 15 , -O-R 16 , -C(O)OR 16 , -C(O)SR 16 , -S-C(O)R 17 , -C(O)R 17 , -O-C(O)R 17 , -P(O)(R 17 )2, -NR 18 R 19 , -C(=NR 18 )R 17 , -N(R 18 )-C(=NR 19 )R 17 , -C(O)NR 18 R 19 and -N(R 18 )-C(O)R 17 ; wherein R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 and r are as described in claim 1.

6. The compound of formula (I) according to claim 1, its stereoisomers or its pharmaceutically acceptable salts, characterized in that, The compound of formula (I) is a compound of formula (IIIa), (IIIb) or (IIIc) as follows: wherein, is a single or double bond; Z1 is O, S or NH; Z2 is CR 1a or N; Z3 is CR 1b or N; Z4 is CR 1c or N; Z5 is CR 1d or N; Z6 is CR 1e or N; Z7 is CR 1f or N; Z8 is CR 1g or N; Z9 is CR 1h or N; m1 is 0, 1, 2, 3, 4, or 5; m2 is 0, 1, or 2; each R1is independently selected from hydrogen, deuterium, halogen, cyano, C1-6alkyl, 1-4 alkyl, halogen-substituted C1-6alkyl, 1-4 alkyl, deuterium-substituted C1-6alkyl, 1-4 alkyl, C1-6alkyl-substituted C3-6cycloalkyl, 2-4 alkenyl, C1-6alkyl-substituted C2-6alkenyl, 2-4 alkynyl, C1-6alkyl-substituted C2-6alkynyl, 3-6 cycloalkyl, 3-6 membered heterocyclyl, C1-6alkyl-substituted C3-6cycloalkyl, 6-8 aryl, 5-8 membered heteroaryl, -SF5, -S(O)mR r R 15 , -O-R 16 , -C(O)OR 16 , -C(O)R 17 , -O-C(O)R 17 , and -NR 18 R 19 ; R 1a , R 1b , R 1c , R 1d , R 1e , R 1f , R 1g and R 1h are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halosubstituted C 1-4 alkyl, deuterium- substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3- 6cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -SF5, -S(O) r R 15 , -O-R 16 , -C(O)OR 16 , -C(O)R 17 , -O-C(O)R 17 and -NR 18 R 19 ; each R2is independently selected from hydrogen, halogen, 3-6 membered heterocyclyl, -(L) s -O-(L) s -R 2a , -(L) s -NR 2b R 2c , or -(L) s -O-(L) s -NR 2b R 2c , the aforementioned 3-6 membered heterocyclyl, -(L) s -O-(L) s -R 2a , -(L) s -NR 2b R 2c , or -(L) s -O-(L) s -NR 2b R 2c is independently optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, C 1-4 alkyl, halosubstituted C 1-4 alkyl, deuterium- substituted C 1-4 alkyl, C 1-4 alkylene, halosubstituted C 1-4 alkylene, deuterium- substituted C 1-4 alkylene, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, =0, =S, -SF5, -O-R 16 and -NR 18 R 19 ; each s is independently 0, 1, 2, or 3; each L is each independently selected from C 1-4 alkylene, C 3-6 cycloalkylene, or 3-6 membered heterocycloalkylene, each of which is independently and optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, C 1-4 alkylene, C 3-6 cycloalkylene, or 3-6 membered heterocycloalkylene, each of which is independently and optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 aryl, 5-8 membered heteroaryl, =0, =S, -SF5, -O-R 16 and -NR 18 R 19 substituted; each R 2a is independently selected from hydrogen, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl, 3-10 membered heterocyclyl, C 6-8 aryl, and 5-8 membered heteroaryl, said groups being optionally further substituted by one or more substituents independently selected from deuterium, halogen, cyano, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 1-4 alkylene, halogen-substituted C 1- alkylene, deuterium-substituted C 1-4 alkylene, C 2-4 alkenylene, C 2-4 alkynylene, C 3-6 cycloalkylene, 3-6 membered heterocyclylene, C 6-8 aryl, 5-8 membered heteroarylene, =0, =S, -SF5, -O-R 16 and -NR 18 R 19 ; each R 2b and each R 2c is each independently selected from hydrogen, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, sulfonyl, methylsulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, and C 1-4 alkanoyl, the aforementioned groups being independently optionally further substituted by one or more substituents selected from deuterium, halogen, hydroxyl, =0, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C 6-8 aryl, C 6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, amino, mono-C 1-4 alkylamino, di-C 1-4 alkylamino, and C 1-4 alkanoyl; or R 2b and R 2c together with the nitrogen atom to which they are directly attached form a 4-6 membered heterocyclyl or 5-8 membered heteroaryl, which is optionally further substituted by one or more substituents selected from the group consisting of deuterium, halogen, hydroxyl, =0, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C 6- aryl, C 6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, amino, mono-C 1-4 alkylamino, di-C 1-4 alkylamino and C 1-4 alkanoyl; each R3is independently selected from the group consisting of C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, and 3-6 membered heterocyclyl, said groups being independently and optionally further substituted by one or more substituents independently selected from the group consisting of deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -SF5, -0-S(0)2R 15 , -S(O) r R 15 , -0-R 16 , -C(0)OR 16 , -C(0)R 17 , -0-C(0)R 17 , -NR 18 R 19 , -C(0)NR 18 R 19 , and -N(R 18 )-C(0)R 17 , said groups being independently and optionally further substituted by one or more substituents independently selected from the group consisting of deuterium, halogen, cyano, C 1-4 alkyl, halosubstituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -SF5, -S(O)(=N-R 12 )R 13 , -N=S(O)R 13 R 14 , -N=SR 13 R 14 , -0-S(0)2R 15 , -S(O) r R 15 , -C 0-1 alkyl-O-R 16 , -C(0)OR 16 , -C(0)SR 16 , -S-C(0)R 17 , -C(0)R 17 , -0-C(0)R 17 , -P(0)(R 17 )2, -C 0-1 alkyl-NR 18 R 19 , -C(=NR 18 )R 17 , -N(R 18 )-C(=NR 19 )R 17 , -C(O)NR 18 R 19 , and -N(R 18 )-C(O)R 17 ; each R5is independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, -O-R 16 and -NR 18 R 19 ; each R6is independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halosubstituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, -O-R 16 and -NR 18 R 19 ; or R5and R6together with the moiety to which they are directly attached form a C 3-6 Cycloalkyl or 3-6 membered heterocyclyl, each of the foregoing groups being independently and optionally further substituted with one or more substituents independently selected from deuterium, halogen, cyano, C 1-4 Alkyl, halosubstituted C 1-4 Alkyl, deuterium-substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, =0, -0-R 16 , -C(O)OR 16 , -C(O)R 17 , -O-C(O)R 17 , -NR 18 R 19 , -C(O)NR 18 R 19 , and -N(R 18 )-C(O)R 17 ; Each R 10 is independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic group, C 6-8 aryl, 5- to 8-membered heteroaryl, -SF5, -O-R 16 and -NR 18 R 19 ; wherein R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 and r are as described in claim 1.

7. The compound of formula (I) according to claim 6, its stereoisomers or its pharmaceutically acceptable salts, characterized in that, The compound of formula (I) is a compound of formula (IVa1), formula (IVb1) or formula (IVc1) as follows: wherein Z1 is O, S or NH; Z2 is CR 1a or N; Z3 is CR 1b or N; Z4 is CR 1c or N; Z5 is CR 1d or N; Z6 is CR 1e or N; Z7 is CR 1f or N; Z8 is CR 1g or N; Z9 is CR 1h or N; R 1a , R 1b , R 1c , R 1d , R 1e , R 1f , R 1g and R 1h are each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, methyl, ethyl, n-propyl, i-propyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, ethenyl, allyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, oxetanyl, azetanyl, amino, methylamino and dimethylamino; In the compound of formula (IVa1), formula (IVb1), or formula (IVc1), R1, R2, R3, R5, R6, R 10 m1and m2are as described in claim 6.

8. The compound of formula (I) according to claim 6, its stereoisomers or its pharmaceutically acceptable salts, characterized in that, The compound of formula (I) is a compound of formula (IVa2), (IVb2) or (IVc2) as follows: wherein Z1 is O, S or NH; Z2 is CR 1a or N; Z3 is CR 1b or N; Z4 is CR 1c or N; Z5 is CR 1d or N; Z6 is CR 1e or N; Z7 is CR 1f or N; Z8 is CR 1g or N; Z9 is CR 1h or N; R 1a , R 1b , R 1c , R 1d , R 1e , R 1f , R 1g and R 1h are each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, methyl, ethyl, n-propyl, i-propyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, ethenyl, allyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, oxetanyl, azetanyl, amino, methylamino and dimethylamino; In the compound of formula (IVa2), formula (IVb2) or formula (IVc2), R1, R2, R3, R5, R6, R 10 m1and m2are as described in claim 6.

9. The compound of formula (I) according to claim 1, its stereoisomers or its pharmaceutically acceptable salts, characterized in that, each R1is independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, methyl, ethyl, n-propyl, i-propyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, ethenyl, allyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, oxetanyl, azetanyl, amino, methylamino, and dimethylamino.

10. The compound of formula (I) according to claim 1, its stereoisomers or its pharmaceutically acceptable salts, characterized in that, R 10 each independently is selected from hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, methyl, ethyl, n-propyl, i-propyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, ethenyl, allyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, oxetanyl, azetanyl, amino, methylamino, and dimethylamino.

11. The compound of formula (I) according to claim 1, its stereoisomers or its pharmaceutically acceptable salts, characterized in that, R5is selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl, n-propyl, i-propyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, ethenyl, allyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, oxetanyl, azetanyl, amino, methylamino, and dimethylamino; R6is selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl, n-propyl, i-propyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, ethenyl, allyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, oxetanyl, azetanyl, amino, methylamino, and dimethylamino.

12. The compound of formula (I) according to claim 1, its stereoisomers or its pharmaceutically acceptable salts, characterized in that, R3is selected from C 1-4 alkyl, C 3-6 cycloalkyl and 3- to 6-membered heterocyclyl, each of which is independently and optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, C 6-8 aryl, 5- to 8-membered heteroaryl, -O-R 16 , -C(O)OR 16 , -C(O)R 17 , -O-C(O)R 17 , -NR 18 R 19 , -C(O)NR 18 R 19 and -N(R 18 )-C(O)R 17 , each of which is independently and optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, C 1-4 alkyl, halosubstituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, C 6- 8aryl, 5- to 8-membered heteroaryl, -S(O) r R 15 , -C 0-1 alkyl-O-R 16 , -C(O)OR 16 , -C(O)R 17 , -O-C(O)R 17 , -P(O)(R 17 )2, -C 0-1 alkyl-NR 18 R 19 , -C(O)NR 18 R 19 and -N(R 18 )-C(O)R 17 ; wherein R 15 , R 16 , R 17 , R 18 , R 19 and r are as described in claim 1.

13. The compound of formula (I) according to claim 1, its stereoisomers or its pharmaceutically acceptable salts, characterized in that, R3is selected from methyl, ethyl, propyl, isopropyl, butyl, and isobutyl, each of which is independently optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, methyl, ethyl, propyl, isopropyl, ethenyl, allyl, propynyl, cyclopropyl, cyclobutyl, oxacyclopropyl, azacyclopropyl, oxacyclobutyl, azacyclobutyl, morpholinyl, phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, imidazolyl, oxazolyl, thiazolyl, quinolinyl, indolyl, and isoquinolinyl, each of which is independently optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, amino, C 1-4 halo-substituted C 1-4 deuterium-substituted C 1-4 halo-substituted C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, -C 0-1 alkyl-O-R 16a and -C 0-1 alkyl-NR 18a R 19a ; R 16a selected from hydrogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, and dideuteromethyl; R 18a and R 19a each independently is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, and dideuteromethyl.

14. The compound of formula (I) according to claim 1, its stereoisomers or its pharmaceutically acceptable salts, characterized in that, R2 is selected from a 3-6 member heterocyclic group, -(L) s -O-(L) s -R 2a or -(L) s -NR 2b R 2c , and the above-mentioned 3-6 member heterocyclic group, -(L) s -O-(L) s -R 2a or -(L) s -NR 2b R 2c are independently optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, halogen-substituted C 1-4 alkyl, halogen-substituted C 1-4 alkoxy, deuterium-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkoxy, C 1-4 alkylene, halogen-substituted C 1-4 alkylene, deuterium-substituted C 1- 4 alkylene, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3-6 member heterocyclic group, 3-6 member heterocyclic oxy group, =O, =S, -SF5, amino, mono-C 1-4 alkylamino and di-C 1-4 alkylamino; each s is independently 0, 1, 2, or 3; each L is independently selected from C 1-4 alkylene, C 3-6 cycloalkylene or 3-6 membered heterocyclylene, said C 1- 4alkylene, C 3-6 cycloalkylene or 3-6 membered heterocyclylene is independently optionally further substituted by one or more substituents independently selected from deuterium, halogen, cyano, hydroxyl, C 1-4 alkyl, C 1-4 halo-substituted C 1-4 alkyl, halo-substituted C 1-4 alkoxy, deuterium-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, C 3- 6cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, =0, =S, -SF5, amino, mono-C 1-4 alkylamino and di-C 1-4 alkylamino substituted; R 2a selected from hydrogen, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl, amino, methylamino, dimethylamino, The above groups are optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, halo-substituted C 1-4 alkyl, halo-substituted C 1-4 alkoxy, deuterium-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkoxy, C 1-4 alkylene, halo-substituted C 1-4 alkylene, deuterium-substituted C 1-4 alkylene, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3- to 6-membered heterocyclic group, 3- to 6-membered heterocyclic oxy group, ═O, ═S, -SF5, amino, mono-C 1-4 alkylamino and di-C 1-4 alkylamino; R 2b and R 2c are each independently selected from the group consisting of hydrogen, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, and 3-6 membered heterocyclyl, said groups being independently and optionally further substituted by one or more substituents selected from the group consisting of deuterium, halogen, hydroxyl, =0, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C 6-8 aryl, 5-8 membered heteroaryl, amino, mono-C 1-4 alkylamino, di-C 1-4 alkylamino, and C 1-4 alkanoyl; Alternatively, R 2b and R 2c together with the nitrogen atom directly connected thereto form a 4-6 membered heterocyclic group or a 5-8 membered heteroaryl group, which 4-6 membered heterocyclic group or 5-8 membered heteroaryl group is optionally further substituted by one or more substituents selected from deuterium, halogen, hydroxy, =O, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy group, C 6- 8 aryl, 5-8 membered heteroaryl, amino, mono-C 1-4 alkylamino, di-C 1-4 alkylamino and C 1-4 alkanoyl; each s is independently 0, 1, 2, or 3.

15. The compound of formula (I) according to claim 1, its stereoisomers or its pharmaceutically acceptable salts, characterized in that, R2is selected from each R is independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, isopropyl, ethenyl, allyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, amino, methylamino, dimethylamino, 2a each R is independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, isopropyl, ethenyl, allyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, amino, methylamino, dimethylamino, the above groups are optionally further substituted with one or more substituents selected from the group consisting of deuterium, halogen, cyano, hydroxyl, methyl, ethyl, i-propyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, methylene, monofluoromethylene, difluoromethylene, ethenyl, ethynyl, cyclopropyl, cyclobutyl, oxetanyl, azetanyl, =0, =S, -SF5, amino, methylamino, and dimethylamino; R 2a1 and R 2a2 each independently is selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, hydroxyl, methyl, ethyl, isopropyl, ethenyl, allyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, amino, methylamino, and dimethylamino; R 2a3 and R 2a4 are each independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, hydroxyl, methyl, ethyl, isopropyl, ethenyl, allyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, amino, methylamino, and dimethylamino; R 2b is selected from hydrogen, deuterium, methyl, ethyl, isopropyl, ethenyl, allyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, and azetidinyl; R 2c1 selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, phenyl, pyridinyl, or pyrimidinyl, which are optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, hydroxy, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, C 1-4 alkylene, halosubstituted C 1-4 alkylene, deuterium-substituted C 1-4 alkylene, vinyl, ethynyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, =0, =S, -SF5, amino, methylamino, and dimethylamino; Each R 2d Each is independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, isopropyl, vinyl, allyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetyl, aziridine, amino, methylamino, and dimethylamino; each R 2e are each independently selected from hydrogen, deuterium, methyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, ethyl, isopropyl, ethenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, or azetidinyl.

16. The compound of formula (I) according to claim 6, stereoisomers thereof, or pharmaceutically acceptable salts thereof, characterized in that, The compound of formula (I) is a compound of formula (Va1-1), formula (Va1-2), formula (Vb1) or formula (Vc1): wherein, In the compounds of Formula (Va1-1) and Formula (Va1-2), each R 1i , each R 1j , and each R 1k is each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, methyl, ethyl, n-propyl, i-propyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, ethenyl, allyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, oxetanyl, azetanyl, amino, methylamino, and dimethylamino; In the compound of formula (Vb1), R 1a , R 1b , R 1c , R 1d and R 1e are each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, methyl, ethyl, n-propyl, i-propyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, ethenyl, allyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, oxetanyl, azetanyl, amino, methylamino and dimethylamino; In the compound of formula (Vc1), R 1f , R 1g and R 1h are each independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, methyl, ethyl, n-propyl, i-propyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, ethenyl, allyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, oxetanyl, azetanyl, amino, methylamino and dimethylamino; R 1L and R 1m each independently is selected from hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, methyl, ethyl, n-propyl, i-propyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, ethenyl, allyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, oxetanyl, azetanyl, amino, methylamino, and dimethylamino; In the compound of Formula (Va1-1), Formula (Vb1), or Formula (Vc1), each R 2a1 and each R 2a2 is each independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, hydroxyl, methyl, ethyl, isopropyl, ethenyl, allyl, propynyl, cyclopropyl, amino, methylamino, and dimethylamino; In the compound of Formula (Va1-1), Formula (Vb1), or Formula (Vc1), each R 2a5 and each R 2a6 is each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, methylene, fluoromethylene, difluoromethylene, ethenyl, ethynyl, cyclopropyl, cyclobutyl, oxetanyl, azetanyl, =0, =S, -SF5, amino, methylamino, and dimethylamino; In the compound of formula (Va1-2), R 2a8 and R 2a9 are each independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, methylene, fluoromethylene, difluoromethylene, ethenyl, ethynyl, cyclopropyl, cyclobutyl, oxetanyl, azetanyl, amino, methylamino, and dimethylamino; Each R 3a Each is independently selected from hydrogen, methyl, trifluoromethyl, difluoromethyl, trideutermethyl, dideutermethyl, ethyl, propyl, isopropyl, butyl, isobutyl and cyclopropyl; Each R 3b Each is independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, amino, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideutermethyl, dideutermethyl, cyclopropyl, cyclobutyl, oxetanebutyl, azirnebutyl, morpholino, methoxy, trifluoromethoxy, difluoromethoxy, trideutermethoxy, dideutermethoxy, -CH2-OH, -CH2-NH2, amino, methylamino, and dimethylamino; each R5is independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, n-propyl, i-propyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, amino, methylamino, and dimethylamino; each R6is independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl, n-propyl, i-propyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, amino, methylamino, and dimethylamino.

17. The compound of formula (I) according to claim 6, its stereoisomers or its pharmaceutically acceptable salts, characterized in that, The compound of formula (I) is a compound of formula (Va2-1), (Va2-2), (Vb2) or (Vc2): wherein, In the compounds of Formula (Va2-1) and Formula (Va2-2), each R 1i , each R 1j , and each R 1k is each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, methyl, ethyl, n-propyl, i-propyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, ethenyl, allyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, oxetanyl, azetanyl, amino, methylamino, and dimethylamino; In the compound of formula (Vb2), R 1a , R 1b , R 1c , R 1d and R 1e are each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, methyl, ethyl, n-propyl, i-propyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, ethenyl, allyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, oxetanyl, azetanyl, amino, methylamino and dimethylamino; In the compound of formula (Vc2), R 1f , R 1g and R 1h are each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, methyl, ethyl, n-propyl, i-propyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, ethenyl, allyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, oxetanyl, azetanyl, amino, methylamino and dimethylamino; R 1L and R 1m each independently is selected from hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, methyl, ethyl, n-propyl, i-propyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, ethenyl, allyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, oxetanyl, azetanyl, amino, methylamino, and dimethylamino; each R 2a1 and each R 2a2 is each independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, hydroxyl, methyl, ethyl, isopropyl, ethenyl, allyl, propynyl, cyclopropyl, amino, methylamino, and dimethylamino; In the compound of Formula (Va2-1), Formula (Vb2), or Formula (Vc2), each R 2a5 and each R 2a6 is each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, methylene, fluoromethylene, difluoromethylene, ethenyl, ethynyl, cyclopropyl, cyclobutyl, oxetanyl, azetanyl, =0, =S, -SF5, amino, methylamino, and dimethylamino; In the compound of formula (Va2-2), R 2a7 is selected from hydrogen, deuterium, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, and azetidinyl; R 2a8 and R 2a9 each independently is selected from hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, methylene, fluoromethylene, difluoromethylene, ethenyl, ethynyl, cyclopropyl, cyclobutyl, oxetanyl, azetanyl, amino, methylamino, and dimethylamino; Each R 3a Each is independently selected from hydrogen, methyl, trifluoromethyl, difluoromethyl, trideutermethyl, dideutermethyl, ethyl, propyl, isopropyl, butyl, isobutyl and cyclopropyl; each R 3b each independently is selected from hydrogen, deuterium, fluorine, chlorine, cyano, amino, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, morpholinyl, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, -CH2-OH, -CH2-NH2, amino, methylamino, and dimethylamino.

18. The compound of formula (I) according to claim 1, its stereoisomers or its pharmaceutically acceptable salts, characterized in that, selected from the group consisting of:

19. A pharmaceutical composition comprising an effective amount of a compound of any one of claims 1-18, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, for administration to a patient in need thereof.

20. Use of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1-18, for the manufacture of a medicament for the treatment and / or prevention of a tumor associated with KRAS.

21. A compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1-18, for use in the treatment and / or prevention of a tumor associated with KRAS.

22. Use according to claim 21, characterized in that, The tumor associated with KRAS is a tumor associated with wild-type KRAS, KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D, or KRAS Q61H.

23. Use according to claim 22, characterised in that, The tumor is an adenoma, a lymphoma, a mesothelioma, a lung cancer, an esophageal cancer, a stomach cancer, a pancreatic cancer, a liver cancer, a bile duct cancer, a gallbladder cancer, an ampullae cancer, a small intestine cancer, a large intestine cancer, a kidney cancer, a testicular cancer, a blood cancer, a hemangioma, a myeloma, a chondroma, a skull cancer, a brain cancer, a glioma, a uterine cancer, a vulva cancer, a vagina cancer, a fallopian tube cancer, a bladder cancer, a urethral cancer, a prostate cancer, an adrenal tumor, a sarcoma, a myxoma, a rhabdomyoma, a fibroma, a lipoma, a bronchial cancer, a Hodgkin's disease, a malignant melanoma, a basal cell carcinoma, a squamous cell carcinoma, a chondrodysplasia, a psoriasis, or a neuroblastoma.

24. The compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1-18 for use in the treatment of a tumor associated with wild-type KRAS, KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D, or KRAS Q61H.

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