KRAS inhibitor containing n-n bond and pharmaceutical use thereof

Abstract

The present invention relates to a KRAS inhibitor containing an N-N bond and a pharmaceutical use thereof. In particular, the present invention relates to a KRAS inhibitor having a structure as shown in formula (I), a preparation method therefor, a pharmaceutical composition containing same, a use thereof as a KRAS inhibitor, and a use thereof in treatment and / or prevention of KRAS-related cancers or tumors. The definition of each substituent in formula (I) is the same as that in the description.

Description

N-N bond-containing KRAS inhibitor and its pharmaceutical use TECHNICAL FIELD

[0001] The present application belongs to the field of drug synthesis, and particularly relates to an N-N bond-containing KRAS inhibitor 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 a malignant phenotype of tumor cells, including the imbalance of cell growth and programmed cell death, the increase of invasiveness and neovascularization. Due to the high affinity of RAS to 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 the GDP / GTP binding state of RAS, causing RAS proteins to be more in the activated GTP-bound state, thereby leading to persistent activation of the RAS downstream signaling pathway.

[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 has been 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 KRAS inhibitor containing N-N bond and its pharmaceutical use. 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, the substituent R 5b and R 6b is absent;

[0011] Y is a bond, O, S or N(R7);

[0012] X1 is CR8 or N; X2 is CR9 or N; X3 is CR 10 or N; 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 is optionally fused to C 6-10aryl or 5-10 membered heteroaryl, or, said C 6-10 aryl or 5-10 membered heteroaryl optionally fused to C 3-12 cycloalkyl or 3-12 membered heterocyclyl;

[0014] m is 0, 1, 2, 3, 4, or 5; each R1is 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 , -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 , or, when m > 2, two adjacent R1groups together with the moiety to which they are directly attached form a C 3-12 cycloalkyl or 3-12 membered heterocyclyl, each of which is independently further optionally substituted by 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-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(=NR19 )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;

[0015] R2 is selected from hydrogen, halogens, and -(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 heterocyclic groups, C 6-10 Aryl and 5-10 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 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 The aryl or 5-10 heteroaryl group is independently and optionally further selected by one or more elements chosen from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halogenated C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 1-10 Alkylene, halogenated C 1-10 Alkylene, deuterated C 1-10 Alkylene, 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 -C0-8 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;

[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 6-10aryl, 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 ;

[0017] each R 2a 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 6-10aryl 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- 10 Alkylene, halogenated C 1-10 Alkylene, deuterated C 1-10 Alkylene, 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)NR18 R 19 and -C 0-8 alkyl-N(R 18 )-C(O)R 17 substituted;

[0018] each R 2b and each R 2c is each independently selected from the group consisting of 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 optionally further substituted by one or more substituents selected from the group consisting of 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] Alternatively, 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 the group consisting of deuterium, halogen, hydroxyl, =O, C 1-10 alkyl, C2-10 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;

[0020] R3 and R4 are each independently selected from hydrogen, deuterium, hydroxyl, cyano, 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, -S(O)2R 15 -C(O)OR 16 -C(O)SR 16 -C(O)R 17 -NR 18 R 19 -C(=NR) 18 )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, nitro, azido, 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- 8alkyl-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 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 0-8 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 0-8alkyl-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 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 -C 0-8 alkyl-N(R 18 )-C(O)R 17

[0021] or R3and R4together with the carbon atom to which they are directly attached form a 3-12 membered heterocyclyl or 5-10 membered heteroaryl, each of which is independently optionally further substituted with one or more substituents selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, halosubstituted C 1-10 alkyl, deuterosubstituted 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- 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] p is 0, 1, 2, or 3; each R 5a and each R 5b is 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 , -C0-8 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 R 5a and R 5b , together 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-R12 )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;

[0023] q is 0, 1, 2, or 3; each R 6a and each R 6b Each is 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, -C0-8 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 R 6a and R 6b , together 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, C3-12 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 ;

[0024] R7is selected from hydrogen, deuterium, hydroxyl, cyano, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-10 Aryl, 5-10 heteroaryl, -S(O)2R 15 -C(O)OR 16 -C(O)SR 16 -C(O)R 17 -NR 18 R 19 -C(=NR) 18 )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, nitro, azido, 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 0-8 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 0-8Alkyl-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 -C0-8 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 ;

[0025] R8, R9, R 10 , and R 11 are each independently selected from hydrogen, 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, -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 R19 , -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 ;

[0026] each R 12 is each independently selected from the group consisting of hydrogen, deuterium, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, 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-C(O)OR 16 , -C 0-8 alkyl-C(O)R 17 , and -C 0-8 alkyl-C(O)NR 18 R 19 , said groups being 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, 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-NR18 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 ;

[0027] each R 13 and each R 14 is each 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 both attached form a 3-10 membered heterocyclyl, optionally further substituted by one or more 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(R18 )-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 ;

[0028] each R 15 is each independently selected from the group consisting of hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, and -NR 18 R 19 , the foregoing groups being independently and optionally further substituted by one or more substituents selected from the group consisting of 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 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 ;

[0029] each R 16 is each 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, the foregoing groups being independently and optionally further substituted by one or more substituents selected from the group consisting of deuterium, halogen, hydroxyl, =O, 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 ;

[0030] each R 17 is each independently selected from the group consisting of hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C1-10 alkoxy, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 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, and -NR 18 R 19 , the aforementioned groups are independently optionally further substituted by 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- 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, and -NR 18 R 19 , the aforementioned groups are independently optionally further substituted by one or more substituents selected from the group consisting of deuterium, halogen, hydroxyl, =0, cyano, C

[0031] each R 18 and each R 19 is each independently selected from the group consisting of hydrogen, deuterium, hydroxyl, 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, sulfinyl, sulfonyl, methylsulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, and C 1-10 alkanoyl, the aforementioned groups are independently optionally further substituted by one or more substituents selected from the group consisting of 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- 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;

[0032] 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

[0033] Each r is independently 0, 1, or 2.

[0034] As a preferred embodiment, in the compound of formula (I), its stereoisomers, or its pharmaceutically acceptable salts, Y is a bond, O, S, or N (R7); X1 is CR8 or N; X2 is CR9 or N; X3 is CR 10 Or N; X4 is N or CR 11 ;

[0035] Ring A is C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups;

[0036] 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 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-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, two adjacent R1together with the moiety to which they are directly attached form a C 3-8 cycloalkyl or 3-8 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, 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 ;

[0037] 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 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, -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 0-4alkyl-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 ;

[0038] each s is independently 0, 1, 2, or 3;

[0039] each L is independently selected from C 1-4 alkylene, C 3-6 cycloalkylene, or 3-6 membered heterocyclylene, provided that each C 1-4 alkylene, 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, C 1-4 alkyl, halosubstituted C 1-4 alkyl, deuterium- substituted 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, =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 0-4alkyl-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 ;

[0040] each R 2a is each independently 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 6-8 aryl, and 5-8 membered heteroaryl, 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- 4alkylene, 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 13 R 14 , -C 0-4 alkyl-N=SR 13 R 14 , -C 0-4 alkyl-O-S(O)2R 15 , -C 0-4alkyl-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 ;

[0041] 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 R19 each of the above groups is 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- to 6-membered heterocyclyl, 3- to 6-membered heterocyclyloxy, C 6- 8aryl, C 6-8 aryloxy, 5- to 8-membered heteroaryl, 5- to 8-membered heteroaryloxy, amino, mono- C 1-4 alkylamino, di-C 1-4 alkylamino and C 1-4 alkanoyl, substituted by one or more substituents selected from deuterium, halogen, hydroxyl, =0, C

[0042] 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 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 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- 8aryl, C 6-8 aryloxy, 5- to 8-membered heteroaryl, 5- to 8-membered heteroaryloxy, amino, mono- C 1-4 alkylamino, di-C 1-4 alkylamino and C 1-4 alkanoyl, substituted by one or more substituents selected from deuterium, halogen, hydroxyl, =0, C

[0043] R3and R4are each independently selected from hydrogen, deuterium, hydroxyl, 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, -S(O)2R 15 , -C(O)OR 16 , -C(O)SR 16 , -C(O)R 17 , -NR 18 R19 -C(=NR) 18 )R 17 and -C(O)NR 18 R 19 The above-mentioned 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 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 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)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 substituted by one or more substituents independently selected from the group consisting of halogen, cyano, nitro, -OR, -NR

[0044] R3and R4together with the carbon atom to which they are directly attached form a 3-10 membered heterocyclyl or 5-8 membered heteroaryl, each of which is independently optionally further substituted with one or more substituents independently selected from the group consisting of deuterium, halogen, cyano, nitro, oxo, thia, -OR, -NR 1-4 alkyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-10 cycloalkyl, 3-10 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- 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;

[0045] p is 0, 1, 2, or 3; each R 5a and each R 5b is 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- 4alkyl-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 )R17 -C 0-4 alkyl-C(O)NR 18 R 19 and -C 0-4 alkyl-N(R 18 )-C(O)R 17 , or R 5a and R 5b , together 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 the above groups being 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 , -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- 4alkyl-P(O)(R 17 )2, -C 0-4 alkyl-NR 18 R 19 , -C 0-4 alkyl-C(=NR 18 )R17 -C 0-4 alkyl-N(R 18 )-C(=NR 19 )R 17 -C 0-4 alkyl-C(O)NR 18 R 19 -C 0-4 alkyl-N(R 18 )-C(O)R 17 ;

[0046] q is 0, 1, 2, or 3; each R 6a and each R 6b is independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 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- 4alkyl-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(=NR18 )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, R 6a and R 6b Together with the carbon atom directly bonded to it, they form a C(O), C 3- A 6-cyclic alkyl or 3-6-membered heterocyclic group, 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 0-4 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;

[0047] R7 is selected from hydrogen, deuterium, hydroxyl, cyano, and C. 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-8 Aryl, 5-8 quinone heteroaryl, -S(O)2R 15 -C(O)OR 16 -C(O)SR 16 -C(O)R 17 -NR 18 R 19 -C(=NR) 18 )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, =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 0-4 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-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 0-4 -C 18 alkyl-N(R 19 )2 0-4 -C 18 alkyl-C(=NR 17 )R 0-4 -C 18 alkyl-N(R 19 )-C(=NR 17 )R 0-4 -C 18 alkyl-C(O)NR 19 R 0-4 -C 18 alkyl-N(R 17 )-C(O)R 10 ;

[0048] R8, R9, R 11 , and R 1-4 are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halosubstituted C 1-4 alkyl, deuterium- substituted C 2-4 alkyl, C 2-4 alkenyl, C 3-6 alkynyl, C 6-8 cycloalkyl, 3-6 membered heterocyclyl, C 0-4 aryl, 5-8 membered heteroaryl, -C 0-4 alkyl-SF5, -C 12 alkyl-S(O)(=N-R 13 )R 0-4 , -C 13 alkyl-N=S(O)R 14 R 0-4 , -C 13 alkyl-N=SR 14 R 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 ;

[0049] 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).

[0050] As a preferred option, in the compound of formula (I), its stereoisomers or its pharmaceutically acceptable salts, 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 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;

[0051] 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 Alkyne group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-8 aryl and 5-8 quinone heteroaryl, or, R 13 and R14 together with the sulfur atom to which it is directly attached, form a 3-6 membered heterocyclyl group, which is 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, 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 ;

[0052] 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 with 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, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C 6-8aryl, C 6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, and -NR 18 R 19 substituted by one or more substituents selected from the group consisting of deuterium, halogen, hydroxyl, =0, cyano, C

[0053] 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, 3-6 membered heterocyclyl, C 6-8 aryl and 5-8 membered heteroaryl, said groups being independently and optionally further substituted by one or more substituents 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, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C 6-8 aryl, C 6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, and -NR 18 R 19 substituted by one or more substituents selected from the group consisting of deuterium, halogen, hydroxyl, =0, cyano, C

[0054] 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- 4alkynyl, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C 6-8 aryl, C 6- aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, and -NR 18 R 19 substituted by one or more substituents 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, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C 6-8 aryl, C 6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, and -NR 18 R 19 substituted by one or more substituents selected from the group consisting of deuterium, halogen, hydroxyl, =0, cyano, C

[0055] each R 18 and each R 19 is independently selected from the group consisting of hydrogen, deuterium, hydroxyl, 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 membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropanesulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, and C 1-4 Alkyl group, wherein the above groups are independently and optionally further divided by one or more groups selected from deuterium, halogen, hydroxyl, =O, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, halogenated C 1-4 Alkyl, deuterated 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 group, C 6-8 Aryl, C 6-8 Aryloxy group, 5-8 membered heteroaryl group, 5-8 membered heteroaryloxy group, amino group, mono-C group 1-4 Alkylamino, diC 1-4 Alkylamino and C 1-4 The alkyl acyl group is replaced by a substituent;

[0056] Or, R 18 and R 19 Together with the nitrogen atom directly attached thereto, a 4-6 membered heterocyclic group or a 5-8 membered heteroaryl group is formed, wherein the 4-6 membered heterocyclic group or the 5-8 membered heteroaryl group is optionally further surrounded by one or more elements selected from deuterium, halogen, hydroxyl, =O, C. 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, halogenated C 1-4 Alkyl, deuterated 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 group, C 6- 8-aryl, C 6-8 Aryloxy group, 5-8 membered heteroaryl group, 5-8 membered heteroaryloxy group, amino group, mono-C group 1-4 Alkylamino, diC 1-4 Alkylamino and C 1-4 The alkyl acyl group is substituted by a substituent; and

[0057] Each r is independently 0, 1, or 2.

[0058] As a preferred embodiment, the compound of formula (I), its stereoisomers, or its pharmaceutically acceptable salts, wherein the structure of the compound of formula (I) contains... Selected from the following structure:

[0059] Among them, R 5a R 5b R 6a R 6b R7, X1, X2, X3 and X4 are as defined in compound (I).

[0060] As a further preferred embodiment, the compound of formula (I), its stereoisomers, or its pharmaceutically acceptable salts, wherein the compound of formula (I) is a compound of formula (II) as follows:

[0061] in, For single or double bonds, when When it is a double bond, the substituent R on the carbon atom directly connected to the double bond 5b and R 6b It does not exist;

[0062] Y represents a bond, O, S, or N (R7); X3 represents a CR bond. 10 Or N; X4 is N or CR 11 ;

[0063] Ring A is C 6-10 Aryl or 5-10 heteroaryl groups;

[0064] 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 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 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 ;

[0065] R2is selected from hydrogen, halogen, -(L) s -O-(L) s -R2a -(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 )R17 -N(R 18 )-C(=NR 19 )R 17 , -C(O)NR 18 R 19 , and -N(R 18 )-C(O)R 17 ;

[0066] each s is independently 0, 1, 2, or 3;

[0067] each L is independently selected from C 1-4 alkylene, C 3-6 ycloalkylene, or 3-6 membered heterocyclyl ene, said C 1-4 alkylene, C 3-6 ycloalkylene, or 3-6 membered heterocyclyl ene is independently optionally further substituted by 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- 4alkynyl, C 3-6 ycloalkyl, 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 17The substituents are replaced;

[0068] R 2a Each is independently 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;

[0069] Each R 2b and each R 2c Each is independently selected from hydrogen, deuterium, and C. 1-4 Alkyl, C 2-4alkynyl, 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 , are each 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;

[0070] 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, said 4-6 membered heterocyclyl or 5-8 membered heteroaryl being 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- 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;

[0071] R3and R4are each independently selected from hydrogen, deuterium, hydroxyl, 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(O)OR 16 , -C(O)R 17 , -NR 18 R 19 and -C(O)NR 18 R 19 , the aforementioned 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, 3-6 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 , the aforementioned groups are 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, -SF5, =0, -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 ;

[0072] or, R3and R4together with the carbon atom to which they are directly attached form a 3-10 membered heterocyclyl or 5-8 membered heteroaryl, each of which is independently optionally further substituted with one or more substituents selected from the group consisting of deuterium, halogen, cyano, nitro, azido, 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, =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-R16 -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 18 -C(=NR 19 )R 18 -N(R 17 )-C(=NR 18 )R 19 -C(O)NR 17 R 18 -N(R 19 )-C(O)R 18 ;

[0073] p is 0, 1, or 2; each R 17 and each R 5a is independently selected from hydrogen, deuterium, halogen, cyano, C 5b 1-6 alkyl, C 1- 1-6 alkenyl, C 2-4 1-6 alkynyl, C 2-4 3-6 cycloalkyl, 3-6 heterocyclyl, C 3-6 6 aryl, 5-8 heteroaryl, -SF5, -S(O)(=N-R 6-8 )R 12 , -N=S(O)R 13 R 13 , -N=SR 14 R 13 , -O-S(O)2R 14 , -S(O) 15 R r , -O-R 15 , -C(O)OR 16 , -C(O)SR 16 , -S-C(O)R 16 , -C(O)R 17 , -O-C(O)R 17 , -P(O)(R 17 )2 17 , -NR 18 R 19 , -C(=NR 18 )R 17 , -N(R 18 )-C(=NR 19 )R 17 , -C(O)NR 18 R 19and -N(R 18 )-C(O)R 17 , or R 5a and R 5b together 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 the foregoing being 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, =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 ;

[0074] q is 0, 1, or 2; each R 6a and each R 6b is each 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 6-8aryl, 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 , or, R 6a and R 6b together 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 the above groups being 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, 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)SR16 -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;

[0075] R7 is selected from hydrogen, deuterium, hydroxyl, cyano, and C. 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-8 Aryl, 5-8 quinone heteroaryl, -C(O)OR 16 -C(O)R 17 -NR 18 R 19 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, =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 , are optionally further substituted by 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, =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 ;

[0076] R 10 and R 11 are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halosubstituted C 1-4alkyl, 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 ;

[0077] 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).

[0078] As a still further preferred option, in the compound of formula (I), stereoisomer thereof, or pharmaceutically acceptable salt thereof, the structure of the compound of formula (I) is selected from the following structures:

[0079] wherein R 5a , R 5b , R 6a , R 6b , R7, R10 and R 11 as defined in the compound of formula (II).

[0080] As a still further preferred aspect, in the compound of formula (I), stereoisomer or pharmaceutically acceptable salt thereof, the compound of formula (I) is a compound of formula (III1), (III2), (III3), (III4), (III5) or (III6):

[0081] wherein, ring A, R1, R2, R3, R4, R 5a , R 5b , R 6a , R 6b , R7, R 10 and m are as defined in the compound of formula (I).

[0082] As a still further preferred aspect, in the compound of formula (I), stereoisomer or pharmaceutically acceptable salt thereof, the compound of formula (I) is a compound of formula (IV1) or (IV2):

[0083] wherein each R2is 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 and 3-6 membered heterocyclyl, and each -(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 or 3-6 membered heterocyclyl 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 1-10 alkylene, halosubstituted C 1-10 alkylene, deuterium- substituted C 1-10 alkylene, C2-4 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 , -C(O)OR 16 , -C(O)R 17 , -O-C(O)R 17 , -P(O)(R 17 )2, -NR 18 R 19 , -C(O)NR 18 R 19 and -N(R 18 )-C(O)R 17 ;

[0084] each s is independently 0, 1, 2, or 3;

[0085] each L is independently selected from C 1-4 alkylene, C 3-6 cycloalkylene, or 3-6 membered heterocyclylene, said C 1-4 alkylene, 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- 4alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, =0, =S, -SF5, -O-R 16 , -C(O)OR 16 , -C(O)R 17 , -O-C(O)R 17 , -P(O)(R 17 )2, -NR 18 R 19 , -C(O)NR 18 R 19 and -N(R 18 )-C(O)R 17 ;

[0086] 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, C6-8 aryl and 5-8 membered heteroaryl, which are optionally further substituted with 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 alkenylene, C 2-4 alkynylene, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, =0, =S, -SF5, -S(O) r R 15 , -O-R 16 , -C(O)OR 16 , -C(O)R 17 , -O-C(O)R 17 , -P(O)(R 17 )2, -NR 18 R 19 , -C(O)NR 18 R 19 and -N(R 18 )-C(O)R 17 ;

[0087] each R 2b and each R 2c is independently selected from the group consisting of hydrogen, deuterium, C 1-4 alkyl, C 2-4 alkenylene, C 2-4 alkynylene, 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)R 17 and -C(O)NR 18 R 19 , which are independently optionally further substituted with one or more substituents independently selected from the group consisting of deuterium, halogen, hydroxyl, =0, C 1-4 alkyl, C 2-4 alkenylene, C 2-4 alkynylene, 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, C6-8 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 deuterium, halogen, hydroxyl, =0, C

[0088] 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, =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 substituted by one or more substituents selected from the group consisting of deuterium, halogen, hydroxyl, =0, C

[0089] each R3and each R4are each independently selected from the group consisting of hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 2-4 alkenyl, C 2- alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -C(O)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- 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 , -NR 18 R19 -C(O)NR 18 R 19 and -N(R 18 )-C(O)R 17 substituted with 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, -SF5, =O, -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 ;

[0090] In the compound of formula (IV1), R 5a is selected from the group consisting of 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 , -C(O)OR 16-C(O)R 17 -OC(O)R 17 -NR 18 R 19 -C(O)NR 18 R 19 and -N(R) 18 )-C(O)R 17 The aforementioned 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 groups, =O, =S, -OR 16 -C(O)OR 16 -C(O)R 17 -OC(O)R 17 -NR 18 R 19 -C(O)NR 18 R 19 and -N(R) 18 )-C(O)R 17 The substituents are replaced;

[0091] In the compound of formula (Ⅳ1), R 6a 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 groups, -OR 16 -C(O)OR 16 -C(O)R 17 -OC(O)R 17 -NR 18 R 19 -C(O)NR 18 R 19 and -N(R) 18 )-C(O)R 17 The aforementioned 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 3-6cycloalkyl, 3-6 membered heterocyclyl, =0, =S, -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 ;

[0092] 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, -O-R 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 ;

[0093] wherein, ring A, R1, R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , m and r are as defined for the compound of formula (I).

[0094] As a still further preferred aspect, in the compound of formula (I), stereoisomer thereof, or pharmaceutically acceptable salt thereof, is selected from the following structures:

[0095] 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.or N; Z8is CR 1g or N; Z9is CR 1h or N;

[0096] m1is 0, 1, 2, 3, 4, or 5; m2is 0, 1, or 2;

[0097] 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 ;

[0098] 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 ;

[0099] wherein, R 15 , R 16 , R 17 , R 18 , R 19and r is defined as for a compound of formula (I).

[0100] As a further preferred embodiment, 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, azetidinyl, amino, methylamino, and dimethylamino;

[0101] 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, azetidinyl, amino, methylamino, and dimethylamino.

[0102] As a further preferred embodiment, in the compound of formula (I), in the stereoisomer thereof, or in the pharmaceutically acceptable salt thereof, R3and R4are each independently selected from the group consisting of hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, and 5-8 membered heteroaryl, each of which is 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, -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(R18 )-C(O)R 17 substituents, the foregoing 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, 3-6 membered heterocyclyl, C 6- aryl, 5-8 membered heteroaryl, =O, -S(O) r R 15 , -O-R 16 , -C(O)OR 16 , -C(O)R 17 , -O-C(O)R 17 , -P(O)(R 17 )2, -NR 18 R 19 , -C(O)NR 18 R 19 and -N(R 18 )-C(O)R 17 substituents;

[0103] each R 5a and each R 5b is each independently selected from the group consisting of 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 , or R 5a and R 5b together with the carbon atom to which they are directly attached form a C(O), C 3-6 cycloalkyl or 3-6 membered heterocyclyl;

[0104] each R 6a and each R 6b is each independently selected from the group consisting of 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 16and -NR 18 R 19 , or R 6a and R 6b together with the carbon atom to which they are directly attached form a C(O), C 3-6 cycloalkyl or 3-6 membered heterocyclyl;

[0105] 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, -SF5, -O-R 16 and -NR 18 R 19 ;

[0106] wherein R 15 , R 16 , R 17 , R 18 , R 19 and r are as defined for the compound of formula (I).

[0107] As a still further preferred option, in the compound of formula (I), in the stereoisomer thereof, or in the pharmaceutically acceptable salt thereof, R3is selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl and 5-8 membered heteroaryl, 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, C 6-8 aryl, 5-8 membered heteroaryl, -S(O) r R 15 , -O-R 16 , -C(O)OR 16 , -C(O)R 17 , -O-C(O)R 17 , -P(O)(R 17 )2, -NR 18 R 19 , -C(O)NR 18 R 19and -N(R 18 -C(O)R 17 substituted with one or more substituents selected from the group consisting of deuterium, halogen, cyano, C

[0108] R4is selected from the group consisting of hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, and 5-8 membered heteroaryl, each of which is independently and 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, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, =O, -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 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, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, =O, -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 ;

[0109] 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).

[0110] As a still further preferred embodiment, in the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, R3is selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, 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 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 ;

[0111] R4is selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, 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 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, 5-8 membered heteroaryl, -O-R 16 , -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, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, =O, -O-R 16 , -C(O)R 17 , and -NR 18 R 19 ;

[0112] wherein R 16 , R 17 , R 18 , and R 19 are as defined for the compound of formula (I).

[0113] As a further preferred option, in the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, R7is selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 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, -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 , 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 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 ;

[0114] 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).

[0115] As a still further preferred option, in the compound of formula (I), stereoisomer thereof, or pharmaceutically acceptable salt thereof, R7is selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, and 3-6 membered heterocyclyl, each of which is independently and 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, 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)(R17 )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 ;

[0116] 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).

[0117] As a still further preferred option, in the compound of formula (I), stereoisomer or pharmaceutically acceptable salt thereof, R2is selected from hydrogen, halogen, -(L) s -O-(L) s -R 2a , -(L) s -O-(L) s -NR 2b R 2c and 3-6 membered heterocyclyl, said -(L) s -O-(L) s -R 2a , -(L) s -O-(L) s -NR 2b R 2c or 3-6 membered heterocyclyl 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, =O, =S, -SF5, -O-R 16 and -NR 18 R 19 ;

[0118] each s is independently 0, 1, 2, or 3;

[0119] each L is 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 alkylene, C 2-4 alkenylene, C 2- alkynylene, 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 each of which is independently and optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, C

[0120] R 2a is selected from hydrogen, deuterium, C 1-4 alkyl, C 2-4 alkenylene, C 3-6 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-8 aryl and 5-8 membered heteroaryl, each of which is optionally and 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 alkylene, 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 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 aryl, 5-8 membered heteroaryl, =0, =S, -SF5, -O-R 16 and -NR 18 R 19 each of which is independently and optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, C

[0121] R 2b and R 2c are each independently selected from hydrogen, deuterium, C 1-4 alkyl, C 2-4 alkenylene, C 2-4 alkynylene, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8aryl, 5-8 membered heteroaryl, sulfonyl, methylsulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, and C 1-4 alkanoyl, the above groups are 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 6-8 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 substituted by one or more substituents selected from the group consisting of deuterium, halogen, hydroxyl, =0, C

[0122] 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, =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 substituted by one or more substituents selected from the group consisting of deuterium, halogen, hydroxyl, =0, C

[0123] wherein R 16 , R 18 and R 19 are as defined for the compound of formula (I).

[0124] As a further preferred option, in the compound of formula (I), stereoisomer thereof, or pharmaceutically acceptable salt thereof, R2is selected from -(L) s -O-(L) s -R2a or 3-6 membered heterocyclyl, and the foregoing -(L) s -O-(L) s -R 2a or 3-6 membered heterocyclyl is independently and optionally further substituted by one or more substituents independently selected from deuterium, halogen, cyano, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, halosubstituted C 1-4 alkyl, halosubstituted C 1-4 alkoxy, deuterium-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkylene, 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, C 3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, =0, =S, -SF5, amino, mono- C 1-4 alkylamino and di- C 1-4 alkylamino, and the foregoing -(L)

[0125] each s is independently 0, 1, 2 or 3;

[0126] each L is independently selected from C 1-4 alkylene, C 3-6 cycloalkylene or 3-6 membered heterocyclylene, and the foregoing C 1-4 alkylene, C 3-6 cycloalkylene or 3-6 membered heterocyclylene is independently and optionally further substituted by one or more substituents independently selected from deuterium, halogen, cyano, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, halosubstituted C 1-4 alkyl, halosubstituted C 1-4 alkoxy, deuterium-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkylene, C 2-4 alkylene, C 2-4 alkynylene, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, =0, =S, -SF5, amino, mono- C 1- alkylamino and di- C 1-4 alkylamino, and the foregoing -(L)

[0127] R 2a is selected from hydrogen, deuterium, C 1-4 alkyl, C 2-4 alkenylene, C 3-6 cycloalkyl, the above-mentioned 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, 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- to 6-membered heterocyclyl, 3- to 6-membered heterocyclyloxy, =0, =S, -SF5, amino, mono- and di-C 1-4 alkylamino and di-C 1-4 alkylamino, substituted by one or more substituents selected from the group consisting of deuterium, halogen, cyano, hydroxyl, C

[0128] each s is independently 0, 1, 2 or 3.

[0129] As a still further preferred option, in the compound of formula (I), in the stereoisomer thereof or in the pharmaceutically acceptable salt thereof, R2is selected from

[0130] each R 2a1 is each independently selected from the group consisting of hydrogen, deuterium, hydroxyl, amino, methylamino, dimethylamino, fluorine, chlorine, methyl, ethyl, isopropyl, ethenyl, allyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, the above-mentioned groups are optionally further substituted by one or more substituents selected from the group consisting of deuterium, halogen, cyano, hydroxyl, C 1-4 alkylene, halogen-substituted C 1-4 alkylene, deuterium-substituted C 1-4 alkylene, ethenyl, ethynyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, =0, =S, -SF5, amino, methylamino and dimethylamino, substituted by one or more substituents selected from the group consisting of deuterium, halogen, cyano, hydroxyl, C

[0131] R 2a2selected from hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, C 1-4 alkylene, halogen-substituted C 1-4 alkylene, deuterium-substituted C 1-4 alkylene, vinyl, allyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl and azetanyl;

[0132] R 2a3 selected from hydrogen, deuterium, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetanyl, the aforementioned groups are 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, C 1-4 alkylene, halogen-substituted C 1-4 alkylene, deuterium-substituted C 1-4 alkylene, vinyl, ethynyl, cyclopropyl, cyclobutyl, oxetanyl, azetanyl, =0, =S, -SF5, amino, methylamino and dimethylamino;

[0133] each R 2a4 and each R 2a5 are each independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl and cyclopropyl;

[0134] R 2b1 selected from hydrogen, deuterium, methyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, ethyl, isopropyl, vinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl and azetanyl.

[0135] As a still further preferred option, in the compound of formula (I), in the stereoisomer thereof or in the pharmaceutically acceptable salt thereof, each R 5a 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 3-6 cycloalkyl and 3-6 membered heterocyclyl;

[0136] each R 6a 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, C3-6 cycloalkyl and 3-6 membered heterocyclyl.

[0137] As a further preferred aspect, in the compound of formula (I), stereoisomer thereof, or pharmaceutically acceptable salt thereof, R 10 is selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, cyano, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 3-6 alkenyl, C 1-1 alkynyl, C 1-2 cycloalkyl, 3-6 membered heterocyclyl, amino, methylamino and dimethylamino.

[0138] As a 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 (V 1-3 ), a compound of formula (V 2-1 ), a compound of formula (V 2-2 ), a compound of formula (V 2-3 ), a compound of formula (V 1-1 ), or a compound of formula (V 2-1 ):

[0139] wherein, in the compound of formula (V 1i ), or the compound of formula (V 1j ), each R 1k , each R 1-4 , and each R 1-4 is independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen-substituted C 2-4 alkyl, deuterium-substituted C 2-4 alkyl, C 3-6 alkenyl, C 16 alkynyl, C 18 cycloalkyl, 3-6 membered heterocyclyl, -O-R 19 , and -NR 1-2 R 2-2 ;

[0140] In the compound of formula (V 1a ), or the compound of formula (V 1b ), each Z1 is independently O, S or NH; each Z2 is independently CR 1e or N; each Z3 is independently CR 1a or N; and each Z6 is independently CR 1b or N.

[0141] each R 1c , each R1d and each R 1e is 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, -O-R 16 and -NR 18 R 19 ;

[0142] In the compound of formula (V 1-3 ) or the compound of formula (V 2-3 ), each Z7is each independently CR 1f or N; each Z9is each independently CR 1h or N;

[0143] each R 1f , each R 1g and each R 1h is 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, -O-R 16 and -NR 18 R 19 ;

[0144] each R 1L and each R 1m is 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, -O-R 16 and -NR 18 R 19 ;

[0145] each R2is each independently selected from

[0146] each R 2a1each independently selected from the group consisting of hydrogen, deuterium, hydroxyl, amino, methylamino, dimethylamino, fluorine, chlorine, methyl, ethyl, isopropyl, vinyl, allyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, the aforementioned 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, C 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;

[0147] each R 2a2 each independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, C 1-4 alkylene, halogen-substituted C 1-4 alkylene, deuterium-substituted C 1-4 alkylene, vinyl, allyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, and azetidinyl;

[0148] each R 2a3 each independently selected from the group consisting of hydrogen, deuterium, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, the aforementioned 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, C 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;

[0149] each R 2a4 and each R 2a5 each independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, and cyclopropyl;

[0150] each R 2b1 is each independently selected from hydrogen, deuterium, methyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, ethyl, isopropyl, ethenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, or azetidinyl;

[0151] each R3is each independently selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, and 5-8 membered heteroaryl, which 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- 6cycloalkyl, 3-6 membered heterocyclyl, -O-R 16 , and -NR 18 R 19 , which are independently optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, C

[0152] each R4is each independently selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, and 5-8 membered heteroaryl, which 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, 3-6 membered heterocyclyl, 5-8 membered heteroaryl, -O-R 16 , -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 deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, =O, -O-R 16 , -C(O)R 17 , and -NR 18 R 19 , which are independently optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, C

[0153] each R 10 is each independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, C1-4 alkyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, amino, methylamino and dimethylamino;

[0154] wherein R 16 , R 17 , R 18 and R 19 are as defined for the compound of formula (I).

[0155] As a preferred option, in the compound of formula (I), stereoisomer thereof or pharmaceutically acceptable salt thereof, the compound of formula (I) is a compound of formula (VI 1-1 ), a compound of formula (VI 1-2 ), a compound of formula (VI 1-3 ), a compound of formula (VI 1-4 ), a compound of formula (VI 1-5 ), a compound of formula (VI 1-6 ), a compound of formula (VI 1-7 ), a compound of formula (VI 1-8 ), a compound of formula (VI 1-9 ), a compound of formula (VI 1-10 ), a compound of formula (VI 1-11 ), a compound of formula (VI 1-12 ), a compound of formula (VI 1-13 ), a compound of formula (VI 1-14 ), or a compound of formula (VI

[0156] wherein each Q1 is independently CH or N; each Q2 is independently CR 3b or N; each Q3 is independently CH or N;

[0157] each R 3b is independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, methyl, ethyl, n-propyl, i-propyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy and dideuteromethoxy;

[0158] In the compound of formula (VI 1-1 ), the compound of formula (VI 1-2 ), the compound of formula (VI 1-3 ), the compound of formula (VI 1-4 ), the compound of formula (VI 1-5 ), or the compound of formula (VI 1-6 ), each R 1i , each R 1jand 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;

[0159] in the compound of formula (VI 1-7 ), the compound of formula (VI 1-8 ), the compound of formula (VI 1-9 ), the compound of formula (VI 1-10 ), the compound of formula (VI 1-11 ), or the compound of formula (VI 1-12 ), each Z7is each independently CR 1f or N; each Z9is each independently CR 1h or N;

[0160] each R 1f , each R 1g , and each R 1h 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;

[0161] each R 1L , and each R 1m 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;

[0162] in the compound of formula (VI 1-13 ) or the compound of formula (VI 1-14 ), each Z1is each independently O, S, or NH; each Z2is each independently CR 1a or N; each Z3is each independently CR 1b or N; each Z6is each independently CR 1e or N;

[0163] each R 1a , each R 1b , and each R1c , each R 1d , and each R 1e is independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, methyl, ethyl, n-propyl, i-propyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, vinyl, allyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, amino, methylamino, and dimethylamino;

[0164] each M1is independently a bond, O, CHR 2a10 , or CR 2a11 ; M2is N or CH; M3is N or CR 2a12 ;

[0165] In the compound of formula (VI 1-3 ) or the compound of formula (VI 1-12 ), each R 2a1 is independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, i-propyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, C 1-4 4alkylene, halosubstituted C 1-4 4alkylene, deuterium- substituted C 1-4 4alkylene, vinyl, allyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, amino, methylamino, and dimethylamino;

[0166] In the compound of formula (VI 1-1 ), the compound of formula (VI 1-4 ), the compound of formula (VI 1-5 ), the compound of formula (VI 1-6 ), the compound of formula (VI 1-7 ), the compound of formula (VI 1-8 ), the compound of formula (VI 1-9 ), or the compound of formula (VI 1-13 ), each R 2a2 is independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, i-propyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, C 1- 4alkylene, halosubstituted C 1-4 4alkylene, deuterium- substituted C 1-4 4alkylene, vinyl, allyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, amino, methylamino, and dimethylamino;

[0167] In the compound of formula (VI 1-1compounds of formula (VI 1-2 compounds of formula (VI 1-4 compounds of formula (VI 1-5 compounds of formula (VI 1-6 compounds of formula (VI 1-7 compounds of formula (VI 1-8 compounds of formula (VI 1-10 compounds of formula (VI 1-11 compounds of formula (VI 1-13 compounds of formula (VI 1-14 each R 2a6 is each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, hydroxyl, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, methylene, fluoromethylene, difluoromethylene, deuterium- substituted C 1-4 alkylene, vinyl, ethynyl, cyclopropyl, cyclobutyl, oxetanyl, azetanyl, =0, =S, -SF5, amino, methylamino, and dimethylamino;

[0168] in compounds of formula (VI 1-1 compounds of formula (VI 1-2 compounds of formula (VI 1-7 compounds of formula (VI 1-10 compounds of formula (VI 1-11 compounds of formula (VI 1-13 compounds of formula (VI 1-14 each R 2a7 is each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, hydroxyl, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, methylene, fluoromethylene, difluoromethylene, deuterium- substituted C 1-4 alkylene, vinyl, ethynyl, cyclopropyl, cyclobutyl, oxetanyl, azetanyl, =0, =S, -SF5, amino, methylamino, and dimethylamino;

[0169] in compounds of formula (VI 1-4 compounds of formula (VI 1-8 compounds of formula (VI 1-9 each R 2a8 is each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, hydroxyl, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, vinyl, ethynyl, cyclopropyl, cyclobutyl, oxetanyl, azetanyl, -SF5, amino, methylamino, and dimethylamino;

[0170] In formula (VI) 1-4 ) compounds, formula (VI) 1-8 ) compounds or formula (VI) 1-9 In the compound, each R 2a9 Each is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideutermethyl, dideutermethyl, methoxy, trifluoromethoxy, difluoromethoxy, trideutermethoxy, dideutermethoxy, vinyl, ethynyl, cyclopropyl, cyclobutyl, oxetyl, aziridine, -SF5, amino, methylamino, and dimethylamino;

[0171] Each R 2a10 Each is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideutermethyl, dideutermethyl, methoxy, trifluoromethoxy, difluoromethoxy, trideutermethoxy, dideutermethoxy, vinyl, ethynyl, cyclopropyl, cyclobutyl, oxetyl, aziridine, -SF5, amino, methylamino, and dimethylamino;

[0172] Each R 2a11 Each is independently selected from monofluoromethylene, difluoromethylene, and deuterium-substituted C. 1-4 Alkylene, =O or =S;

[0173] Each R 2a12 Each is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideutermethyl, dideutermethyl, methoxy, trifluoromethoxy, difluoromethoxy, trideutermethoxy, dideutermethoxy, vinyl, ethynyl, cyclopropyl, cyclobutyl, oxetyl, aziridine, -SF5, amino, methylamino, and dimethylamino;

[0174] In formula (VI) 1-12 In the compound, R 2b1 Selected from hydrogen, deuterium, methyl, trifluoromethyl, difluoromethyl, trideuterium methyl, dideuterium methyl, ethyl, isopropyl, vinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl or aziridine;

[0175] In formula (VI) 1-6 ) compounds or formula (VI) 1-9 In the compound, each R 2b2 Each is independently selected from hydrogen, deuterium, methyl, trifluoromethyl, difluoromethyl, trideuterium methyl, dideuterium methyl, ethyl, isopropyl, vinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl or aziridine;

[0176] Each R4 is independently selected from hydrogen, C 1-4 Alkyl, C 3-6cycloalkyl and 3-6 membered heterocyclyl, each of which is independently and optionally further substituted by one or more substituents selected from the group consisting of deuterium, halogen, cyano, C1-6alkyl, 1-4 C1-6alkyl, 2-4 C1-6alkenyl, 2- C1-6alkynyl, 3-6 cycloalkyl, 3-6 membered heterocyclyl, 5-8 membered heteroaryl, -O-R 16 , -C(O)R 18 R 19 , -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 the group consisting of deuterium, halogen, cyano, C1-6alkyl, 1-4 C1-6alkyl, 2-4 C1-6alkenyl, 2-4 C1-6alkynyl, 3-6 cycloalkyl, 3-6 membered heterocyclyl, =O, -O-R 16 , -C(O)R 17 and -NR 18 R 19 ;

[0177] wherein R 16 , R 17 , R 18 and R 19 are as defined for the compound of formula (I).

[0178] As a 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 (VI 2-1 ), a compound of formula (VI 2-2 ), or a compound of formula (VI 2-3 ):

[0179] wherein each Q1is independently CH or N; each Q2is independently CR 3b or N; and each Q3is independently CH or N.

[0180] each R 3b is 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, and dideuteromethoxy;

[0181] In the compound of formula (VI 2-1 ), R 1i , R 1j and R 1keach 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, vinyl, allyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, oxetanyl, azetanyl, amino, methylamino, and dimethylamino;

[0182] In the compound of formula (VI 2-2 ), Z7is CR 1f or N; Z9is CR 1h or N;

[0183] 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, i-propyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, vinyl, allyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, oxetanyl, azetanyl, amino, methylamino, and dimethylamino;

[0184] R 1L , and R 1m 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, vinyl, allyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, oxetanyl, azetanyl, amino, methylamino, and dimethylamino;

[0185] In the compound of formula (VI 2-3 ), Z1is O, S, or NH; Z2is CR 1a or N; Z6is CR 1e or N;

[0186] R 1a , R 1c , R 1d , and R 1e 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, vinyl, allyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, oxetanyl, azetanyl, amino, methylamino, and dimethylamino;

[0187] each R 2a2each independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, C 1-4 alkylene, halo-substituted C 1-4 alkylene, deuterium-substituted C 1-4 alkylene, vinyl, allyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, and azetidinyl;

[0188] each R 2a6 is each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, hydroxyl, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, C 1-4 alkylene, halo-substituted C 1-4 alkylene, deuterium-substituted C 1-4 alkylene, vinyl, acetylenic, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, =0, =S, -SF5, amino, methylamino, and dimethylamino;

[0189] each R 2a7 is each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, hydroxyl, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, C 1-4 alkylene, halo-substituted C 1-4 alkylene, deuterium-substituted C 1-4 alkylene, vinyl, acetylenic, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, =0, =S, -SF5, amino, methylamino, and dimethylamino;

[0190] each R4is each independently selected from the group consisting of hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl, said groups 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- 4alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, 5-8 membered heteroaryl, -O-R 16 , -NR 18 R 19 , -C(O)NR 18 R 19 , and -N(R 18 )-C(O)R 17 , said groups are independently optionally further substituted by one or more substituents selected from the group consisting of deuterium, halogen, cyano, C1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, =0, -0-R 16 , -C(O)R 17 , and -NR 18 R 19 substituted by R

[0191] wherein R 16 , R 17 , R 18 , and R 19 are as defined for the compound of formula (I).

[0192] As most preferred, the compound of formula (I), stereoisomer thereof, or pharmaceutically acceptable salt thereof includes, but is not limited to, the following compounds:

[0193] 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.

[0194] 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 the treatment of a KRAS-associated tumor.

[0195] As preferred, the KRAS-associated tumor 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.

[0196] As further preferred, the tumor is a cancer.

[0197] As a further preferred aspect, 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 gall bladder cancer, an ampullae cancer, a small intestine cancer, a large intestine cancer, a kidney cancer, a testicular cancer, a blood cancer, an angioma, a myeloma, a chondroma, a skull cancer, a brain cancer, a neuroglioma, 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.

[0198] 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.

[0199] 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.

[0200] As a preferred aspect, 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 gall bladder cancer, an ampullae cancer, a small intestine cancer, a large intestine cancer, a kidney cancer, a testicular cancer, a blood cancer, an angioma, a myeloma, a chondroma, a skull cancer, a brain cancer, a neuroglioma, 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. DETAILED DESCRIPTION

[0201] The inventors of the present application have made extensive and in-depth research and first developed a KRAS inhibitor having 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.

[0202] DETAILED DESCRIPTION: Unless otherwise indicated, the following terms used in the specification and claims have the following meanings.

[0203] "Alkyl" refers to straight chain or branched chain saturated aliphatic hydrocarbon groups, preferably including alkyl groups of from 1 to 10 or 1 to 6 carbon atoms or 1 to 4 carbon atoms, including but not limited to methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, s-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 isomers thereof, and the like. "C 1-21 "Alkyl" refers to straight chain and branched chain alkyl groups including 1 to 21 carbon atoms, "C 1-10 "Alkyl" refers to straight chain and branched chain alkyl groups including 1 to 10 carbon atoms, "C 1-4 "Alkyl" refers to straight chain and branched chain alkyl groups including 1 to 4 carbon atoms, "C 0-8 "Alkyl" refers to straight chain and branched chain alkyl groups including 0 to 8 carbon atoms, "C 0-4 "Alkyl" refers to straight chain and branched chain alkyl groups including 0 to 4 carbon atoms.

[0204] Alkyl 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, 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- 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 .

[0205] "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:

[0206] The boxed line with the arrow indicates a methylene group.

[0207] "Alkylene" when attached at different atoms refers to a group of the formula "-R-" preferably including straight-chain alkylene 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.

[0208] Alkylene can be optionally substituted or unsubstituted, when substituted the substituent is preferably one or more (preferably 1, 2, 3, or 4) group 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 0-8 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 R19 , -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 .

[0209] "Cycloalkyl" or "carbocyclic" refers to saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituents, which means that the cyclic hydrocarbon can contain one or more (preferably 1, 2, or 3) double bonds, but no ring has a completely conjugated pi-electron system. Cycloalkyl groups are classified as monocyclic cycloalkyl groups, polycyclic cycloalkyl groups, preferably including cycloalkyl groups of 3 to 12 or 3 to 8 or 3 to 6 carbon atoms, for example, "C 3-12 ycloalkyl" refers to cycloalkyl groups including 3 to 12 carbon atoms, "C 3-10 ycloalkyl" refers to cycloalkyl groups including 3 to 10 carbon atoms, "C 3-8 ycloalkyl" refers to cycloalkyl groups including 3 to 8 carbon atoms, "C 3-6 ycloalkyl" refers to cycloalkyl groups including 3 to 6 carbon atoms, wherein:

[0210] Monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like.

[0211] Polycyclic cycloalkyl groups include spirocyclic, fused, and bridged cycloalkyl groups. "Spirocycloalkyl" refers to polycyclic groups in which single rings share one 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 completely conjugated pi-electron system. Spirocycloalkyl groups are classified as monospirocycloalkyl, dispirocycloalkyl, or polyspirocycloalkyl groups depending on the number of spiro atoms shared between rings, and include, but are not limited to:

[0212] "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 completely conjugated pi-electron system. Fused cycloalkyl groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused cycloalkyl groups depending on the number of rings comprising the group, and include, but are not limited to:

[0213] "Bridged cycloalkyl" refers to a polycyclic aromatic hydrocarbon group in which any two rings share two non-directly bonded carbon atoms. These groups may contain one or more (preferably 1, 2, or 3) double bonds, but none of the rings has a fully conjugated π-electron system. Based on the number of constituent rings, bridged cycloalkyl groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic. Bridged cycloalkyl groups include, but are not limited to:

[0214] The cycloalkyl ring can be fused to an aryl, heteroaryl, or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl ring, including but not limited to indanyl, tetrahydronaphthyl, benzocycloheptyl, etc.

[0215] When a "cycloalkyl" group is attached to two different groups, it is called a "cycloalkylene group," including but not limited to:

[0216] The cycloalkyl or cycloalkylene 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 0-8alkyl-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 .

[0217] "Heterocyclyl" or "heterocycle" means a saturated or partially unsaturated monocyclic or polycyclic ring cyclic hydrocarbon substituent, which partially unsaturated cyclic hydrocarbon means that the cyclic hydrocarbon can contain one or more (preferably 1, 2, or 3) double bonds, but no ring has a completely conjugated pi-electron system, one or more (preferably 1, 2, 3, or 4) ring atoms of the heterocyclyl are selected from N, O, N-O, or S(O) r (where r is an integer 0, 1, 2) heteroatoms, but excluding ring members of -O-O-, -O-S-, or -S-S-, the remaining ring atoms are carbon. Preferred heterocyclyl groups include 3 to 12 or 3 to 8 or 3 to 6 ring atoms, for example, "3-6 membered heterocyclyl" means a heterocyclyl group comprising 3 to 6 ring atoms, "3-8 membered heterocyclyl" means a heterocyclyl group comprising 3 to 8 ring atoms, "4-8 membered heterocyclyl" means a heterocyclyl group comprising 4 to 8 ring atoms, "4-10 membered heterocyclyl" means a heterocyclyl group comprising 4 to 10 ring atoms, "5-8 membered heterocyclyl" means a heterocyclyl group comprising 5 to 8 ring atoms, "3-12 membered heterocyclyl" means a heterocyclyl group comprising 3 to 12 ring atoms.

[0218] Monocyclic heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, oxetanyl, tetrahydrofuranyl, and the like.

[0219] Polycyclic heterocyclyl groups include spiro, fused, and bridged ring heterocyclyl groups. "Spiroheterocyclyl" means a polycyclic heterocyclyl group that shares one atom (referred to as a spiro atom) between single rings, wherein one or more (preferably 1, 2, 3, or 4) ring atoms are selected from N, O, N-O, or S(O) rheteroatoms, the remaining ring atoms being carbon. These can contain one or more double bonds (preferably 1, 2, or 3), but no ring has a completely conjugated pi-electron system. Spiroheterocyclyl groups are classified as mono-, bi-, or polycyclic depending on the number of rings that share a common spiro atom between rings. Spiroheterocyclyl groups include, but are not limited to:

[0220] “Fused heterocyclyl” refers to a polycyclic heterocyclic radical wherein each ring in the system shares a pair of adjacent atoms with another ring 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 no ring has a completely 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 heteroatoms, the remaining ring atoms being carbon. Depending on the number of rings that make up the ring system, fused heterocycloalkyl groups can be bicyclic, tricyclic, tetracyclic, or polycyclic, fused heterocyclyl groups include, but are not limited to:

[0221] “Bridged heterocyclyl” refers to a polycyclic heterocyclic radical wherein any two rings share two non-adjacent atoms, these can contain one or more (preferably 1, 2, or 3) double bonds, but no ring has a completely 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 heteroatoms, the remaining ring atoms being carbon. Depending on the number of rings that make up the ring system, bridged heterocycloalkyl groups can be bicyclic, tricyclic, tetracyclic, or polycyclic, bridged heterocyclyl groups include, but are not limited to:

[0222] The heterocyclyl ring can be fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring that is attached to the parent structure is a heterocyclyl, including, but not limited to:

[0223] When “heterocycloalkyl” is attached to a different radical it is referred to as “heterocycloalkylene”, including, but not limited to:

[0224] Heterocyclyl or heterocycloalkylene groups 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, halosubstituted C 1-10 alkyl, deuterium-substituted C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12cycloalkyl, 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 .

[0225] "aryl" or "aromatic ring" means a monocyclic or fused polycyclic (that is, rings that share adjacent pairs of carbon atoms) ring radical, a polycyclic (that is, rings that share adjacent pairs of carbon atoms) ring radical having a conjugated pi electron system, preferably a homocyclic aryl radical containing 6-10 or 6-8 carbons, for example, "C 6-10"Aryl" means a fully carbon-based aryl group containing 6-10 carbons. Examples include, but are not limited to, phenyl and naphthyl. "C 6-8 "Aryl" means a fully carbon-based aryl group containing 6-8 carbons. The aryl ring can be fused to a heteroaryl, heterocyclyl, or cycloalkyl ring, where the ring that is attached to the parent structure is the aryl ring, including, but not limited to:

[0226] "Aryl" can be 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, =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 )R17 -C(=O)R 0-8 -C(=O)N(R 18 )2 19 -C(=NR 17 )R 0-8 -C(=O)OR 18 R 19 -C(=O)SR 0-8 R 18 -C(=O)N(R 17 )2

[0227] "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:

[0228] "Heteroaryl" 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, =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 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 .

[0229] "Alkenyl" refers to 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 2-10 or 2-4 carbons, for example, "C 2-10 "Alkenyl" refers to a straight-chain or branched alkenyl group containing 2-10 carbons. 2-4 "Alkenyl" refers to straight-chain or branched alkenyl groups containing 2-4 carbons. These include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl groups.

[0230] The "alkenyl" 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 6-10aryl, 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 .

[0231] "alkynyl" means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, preferably a straight-chain or branched alkynyl group having 2 to 10 or 2 to 4 carbons, for example, "C 2-10 alkynyl" means a straight-chain or branched alkynyl group having 2 to 10 carbons, "C 2-4"Alkynyl" refers to straight-chain or branched-chain alkynyl groups having from 2 to 4 carbons. Included within this term are ethynyl, 1 -propynyl, 2-propynyl, 1 -, 2-, or 3-butynyl, and the like.

[0232] "Alkynyl" can be substituted or unsubstituted, and when substituted is preferably substituted with one or more (preferably 1, 2, 3, or 4) groups independently selected from deuterium, halo, cyano, nitro, azido, C 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 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 )R17 , -C 0-8 alkyl-C(O)NR 18 R 19 and -C 0-8 alkyl-N(R 18 )-C(O)R 17 .

[0233] "Alkoxy" means -O-alkyl, where 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.

[0234] "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, 3-12 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)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 .

[0235] "Cycloalkoxy" or "cycloalkyloxy" refers to -O-cycloalkyl where 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.

[0236] "Cycloalkoxy" or "cycloalkyloxy" can be optionally substituted or unsubstituted, and when substituted, is preferably substituted with 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- 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)2R15 -C(O)OR 0-8 r R 15 -C(O)SR 0-8 16 -C(O)R 0-8 16 -C(O)OR 0-8 16 -C(O)SR 0-8 17 -C(O)R 0-8 17 -C(O)OR 0- 17 -C(O)SR 0-8 17 -C(O)R 0-8 18 -C(=NR 19 )R 0-8 18 -C(=NR 17 )R 0-8 18 -C(=NR 19 )R 17 0-8 -C(O)NR 18 19 -C(O)R 0-8 18 -C(O)R 17 .

[0237] "Heterocyclyloxy" or "heterocyclyl-oxy" means -O-heterocyclyl, where heterocyclyl is as defined above, including, but not limited to, azetidinyloxy, oxetanyloxy, azetidinyl, oxetanyl, azetidinyl, oxetanyl, and the like.

[0238] "Heterocyclyloxy" or "heterocyclyl-oxy" can be optionally substituted or unsubstituted, and when substituted, is preferably substituted with one or more (preferably 1, 2, 3, or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C 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, 3-12 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)(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 .

[0239] "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" is acetyl; "C2alkanoyl" is propionyl; and "C3alkanoyl" is butanoyl or isobutanoyl.

[0240] "C0-8 alkyl-S(O)(=N-R 12 )R 13 " indicates the sulfur atom in -S(O)(=N-R 12 )R 13 is attached to a C 0-8 alkyl group, wherein C 0-8 alkyl is as defined above.

[0241] "C 0-8 alkyl-N=S(O)R 13 R 14 " indicates 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.

[0242] "C 0-8 alkyl-N=SR 13 R 14 " indicates the nitrogen atom in -N=SR 13 R 14 is attached to a C 0-8 alkyl group, wherein C 0-8 alkyl is as defined above.

[0243] "C 0-8 alkyl-O-S(O)2R 15 " indicates the oxygen atom in -O-S(O)2R 15 is attached to a C 0-8 alkyl group, wherein C 0- 8alkyl is as defined above.

[0244] "C 0-8 alkyl-S(O) r R 15 " indicates the sulfur atom in -S(O) r R 15 is attached to a C 0-8 alkyl group, wherein C 0-8 alkyl is as defined above.

[0245] "C 0-8 alkyl-O-R 16 " indicates the oxygen atom in -O-R 16 is attached to a C 0-8 alkyl group, wherein C 0-8 alkyl is as defined above.

[0246] "C 0-8 alkyl-C(O)OR 16 " indicates -C(O)OR 16The carbonyl group in the C10 group is linked to the carbonyl group in the C10 group. 0-8 On alkyl groups, where C 0-8 The definition of alkyl is as described above.

[0247] -C 0-8 Alkyl-C(O)SR 16 "Refers to -C(O)SR 16 The carbonyl group in the C10 group is linked to the carbonyl group in the C10 group. 0-8 On alkyl groups, where C 0-8 The definition of alkyl is as described above.

[0248] -C 0-8 Alkyl-SC(O)R 17 "Referring to -SC(O)R" 17 The sulfur atom in C is attached to C 0-8 On alkyl groups, where C 0-8 The definition of alkyl is as described above.

[0249] -C 0-8 Alkyl-C(O)R 17 "Referring to -C(O)R" 17 The carbonyl group in the C10 group is linked to the carbonyl group in the C10 group. 0-8 On alkyl groups, where C 0-8 The definition of alkyl is as described above.

[0250] -C 0-8 Alkyl-OC(O)R 17 "Refers to -OC(O)R 17 The oxygen atom in C is attached to C 0-8 On alkyl groups, where C 0-8 The definition of alkyl is as described above.

[0251] -C 0-8 Alkyl-P(O)(R) 17 )2” refers to -P(O)(R 17 The phosphorus atom in )2 is attached to C 0-8 On alkyl groups, where C 0-8 The definition of alkyl is as described above.

[0252] -C 0-8 Alkyl-NR 18 R 19 "Referring to -NR" 18 R 19 The nitrogen atom in C is attached to C 0-8 On alkyl groups, where C 0-8 The definition of alkyl is as described above.

[0253] -C 0-8 Alkyl-C (=NR) 18 )R 17 "Refers to -C(=NR)" 18)R 17 wherein the carbon atom is attached to a C 0-8 alkyl group, wherein the carbon atom is attached to a C 0-8 alkyl group, wherein the carbon atom is attached to a C

[0254] "-C 0-8 alkyl-N(R 18 )-C(=NR 19 )R 17 " means a -C(=NR 18 )R 19 group wherein the nitrogen atom is attached to a C 17 alkyl group, wherein the carbon atom is attached to a C 0-8 alkyl group, wherein the carbon atom is attached to a C 0-8 alkyl group, wherein the carbon atom is attached to a C

[0255] "-C 0-8 alkyl-C(O)NR 18 R 19 " means a -C(O)NR 18 R 19 group wherein the carbonyl group is attached to a C 0-8 alkyl group, wherein the carbon atom is attached to a C 0- 8alkyl group, wherein the carbon atom is attached to a C

[0256] "-C 0-8 alkyl-N(R 18 )-C(O)R 17 " means a -N(R 18 )-C(O)R 17 group wherein the nitrogen atom is attached to a C 0-8 alkyl group, wherein the carbon atom is attached to a C 0-8 alkyl group, wherein the carbon atom is attached to a C

[0257] "halo-substituted C 1-10 alkyl" means an alkyl group of 1 to 10 carbons in which the hydrogens are optionally replaced with fluorine, chlorine, bromine, or iodine atoms. Included, but not limited to, difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, and the like.

[0258] "halo-substituted C 1-10 alkoxy" means an alkoxy group of 1 to 10 carbons in which the hydrogens are optionally replaced with fluorine, chlorine, bromine, or iodine atoms. Included, but not limited to, difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, tribromomethoxy, and the like.

[0259] "deuterium-substituted C 1-10 alkyl" means an alkyl group of 1 to 10 carbons in which the hydrogens are optionally replaced with deuterium atoms. Included, but not limited to, monodeuteromethyl, diduteromethyl, trideuteromethyl, and the like.

[0260] "halogen" means fluorine, chlorine, bromine, or iodine.

[0261] "Optional" 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. For example, "heterocyclic groups optionally substituted with alkyl" means that alkyl can or can not be present, and the description includes instances where the heterocyclic group is substituted with alkyl and instances where the heterocyclic group is not substituted with alkyl.

[0262] "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 those skilled in the art can determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, an amino group with free hydrogen or a hydroxyl group can be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0263] "Stereoisomer", the English name of which is stereoisomer, refers to isomers produced by the different spatial arrangement of atoms in the molecule, which can be divided into cis-trans isomers, enantiomers, and also into enantiomers and diastereoisomers. The stereoisomer caused by the rotation of single bond is called conformational stereo-isomer, sometimes also called rotamer. The stereoisomer caused by bond length, bond angle, double bond in the molecule, ring, etc. is called configuration stereo-isomer, which is divided into two categories. Among them, the isomer caused by the non-free rotation of the single bond of the double bond or the ring carbon atom becomes geometric isomer (geometric isomer), also known as cis-trans isomer, which is divided into Z, E two 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 anti-symmetry in the molecule is called optical isomer, which is divided into R, S configuration. In the present invention, "stereoisomer" is understood to include one or more of the above enantiomers, configuration isomers and conformational isomers unless otherwise specified.

[0264] "Pharmaceutically acceptable salt" in the present invention 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.

[0265] "Prodrug" or "precursor drug" in the present invention means a compound which is converted or solvolyzed into a specific compound or a pharmaceutically acceptable salt of such compound under physiological conditions before exhibiting its physiological effect. Although not necessarily, the prodrug is usually pharmacologically inactive before being converted into the specific compound (also called parent drug or parent compound). Typically, the purpose of the prodrug is to improve chemical stability, improve patient acceptance and compliance, improve bioavailability, prolong the action time, improve organ selectivity, increase water solubility and / or reduce side effects, etc. The preparation technique of the prodrug can use the methods known in the art, such as Burger's Medicinal Chemistry and Drug Chemistry, 1, 172-178, 949-982 (1995), etc.

[0266] "Pharmaceutical composition" means a mixture containing one or more compounds described herein or a physiologically / pharmaceutically acceptable salt or prodrug thereof with other chemical components, such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate the administration to the organism, facilitate the absorption of the active ingredient and thus exert the biological activity.

[0267] "Effective amount" in the present invention means a dose or concentration that is clinically capable of causing a minimum pharmacological effect, also known as minimum effective amount or threshold dose.

[0268] The present invention is further described in detail below with reference to the examples, but is by no means limited to the contents of the examples, and the present invention is not limited only to the contents of the examples.

[0269] The structure of the compounds of the present invention is determined by nuclear magnetic resonance (NMR) or / and liquid chromatography-mass spectrometry (LC-MS). The NMR chemical shift (δ) is given in units of parts per million (ppm). The NMR determination is made with a Bruker AVANCE-400 / 500 nuclear magnetic instrument, and the determination solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD or MeOH-d4) and deuterated chloroform (CDCl3), and the internal standard is tetramethylsilane (TMS).

[0270] The determination of liquid chromatography-mass spectrometry LC-MS uses an Agilent 6120 mass spectrometer. The determination of HPLC uses an Agilent 1200 DAD high-pressure liquid chromatograph (Sunfire C18 150x4.6mm chromatographic column) and a Waters 2695-2996 high-pressure liquid chromatograph (Gimini C18 150x4.6mm chromatographic column).

[0271] Thin layer chromatography silica gel plates were used Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates, TLC used specifications are 0.15mm-0.20mm, thin layer chromatography separation and purification of products used specifications are 0.4mm-0.5mm. Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as a carrier.

[0272] The starting materials in the embodiments of the present application are known and commercially available, or can be synthesized using or according to methods known in the art.

[0273] Unless otherwise specified, all reactions of the present application were carried out under continuous magnetic stirring, under a dry nitrogen or argon atmosphere, with dry solvents, and the reaction temperature unit is Celsius (°C).

[0274] I. Preparation of intermediates

[0275] Preparation of intermediate 1-1: 3-(2-(diphenylmethylene)-1-methylhydrazino)-N,N- di(4-methoxybenzyl)pyridin-2-amine

[0276] First step: synthesis of 3-bromo-N,N-di(4-methoxybenzyl)pyridin-2-amine

[0277] 3-bromo-pyridin-2-amine (5.0 g, 28.90 mmol) was dissolved in anhydrous THF (100 mL), and NaH (3.468 g, 86.70 mmol, purity: 60%) was slowly added under ice water bath cooling. After the addition was completed, the reaction was stirred at room temperature for 1 hour. PMBCl (11.81 mL, 86.7 mmol) was slowly added dropwise under ice water bath cooling, and the temperature was increased to 50°C and stirred overnight. After the reaction was completed, saturated aqueous ammonium chloride solution was added to quench, and extracted with ethyl acetate. The organic phase was concentrated, and the obtained residue was separated by flash silica gel column chromatography (ethyl acetate / petroleum ether 0-10%) to obtain 3-bromo-N,N-di(4-methoxybenzyl)pyridin-2-amine (5.61 g, yield: 47%). ESI-MS: 413.0 [M+1] + .

[0278] Second step: synthesis of 3-(2-(diphenylmethylene)hydrazino)-N,N-di(4-methoxybenzyl)pyridin-2-amine

[0279] 3-bromo-N,N-di(4-methoxybenzyl)pyridin-2-amine (3.00 g, 7.26 mmol) and (diphenylmethylene)hydrazine (2.14 g, 10.89 mmol) were dissolved in toluene (45 mL), and NaO tBu (1.40 g, 14.52 mmol), Pd(OAc)2(163 mg, 0.73 mmol) and Xantphos (420 mg, 0.73 mmol) were heated at 90 °C under nitrogen for 2 h. After the reaction was completed, it was cooled, quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was concentrated and the crude product was purified by flash column chromatography on silica gel (ethyl acetate / petroleum ether 5-15%) to give 3-(2-(diphenylmethylene)hydrazinyl)-N,N-bis(4-methoxybenzyl)pyridin-2-amine (3.70 g, yield: 96%). ESI-MS: 529.4 [M+1] + Third step: synthesis of 3-(2-(diphenylmethylene)-l-methylhydrazinyl)-N,N-bis(4- methoxybenzyl)pyridin-2-amine

[0280] 3-(2-(diphenylmethylene)hydrazinyl)-N,N-bis(4-methoxybenzyl)pyridin-2-amine (3.00 g, 5.675 mmol) was dissolved in dry THF (60 mL) and NaH (454 mg, 11.349 mmol, purity: 60%) was added slowly under ice-water bath cooling. The reaction was maintained at low temperature for 1 h. Then iodomethane (0.459 mL, 7.377 mmol) was added slowly dropwise to the reaction. After the addition was completed, the reaction was allowed to warm to room temperature and left overnight. After the reaction was completed, it was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was concentrated and the residue was purified by flash column chromatography on silica gel (ethyl acetate / petroleum ether 0-10%) to give 3-(2-(diphenylmethylene)-l-methylhydrazinyl)-N,N-bis(4-methoxybenzyl)pyridin-2-amine (2.632 g, yield: 85%). ESI-MS: 543.4 [M+1] + .

[0281] Intermediate 1-2: preparation of 3-(2-(diphenylmethylene)-l-ethylhydrazinyl)-N,N-bis(4- methoxybenzyl)pyridin-2-amine

[0282] 3-(2-(diphenylmethylene)hydrazinyl)-N,N-bis(4-methoxybenzyl)pyridin-2-amine (2g, 3.78 mmol) and iodoethane (3.63 mL, 45.40 mmol) were dissolved in anhydrous THF (50 mL), and a solution of LiHMDS / THF (7.57 mL, 7.57 mmol) was added dropwise slowly. After the addition was completed, the reaction was stirred for another 30 minutes. TLC monitoring of the reaction showed that the starting material had been consumed. It was quenched with an aqueous solution of ammonium chloride (100 mL), and the aqueous phase was extracted with ethyl acetate (50 mL) three times. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the concentrated residue was separated by flash silica gel column chromatography (eluent: EA / PE 0~8%) to obtain 3-(2-(diphenylmethylene)-1-ethylhydrazinyl)-N,N-bis(4-methoxybenzyl)pyridin-2-amine (1.9g, 3.41 mmol). ESI-MS: 557.2 [M+1] + .

[0283] 1 H NMR (400 MHz, CDCl3) δ 7.91 (s, 1H), 7.68 (d, J = 7.6 Hz, 1H), 7.63-7.57 (m, 2H), 7.40-7.31 (m, 3H), 7.05-6.98 (m, 5H), 6.88-6.82 (m, 4H), 6.79-6.72 (m, 5H), 4.23 (s, 4H), 3.79 (s, 6H), 3.57-3.48 (m, 2H), 1.04 (t, J = 7.2 Hz, 3H).

[0284] Preparation of Intermediate 1-3: 3-(2-(diphenylmethylene)-1-(4-methoxybenzyl)hydrazinyl)-N,N-bis(4-methoxybenzyl)pyridin-2-amine

[0285] Prepared according to Intermediate 1-2. ESI-MS: 649.3 [M+1] + .

[0286] 1 H NMR (400 MHz, CDCl3) δ 8.19 (d, J = 6.0 Hz, 1H), 7.91 (d, J = 8.0, 1H), 7.53-7.50 (m, 2H), 7.47-7.42 (m, 1H), 7.37-7.32 (m, 2H), 7.06-7.01 (m, 1H), 7.00-6.96 (m, 6H), 6.92-6.88 (m, 1H), 6.86-6.81 (m, 6H), 6.78-6.73 (m, 4H), 4.62 (s, 4H), 4.31 (s, 2H), 3.80 (s, 6H), 3.78 (s, 3H).

[0287] Preparation of Intermediate 1-4: 3-(2-(diphenylmethylene)-l-(2- methoxyethyl)hydrazino)-N,N-di(4-methoxybenzyl)pyridin-2-amine

[0288] Prepared according to the procedure of Intermediate 1-2. ESI-MS: 587.2 [M+1] + .

[0289] 1 H NMR (400 MHz, CDC13) δ 7.89 (s, 1H), 7.70-7.56 (m, 3H), 7.43-7.30 (m, 3H), 7.03-6.96 (m, 5H), 6.87-6.80 (m, 4H), 6.76-6.69 (m, 5H), 4.18 (s, 4H), 3.80-3.73 (m, 8H), 3.54 (t, J = 6.4 Hz, 2H), 3.26 (s, 3H).

[0290] Preparation of Intermediate 1-5: (R)-l-(l-(2-(di(4-methoxybenzyl)amino)pyridin-3-yl)-2- (diphenylmethylene)hydrazino)propan-2-ol

[0291] 3-(2-(diphenylmethylene)hydrazino)-N,N-di(4-methoxybenzyl)pyridin-2-amine (1.6 g, 3.03 mmol) and (R)-epoxypropane (2.12 mL, 30.27 mmol) were dissolved in dry THF (30 mL), a solution of LiHMDS / THF (6.05 mL, 6.05 mmol) was added dropwise at 0 °C, after the addition was completed, the reaction was continued to stir at 0 °C for 2.5 hours. LCMS monitoring of the reaction showed that the starting material had been consumed. Quench with water (60 mL), the aqueous phase was extracted with ethyl acetate (25 mL) three times. The combined organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated, and the concentrated residue was separated by flash silica gel column chromatography (eluent: EA / PE 0~20%) to give (R)-l-(l-(2-(di(4-methoxybenzyl)amino)pyridin-3-yl)-2- (diphenylmethylene)hydrazino)propan-2-ol (1.6 g, 2.73 mmol). ESI-MS: 587.4 [M+1] + .

[0292] 1H NMR (400 MHz, CDC13) δ 7.92 (d, J = 4.8, 1H), 7.55-7.51 (m, 2H), 7.50-7.45 (m, 1H), 7.43-7.38 (m, 1H), 7.36-7.30 (m, 2H), 6.96-6.88 (m, 5H), 6.84-6.78 (m, 4H), 6.77-6.73 (m, 4H), 6.72-6.67 (m, 1H), 4.33-4.19 (m, 3H), 4.10-4.01 (m, 2H), 3.79 (s, 6H), 3.76-3.70 (m, 1H), 3.40-3.32 (m, 1H), 1.10 (d, J = 6.4 Hz, 3H).

[0293] Intermediate 1-6: Preparation of (S)-1-(1-(2-(di(4-methoxybenzyl)amino)pyridin-3-yl)-2- (diphenylmethylene)hydrazino)propan-2-ol

[0294] Referring to Intermediate 1-5, the corresponding starting materials were selected for preparation. ESI-MS: 587.4 [M+1] + .

[0295] Intermediate 1-7: Preparation of 3-(2-(diphenylmethylene)-1-((tetrahydrofuran-2-yl)methyl)hydrazino)-N,N-di(4-methoxybenzyl)pyridin-2-amine

[0296] Referring to Intermediate 1-2, the corresponding starting materials were selected for preparation. ESI-MS: 613.3 [M+1] + .

[0297] Intermediate 1-8: Preparation of 2-(1-(2-(di(4-methoxybenzyl)amino)pyridin-3-yl)-2-(1- phenylethylidene)hydrazino)acetamide

[0298] Step 1: Synthesis of (1-phenylethylidene)hydrazine

[0299] To a solution of acetophenone (30 g, 249.686 mmol) in ethanol (300 mL) was added hydrazine hydrate (45.5 mL, 749.06 mmol, purity: 85%) at room temperature. The reaction was heated at 80 °C for 14 h. The reaction was quenched by adding water (600 mL) and extracted with ethyl acetate (300 mL) for 3 times. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The obtained crude product was separated by flash silica gel column chromatography (EA / PE = 0-20%) to give (1-phenylethylidene)hydrazine (20.2 g, 150.5 mmol, yield: 60.3%). ESI-MS: 134.9 [M+1] + .

[0300] Second step: Synthesis of N,N-bis(4-methoxybenzyl)-3-(2-(1-phenylethylidene)hydrazinyl)pyridin-2-amine

[0301] 3-bromo-N,N-bis(4-methoxybenzyl)pyridin-2-amine (33.5 g, 81.053 mmol) was dissolved in toluene (350 mL), (1-phenylethylidene)hydrazine (14.14 g, 105.369 mmol), Xantphos (4.69 g, 8.105 mmol), sodium tert-butoxide (15.58 g, 162.106 mmol) and palladium acetate (0.91 g, 4.053 mmol) were added. The reaction was heated at 90 °C for 14 h under nitrogen protection. After the reaction was cooled, celite was used to filter the reaction mixture. The filtrate was directly concentrated. The obtained crude product was separated by flash silica gel column chromatography (EA / PE = 0-10%) to give N,N-bis(4-methoxybenzyl)-3-(2-(1-phenylethylidene)hydrazinyl)pyridin-2-amine (26.5 g, 56.796 mmol, yield: 70.1%). ESI-MS: 467.2 [M+1] + .

[0302] Third step: Synthesis of ethyl-N-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)-N-((1-phenylethylidene)amino)glycinate

[0303] N,N-di(4-methoxybenzyl)-3-(2-(1-phenylethylidene)hydrazinyl)pyridin-2-amine (5g, 10.716 mmol) was dissolved in THF (100 mL), and a solution of LiHMDS (32.148 mL, 32.148 mmol) was added dropwise at 0 °C. After stirring for 1 h, a solution of ethyl bromoacetate (3.565 mL, 32.148 mmol, dissolved in THF (10 mL)) was added dropwise, and the reaction was allowed to proceed naturally to room temperature for 14 h. The reaction was poured into ice water (300 mL), and extracted with ethyl acetate (200 mL*3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was separated by flash silica gel column chromatography (EA / PE = 0~20%) to obtain ethyl-N-(2-(di(4-methoxybenzyl)amino)pyridin-3-yl)-N-((1-phenylethylidene)amino)glycinate (5.1 g, 9.228 mmol, yield: 86.1%). ESI-MS: 553.2 [M+1] + .

[0304] Fourth step: Synthesis of N-(2-(di(4-methoxybenzyl)amino)pyridin-3-yl)-N-((1-phenylethylidene)amino)glycine

[0305] Ethyl-N-(2-(di(4-methoxybenzyl)amino)pyridin-3-yl)-N-((1-phenylethylidene)amino)glycinate (5.1 g, 7.382 mmol) was dissolved in a mixture of THF (30 mL), MeOH (10 mL), and water (10 mL), and LiOH (0.93 g, 22.147 mmol) was added. The reaction was stirred for 6 h. The reaction was poured into ice water (100 mL), and the pH was adjusted to 4~5 with HOAc. The reaction was extracted with ethyl acetate (50 mL*3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was separated by flash silica gel column chromatography (EA / PE = 0~60%) to obtain N-(2-(di(4-methoxybenzyl)amino)pyridin-3-yl)-N-((1-phenylethylidene)amino)glycine (3.2 g, 6.100 mmol, yield: 82.6%). ESI-MS: 525.2 [M+1] + .

[0306] Fifth step: Synthesis of 2-(1-(2-(di(4-methoxybenzyl)amino)pyridin-3-yl)-2-(1-phenylethylidene)hydrazinyl)acetamide

[0307] N-(2-(di(4-methoxybenzyl)amino)pyridin-3-yl)-N-((1-phenylethyl)amino) glycine (1g, 1.906 mmol) was dissolved in DMF (10 mL), HATU (0.87 g, 2.287 mmol) and DIPEA (0.630 mL, 3.812 mmol) were added at room temperature. After stirring for 1 h, NH4Cl (0.20 g, 3.812 mmol) was added to the reaction solution, and the reaction was carried out at room temperature for 14 h. The reaction solution was poured into ice water (80 mL), and then extracted with ethyl acetate (20 mL*3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was separated by flash silica gel column chromatography (EA / PE = 0~60%) to obtain 2-(1-(2-(di(4-methoxybenzyl)amino)pyridin-3-yl)-2-(1- phenylethyl)hydrazino)acetamide (750 mg, 1.432 mmol, yield: 75.1%). ESI-MS: 524.3 [M+1] + .

[0308] Preparation of intermediate 1-9: 2-(1-(2-(di(4-methoxybenzyl)amino)pyridin-3-yl)-2-(1- phenylethyl)hydrazino)-N-isopropylacetamide

[0309] N,N-di(4-methoxybenzyl)-3-(2-(1-phenylethyl)hydrazino)pyridin-2-amine (466.0 mg, 1.0 mmol) was dissolved in dry THF (15.0 mL), and cooled to 0°C. LiHMDS (3.0 mL, 1M, 3.0 mmol) was added dropwise, and after maintaining the reaction at 0°C for 30 min, a solution of 2-bromo-N-isopropylacetamide (540.0 mg, 3.0 mmol) in THF (5.0 mL) was added dropwise. After the addition was completed, the reaction was maintained at 0°C for 2 h. The reaction solution was quenched with water, and extracted with ethyl acetate (30 mL*2). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was separated by flash silica gel column chromatography (petroleum ether / ethyl acetate = 2.5:1) to obtain 2-(1-(2-(di(4-methoxybenzyl)amino)pyridin-3-yl)-2-(1- phenylethyl)hydrazino)-N-isopropylacetamide (320.0 mg, yield: 56.6%). ESI-MS: 566.3 [M+1] + .

[0310] Intermediates 1-10~1-14 were prepared by referring to intermediate 1-8 or 1-9, and selecting the corresponding starting materials.

[0311] Preparation of Intermediate 1-15: N,N-di(4-methoxybenzyl)-3-(1-((1-methyl-1H- pyrazol-4-yl)methyl)-2-(1-phenylethylene)hydrazinyl)pyridin-2-amine

[0312] N,N-di(4-methoxybenzyl)-3-(2-(1-phenylethylene)hydrazinyl)pyridin-2-amine (800 mg, 1.715 mmol), 4-(bromomethyl)-1-methyl-1H-pyrazole hydrobromide (1316.49 mg, 5.144 mmol) and sodium bicarbonate (576.17 mg, 6.858 mmol) were dissolved in 1,4-dioxane (25 mL), stirred at 100 °C for 0.5 h under nitrogen protection, then LiHMDS (8.573 mL, 8.573 mmol) was added dropwise at 100 °C. After stirring for 5 h, it was cooled to room temperature, extracted with ethyl acetate (100 mL*3), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the obtained crude product was separated by flash silica gel column chromatography (ethyl acetate / petroleum ether = 0~40%) to give N,N-di(4-methoxybenzyl)-3-(1-((1-methyl-1H-pyrazol-4-yl)methyl)-2-(1-phenylethylene)hydrazinyl)pyridin-2-amine (400 mg, 0.713 mmol, yield: 41.61%). ESI-MS: 561.4 [M+1] + .

[0313] Intermediate 1-16~1-22 were prepared by referring to the method of Intermediate 1-15 or 1-2 with the corresponding starting materials.

[0314] Preparation of Intermediate 1-23: (S)-N,N-di(4-methoxybenzyl)-3-(1-(oxetan-2-ylmethyl)-2-(1-phenylethylene)hydrazinyl)pyridin-2-amine

[0315] First step: Synthesis of (R)-N,N-di(4-methoxybenzyl)-3-(1-(oxetan-2-ylmethyl)-2-(1-phenylethylene)hydrazinyl)pyridin-2-amine

[0316] N,N-di(4-methoxybenzyl)-3-(2-(1-phenylethylidene)hydrazinyl)pyridin-2-amine (1.40 g, 3.00 mmol) and (S)-2-(chloromethyl)oxetane (0.69 g, 7.50 mmol) were dissolved in dry THF (30 mL), cooled to 0 °C, and a solution of KHMDS (7.50 mL, 7.50 mmol, 1 M in THF) was added dropwise. After the addition was complete, the reaction was allowed to warm to room temperature and stirred for 3 h. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution and extracted twice with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was separated by flash silica gel column (PE / EA = 9:1) to give (R)-N,N-di(4-methoxybenzyl)-3-(1-(oxetan-2-ylmethyl)-2-(1- phenylethylidene)hydrazinyl)pyridin-2-amine (0.83 g, yield 51.2%). ESI-MS: 523.2 [M+1] + .

[0317] Second step: Synthesis of (S)-N,N-di(4-methoxybenzyl)-3-(1-(oxetan-2-ylmethyl)-2-(1- phenylethylidene)hydrazinyl)pyridin-2-amine

[0318] Trimethylsulfoxonium iodide (1.88 g, 8.54 mmol) was dissolved in tert-butanol solution (20 mL), KOtBu (0.96 g, 8.54 mmol) was added at room temperature, and the reaction was heated at 60 °C for 30 min. Then a solution of (R)-N,N-di(4-methoxybenzyl)-3-(1-(oxetan-2-ylmethyl)-2-(1- phenylethylidene)hydrazinyl)pyridin-2-amine (1.58 g, 2.85 mmol) in THF (4 mL) was added dropwise, and the reaction was heated at 80 °C overnight. After cooling to room temperature, the reaction was quenched by the addition of saturated aqueous ammonium chloride solution and extracted twice with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was separated by flash silica gel column (PE / EA = 9:1) to give (S)-N,N-di(4-methoxybenzyl)-3-(1-(oxetan-2-ylmethyl)-2-(1- phenylethylidene)hydrazinyl)pyridin-2-amine (1.08 g, yield: 70.0%). ESI-MS: 537.2 [M+1] + .

[0319] Intermediate 1-24: Preparation of (R)-N,N-di(4-methoxybenzyl)-3-(1-(oxetan-2-ylmethyl)-2-(1- phenylethylidene)hydrazinyl)pyridin-2-amine

[0320] Refer to Intermediate 1-23, and the corresponding starting materials were selected for the preparation.

[0321] Preparation of Intermediate 2-1 : 2-(7-chloro-8-fluoro-4-hydroxy-2- (methylthio)pyrido[4,3-d]pyrimidin-5-yl)acetaldehyde

[0322] First Step: Synthesis of 7-chloro-5-(2-ethoxyvinyl)-8-fluoro-2- (methylthio)pyrido[4,3-d]pyrimidin-4-ol

[0323] 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (3.00 g, 10.71 mmol) was dissolved in DMF (60 mL), (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (2.757 g, 13.92 mmol), [1,1'-bis(ditert-butylphosphino)ferrocene] palladium dichloride (365 mg, 0.536 mmol) and potassium phosphate (6.82 g, 32.131 mmol) were added at room temperature, and the mixture was heated at 75 °C under nitrogen protection overnight. The reaction solution was filtered, washed with a mixture of methanol / dichloromethane (10 mL / 100 mL), and the filtrate was concentrated. The residue was separated by flash silica gel column chromatography (ethyl acetate / dichloromethane 0-10%) to give (E)-7-chloro-5-(2-ethoxyvinyl)-8-fluoro-2- (methylthio)pyrido[4,3-d]pyrimidin-4-ol (3.01 g, yield: 75%). ESI-MS: 316.0 [M+1] + .

[0324] 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).

[0325] Second Step: Synthesis of 2-(7-chloro-8-fluoro-4-hydroxy-2- (methylthio)pyrido[4,3-d]pyrimidin-5-yl)acetaldehyde

[0326] (E)-7-chloro-5-(2-ethoxyvinyl)-8-fluoro-2-(methylthio)pyrido[4,3- d]pyrimidin-4-ol (700 mg, 2.217 mmol) was dissolved in dichloromethane (50 mL) and acetonitrile (50 mL), hydrochloric acid aqueous solution (2.22 mL, 4.44 mmol, 2N) was added at room temperature, the reaction was stirred at 50 °C for 1.5 hours. The reaction solution was added with sodium bicarbonate solid (373 mg, 4.44 mmol), stirred at room temperature for 5 minutes, dried with anhydrous sodium sulfate, filtered, and the filtrate was directly concentrated to obtain 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] + .

[0327] Preparation of intermediate 3-1: 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

[0328] First step: synthesis of N,N-di(4-methoxybenzyl)-3-(1-methylhydrazino)pyridin-2-amine

[0329] 3-(2-(Diphenylmethylene)-1-methylhydrazino)-N,N-di(4-methoxybenzyl)pyridin-2-amine (700 mg, 1.290 mmol) was dissolved in pyridine (5 mL), hydroxylamine hydrochloride (179 mg, 2.58 mmol) was added, and the reaction was heated at 60 °C overnight. After the reaction was completed, saturated brine was added after cooling, and extracted with ethyl acetate. The organic phase was concentrated to obtain 3-(2-(diphenylmethylene)-1-methylhydrazino)-N,N-di(4-methoxybenzyl)pyridin-2-amine (600 mg, purity: 40%), which was directly used in the next step. ESI-MS: 379.2 [M+1] + .

[0330] Second step: synthesis of 5-(2-(2-(2-(di(4-methoxybenzyl)amino)pyridin-3-yl)-2- methylhydrazino)ethyl)-7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol

[0331] 2-(7-chloro-8-fluoro-4-hydroxy-2-(methylthio)pyrido[4,3-d]pyrimidin-5-yl)acetaldehyde (182 mg, 0.634 mmol) was dissolved in dichloromethane (15 mL), then 3-(2-(diphenylmethylene)-1-methylhydrazino)-N,N-di(4-methoxybenzyl)pyridin-2-amine (600 mg, 0.634 mmol, purity: 40%) and sodium cyanoborohydride (598 mg, 9.51 mmol) were added, and the reaction was allowed to proceed at room temperature overnight. The reaction solution was quenched with saturated brine and extracted with dichloromethane. The organic phase was concentrated to obtain 5-(2-(2-(2-(di(4-methoxybenzyl)amino)pyridin-3-yl)-2-methylhydrazino)ethyl)-7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (600 mg, crude), which was used directly in the next step. ESI-MS: 650.3 [M+1] + .

[0332] Third step: Synthesis of N 3 -(8-chloro-9-fluoro-2-(methylthio)-5,6-dihydro-4H-pyrimido[4,5,6-de][1,6]naphthyridin-4-yl)-N 2 ,N 2 -di(4-methoxybenzyl)-N 3 -methylpyridine-2,3-diamine

[0333] 5-(2-(2-(2-(di(4-methoxybenzyl)amino)pyridin-3-yl)-2-methylhydrazino)ethyl)-7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (600 mg, crude) was dissolved in dichloromethane (10 mL), then DIPEA (596 mg, 4.614 mmol) and BOP-Cl (705 mg, 2.769 mmol) were added, and the reaction was allowed to proceed with stirring at room temperature for 3 hours. The reaction solution was added to saturated brine and extracted with dichloromethane. The organic phase was concentrated, and the resulting residue was separated by reverse phase column chromatography (acetonitrile / water: 0~80%) to obtain N 3 -(8-chloro-9-fluoro-2-(methylthio)-5,6-dihydro-4H-pyrimido[4,5,6-de][1,6]naphthyridin-4-yl)-N 2 ,N 2 -di(4-methoxybenzyl)-N 3 -methylpyridine-2,3-diamine (140 mg, total yield: 17% over three steps). ESI-MS: 632.4 [M+1] + .

[0334] The following intermediate compounds can be prepared by selecting the corresponding starting materials with reference to all or part of the synthesis method of Intermediate 3-1:

[0335] Intermediate 3-9: (S)-N 3 -(8-chloro-9-fluoro-2-(methylthio)-5,6-dihydro-4H- pyrimido[4,5,6-de][1,6]naphthyridin-4-yl)-N 2 ,N 2 -di(4-methoxybenzyl)-N 3 Preparation of (oxetan-2-ylmethyl)pyridine-2,3-diamine

[0336] First step: Synthesis of (S)-N,N-di(4-methoxybenzyl)-3-(1-(oxetan-2- ylmethyl)hydrazinyl)pyridin-2-amine

[0337] (S)-N,N-di(4-methoxybenzyl)-3-(1-(oxetan-2-ylmethyl)-2-(1- phenylethylidene)hydrazinyl)pyridin-2-amine (1.08 g, 1.99 mmol) was dissolved in acetonitrile (10 mL) and methanol (10 mL), then pyridine (0.32 mL, 3.99 mmol) and hydroxylamine hydrochloride (1.39 g, 19.94 mmol) were added, and the reaction was allowed to proceed at room temperature for 1 hour. It was quenched by adding saturated brine, and extracted twice with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the resulting crude product was separated on a flash silica gel column (CH2Cl2 / MeOH = 25:1) to give (S)-N,N-di(4-methoxybenzyl)-3-(1-(oxetan-2-ylmethyl)hydrazinyl)pyridin-2-amine (0.66 g, yield: 73.1%). ESI-MS: 435.2 [M+1] + .

[0338] Second step: Synthesis of (S)-N 3 -(8-chloro-9-fluoro-2-(methylthio)-5,6-dihydro-4H- pyrimido[4,5,6-de][1,6]naphthyridin-4-yl)-N 2 ,N 2 -di(4-methoxybenzyl)-N 3 Preparation of (oxetan-2-ylmethyl)pyridine-2,3-diamine

[0339] (S)-N,N-di(4-methoxybenzyl)-3-(1-(oxetan-2-ylmethyl)hydrazino)pyridin-2-amine (0.66 g, 1.46 mmol) was dissolved in CH2Cl2(10 mL), then 2-(7-chloro-8-fluoro-4-hydroxy-2-(methylthio)pyrido[4,3-d]pyrimidin-5-yl)acetaldehyde (0.66 g, 1.60 mmol) was added, and the reaction was allowed to proceed at room temperature for 1 hour. The reaction was concentrated, then methanol (10 mL) was added, and NaBH3CN (1.37 g, 21.87 mmol) was added under nitrogen protection, and the reaction was allowed to proceed at room temperature for 2 hours. Water was added to quench the reaction, and the reaction was extracted twice with ethyl acetate. The organic phase was combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Anhydrous acetonitrile (100 mL) was added to the obtained crude product, and then DIPEA (1.91 mL, 10.94 mmol) and BOPCl (1.67 g, 6.56 mmol) were sequentially added, and the reaction was allowed to proceed at room temperature overnight. The reaction was concentrated, diluted with ethyl acetate, and sequentially washed with saturated NaHCO3aqueous solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained crude product was separated by flash silica gel column (CH2Cl2 / MeOH = 25:1) to obtain (S)-N,N-di(4-methoxybenzyl)-3-(1-(oxetan-2-ylmethyl)hydrazino)pyridin-2-amine (0.66 g, 1.46 mmol) was dissolved in CH2Cl2(10 mL), then 2-(7-chloro-8-fluoro-4-hydroxy-2-(methylthio)pyrido[4,3-d]pyrimidin-5-yl)acetaldehyde (0.66 g, 1.60 mmol) was added, and the reaction was allowed to proceed at room temperature for 1 hour. The reaction was concentrated, then methanol (10 mL) was added, and NaBH3CN (1.37 g, 21.87 mmol) was added under nitrogen protection, and the reaction was allowed to proceed at room temperature for 2 hours. Water was added to quench the reaction, and the reaction was extracted twice with ethyl acetate. The organic phase was combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Anhydrous acetonitrile (100 mL) was added to the obtained crude product, and then DIPEA (1.91 mL, 10.94 mmol) and BOPCl (1.67 g, 6.56 mmol) were sequentially added, and the reaction was allowed to proceed at room temperature overnight. The reaction was concentrated, diluted with ethyl acetate, and sequentially washed with saturated NaHCO3aqueous solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained crude product was separated by flash silica gel column (CH2Cl2 / MeOH = 25:1) to obtain (S)-N 3 -(8-chloro-9-fluoro-2-(methylthio)-5,6-dihydro-4H-pyrimido[4,5,6-de][1,6]naphthyridin-4-yl)-N 2 ,N 2 -di(4-methoxybenzyl)-N 3 -(oxetan-2-ylmethyl)pyridine-2,3-diamine (0.97 g, yield: 85.3%). ESI-MS: 688.2 [M+1] + .

[0340] The intermediates 3-10 to 3-21 were prepared according to the synthesis method of the intermediates 3-9 or 3-1 by selecting the corresponding starting materials:

[0341] Preparation of intermediate 3-22: 1-((S)-2-(((8-chloro-9-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizidin-7a(5H)-yl)methoxy)-5,6-dihydro-4H-pyrimido[4,5,6-de][1,6]naphthyridin-4-yl)(2-((4-methoxybenzyl)amino)pyridin-3-yl)amino)methyl)pyrrolidin-1-yl)ethan-1-one

[0342] Step 1: Synthesis of (S)-2-((l-(2-(di(4-methoxybenzyl)amino)pyridin-3-yl)-2- (diphenylmethylene)hydrazino)methyl)pyrrolidine- 1 -sulfonic acid

[0343] 3-(2-(Diphenylmethylene)hydrazino)-N,N-di(4-methoxybenzyl)pyridin-2-amine (1.00 g, 1.89 mmol) was dissolved in THF (20 mL), cooled in an ice water bath, and LiHMDS (3.78 mL, 3.78 mmol, 1 M in THF) was added slowly under nitrogen protection. After the dropwise addition was completed, the reaction was stirred at 0 °C for another 20 min. (S)-Tetrahydro-3H-pyrrolo[l,2-c][l,2,3]oxathiazole 1,1-dioxide (926 mg, 5.28 mmol) in THF (10 mL) was added to the reaction mixture, and the reaction was stirred at 0 °C for 1 h. The reaction mixture was added to saturated aqueous sodium bicarbonate solution (100 mL), and extracted with ethyl acetate (50 mL*3). The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The concentrated residue was separated by silica gel column chromatography (MeOH / CH2Cl2=0~5%) to give (S)-2-((l-(2-(di(4-methoxybenzyl)amino)pyridin-3-yl)-2- (diphenylmethylene)hydrazino)methyl)pyrrolidine- 1 -sulfonic acid (1.17 g, yield: 87%). ESI-MS: 692.3 [M+1] + .

[0344] Step 2: Synthesis of (S)-3-(2-(diphenylmethylene)-l-(pyrrolidin-2-ylmethyl)hydrazino)-N,N- di(4-methoxybenzyl)pyridin-2-amine

[0345] (S)-2-((l-(2-(di(4-methoxybenzyl)amino)pyridin-3-yl)-2-(diphenylmethylene)hydrazino)methyl)pyrrolidine- 1 -sulfonic acid (1.17 g, 1.69 mmol) was dissolved in DMF (12 mL), and TMSI (0.48 mL, 3.38 mmol) was added at room temperature. The reaction was heated at 105 °C for 1 h. The reaction mixture was quenched by adding saturated aqueous sodium bicarbonate solution (100 mL), and extracted with ethyl acetate (50 mL*3). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give (S)-3-(2-(diphenylmethylene)-l-(pyrrolidin-2-ylmethyl)hydrazino)-N,N-di(4-methoxybenzyl)pyridin-2-amine (1034 mg). The crude product was used directly in the next step. ESI-MS: 612.4 [M+1] + .

[0346] Step 3: Synthesis of tert-butyl (S)-2-((l-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)-2- (diphenylmethylene)hydrazino)methyl)pyrrolidine-l-carboxylate

[0347] (S)-3-(2-(diphenylmethylene)-l-(pyrrolidin-2-ylmethyl)hydrazino)-N,N-di(4- methoxybenzyl)pyridin-2-amine (1034 mg, 1.69 mmol) was dissolved in CH2Cl2(10 mL), Et3N (0.70 mL, 5.07 mmol), DMAP (42 mg, 0.42 mmol) and Boc20 (737 mg, 3.38 mmol) were added at room temperature, and it was stirred at room temperature overnight. The reaction solution was directly concentrated, and the resulting residue was separated by column chromatography on silica gel (EA / PE = 5-20%) to obtain tert-butyl (S)-2-((l-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)-2- (diphenylmethylene)hydrazino)methyl)pyrrolidine-l-carboxylate (600 mg, purity: 60%; yield: 30%). ESI-MS: 712.4 [M+1] + .

[0348] Step 4: Synthesis of tert-butyl (S)-2-((l-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)hydrazino)methyl)pyrrolidine-l-carboxylate

[0349] Tert-butyl (S)-2-((l-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)-2- (diphenylmethylene)hydrazino)methyl)pyrrolidine-l-carboxylate (600 mg, 0.51 mmol, purity: 60%) was dissolved in CH3CN (6 mL) and MeOH (4 mL), and then pyridine (0.14 mL, 1.77 mmol) and hydroxylamine hydrochloride (527 mg, 7.58 mmol) were added, and it was stirred at room temperature overnight. After the reaction was completed, saturated aqueous sodium bicarbonate solution (100 mL) was added to quench, and ethyl acetate (50 mL*3) was extracted. The organic phase was combined, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and the resulting residue was separated by column chromatography on flash silica gel (EA / PE = 10-40%) to obtain tert-butyl (S)-2-((l-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)hydrazino)methyl)pyrrolidine-l-carboxylate (215 mg, yield: 78%). ESI-MS: 548.2 [M+1] + .

[0350] Step 5: Synthesis of tert-butyl (S)-2-(((2-(di(4-methoxybenzyl)amino)pyridin-3-yl)(8-chloro-9-fluoro-2-(methylthio)-5,6-dihydro-4H-pyrimido[4,5,6-de][1,6]naphthyridin-4-yl)amino)methyl)pyrrolidine-1-carboxylate

[0351] Tert-butyl (S)-2-((1-(2-(di(4-methoxybenzyl)amino)pyridin-3-yl)hydrazinyl)methyl)pyrrolidine-1-carboxylate (215 mg, 0.39 mmol) was dissolved in MeOH (6 mL), then 2-(7-chloro-8-fluoro-4-hydroxy-2-(methylthio)pyrido[4,3-d]pyrimidin-5-yl)acetaldehyde (158 mg, 0.55 mmol) was added. After stirring at room temperature for 1 h, NaBH3CN (247 mg, 3.93 mmol) was added and stirred at room temperature overnight. The reaction was quenched by adding saturated aqueous NaHCO3solution (50 mL), and extracted with ethyl acetate (30 mL*3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give tert-butyl (S)-2-((1-(2-(di(4-methoxybenzyl)amino)pyridin-3-yl)-2-(2-(7-chloro-8-fluoro-4-hydroxy-2-(methylthio)pyrido[4,3-d]pyrimidin-5-yl)ethyl)hydrazinyl)methyl)pyrrolidine-1-carboxylate (321 mg), which was dissolved in CH2Cl2(10 mL), then DIPEA (0.37 mL, 2.12 mmol) and BOPCl (361 mg, 1.42 mmol) were added. After stirring at room temperature overnight, the reaction was complete. The reaction was quenched by adding saturated aqueous NaHCO3solution (50 mL), and the aqueous phase was extracted with CH2Cl2(30 mL*3). The organic phase was concentrated, and the residue was separated by flash silica gel column chromatography (EA / PE = 5-20%) to give tert-butyl (S)-2-(((2-(di(4-methoxybenzyl)amino)pyridin-3-yl)(8-chloro-9-fluoro-2-(methylthio)-5,6-dihydro-4H-pyrimido[4,5,6-de][1,6]naphthyridin-4-yl)amino)methyl)pyrrolidine-1-carboxylate (180 mg, yield: 64%). ESI-MS: 801.4 [M+1] + .

[0352] Step 6: Synthesis of tert-butyl (2S)-2-(((2-(di(4-methoxybenzyl)amino)pyridin-3-yl)(8-chloro-9-fluoro-2-(methylsulfinyl)-5,6-dihydro-4H-pyrimido[4,5,6-de][1,6]naphthyridin-4-yl)amino)methyl)pyrrolidine-1-carboxylate

[0353] tert-butyl (2S)-2-(((2-(di(4-methoxybenzyl)amino)pyridin-3-yl)(8-chloro-9-fluoro-2- (methylsulfmyl)-5,6-dihydro-4H-pyrimido[4,5,6-de][l,6]naphthyridin-4-yl)amino)methyl) pyrrolidine- 1-carboxylate (183 mg, 0.225 mmol) was dissolved in trifluoroethanol (3 mL), DIPEA (58 mg, 0.45 mmol) was added, and the reaction was heated at 60 °C for 1 h. The reaction was concentrated, and the residue was purified by column chromatography on silica gel (EA / PE = 10-40%) to give tert-butyl (S)-2-(((2-(di(4-methoxybenzyl)amino)pyridin-3-yl)(8-chloro-9-fluoro-2-(2,2,2- trifluoroethoxy)-5,6-dihydro-4H-pyrimido[4,5,6-de][l,6]naphthyridin-4-yl)amino)methyl)pyrrolidine- 1-carboxylate (150 mg, 78% yield). ESI-MS: 853.2 [M+l] + .

[0354] Step 7: Synthesis of tert-butyl (S)-2-(((2-(di(4-methoxybenzyl)amino)pyridin-3-yl)(8-chloro-9- fluoro-2-(2,2,2-trifluoroethoxy)-5,6-dihydro-4H-pyrimido[4,5,6-de][l,6]naphthyridin-4-yl)amino)methyl) pyrrolidine- 1-carboxylate

[0355] tert-butyl (2S)-2-(((2-(di(4-methoxybenzyl)amino)pyridin-3-yl)(8-chloro-9-fluoro-2- (methylsulfmyl)-5,6-dihydro-4H-pyrimido[4,5,6-de][l,6]naphthyridin-4-yl)amino)methyl) pyrrolidine- 1-carboxylate (183 mg, 0.225 mmol) was dissolved in trifluoroethanol (3 mL), DIPEA (58 mg, 0.45 mmol) was added, and the reaction was heated at 60 °C for 1 h. The reaction was concentrated, and the residue was purified by column chromatography on silica gel (EA / PE = 10-40%) to give tert-butyl (S)-2-(((2-(di(4-methoxybenzyl)amino)pyridin-3-yl)(8-chloro-9-fluoro-2-(2,2,2- trifluoroethoxy)-5,6-dihydro-4H-pyrimido[4,5,6-de][l,6]naphthyridin-4-yl)amino)methyl)pyrrolidine- 1-carboxylate (150 mg, 78% yield). ESI-MS: 853.2 [M+l] + .

[0356] Step 8: Synthesis of tert-butyl (S)-2-(((2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)(8-chloro-9-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,6-dihydro-4H- pyrimido[4,5,6-de][1,6]naphthyridin-4-yl)amino)methyl)pyrrolidine-1-carboxylate

[0357] ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (42 mg, 0.264 mmol) and tert-butyl (S)-2-(((2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)(8-chloro-9-fluoro-2-(2,2,2- trifluoroethoxy)-5,6-dihydro-4H-pyrimido[4,5,6-de][1,6]naphthyridin-4-yl)amino)methyl)pyrrolidine-1- carboxylate (150 mg, 0.176 mmol, purity: 76%) were dissolved in THF (5 mL), and sodium tert- pentoxide (58 mg, 0.527 mmol) was added under ice water bath cooling. The reaction was stirred at 0 °C for 1.5 h. The reaction was quenched by adding saturated brine, and extracted with ethyl acetate. The organic phase was directly concentrated, and the residue was separated by column chromatography (MeOH / CH2Cl2= 0~5%) to give tert-butyl (S)-2-(((2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)(8-chloro-9-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,6-dihydro-4H-pyrimido[4,5,6-de][1,6]naphthyridin-4- yl)amino)methyl)pyrrolidine-1-carboxylate (157 mg, yield: 97%). ESI-MS: 912.4 [M+1] + .

[0358] Step 9: Synthesis of N 3 -(8-chloro-9-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,6-dihydro-4H- pyrimido[4,5,6-de][1,6]naphthyridin-4-yl)-N 2 -(4-methoxybenzyl)-N 3 -(((S)-pyrrolidin-2-yl)methyl)pyridine-2,3-diamine

[0359] tert-butyl (S)-2-(((2-(di(4-methoxybenzyl)amino)pyridin-3-yl)(8-chloro-9-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizine-7a(5H)-yl)methoxy)-5,6-dihydro-4H- pyrimido[4,5,6-de][l,6]naphthyridin-4-yl)amino)methyl)pyrrolidine-l-carboxylate (157 mg, 0.17 mmol) was dissolved in CH2Cl2(3 mL), TFA (0.6 mL, 8.08 mmol) was added at 0 °C, and the reaction was maintained at 0 °C for 2 h. The solvent was blown off under nitrogen, the residue was diluted with CH2Cl2, and the pH was adjusted to 9-10 with saturated aqueous NaHCO3solution. The organic phase was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to give N 3 -(8-chloro-9-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizine-7a(5H)-yl)methoxy)-5,6-dihydro-4H-pyrimido[4,5,6-de][l,6]naphthyridin-4-yl)-N 2 -(4-methoxybenzyl)-N 3 -(((S)-pyrrolidin-2-yl)methyl)pyridine-2,3-diamine (119 mg). ESI-MS: 692.2 [M+l] + .

[0360] Step 10: Synthesis of l-((S)-2-(((8-chloro-9-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizine-7a(5H)-yl)methoxy)-5,6-dihydro-4H-pyrimido[4,5,6-de][l,6]naphthyridin-4-yl)(2-((4-methoxybenzyl)amino)pyridin-3-yl)amino)methyl)pyrrolidin-l-yl)ethan-l-one

[0361] N 3 -(8-chloro-9-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizine-7a(5H)-yl)methoxy)-5,6-dihydro-4H-pyrimido[4,5,6-de][l,6]naphthyridin-4-yl)-N 2 -(4-methoxybenzyl)-N 3-(((S)-pyrrolidin-2-yl)methyl)pyridine-2,3-diamine (100 mg, 0.144 mmol) was dissolved in CH2Cl2(3 mL), DIPEA (75 mg, 0.578 mmol) and acetyl chloride (17 mg, 0.217 mmol) were added at 0 °C, and stirring was continued at 0 °C for 30 min. The reaction was quenched with saturated aqueous NH4Cl solution (20 mL), and extracted with CH2Cl2(20 mL*2). The organic phase was combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was separated by column chromatography (MeOH / CH2Cl2= 0~5%) to give 1-((S)-2-(((8-chloro-9-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,6-dihydro-4H- pyrimido[4,5,6-de][1,6]naphthyridin-4-yl)(2-((4-methoxybenzyl)amino)pyridin-3-yl)amino)methyl)pyrrolidin-1-yl)ethan-1-one (83 mg, yield: 78%). ESI-MS: 734.2 [M+1] + .

[0362] The intermediates 3-23~3-26 were prepared according to the synthetic method of the whole or part of the intermediate 3-22 by selecting the corresponding starting materials.

[0363] Preparation of intermediate 4-1: (5-(di(4-methoxybenzyl)amino)-4-fluoro-3-methyl-2- (trifluoromethyl)phenyl)boronic acid

[0364] First step: synthesis of 5-bromo-2-fluoro-1-methyl-3-nitrobenzene

[0365] 2-Fluoro-1-methyl-3-nitrobenzene (10.0 g, 64.46 mmol) was dissolved in concentrated sulfuric acid (50 mL), and then NBS (13.2 g, 74.1 mmol) was added. The reaction was stirred at 50 °C for 18 h. The reaction was monitored by LCMS, and the reaction was completed. The reaction was cooled to room temperature, poured into an ice water bath, and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was separated by flash silica gel column chromatography (ethyl acetate / petroleum ether 0~10%) to give 5-bromo-2-fluoro-1-methyl-3-nitrobenzene (14.5 g, yield: 96.1%). ESI-MS: 234.3 [M+1] + .

[0366] Second step: synthesis of 5-bromo-2-fluoro-3-methylaniline

[0367] 5-bromo-2-fluoro-l-methyl-3-nitrobenzene (14.5 g, 61.96 mmol) was dissolved in ethanol (100 mL) and water (50 mL), and iron powder (17.3 g, 309.8 mmol) and ammonium chloride (16.0 g, 299.1 mmol) were added. The reaction was heated at 80 °C for 6 hours. The reaction was monitored by LCMS and was completed. The reaction mixture was filtered hot using celite, and the filtrate was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was separated by flash column chromatography using silica gel (ethyl acetate / petroleum ether 0-20%) to give 5-bromo-2-fluoro-3-methylaniline (8.28 g, yield: 65.5%). ESI-MS: 204.3 [M+1] + .

[0368] Third step: synthesis of 5-bromo-2-fluoro-N,N-di(4-methoxybenzyl)-3-methylaniline

[0369] 5-bromo-2-fluoro-3-methylaniline (7.2 g, 35.29 mmol) was dissolved in anhydrous DMF (100 mL), and NaH (4.2 g, purity: 60%, 105.86 mmol) was added under ice water bath cooling. The reaction was maintained at 0 °C for 1 hour, and PMBCl (13.8 g, 88.2 mmol) was added dropwise slowly. The reaction was maintained at room temperature for 6 hours. The reaction was monitored by LCMS and was completed. The reaction mixture was poured into an ice water bath, and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was added to methanol (100 mL), stirred for 1 hour, and a solid was precipitated. The solid was filtered to give 5-bromo-2-fluoro-N,N-di(4-methoxybenzyl)-3-methylaniline (13.5 g, yield: 86.4%). ESI-MS: 444.1 [M+1] + .

[0370] Fourth step: synthesis of 5-bromo-2-fluoro-4-iodo-N,N-di(4-methoxybenzyl)-3-methylaniline

[0371] 5-Bromo-2-fluoro-N,N-di(4-methoxybenzyl)-3-methylaniline (5.0 g, 11.25 mmol) was dissolved in acetic acid (100 mL), then NIS (2.78 g, 12.38 mmol) was added, and the reaction was allowed to proceed at room temperature for 1 hour. The reaction was monitored by LCMS, and when the reaction was complete, the reaction solution was poured into an ice water bath, saturated aqueous Na2S2O3 was added to quench the reaction, and the reaction was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The resulting residue was separated by flash column chromatography on silica gel (ethyl acetate / petroleum ether 0-3%) to give 5-bromo-2-fluoro-4-iodo-N,N-di(4-methoxybenzyl)-3-methylaniline (4.19 g, yield: 65.3%). ESI-MS: 570.0 [M+1] + .

[0372] Fifth step: Synthesis of 5-bromo-2-fluoro-N,N-di(4-methoxybenzyl)-3-methyl-4- (trifluoromethyl)aniline

[0373] 5-Bromo-2-fluoro-4-iodo-N,N-di(4-methoxybenzyl)-3-methylaniline (3.0 g, 5.26 mmol) and CuI (10.0 g, 52.6 mmol) were added to DMF (60 mL), and then methyl fluorosulfonyl difluoroacetate (10.1 g, 52.6 mmol) was added. The reaction was allowed to proceed at 75°C for 2 hours. The reaction was monitored by LCMS, and when the reaction was complete, the reaction solution was poured into an ice water bath, ammonia was added to quench the reaction, and the reaction was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The resulting residue was separated by flash column chromatography on silica gel (ethyl acetate / petroleum ether 0-5%) to give 5-bromo-2-fluoro-N,N-di(4-methoxybenzyl)-3-methyl-4- (trifluoromethyl)aniline (1.97 g, yield: 72.8%). ESI-MS: 512.0 [M+1] + .

[0374] Sixth step: Synthesis of (5-(di(4-methoxybenzyl)amino)-4-fluoro-3-methyl-2- (trifluoromethyl)phenyl)boronic acid

[0375] 5-Bromo-2-fluoro-N,N-di(4-methoxybenzyl)-3-methyl-4-(trifluoromethyl)aniline (1.97 g, 3.84 mmol) was dissolved in dry THF (50 mL) and n-BuLi solution (1.84 mL, 4.61 mmol) was added dropwise at low temperature under ice-acetone bath. After 30 minutes, triisopropyl borate (1.08 g, 5.76 mmol) was added and the reaction was carried out at -78 °C for 2 hours. The reaction was monitored by LCMS and quenched by saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was separated by reverse phase column chromatography (acetonitrile / water: 0-80%) to give (5-(di(4-methoxybenzyl)amino)-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)boronic acid (565 mg, yield: 30.9%). ESI-MS: 478.3 [M+1] + .

[0376] Preparation of intermediate 4-2: (5-(di(4-methoxybenzyl)amino)-3-methyl-2- (trifluoromethyl)phenyl)boronic acid

[0377] Intermediate 4-2 was prepared according to the above route by following the synthetic procedure of intermediate 4-1.

[0378] Preparation of intermediate 4-3: N,N-di(4-methoxybenzyl)-6-methyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)pyridin-2-amine

[0379] First step: Synthesis of 4-chloro-N,N-di(4-methoxybenzyl)-6-methylpyridin-2- amine

[0380] 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 added slowly under ice-water bath cooling. After 1 hour of reaction at 0 °C, 4-methoxybenzyl chloride (24.16 g, 156.61 mmol) was added dropwise slowly and stirred at room temperature overnight. The reaction was monitored by LCMS and the reaction mixture was poured into ice-water bath and extracted with ethyl acetate. The organic phase was washed with saturated brine once. The organic phase was dried, filtered and the filtrate was concentrated. The residue was added with methanol (100 mL) and stirred at room temperature for 1 hour. The mixture was 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] + .

[0381] Step 2: Synthesis of 4-chloro-5-iodo-N,N-di(4-methoxybenzyl)-6-methylpyridin-2-amine

[0382] 4-chloro-N,N-di(4-methoxybenzyl)-6-methylpyridin-2-amine (10.0 g, 26.12 mmol) was dissolved in DMF (200 mL), HOAc (15.0 mL, 261.2 mmol) and NIS (7.05 g, 31.34 mmol) were added at room temperature, the reaction was stirred at room temperature for 2 hours. The reaction was monitored by LCMS, the reaction was completed, the reaction solution was poured into ice water (600 mL), extracted with ethyl acetate (200 mL) twice, the organic phase was combined, and washed with saturated sodium thiosulfate, saturated sodium bicarbonate solution and saturated brine in turn. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was added to methanol (100 mL) and stirred at room temperature overnight, filtered, and the filter cake was dried under vacuum to give 4-chloro-5-iodo-N,N-di(4-methoxybenzyl)-6-methylpyridin-2-amine (10.6 g, yield: 79.8%). ESI-MS: 509.2 [M+1] + .

[0383] Step 3: Synthesis of 4-chloro-N,N-di(4-methoxybenzyl)-6-methyl-5-(trifluoromethyl)pyridin-2-amine

[0384] 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), methyl fluorosulfonyl difluoroacetate (6.80 g, 35.38 mmol) and cuprous iodide (6.74 g, 35.38 mmol) were added at room temperature, and the reaction was stirred at 100°C for 2 hours. The reaction was monitored by LCMS, the reaction was completed, the reaction solution was poured into ice water, extracted with ethyl acetate, and the organic phase was washed with 10% ammonia water and saturated brine in turn. The organic phase was dried and filtered, the filtrate was concentrated, and the residue was separated by flash silica gel column chromatography (ethyl acetate / petroleum ether 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] + .

[0385] Step 4: Synthesis of N,N-di(4-methoxybenzyl)-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)pyridin-2-amine

[0386] 4-chloro-N,N-di(4-methoxybenzyl)-6-methyl-5-(trifluoromethyl)pyridin-2-amine (1.50 g, 3.33 mmol), bis(pinacolato)diboron (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, the reaction vessel was purged with nitrogen and heated to 110 °C under nitrogen for 4 h. The reaction was monitored by LCMS and was complete. The reaction mixture was diluted with saturated brine and extracted with ethyl acetate. The organic phase was concentrated and the residue was purified by flash column chromatography on silica gel (ethyl acetate / petroleum ether 0-10%) to give N,N-di(4-methoxybenzyl)-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5- (trifluoromethyl)pyridin-2-amine (900 mg, yield: 49.4%). ESI-MS: 543.4 [M+1] + .

[0387] Preparation of intermediate 4-4: tert-butyl (3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-7- fluorobenzo[b]thiophen-2-yl)carbamate

[0388] First step: synthesis of ethyl (4-bromo-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate

[0389] 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 stirring was continued at 0 °C for 30 min. Then ethyl isothiocyanate (2.58 g, 19.65 mmol) was added and the reaction was heated at 100 °C for 18 h. The reaction was monitored by LCMS and was complete. The reaction mixture was cooled to room temperature and 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 purified by flash column chromatography on silica gel (ethyl acetate / petroleum ether 0-10%) to give ethyl (4-bromo-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (4.78 g, yield: 85.1%). ESI-MS: 344.4 [M+1] + .

[0390] Second step: synthesis of 2-amino-4-bromo-7-fluorobenzo[b]thiophene-3-carbonitrile

[0391] (4-bromo-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamic acid ethyl ester (4.78 g, 13.93 mmol) was dissolved in DMSO (19 mL) and aqueous NaOH (15.6 mL, 78 mmol, 5 N) was added at 0 °C. After the addition was complete, the reaction was heated to 125 °C and stirred for 18 h. The reaction was monitored by LCMS and was complete. The reaction 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 purified by flash chromatography on silica gel (ethyl acetate / petroleum ether 0-20%) to give 2-amino-4-bromo-7-fluorobenzo[b]thiophene-3-carbonitrile (1.91 g, 50.5% yield). ESI-MS m / z 272.3 [M+1] + .

[0392] Third Step: Synthesis of tert-butyl (4-bromo-3-cyano-7-fluorobenzo[b]thiophen-2- yl)carbamate

[0393] 2-amino-4-bromo-7-fluorobenzo[b]thiophene-3-carbonitrile (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) and Boc20 (1.69 g, 7.75 mmol) was added with ice water bath cooling. After the addition was complete, the reaction was stirred at room temperature for 18 h. The reaction was monitored by LCMS and was complete. The reaction was diluted with ethyl acetate and the organic phase was separated and washed with saturated brine once. The organic phase was dried, filtered, and the filtrate was concentrated. The residue was purified by flash chromatography on silica gel (ethyl acetate / petroleum ether 0-10%) to give tert-butyl (4-bromo-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (1.69 g, 64.5% yield). ESI-MS m / z 372.3 [M+1] + .

[0394] Fourth Step: Synthesis of tert-butyl (3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-7- fluorobenzo[b]thiophen-2-yl)carbamate

[0395] Tert-butyl (4-bromo-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (1.59 g, 4.28 mmol), KOAc (1.26 g, 12.85 mmol), bis(neopentyl glycolato)diboron (3.68 g, 16.28 mmol) were dissolved in 1,4-dioxane (40 mL), DPEPhos PdCl2 (230 mg, 0.43 mmol) was added, and the mixture was stirred at 95 °C for 18 h under nitrogen. The reaction was monitored by LCMS and was complete. The reaction mixture was concentrated and the residue was purified by flash silica gel column chromatography (ethyl acetate / petroleum ether 0-10%) to give tert-butyl (3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-7-fluorobenzo[b]thiophen-2-yl)carbamate (1.08 g, yield: 62.4%). ESI-MS m / z 405.4 [M+1] + .

[0396] Preparation of Intermediate 4-5: tert-butyl (3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)benzo[b]thiophen-2-yl)carbamate

[0397] The preparation was performed according to the synthetic procedure of Intermediate 4-4 by selecting the corresponding starting materials.

[0398] Preparation of Intermediate 4-6: tert-butyl (3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)benzofuran-2-yl)carbamate

[0399] First Step: Synthesis of 4-bromo benzofuran-2-carboxylic acid ethyl ester

[0400] 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), K2CO3 (20.62 g, 149.239 mmol) was added, and the mixture was stirred at 130 °C for 4 h. The reaction was monitored by LCMS and was complete. Water (200 mL) was added and the mixture was extracted with EtOAc (200 mL) three times. The organic layers were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether 0-3%) to give 4-bromo benzofuran-2-carboxylic acid ethyl ester (9 g, yield: 67.2%).

[0401] 1H NMR (400 MHz, DMSO-d6) δ 7.80 (dt, J = 8.4, 0.9 Hz, 1H), 7.68 - 7.54 (m, 2H), 7.49 (t, J = 8.0 Hz, 1H), 4.38 (q, J = 7.2 Hz, 2H), 1.36 (t, J = 7.2 Hz, 3H).

[0402] Second Step: Synthesis of 4-bromobenzofuran-2-carboxylic acid

[0403] Ethyl 4-bromobenzofuran-2-carboxylate (2 g, 7.432 mmol) was dissolved in DMF (10 mL), 20% aqueous sodium hydroxide solution (2 mL) was added and heated at 60 °C for 1 hour. Water (50 mL) was added and extracted with EtOAc (50 mL) three times, the organic phase was combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to obtain 4-bromobenzofuran-2-carboxylic acid (1 g, yield: 55.8%).

[0404] Third Step: Synthesis of tert-butyl (4-bromobenzofuran-2-yl)carbamate

[0405] 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), DPPA (1.166 mL, 5.393 mmol) was added, and after stirring for 10 minutes, the temperature was raised to 95 °C for 4 hours. After the reaction was completed, it was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (ethyl acetate / petroleum ether 0-10%) to obtain tert-butyl (4-bromobenzofuran-2-yl)carbamate (1 g, yield: 77.2%).

[0406] 1 H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.09 (t, J = 8.0 Hz, 1H), 6.31 (s, 1H), 1.50 (s, 9H).

[0407] Fourth Step: Synthesis of tert-butyl (4-bromo-3-cyanobenzofuran-2-yl)carbamate

[0408] The intermediate tert-butyl (4-bromobenzofuran-2-yl)carbamate (500 mg, 1.602 mmol) from the previous step was dissolved in dry THF (10 mL) and cooled to -70 °C under nitrogen. Chlorosulfonic acid isocyanate (1.394 mL, 16.020 mmol) was added and stirred for 1 h. Additional chlorosulfonic acid isocyanate (0.42 mL) was added and stirred for 1 h. Dry DMF (10 mL) was added and stirred for 1 h. The reaction was complete. The reaction was quenched with water (30 mL) and extracted with EtOAc (30 mL) three times. The organic phase was combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether 0-10%) to give tert-butyl (4-bromo-3-cyanobenzofuran-2-yl)carbamate (430 mg, 1.104 mmol, 68.9% yield). ESI-MS m / z 356.0 [M+18+1] + .

[0409] Fifth step: Synthesis of tert-butyl (3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborinan-2- yl)benzofuran-2-yl)carbamate

[0410] Tert-butyl (4-bromo-3-cyanobenzofuran-2-yl)carbamate (280 mg, 0.830 mmol) and 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinane (562.8 mg, 2.491 mmol) were dissolved in 1,4-dioxane (3 mL), then Pd(DPEPhos)Cl2(297.1 mg, 0.415 mmol) and KOAc (269 mg, 2.740 mmol) were added and stirred at 100 °C for 2 h under nitrogen. The reaction was complete by LCMS. After cooling, water (30 mL) was added and extracted with EtOAc (30 mL) three times. The organic phase was combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether 0-10%) to give tert-butyl (3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)benzofuran-2- yl)carbamate (170 mg, 55.3% yield). ESI-MS: 320.2 [M-51+1] + .

[0411] Preparation of intermediate tert-butyl (4-chloro-3-cyano-7-fluorothieno[3,2-c]pyridin-2- yl)carbamate

[0412] First Step: Synthesis of 4-(4-chloro-5-fluoropyridin-3-yl)isothiazole

[0413] 3-bromo-4-chloro-5-fluoropyridine (14 g, 66.5 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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 solution was stirred at 90 °C for 2 hours. After the reaction was completed, the reaction solution was directly used in the next step.

[0414] Second Step: Synthesis of 2-(4-chloro-5-fluoropyridin-3-yl)acetonitrile

[0415] To the reaction solution of the previous step, methanol (50 mL) and water (0.5 mL) were added, and then KF (11.6 g, 200 mmol) was added, and the reaction solution was stirred at 90 °C for 16 hours. The reaction solution was extracted with water (200 mL) and ethyl acetate (200 mL) for 3 times, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the residue was separated by flash silica gel column (ethyl acetate / petroleum ether 0-3%) to obtain 2-(4-chloro-5-fluoropyridin-3-yl)acetonitrile (8.5 g, yield: 90.0%). ESI-MS: 170.8 [M+1] + .

[0416] Third Step: Synthesis of ethyl (3-cyano-7-fluorothieno[3,2-c]pyridin-2-yl)carbamate

[0417] 2-(4-chloro-5-fluoropyridin-3-yl)acetonitrile (7.5 g, 43.9 mmol) was dissolved in DMF (80 mL), then t-BuOK (5.96 mL, 48.4 mmol) and ethoxycarbonylisothiocyanate (5.70 mL, 48.3 mmol) were added, and the reaction was stirred at 25 °C for 15 hours. The reaction solution was filtered, and the filter cake was dried to obtain ethyl (3-cyano-7-fluorothieno[3,2-c]pyridin-2-yl)carbamate (11 g, yield: 94.3%), which was directly used in the next step. ESI-MS: 266.0 [M+1] + .

[0418] Fourth Step: Synthesis of 2-amino-7-fluorothieno[3,2-c]pyridine-3-carbonitrile

[0419] Ethyl (3-cyano-7-fluorothieno[3,2-c]pyridin-2-yl)carbamate (5 g, 18.8 mmol) was dissolved in DMSO (32 mL), then 4N NaOH aqueous solution (33 mL, 132 mmol) was added. The reaction was heated at 105 °C for 10 h. The reaction was poured into water (500 mL), filtered, and the filter cake was dried to remove the solvent to give 2-amino-7-fluorothieno[3,2-c]pyridine-3-carbonitrile (3.60 g, yield: 98.9 %), which was used directly in the next step.

[0420] Fifth step: Synthesis of tert-butyl (3-cyano-7-fluorothieno[3,2-c]pyridin-2- yl)carbamate

[0421] 2-Amino-7-fluorothieno[3,2-c]pyridine-3-carbonitrile (3.60 g, 18.6 mmol) was dissolved in THF (70 mL), then DIPEA (9.24 mL, 55.9 mmol) and DMAP (0.23 g, 1.86 mmol) were added, and finally Boc20 (5.98 mL, 27.9 mmol) was added portionwise. The reaction was heated at 40 °C for 2 h. Then the reaction was extracted with aqueous citric acid solution (60 mL, 5 %) and EtOAc (60 mL) three times, and the organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to give tert-butyl (3-cyano-7-fluorothieno[3,2-c]pyridin-2-yl)carbamate (5 g, yield: 91.5 %). ESI-MS: 237.9 [M-56+1] + .

[0422] Sixth step: Synthesis of 2-((tert-butoxycarbonyl)amino)-3-cyano-7- fluorothieno[3,2-c]pyridine 5-oxide

[0423] Tert-butyl (3-cyano-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 portionwise at room temperature. After the addition was completed, the reaction was continued for 12 h. After the reaction was completed, water (200 mL) was added, and the reaction was extracted with ethyl acetate (200 mL) three times. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was separated by flash silica gel column chromatography (ethyl acetate / petroleum ether 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: 253.9 [M-56+1] + .

[0424] Step 7: Synthesis of tert-butyl (4-chloro-3-cyano-7-fluorothieno[3,2-c]pyridin-2- yl)carbamate

[0425] 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 completed, the reaction was heated at 45 °C for 1 hour. A large amount of solid precipitated. The reaction solution was filtered, the filter cake was added to saturated NaHCO3aqueous solution (100 mL), and extracted with dichloromethane (100 mL) three times. The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was separated by flash silica gel column (ethyl acetate / petroleum ether 0-10%) to obtain tert-butyl (4-chloro-3-cyano-7-fluorothieno[3,2-c]pyridin-2-yl)carbamate (2.7 g, yield: 41.6%). ESI-MS: 271.9 [M-100+1] + .

[0426] 1 H NMR (400 MHz, DMSO-d6) δ 8.33 (br s, 1H), 8.14 (s, 1H), 1.62 (s, 9H).

[0427] Intermediate 4-8: Preparation of tert-butyl (5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)naphthalen-2-yl)carbamate

[0428] Step 1: Synthesis of tert-butyl ((5-ethynyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)naphthalen-2-yl))carbamate

[0429] tert-butyl (6-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)carbamate (500 mg, 0.88 mmol) was dissolved in DMF (5 mL), CsF (1.338 g, 8.81 mmol) was added at room temperature, and the reaction was stirred at 50 °C for 1 h. The reaction was extracted with EtOAc and saturated aqueous NaHCO3. The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to give crude tert-butyl ((5-ethynyl-6-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)naphthalen-2-yl))carbamate (362 mg, yield: 99%). ESI-MS: 410.2 [M-H] - .

[0430] Second Step: Synthesis of tert-butyl (5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)naphthalen-2-yl)carbamate

[0431] tert-butyl (5-ethynyl-6-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)naphthalen-2-yl))carbamate (362 mg, 0.87 mmol) was dissolved in EtOAc (20 mL), Pd-C (10%, 60 mg) was added at room temperature, and the reaction was stirred at room temperature for 2 h under an atmosphere of H2at normal pressure. The reaction was filtered through celite, washed with EtOAc (20 mL), and the filtrate was concentrated to give tert-butyl (5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)naphthalen-2-yl)carbamate (360 mg, yield: 98%). ESI-MS: 360.2 [M-56+H] + .

[0432] II. Preparation of Specific Examples

[0433] Example 1: Preparation of N 3 -(8-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-9-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizine-7a(5H)-yl)methoxy)-5,6-dihydro-4H-pyrimido[4,5,6-de][l,6]naphthyridin-4-yl)-N 3 -methylpyridine-2,3-diamine

[0434] First Step: Preparation of N 3-(8-chloro-9-fluoro-2-(methylsulfanyl)-5,6-dihydro-4H-pyrimido[4,5,6-de][1,6]naphthyridin-4-yl)-N 2 ,N 2 -(8-chloro-9-fluoro-2-(methylsulfanyl)-5,6-dihydro-4H-pyrimido[4,5,6-de][1,6]naphthyridin-4-yl)-N 3 - Synthesis of methylpyridine-2,3-diamine

[0435] N 3 -(8-chloro-9-fluoro-2-(methylsulfanyl)-5,6-dihydro-4H-pyrimido[4,5,6-de][1,6]naphthyridin-4-yl)-N 2 ,N 2 -(8-chloro-9-fluoro-2-(methylsulfanyl)-5,6-dihydro-4H-pyrimido[4,5,6-de][1,6]naphthyridin-4-yl)-N 3 - Synthesis of methylpyridine-2,3-diamine (140 mg, 0.221 mmol) was dissolved in dichloromethane (5 mL) and m-CPBA (180 mg, purity: 85%, 0.886 mmol) was added under ice water bath cooling. The reaction was carried out at 0 °C for 2 hours. Dilution with dichloromethane was followed by quenching with saturated aqueous sodium bicarbonate and sodium thiosulfate solution, and extraction was performed by liquid-liquid separation. The organic phase was concentrated, and the resulting residue was separated by flash silica gel column chromatography (ethyl acetate / petroleum ether 0-70%) to obtain N 3 -(8-chloro-9-fluoro-2-(methylsulfanyl)-5,6-dihydro-4H-pyrimido[4,5,6-de][1,6]naphthyridin-4-yl)-N 2 ,N 2 -(8-chloro-9-fluoro-2-(methylsulfanyl)-5,6-dihydro-4H-pyrimido[4,5,6-de][1,6]naphthyridin-4-yl)-N 3 - Synthesis of methylpyridine-2,3-diamine (100 mg, yield: 68%). ESI-MS: 664.3 [M+1] + .

[0436] N 3 -(8-chloro-9-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)-5,6-dihydro-4H-pyrimido[4,5,6-de][1,6]naphthyridin-4-yl)-N 2 ,N 2 -(8-chloro-9-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)-5,6-dihydro-4H-pyrimido[4,5,6-de][1,6]naphthyridin-4-yl)-N 3 - Synthesis of methylpyridine-2,3-diamine

[0437] ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methanol (31.2 mg, 0.196 mmol) was dissolved in anhydrous THF (3 mL), and a LiHMDS solution (0.230 mL, 0.230 mmol, 1 N) was added at 0 °C. After stirring at 0 °C for 30 minutes, N3 - (8-chloro-9-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-lH-pyrrolizine-7a(5H)- yl)methoxy)-5,6-dihydro-4H-pyrimido[4,5,6-de][l,6]naphthyridin-4-yl)-N 2 ,N 2 - (8-chloro-9-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-lH-pyrrolizine-7a(5H)- yl)methoxy)-5,6-dihydro-4H-pyrimido[4,5,6-de][l,6]naphthyridin-4-yl)-N 3 - (8-chloro-9-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-lH-pyrrolizine-7a(5H)- yl)methoxy)-5,6-dihydro-4H-pyrimido[4,5,6-de][l,6]naphthyridin-4-yl)-N 3 - (8-chloro-9-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-lH-pyrrolizine-7a(5H)- yl)methoxy)-5,6-dihydro-4H-pyrimido[4,5,6-de][l,6]naphthyridin-4-yl)-N 2 ,N 2 - (8-chloro-9-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-lH-pyrrolizine-7a(5H)- yl)methoxy)-5,6-dihydro-4H-pyrimido[4,5,6-de][l,6]naphthyridin-4-yl)-N 3 - (8-chloro-9-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-lH-pyrrolizine-7a(5H)- yl)methoxy)-5,6-dihydro-4H-pyrimido[4,5,6-de][l,6]naphthyridin-4-yl)-N + .

[0438] Third step: N 3 - (8-chloro-9-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-lH-pyrrolizine-7a(5H)- yl)methoxy)-5,6-dihydro-4H-pyrimido[4,5,6-de][l,6]naphthyridin-4-yl)-N 2 ,N 2 - (8-chloro-9-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-lH-pyrrolizine-7a(5H)- yl)methoxy)-5,6-dihydro-4H-pyrimido[4,5,6-de][l,6]naphthyridin-4-yl)-N 3 - (8-chloro-9-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-lH-pyrrolizine-7a(5H)- yl)methoxy)-5,6-dihydro-4H-pyrimido[4,5,6-de][l,6]naphthyridin-4-yl)-N

[0439] N 3 - (8-chloro-9-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-lH-pyrrolizine-7a(5H)- yl)methoxy)-5,6-dihydro-4H-pyrimido[4,5,6-de][l,6]naphthyridin-4-yl)-N 2 ,N 2 - (8-chloro-9-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-lH-pyrrolizine-7a(5H)- yl)methoxy)-5,6-dihydro-4H-pyrimido[4,5,6-de][l,6]naphthyridin-4-yl)-N 3- methylpyridin-2,3-diamine (32.0 mg, 0.043 mmol) and 3-chloro-5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline (18.0 mg, 0.056 mmol) were dissolved in 1,4-dioxane (2.0 mL), H2O (0.2 mL), chloro[(n-butyldi(1-adamantyl)phosphine)-2-(2- aminobiphenyl)]palladium(II) (5.8 mg, 0.009 mmol), potassium phosphate (27.5 mg, 0.129 mmol) were added, and the reaction was heated at 100 °C for 1 h under nitrogen. The reaction mixture was added to saturated brine and extracted with ethyl acetate. The organic phase was concentrated, and the resulting residue was separated by flash column chromatography (acetonitrile / water: 0-80%) to give N 3 -(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-pyrimido[4,5,6- de][1,6]naphthyridin-4-yl)-N 2 ,N 2 -dibenzyl-N 3 -methylpyridin-2,3-diamine (26 mg, yield: 27%). ESI-MS: 902.4 [M+1] + .

[0440] Fourth step: N 3 -(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-pyrimido[4,5,6- de][1,6]naphthyridin-4-yl)-N 3 -Synthesis of methylpyridin-2,3-diamine

[0441] N 3 -(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-pyrimido[4,5,6- de][1,6]naphthyridin-4-yl)-N 2 ,N 2 -dibenzyl-N 3Methylpyridine-2,3-diamine (26 mg, 0.012 mmol) was dissolved in trifluoroacetic acid (2.0 mL), and methane sulfonic acid (0.2 mL) was added at 0 °C. The reaction was stirred at 0 °C for 1 h. The solvent was blown off with nitrogen, and the residue was diluted with dichloromethane and poured into ice water. The aqueous solution was neutralized with saturated aqueous NaHC03solution and extracted with dichloromethane. The organic phase was concentrated, and the residue was separated by preparative HPLC (acetonitrile / (water + 10 mM NH4HC03) = 30-55%) to give N 3 -(8-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-9-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizine-7a(5H)-yl)methoxy)-5,6-dihydro-4H- pyrimido[4,5,6-de][l,6]naphthyridin-4-yl)-N 3 -methylpyridine-2,3-diamine (1.34 mg, yield: 17%). ESI-MS: 662.4 [M+1] + .

[0442] 1 H NMR (400 MHz, DMSO-d6) δ 7.81 (d, J = 4.9 Hz, 1H), 7.59 (d, J = 7.7 Hz, 1H), 6.87 (d, J = 2.3 Hz, 1H), 6.63 (dd, J = 7.6, 4.9 Hz, 1H), 6.44 (d, J = 2.3 Hz, 1H), 6.31 (s, 2H), 5.93 (s, 2H), 5.29 (d, J = 54.4 Hz, 1H), 4.21 - 4.09 (m, 2H), 3.16 - 3.08 (m, 4H), 3.05 (s, 3H), 3.00 - 2.71 (m, 4H), 2.21 - 1.93 (m, 3H), 1.92 - 1.69 (m, 3H).

[0443] Example 2: N 3 -(8-(3-amino-8-ethynyl-7-fluoronaphthalen-l-yl)-9-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizine-7a(5H)-yl)methoxy)-5,6-dihydro-4H- pyrimido[4,5,6-de][l,6]naphthyridin-4-yl)-N 3 -preparation of methylpyridine-2,3-diamine

[0444] First step: N 3- (8-chloro-9-fluoro-2-(((2R)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl)methoxy)-5,6-dihydro-4H-pyrimido[4,5,6-de] [l,6]naphthyridin-4-yl)-N 2 ,N 2 - di(4-methoxybenzyl)-N 3 - methylpyridine-2,3-diamine

[0445] N 3 - (8-chloro-9-fluoro-2-(((2R)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl)methoxy)-5,6-dihydro-4H-pyrimido[4,5,6-de] [l,6]naphthyridin-4-yl)-N 2 ,N 2 - di(4-methoxybenzyl)-N 3 - methylpyridine-2,3-diamine (175.0 mg, 0.235 mmol) and 6-fluoro-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-amine (220.0 mg, 0.471 mmol) were dissolved in 1,4-dioxane (5.0 mL), followed by the addition of H20 (0.50 mL), cataxium A-Pd-G2 (47 mg, 0.071 mmol), K3PO4 (299.2 mg, 1.410 mmol), and the mixture was degassed with nitrogen. The reaction was heated at 100 °C for 2 h in a microwave. The reaction was added to saturated brine and extracted with ethyl acetate. The organic phase was directly concentrated and the resulting residue was separated by flash column chromatography (MeOH / CH2Cl2= 0-5%) to give N 3 - (8-chloro-9-fluoro-2-(((2R)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl)methoxy)-5,6-dihydro-4H-pyrimido[4,5,6-de] [l,6]naphthyridin-4-yl)-N 2 ,N 2 - di(4-methoxybenzyl)-N 3 - methylpyridine-2,3-diamine (170 mg, yield: 68%). ESI-MS: 1048.6 [M+1] + .

[0446] Second step: N 3- (8-(3-amino-7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-9-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5,6-dihydro-4H- pyrimido[4,5,6-de] [l,6]naphthyridin-4-yl)-N 3 - Synthesis of methylpyridine-2,3-diamine

[0447] N 3 - (8-(3-amino-7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-9-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5,6-dihydro-4H- pyrimido[4,5,6-de] [l,6]naphthyridin-4-yl)-N 2 ,N 2 - (8-(3-amino-7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-9-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5,6-dihydro-4H- pyrimido[4,5,6-de] [l,6]naphthyridin-4-yl)-N 3 - Synthesis of methylpyridine-2,3-diamine (170 mg, 0.162 mmol) was dissolved in TFA (2.0 mL), MsOH (0.2 mL) was added at 0 °C, the reaction was stirred at 0 °C for 1 h. The reaction solution was blown dry with nitrogen, the residue was diluted with dichloromethane, poured into ice water, then neutralized with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, the organic phase was concentrated, and the obtained crude product (130 mg) was directly used in the next step. ESI-MS: 808.6 [M+l] + .

[0448] Third step: N 3 - (8-(3-amino-7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-9-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5,6-dihydro-4H- pyrimido[4,5,6-de] [l,6]naphthyridin-4-yl)-N 3 - Synthesis of methylpyridine-2,3-diamine

[0449] The crude product N 3 - (8-(3-amino-7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-9-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5,6-dihydro-4H- pyrimido[4,5,6-de] [l,6]naphthyridin-4-yl)-N 3Methylpyridine-2,3-diamine (130 mg) was dissolved in DMF (2.0 mL), CsF (481 mg, 3.168 mmol) was added, and the reaction was heated at 60 °C for 2 hours. The reaction was added to saturated brine and ethyl acetate, and the organic phase was directly concentrated. The resulting residue was separated by preparative HPLC (CH3CN / (H2O + 10 mM NH4HCO3) = 30-60%) to give N 3 -(8-(3-amino-8-ethynyl-7-fluoronaphthalen-1-yl)-9-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)-5,6-dihydro-4H- pyrimido[4,5,6-de][1,6]naphthyridin-4-yl)-N 3 -methylpyridine-2,3-diamine (26.4 mg, two-step yield: 25%). ESI-MS: 652.4 [M+1] + .

[0450] 1 H NMR (400 MHz, DMSO-d6) δ 7.81 (dd, J = 4.9, 1.6 Hz, 1H), 7.76 (dd, J = 9.2, 5.9 Hz, 1H), 7.61 (dd, J = 7.7, 1.7 Hz, 1H), 7.33 (t, J = 9.0 Hz, 1H), 7.08 - 6.98 (m, 2H), 6.63 (dd, J = 7.7, 4.9 Hz, 1H), 6.01 (s, 2H), 5.63 (s, 2H), 5.30 (d, J = 54.2 Hz, 1H), 4.13 (dt, J = 28.6, 10.2 Hz, 2H), 3.96 (s, 1H), 3.20 - 3.00 (m, 9H), 2.87 - 2.80 (m, 1H), 2.20 - 1.95 (m, 3H), 1.88 - 1.76 (m, 3H).

[0451] Example 3: Preparation of 2-amino-4-(4-((2-aminopyridin-3-yl)(methyl)amino)-9- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)-5,6- dihydro-4H-pyrimido[4,5,6-de][1,6]naphthyridin-8-yl)-7-fluorobenzo[b]thiophene-3- carbonitrile

[0452] Step 1: Synthesis of tert-butyl 4-(4-((2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)(methyl)amino)-9-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5,6-dihydro-4H-pyrimido[4,5,6-de][l,6]naphthyridin-8-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate

[0453] N 3 -(8-chloro-9-fluoro-2-(((2R)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5,6-dihydro-4H-pyrimido[4,5,6-de][l,6]naphthyridin-4-yl)-N 2 ,N 2 -di(4-methoxybenzyl)-N 3 -methylpyridine-2,3-diamine (160 mg, 0.192 mmol) and tert-butyl (3-cyano-4-(5,5-dimethyl-l,3,2-dioxaborinane-2-yl)-7-fluorobenzo[b]thiophen-2-yl)carbamate (155 mg, 0.384 mmol) were dissolved in 1,4-dioxane (2.0 mL), H2O (0.2 mL), Pd-118 (25 mg, 0.038 mmol), K2CO3 (80 mg, 0.576 mmol) were added, and the mixture was degassed with nitrogen. The mixture was heated at 100 °C for 1 h in a microwave reactor. The reaction was complete, and the mixture was extracted with saturated brine and ethyl acetate. The organic phase was directly concentrated, and the residue was purified by flash column chromatography (MeOH / CH2Cl2= 0-5%) to give tert-butyl 4-(4-((2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)(methyl)amino)-9-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5,6-dihydro-4H-pyrimido[4,5,6-de][l,6]naphthyridin-8-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (92 mg, yield: 43%). ESI-MS: 999.6 [M+1] + .

[0454] Step 2: Synthesis of 2-amino-4-(4-((2-aminopyridin-3-yl)(methyl)amino)-9-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5,6-dihydro-4H-pyrimido[4,5,6-de][l,6]naphthyridin-8-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0455] tert-Butyl 4-(4-((2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)(methyl)amino)-9-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,6-dihydro-4H-pyrimido[4,5,6-de][1,6]naphthyridin-8-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)aminocarbamate (90 mg, 0.090 mmol) was dissolved in TFA (2.0 mL) and heated at 50 °C for 3 hours. The reaction was blown dry with nitrogen, the residue was diluted with dichloromethane and poured into ice water, then neutralized with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, and the organic phase was concentrated. The residue was separated by preparative HPLC (CH3CN / (H2O + 10 mM NH4HCO3) = 30-60%) to give 2-amino-4-(4-((2-aminopyridin-3-yl)(methyl)amino)-9-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,6-dihydro-4H-pyrimido[4,5,6-de][1,6]naphthyridin-8-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (23.2 mg, yield: 37%). ESI-MS: 659.4 [M+1] + .

[0456] 1 H NMR (400 MHz, DMSO-d6) δ 8.08 (s, 2H), 7.81 (dd, J = 5.0, 1.5 Hz, 1H), 7.60 (dd, J = 7.7, 1.7 Hz, 1H), 7.38 (dd, J = 8.4, 5.4 Hz, 1H), 7.13 (t, J = 8.9 Hz, 1H), 6.64 (dd, J = 7.6, 4.9 Hz, 1H), 5.94 (s, 2H), 5.31 (d, J = 54.1 Hz, 1H), 4.20 - 4.10 (m, 2H), 3.20 - 3.00 (m, 9H), 2.85 (d, J = 7.1 Hz, 1H), 2.17 (s, 1H), 2.06 (dd, J = 19.9, 7.3 Hz, 2H), 1.90 - 1.74 (m, 3H).

[0457] Example 4: Preparation of N 3 -(8-(3-amino-8-ethynyl-7-fluoronaphthalen-1-yl)-9-fluoro-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-5,6-dihydro-4H-pyrimido[4,5,6-de][1,6]naphthyridin-4-yl)-N 3 Preparation of 3-amino-8-ethynyl-7-fluoronaphthalene-1-carboxylic acid

[0458] First step:3 - (8-chloro-9-fluoro-2-(2,2,2-trifluoroethoxy)-5,6-dihydro-4H- pyrimido[4,5,6-de][l,6]naphthyridin-4-yl)-N 2 ,N 2 - di(4-methoxybenzyl)-N 3 - methylpyridine-2,3-diamine

[0459] N 3 - (8-chloro-9-fluoro-2-(2,2,2-trifluoroethoxy)-5,6-dihydro-4H- pyrimido[4,5,6-de][l,6]naphthyridin-4-yl)-N 2 ,N 2 - di(4-methoxybenzyl)-N 3 - methylpyridine-2,3-diamine (2100 mg, 3.162 mmol) was dissolved in trifluoroethanol (60 mL), DIPEA (1.6 mL, 9.486 mmol) was added, and the reaction was stirred at 60 °C for 3 hours. The reaction solution was added to saturated brine and ethyl acetate, and the organic phase was concentrated. The residue was separated by flash column chromatography (EA / PE = 40-50%) to obtain N 3 - (8-chloro-9-fluoro-2-(2,2,2-trifluoroethoxy)-5,6-dihydro-4H- pyrimido[4,5,6-de][l,6]naphthyridin-4-yl)-N 2 ,N 2 - di(4-methoxybenzyl)-N 3 - methylpyridine-2,3-diamine (1097 mg, yield: 50%). ESI-MS: 684.4 [M+1] + .

[0460] Second Step: Synthesis of tert-butyl (4-(4-((2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)(methyl)amino)-9-fluoro-2-(2,2,2-trifluoroethoxy)-5,6-dihydro-4H-pyrimido[4,5,6-de][l,6]naphthyridin-8-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)carbamate

[0461] N 3 - (8-chloro-9-fluoro-2-(2,2,2-trifluoroethoxy)-5,6-dihydro-4H- pyrimido[4,5,6-de][l,6]naphthyridin-4-yl)-N 2 ,N 2 - di(4-methoxybenzyl)-N 3- methylpyridine-2,3-diamine (400 mg, 0.585 mmol) and tert-butyl (6-fluoro 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)carbamate (431 mg, 0.760 mmol) were dissolved in 1,4-dioxane (5.0 mL), H2O (0.5 mL), cataxium A-Pd-G2 (78 mg, 0.117 mmol), K3PO4 (496 mg, 2.339 mmol) were added, and the mixture was microwaved at 100 °C for 2 h. The reaction was complete, saturated brine was added, and the mixture was extracted with ethyl acetate. The organic phase was directly concentrated, and the resulting residue was separated by flash column chromatography (EA / PE = 20-35%) to give tert-butyl (4-(4-((2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)(methyl)amino)-9-fluoro-2-(2,2,2-trifluoroethoxy)-5,6-dihydro-4H-pyrrolo[4,5,6-de][l,6]naphthyridin-8-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)carbamate (630 mg, yield: 98%). ESI-MS: 1090.6 [M+1] + .

[0462] Third step: synthesis of tert-butyl (4-(4-((2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)(methyl)amino)-9-fluoro-2-((l-(morpholinomethyl)cyclopropyl)methoxy)-5,6-dihydro-4H-pyrrolo[4,5,6-de][l,6]naphthyridin-8-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)carbamate

[0463] tert-Butyl (4-(4-((2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)(methyl)amino)-9-fluoro-2-(2,2,2-trifluoroethoxy)-5,6-dihydro-4H-pyrimido[4,5,6-de][1,6]naphthyridin-8-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)carbamate (100.0 mg, 0.092 mmol) and (1-(morpholinomethyl)cyclopropyl)methanol (20.4 mg, 0.119 mmol) were dissolved in anhydrous THF (3.0 mL), sodium tert-pentoxide (30.33 mg, 0.275 mmol) was added, and the reaction was heated at 40 °C for 16 h. After the reaction was completed, saturated brine and ethyl acetate were added, and the organic phase was directly concentrated. The residue was separated by flash column chromatography (EA / PE = 0-50%) to give tert-butyl (4-(4-((2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)(methyl)amino)-9-fluoro-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-5,6-dihydro-4H-pyrimido[4,5,6-de][1,6]naphthyridin-8-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)carbamate (80 mg, yield: 75%). ESI-MS: 1160.7 [M+1] + .

[0464] Fourth step: Synthesis of N 3 -(8-(3-amino-7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-9-fluoro-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-5,6-dihydro-4H-pyrimido[4,5,6-de][1,6]naphthyridin-4-yl)-N 3 -methylpyridine-2,3-diamine

[0465] tert-Butyl (4-(4-((2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)(methyl)amino)-9-fluoro-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-5,6-dihydro-4H-pyrimido[4,5,6-de][1,6]naphthyridin-8-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)carbamate (80.0 mg, 0.069 mmol) was dissolved in TFA (1.0 mL), and MsOH (0.2 mL) was added dropwise at 0 °C. The reaction was stirred at 0 °C for 1 h. The solvent was blown dry with nitrogen, and the residue was diluted with dichloromethane, poured into ice water, neutralized with saturated aqueous sodium bicarbonate solution, and extracted with dichloromethane. The organic phase was concentrated, and the obtained crude product was directly used in the next step. ESI-MS: 410.7 [M / 2+H] + .

[0466] Fifth step: N 3 - (8-(3-amino-8-ethynyl-7-fluoronaphthalen-l-yl)-9-fluoro-2-((l- (morpholinomethyl)cyclopropyl)methoxy)-5,6-dihydro-4H-pyrimido[4,5,6- de][l,6]naphthyridin-4-yl)-N 3 - Synthesis of methylpyridine-2,3-diamine

[0467] N 3 - (8-(3-amino-7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-9-fluoro-2-((l- (morpholinomethyl)cyclopropyl)methoxy)-5,6-dihydro-4H-pyrimido[4,5,6- de][l,6]naphthyridin-4-yl)-N 3 - methylpyridine-2,3-diamine (56.5 mg, 0.159 mmol) was dissolved in DMF (1.5 mL), CsF (300.0 mg, 1.975 mmol) was added, and the reaction was heated at 60 °C for 2 hours. The reaction was complete, and the crude product was separated by preparative HPLC (ACN / H2O (+ 10.0 mM NH4HCO3) = 0-70%) to give N 3 - (8-(3-amino-8-ethynyl-7-fluoronaphthalen-l-yl)-9-fluoro-2-((l- (morpholinomethyl)cyclopropyl)methoxy)-5,6-dihydro-4H-pyrimido[4,5,6- de][l,6]naphthyridin-4-yl)-N 3 - methylpyridine-2,3-diamine (24.0 mg, two-step yield: 52%). ESI-MS: 664.4 [M+1] + .

[0468] 1 H NMR (400 MHz, DMSO-d6) δ 7.84 - 7.72 (m, 2H), 7.61 (dd, J = 7.7, 1.6 Hz, 1H), 7.33 (t, J = 9.0 Hz, 1H), 7.06 - 6.97 (m, 2H), 6.63 (dd, J = 7.6, 4.9 Hz, 1H), 6.02 (s, 2H), 5.63 (s, 2H), 4.32 (q, J = 11.1 Hz, 2H), 3.96 (s, 1H), 3.55 (t, J = 4.7 Hz, 4H), 3.30 (d, J = 10.0 Hz, 3H), 3.08 (d, J = 8.3 Hz, 5H), 2.44 - 2.37 (m, 4H), 2.33 (s, 2H), 0.67 (d, J = 4.4 Hz, 2H), 0.43 (d, J = 5.1 Hz, 2H).

[0469] Example 5: (R)-N 3 - (8-chloro-9-fluoro-2-(methylthio)-5,6-dihydro-4H-pyrimido[4,5,6-de][l,6]naphthyridin-4-yl)-N 3 - Preparation of methylpyridine-2,3-diamine

[0470] First Step: Synthesis of tert-butyl 4-(4-((2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)(methyl)amino)-9-fluoro-2-(methylthio)-5,6-dihydro-4H-pyrimido[4,5,6-de][l,6]naphthyridin-8-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)carbamate

[0471] N 3 - (8-chloro-9-fluoro-2-(methylthio)-5,6-dihydro-4H-pyrimido[4,5,6-de][l,6]naphthyridin-4-yl)-N 2 ,N 2 - bis(4-methoxybenzyl)-N 3 - methylpyridine-2,3-diamine (450 mg, 0.712 mmol) and tert-butyl (6-fluoro 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)carbamate (525 mg, 0.925 mmol) were dissolved in 1,4-dioxane (5.0 mL), H2O (0.5 mL), cataxium A-Pd-G2 (103 mg, 0.142 mmol) and K3PO4 (453 mg, 2.136 mmol) were added, and the mixture was microwaved at 100 °C for 2 hours. The reaction was complete, saturated brine was added and the mixture was extracted with ethyl acetate. The organic phase was directly concentrated, and the resulting residue was separated by flash column chromatography (EA / PE = 20-35%) to give tert-butyl 4-(4-((2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)(methyl)amino)-9-fluoro-2-(methylthio)-5,6-dihydro-4H-pyrimido[4,5,6-de][l,6]naphthyridin-8-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)carbamate (690 mg, yield: 93%). ESI-MS: 1037.6 [M+1] + .

[0472] Step 2: Synthesis of tert-butyl 4-(4-((2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)(methyl)amino)-9-fluoro-2-(methylsulfonyl)-5,6-dihydro-4H- pyrimido[4,5,6-de][l,6]naphthyridin-8-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)carbamate

[0473] Tert-butyl 4-(4-((2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)(methyl)amino)-9-fluoro-2-(methylsulfonyl)-5,6-dihydro-4H- pyrimido[4,5,6-de][l,6]naphthyridin-8-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)carbamate (670 mg, 0.646 mmol) was dissolved in CH2Cl2(20 mL) and m-CPBA (524 mg, 2.583 mmol) was added at 0 °C. The reaction was kept at 0 °C for 2 h. The reaction was quenched with saturated aqueous NaHC03and NaS03solution and extracted with CH2Cl2. The organic phase was concentrated directly and the residue was purified by flash silica gel column chromatography (EA / PE = 0-70%) to give tert-butyl 4-(4-((2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)(methyl)amino)-9-fluoro-2-(methylsulfonyl)-5,6-dihydro-4H- pyrimido[4,5,6-de][l,6]naphthyridin-8-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)carbamate (330 mg, yield: 47%). ESI-MS: 1069.6 [M+l] + .

[0474] Step 3: Synthesis of tert-butyl (R)-(4-(4-((2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)(methyl)amino)-2-(3-(dimethylamino)pyrrolidin-l-yl)-9-fluoro-5,6-dihydro-4H-pyrimido[4,5,6-de][l,6]naphthyridin-8-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)carbamate

[0475] Tert-butyl 4-(4-((2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)(methyl)amino)-9-fluoro-2-(methylsulfonyl)-5,6-dihydro-4H-pyrimido[4,5,6-de][1,6]naphthyridin-8-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)carbamate (40 mg, 0.037 mmol) was dissolved in 1,4-dioxane (2 mL), DIPEA (38 mg, 0.296 mmol) and (R)-N,N-dimethylpyrrolidin-3-amine (17 mg, 0.111 mmol) were added and the reaction was stirred at 100 °C for 18 h. The reaction was complete, saturated brine and ethyl acetate were added and the organic phase was concentrated directly to give tert-butyl (R)-(4-(4-((2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)(methyl)amino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-9-fluoro-5,6-dihydro-4H-pyrimido[4,5,6-de][1,6]naphthyridin-8-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)carbamate (40 mg) which was used directly in the next step. ESI-MS: 552.4 [M / 2+H] + .

[0476] Fourth step: (R)-N 3 -(8-(3-amino-7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(3-(dimethylamino)pyrrolidin-1-yl)-9-fluoro-5,6-dihydro-4H-pyrimido[4,5,6-de][1,6]naphthyridin-4-yl)-N 3 Synthesis of (R)-N

[0477] Tert-butyl (R)-(4-(4-((2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)(methyl)amino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-9-fluoro-5,6-dihydro-4H-pyrimido[4,5,6-de][1,6]naphthyridin-8-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)carbamate (40 mg) was dissolved in TFA (2.0 mL) and MsOH (0.2 mL) was added at 0 °C. The reaction was stirred at 0 °C for 1 h. The reaction was blown dry with nitrogen and the residue was diluted with dichloromethane and poured into ice water, then neutralized with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The organic phase was concentrated to give crude (R)-N 3- (8-(3-amino-8-ethynyl-7-fluoronaphthalen-l-yl)-2-(3-(dimethylamino)pyrrolidin-l- yl)-9-fluoro-5,6-dihydro-4H-pyrimido[4,5,6-de][l,6]naphthyridin-4-yl)-N 3 - methylpyridine-2,3-diamine (27 mg). ESI-MS: 763.6 [M+l] + .

[0478] Fifth step: (R)-N 3 - (8-(3-amino-8-ethynyl-7-fluoronaphthalen-l-yl)-2-(3-(dimethylamino)pyrrolidin-l- yl)-9-fluoro-5,6-dihydro-4H-pyrimido[4,5,6-de][l,6]naphthyridin-4-yl)-N 3 - Synthesis of methylpyridine-2,3-diamine

[0479] The (R)-N 3 - (8-(3-amino-8-ethynyl-7-fluoronaphthalen-l-yl)-2-(3-(dimethylamino)pyrrolidin-l- yl)-9-fluoro-5,6-dihydro-4H-pyrimido[4,5,6-de][l,6]naphthyridin-4-yl)-N 3 - methylpyridine-2,3-diamine (27 mg) was dissolved in DMF (2.0 mL), CsF (213 mg, 1.400 mmol) was added, and the reaction was heated at 60 °C for 2 hours. The reaction was complete, saturated brine and ethyl acetate were added and the organic phase was directly concentrated. The residue obtained was separated by preparative HPLC (CH3CN / (H2O + 10 mM NH4HCO3) = 30-60%) to give (R)-N 3 - (8-(3-amino-8-ethynyl-7-fluoronaphthalen-l-yl)-2-(3-(dimethylamino)pyrrolidin-l- yl)-9-fluoro-5,6-dihydro-4H-pyrimido[4,5,6-de][l,6]naphthyridin-4-yl)-N 3 - methylpyridine-2,3-diamine (5.3 mg, yield: 24%). ESI-MS: 607.3 [M+l] + .

[0480] 1H NMR (400 MHz, DMSO-d6) δ 7.82 - 7.71 (m, 2H), 7.57 (d, J = 7.6 Hz, 1H), 7.31 (t, J = 9.0 Hz, 1H), 6.99 (dd, J = 10.7, 2.5 Hz, 2H), 6.60 (dd, J = 7.6, 4.9 Hz, 1H), 6.13 (s, 2H), 5.59 (s, 2H), 4.02 - 3.80 (m, 3H), 3.50 (m, 1H), 3.32 - 3.21 (m, 2H), 3.07 (d, J = 9.0 Hz, 3H), 3.01 (d, J = 6.1 Hz, 2H), 2.77 (d, J = 9.3 Hz, 1H), 2.25 - 2.10 (m, 7H), 1.90 - 1.70 (m, 1H).

[0481] Example 117: N 3 - (8-chloro-9-fluoro-2-((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5,6-dihydro-4H- pyrimido[4,5,6-de][l,6]naphthyridin-4-yl)-N 3 Preparation of (S)-N

[0482] First step: (S)-N 3 - (8-chloro-9-fluoro-2-((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5,6-dihydro-4H- pyrimido[4,5,6-de][l,6]naphthyridin-4-yl)-N 2 ,N 2 - di(4-methoxybenzyl)-N 3 Synthesis of (S)-N

[0483] (S)-N 3 - (8-chloro-9-fluoro-2-((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5,6-dihydro-4H- pyrimido[4,5,6-de][l,6]naphthyridin-4-yl)-N 2 ,N 2 - di(4-methoxybenzyl)-N 3-(oxetan-2-ylmethyl)pyridine-2,3-diamine (0.63 g, 0.81 mmol) was dissolved in CH2Cl2(10 mL) and cooled to 0 °C in an ice water bath, then m-CPBA (0.49 g, 4.40 mmol) was added and the reaction was allowed to proceed for 1 h at 0 °C, then quenched with saturated aqueous sodium sulfite and extracted with dichloromethane twice. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting crude was dissolved in trifluoroethanol (5.0 mL) and DIPEA (0.42 mL, 2.42 mmol) and heated to 60 °C for 1 h. The reaction was complete and concentrated. The resulting crude was purified by flash silica gel column (PE / EA = 2:1) to give (S)-N 3 -(8-chloro-9-fluoro-2-(2,2,2-trifluoroethoxy)-5,6-dihydro-4H-pyrimido[4,5,6- de][l,6]naphthyridin-4-yl)-N 2 ,N 2 -bis(4-methoxybenzyl)-N 3 -(oxetan-2-ylmethyl)pyridine-2,3-diamine (0.32 g, 51.3% yield). ESI-MS: 740.2 [M+1] + .

[0484] Second step: N 3 -(8-chloro-9-fluoro-2-(2,2,2-trifluoroethoxy)-5,6-dihydro-4H-pyrimido[4,5,6- de][l,6]naphthyridin-4-yl)-N 2 ,N 2 -bis(4-methoxybenzyl)-N 3 Synthesis of (S)-oxetan-2-yl)methyl)pyridine-2,3-diamine

[0485] ((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizidin-7a(5H)-yl)methanol (0.13 g, 0.83 mmol) was dissolved in dry THF (10 mL) and cooled in an ice water bath. NaOtAm (0.14 g, 1.24 mmol) was added and the reaction was allowed to proceed for 30 min at 0 °C, then (S)-N 3 -(8-chloro-9-fluoro-2-(2,2,2-trifluoroethoxy)-5,6-dihydro-4H-pyrimido[4,5,6- de][l,6]naphthyridin-4-yl)-N 2 ,N 2 -bis(4-methoxybenzyl)-N 3-(oxetan-2-ylmethyl)pyridine-2,3-diamine solution (0.32 g, 0.41 mmol, dissolved in THF (4.0 mL)) was added and the reaction was continued for 1 hour after the addition was completed. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution and extracted with ethyl acetate twice. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained crude product was separated by flash silica gel column (DCM / MeOH = 25:1) to give N 3 -(8-chloro-9-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)- 5,6-dihydro-4H-pyrimido[4,5,6-de][1,6]naphthyridin-4-yl)-N 2 ,N 2 -di(4-methoxybenzyl)-N 3 -(((S)-oxetan-2-yl)methyl)pyridine-2,3-diamine (0.25 g, yield: 75.1%). ESI-MS: 799.2 [M+1] + .

[0486] Third step: Synthesis of tert-butyl (4-(4-((2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)(((S)- oxetan-2-yl)methyl)amino)-9-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-5,6-dihydro-4H-pyrimido[4,5,6-de][1,6]naphthyridin-8-yl)-6-fluoro-5- (trisopropylsilyl)ethynyl)naphthalen-2-yl)carbamate

[0487] N 3 -(8-chloro-9-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)- 5,6-dihydro-4H-pyrimido[4,5,6-de][1,6]naphthyridin-4-yl)-N 2 ,N 2 -di(4-methoxybenzyl)-N 3-(((S)-oxetan-2-yl)methyl)pyridine-2,3-diamine (0.16 g, 0.20 mmol) and tert-butyl (6-fluoro 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)carbamate (0.17 g, 0.30 mmol) were dissolved in 1,4-dioxane (4.0 mL) and water (0.4 mL), followed by the addition of K3PO4(0.13 g, 0.60 mmol) and CataXium A-Pd-G2 (40 mg, 0.060 mmol) successively, and then the reaction was carried out by microwave at 100 °C for 1 hour after replacement with nitrogen. The reaction solution was concentrated, and the obtained crude product was separated by a flash silica gel column (DCM / MeOH = 25: 1) to obtain tert-butyl (4-(4-((2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)(((S)-oxetan-2-yl)methyl)amino)-9-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5,6-dihydro-4H-pyrrolo[4,5,6-de][l,6]naphthyridin-8-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)carbamate (0.21 g, yield: 68.2%). ESI-MS: 603.0 [M / 2+1] + .

[0488] Fourth step: Synthesis of tert-butyl (4-(4-((2-aminopyridin-3-yl)(((S)-oxetan-2-yl)methyl)amino)-9-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5,6-dihydro-4H-pyrrolo[4,5,6-de][l,6]naphthyridin-8-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)carbamate

[0489] tert-Butyl (4-(4-((2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)(((S)-oxetan-2-yl)methyl)amino)-9-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5,6-dihydro-4H- pyrimido[4,5,6-de][l,6]naphthyridin-8-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)carbamate (210 mg, 0.14 mmol) was dissolved in CH2Cl2(10 mL) and water (2 mL), DDQ (460 mg, 2.04 mmol) was added, after reaction at room temperature for 1.5 hours, saturated aqueous sodium sulfite was added to quench, then extracted with ethyl acetate twice, the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, the obtained crude was separated by flash silica gel column (DCM / MeOH = 20: 1) to give tert-butyl (4-(4-((2-aminopyridin-3-yl)(((S)-oxetan-2-yl)methyl)amino)-9-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5,6-dihydro-4H-pyrimido[4,5,6-de][l,6]naphthyridin-8-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)carbamate (73 mg, yield: 53.9%). ESI-MS: 964.4 [M+1] + .

[0490] Fifth step: Synthesis of N 3 -(8-(3-amino-8-ethynyl-7-fluoronaphthalen-l-yl)-9-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5,6-dihydro-4H-pyrimido[4,5,6-de][l,6]naphthyridin-4-yl)-N 3 Synthesis of N

[0491] tert-Butyl (4-(4-((2-aminopyridin-3-yl)(((S)-oxetan-2-yl)methyl)- amino)-9-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)- 5,6-dihydro-4H-pyrimido[4,5,6-de][l,6]naphthyridin-8-yl)-6-fluoro-5- ((trisopropylsilyl)ethynyl)naphthalen-2-yl)carbamate (73 mg, 0.073 mmol) was dissolved in CH2Cl2(1.0 mL), TFA (0.3 mL) was added at room temperature, and the reaction was stirred at room temperature for 0.5 h. LC-MS showed the reaction was complete. The reaction was concentrated to dryness at low temperature, then DMF (2.0 mL) and CsF (231 mg, 1.52 mmol) were added, and the reaction was heated at 60 °C for 1 h. The reaction was cooled to room temperature, quenched with saturated aqueous NaHC03solution, then extracted with ethyl acetate twice, the organic phases were combined, washed with saturated brine, and dried over anhydrous Na2S04. After filtration, the solution was concentrated, and the resulting crude product was directly separated by preparative chromatography (ACN / H20 (+10.0 mM NH4HC03) = 0-70%) to give N 3 -(8-(3-amino-8-ethynyl-7-fluoronaphthalen-l-yl)-9-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5,6-dihydro-4H-pyrimido[4,5,6- de][l,6]naphthyridin-4-yl)-N 3 -(((S)-oxetan-2-yl)methyl)pyridine-2,3-diamine (19.9 mg, yield: 37.0%). ESI-MS: 708.2 [M+l] + .

[0492] 1 HNMR (400 MHz, DMSO-d6) δ 7.83 (d, J = 4.9 Hz, 1H), 7.81-7.67 (m, 2H), 7.32 (t, J = 9.0 Hz, 1H), 7.06-6.98 (m, 2H), 6.59 (ddd, J = 7.5, 4.9, 2.4 Hz, 1H), 6.55-6.24 (m, 2H), 5.62 (d, J = 5.9 Hz, 2H), 5.32 (d, J = 54.3 Hz, 1H), 5.10-4.73 (m, 1H), 4.41 (s, 2H), 4.14 (s, 3H), 3.90 (s, 1H), 3.77-3.56 (m, 2H), 3.44 (s, 1H), 3.15-2.97 (m, 4H), 2.87 (s, 1H), 2.19-1.98 (m, 3H), 1.85 (s, 3H).

[0493] Embodiments 6-116, 118-162 can be prepared by selecting corresponding starting materials and reagents according to all or part of the synthetic methods of Embodiments 1, 2, 3, 4, 5, or 117:

[0494] The nuclear magnetic resonance data of the compounds prepared in the above embodiments are as follows:

[0495] Comparative compounds 1-2 were prepared by selecting corresponding starting materials and reagents according to all or part of the synthetic methods of E21 in patent WO2024104453A1 and E5 in WO2024083168, respectively.

[0496] Biological test evaluation

[0497] I. KRAS G12V / c-RAF biochemical activity detection

[0498] 1. Experimental procedure

[0499] 1.1 Preparation of experimental buffer solution

[0500] First, prepare 5X buffer solution (250mM PH 7.4 HEPES, 500mM NaCl, 2.5% TritionX-100), and then prepare 1X buffer solution (50mM PH 7.4 HEPES, 100mM NaCl, 0.5% TritionX-100, 0.5% BSA) based on the 5X buffer solution.

[0501] 1.2 Compound dilution and preparation

[0502] Dilute 9 points serially from a 10 mM stock at a 1 :5 ratio into 10X compound containing solution with IX buffer solution, transfer 2 μL to the appropriate well of a 384 well plate, centrifuge (1000 rpm, 1 min). 1.3 Preparation of KRAS and GMPPNP working solutions

[0503] Prepare 5X KRAS and GMPPNP mix (50 nM KRAS G12D, 400 nM GMPPNP) with IX buffer solution, place on ice for 30 min pre-incubation, then transfer 4 μL to the appropriate well of a 384 well plate, centrifuge (1000 rpm, 1 min). Then incubate at room temperature for 15 min.

[0504] 1.4 Preparation of cRAF working solution

[0505] Prepare 5X cRAF working solution (250 nM cRAF) with IX buffer solution, transfer 4 μL to the appropriate well of a 384 well plate, centrifuge (1000 rpm, 1 min). Then incubate at room temperature for 15 min.

[0506] 1.5 Addition of detection reagents

[0507] Prepare 2X detection reagents (4x Alphascreen GSH donor beads, 4X Alphalisa NICKEL Acceptor beads) with IX buffer solution, transfer 10 μL to the appropriate well of a 384 well plate, centrifuge (1000 rpm, 1 min). Then incubate at room temperature for 1 h. Read values on a SpectraMax Paradigm (MD) plate reader.

[0508] 2. Test results

[0509] Table 1: Biological test results

[0510] From the activity data of the specific example compounds, the series of compounds of the present application have stronger inhibitory activity on KRAS G12V / c-RAF compared to the comparative compounds.

[0511] II. KRas mutant cell anti-proliferation 2D CTG test

[0512] 1. Experimental procedure

[0513] 1.1 Day 0 Cell culture and plating

[0514] Cells in log phase were harvested and counted using a hemocytometer. Cell viability was checked by trypan blue exclusion to ensure that cell viability was above 90%. Cell concentration was adjusted to reach the desired final density and 90 μL of cell suspension was added to a 96-well plate and incubated overnight at 37°C, 5% CO2 and 95% humidity. Cell density and cell culture conditions are shown in the following table.

[0515] 1.2 Day 1 Baseline reading

[0516] To each well of the TO plate with cells, 10 μL of PBS was added. The CTG reagent was thawed and the cell plate was equilibrated to room temperature for 30 minutes. 50 μL / well of CTG solution was added to each well. Cells were lysed by shaking on an orbital shaker for 5 minutes. The cell plate was left at room temperature for 20 minutes to stabilize the luminescent signal. The TO fluorescence signal value was read.

[0517] 1.3 Day 1 Compound treatment

[0518] Nine points were serially diluted 1 :5 from a 10 mM stock. The 10X compound containing media was transferred to the corresponding wells of a 96-well plate. The final highest compound concentration was 10 μM and the final DMSO concentration was 0.1%. The 96-well plate was placed in a 37°C incubator for 4 days.

[0519] 1.4 Day 5 Read signal

[0520] Cells were added 50 μL / well of detection reagent (CTG) and the signal was read in an Envision machine and IC 50 values (unit: nM) were calculated.

[0521] 2. Test results

[0522] Table 2: Biological test results

[0523] From the activity data of the specific example compounds, the series of compounds of the present application have strong inhibitory activity against each type of KRAS mutant cell.

[0524] III. Compound hERG inhibition rate test (manual patch clamp Q-Patch)

[0525] hERG refers to the human ether-a-go-go related gene, which encodes a potassium channel protein that is critical for normal cardiac electrical activity. Specifically, it encodes the Kv 11.1 channel, which is responsible for the rapid component of the delayed rectifier potassium current (IKr) in the heart. The hERG channel is a voltage-gated potassium channel that plays a key role in regulating cardiac electrical activity, and dysfunction of the channel can lead to long QT syndrome (LQTS) and potentially fatal cardiac arrhythmias. Inhibition of the hERG channel by a compound can result in a potential prolongation of the electrocardiographic QT interval and an increased risk of arrhythmias.

[0526] 1. Experimental Procedure

[0527] 1.1 The cells used in this experiment are a CHO cell line stably expressing the hERG channel (provided by B'SYS) transfected with hERG cDNA. The cell culture medium is Ham's F12 medium containing 10% (v / v) fetal bovine serum, 100 μg / ml hygromycin B, 100 μg / ml Geneticin and incubated at 37°C in 5% CO2.

[0528] 1.2 Prior to recording experiments, cells were plated on glass coverslips for 24 to 48 hours to ensure that the cells are mostly single and facilitate single cell recording.

[0529] 1.3 During electrophysiological measurements, both extracellular and intracellular solutions were used. The extracellular solution consists of 145 mM NaCl, 4 mM KCl, 2 mM CaCl2, 1 mM MgCl2, 10 mM glucose and 10 mM HEPES, pH 7.4 with NaOH, and has an osmolarity of approximately 305 mOsm. The intracellular solution consists of 120 mM KCl, 5.374 mM CaCl2, 1.75 mM MgCl2, 10 mM HEPES, 5 mM EGTA and 4 mM Na-ATP, pH 7.25 with KOH, and has an osmolarity of approximately 295 mOsm.

[0530] 1.4 Prior to experiments, DMSO stock solutions were diluted into the final μM test concentrations using extracellular solution. All compound solutions were routinely sonicated and shaken for 5 to 10 minutes to ensure complete dissolution of the compounds.

[0531] 1.5 Electrophysiological recordings were made using whole-cell recording with a HEKA EPC 10 USB patch-clamp amplifier from HEKA Elektronik, Germany.

[0532] 1) Coverslips with a large number of single CHO hERG cells were removed and placed in the recording bath, which was continuously perfused (flow rate of approximately 1 mL / min).

[0533] 2) Single cell hERG currents were recorded by standard whole-cell recording techniques and performed at room temperature (~25°C).

[0534] 3) Cells were clamped at -80 mV, depolarized to +20 mV to activate the hERG potassium channel, and 5 seconds later clamped to -50 mV to de-inactivate and generate tail currents.

[0535] 4) The peak tail current was used as a measure of the size of the hERG current. The voltage protocol was repeated every 15 seconds throughout the experiment.

[0536] 5) To ensure that the test cells were responding normally and reliably, each cell was tested with 0.1 μM cisapride as a positive control compound prior to the test compound. The cells were washed again with extracellular solution until the current amplitude returned to near the value measured prior to the positive control drug application.

[0537] 6) The test compound was then applied to the cell until the inhibitory effect at the compound concentration reached a steady state. After the compound test was complete, the cells were washed with extracellular solution.

[0538] 7) Finally, the hERG current at the compound concentration was compared to the current at the solvent baseline phase to calculate the percent inhibition at that single dose.

[0539] 1.6 Experimental data were processed and analyzed by Patchmaster software in Microsoft Excel.

[0540] 2、Test Results

[0541] Table 3: The inhibition results of the example compounds on hERG at a concentration of 10 μM are as follows:

[0542] From the data in the above table, it can be seen that the compounds of the present application have a lower inhibition rate on hERG compared to the comparative compounds, and the inhibition rate of some example compounds on hERG can be less than 10%.

[0543] Four, Evaluation of Canine Pharmacokinetics

[0544] 1、Test Scheme

[0545] 1.1 Test Drug

[0546] The compounds used in this test are from the specific example compounds of the present application and the listed comparative compounds.

[0547] 1.2 Test Animals

[0548] Male Beagle dogs 3 / compound. Weighing before administration, according to the body weight, the amount of administration was calculated. Administration by gavage (or intravenous injection).

[0549] 1.3 Drug preparation and administration

[0550] The compounds were weighed and dissolved in the corresponding solvent (PO: 10% HP-β-CD in 50mM pH=4.7 Acetate buffer; IV: 20% HP-β-CD in 50mM pH=4.7 Acetate buffer), shaken and ultrasonicated to prepare the solution. The animals in the oral administration group were fasted for not less than 10 hours before administration, and fed 4 hours after administration. The oral administration dose was 5mg / kg (or IV 1mg / kg).

[0551] 1.4 Sample collection

[0552] Blood was collected through the jugular vein or other suitable ways, about 1mL / time point for each sample collection, anticoagulated with sodium heparin, and the blood sampling time points were 0, 0.25, 0.5, 1, 2, 4, 6, 8, 24 hours. After blood sample collection, the blood was placed on ice, and the plasma was separated by centrifugation (centrifugation conditions: 2200g, 10 minutes, 2-8℃) within 1 hour. The plasma samples were stored in a -80℃ refrigerator when stored before analysis.

[0553] 40μL of the plasma sample was added with 160μL of ice-cold acetonitrile containing an internal standard, vortexed for 3 minutes, and centrifuged at 11000rpm for 5 minutes. 100μL of the supernatant was added to 100μL of water, and 5μL was injected into LC / MS / MS for analysis.

[0554] 2. Test results

[0555] Table 4: Results of the dog pharmacokinetic experiment

[0556] From the data in the above table, it can be seen that the oral exposure of the compound of the present application in dogs is significantly improved compared with the comparative compound.

[0557] All the documents mentioned in the present application are cited as references in the present application, just as each document is cited as a reference individually. In addition, it should be understood that various modifications or changes can be made to the present application by those skilled in the art after reading the above disclosure of the present application, and these equivalent forms also fall within the scope defined by the claims attached to the present application.

Claims

a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: wherein, is a single or double bond, when R is a substituent on the carbon atom directly attached to the double bond when the double bond is present 5b and R 6b is absent; Y is a bond, O, S, or N(R7); 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 optionally fused to C 6-10 Aryl or 5-10 membered heteroaryl, or, said C 6-10 Aryl or 5-10 membered heteroaryl optionally fused to 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, C1-C6alkyl- substituted 3- to 12-membered heterocyclyl, C6-C10aryl, C1-C6alkyl-substituted C6-C10aryl, 5- to 10-membered heteroaryl, C1-C6alkyl-substituted 5- to 10-membered heteroaryl, -C1-C6alkyl-SF5, -C1-C6alkyl-S(O)2R2, -C1-C6alkyl-S(O)2NR2R3, -C1-C6alkyl-S(O)(=N-R2), -C1-C6alkyl-N=S(O)R2R3, -C1-C6alkyl-N=SR2, -C1-C6alkyl-O-S(O)2R2, -C1-C6alkyl-S(O)2R2, -C1-C6alkyl-O-R2, -C1-C6alkyl-C(O)OR2, -C1-C6alkyl-C(O)SR2, -C1-C6alkyl-S-C(O)R2, -C1-C6alkyl-C(O)R2, -C1-C6alkyl-O-C(O)R2, -C1-C6alkyl-P(O)(R2)2, -C1-C6alkyl-NR2R3, -C1-C6alkyl-C(=NR2)R3, -C1-C6alkyl-N(R2)-C(=NR3)R2, -C1-C6alkyl-C(O)NR2R3, and -C1-C6alkyl-N(R2)-C(O)R3, or, when m is > 2, wherein two adjacent R1are taken together with the portions of the molecule to which they are directly attached to form a C3-C12cycloalkyl, 3- to 12-membered heterocyclyl, C6-C10aryl, or 5- to 10-membered heteroaryl ring, wherein the C3-C12cycloalkyl, 3- to 12-membered heterocyclyl, C6-C10aryl, or 5- to 10-membered heteroaryl ring is optionally substituted with one, two, three, or four halogen, cyano, nitro, oxo, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6haloalkenyl, C2-C6alkynyl, C2-C6haloalkynyl, C3-C6cycloalkyl, 3- to 12-membered heterocyclyl, C1-C6alkyl- substituted 3- to 12-membered heterocyclyl, C6-C10aryl, C1-C6alkyl-substituted C6-C10aryl, 5- to 10-membered heteroaryl, or C1-C6alkyl-substituted 5- to 10-membered heteroaryl substituents; 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 ; 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 0-8 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 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, and 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, -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 1-10 alkyl, halosubstituted C 1-10 alkyl, deuterium-substituted C 1-10 alkyl, C 1-10 alkylene, halosubstituted 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, 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 ; 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 substituted by one or more substituents independently selected from the group consisting of each R 2a is independently selected from the group consisting of 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 groups being optionally further substituted with one or more 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 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- 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 substituted; each R 2b and each R 2c is each independently selected from the group consisting of 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 the group consisting of 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; R3and R4are each independently 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, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -S(O)2R 15 , -C(O)OR 16 , -C(O)SR 16 , -C(O)R 17 , -NR 18 R 19 , -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, 3-12 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- 8alkyl-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 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 0-8 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 ; Alternatively, R3 and R4 together with the carbon atom directly attached to them form a 3-12 membered heterocyclic group or a 5-10 membered heteroaryl group, wherein the above groups are independently and optionally further surrounded by one or more elements 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- 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 p is 0, 1, 2, or 3; each R 5a and each R 5b is 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)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, R 5a and R 5b together with the carbon atom they are attached to form a C(O), C 3-12 cycloalkyl or 3-12 membered heterocyclyl, each of the above groups being independently optionally further substituted by one or more, preferably one, to six, more preferably one, to four, even more preferably one, to three, 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, 3-12 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 one substituent selected from the group consisting of q is 0, 1, 2, or 3; each R 6a and each R 6b is 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)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, R 6a and R 6b together with the carbon atom they are attached to form a C(O), C 3-12 cycloalkyl or 3-12 membered heterocyclyl, each of the above groups being independently optionally further substituted by one or more, preferably one, to six, more preferably one, to four, even more preferably one, to three, 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, 3-12 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 one or more substituents selected from the group consisting of R7is 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 , -NR 18 R 19 , -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- 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 , are optionally independently 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)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; 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 each 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 both attached form a 3-10 membered heterocyclyl, 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, 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 is independently selected from hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, and -NR 18 R 19 , the aforementioned groups are independently optionally further substituted by one or more substituents selected from deuterium, halogen, hydroxyl, nitro, cyano, =0, 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 ; Each R 16 Each is 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 Each is independently selected from hydrogen, deuterium, hydroxyl, and 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 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 each r is independently 0, 1, or 2. The compound of formula (I), stereoisomer thereof, or pharmaceutically acceptable salt thereof according to claim 1, characterized in that, Y is a bond, O, S, or N(R7); X1is CR8or N; X2is CR9or N; X3is CR 10 or N; 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 R2 is selected from hydrogen, halogens, and -(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, -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-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 substituted by one or more substituents independently selected from the group consisting of 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 heterocyclyl, said C 1-4 alkylene, C 3-6 cycloalkylene or 3-6 membered heterocyclyl 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 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 substituent selected from the group consisting of 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, halosubstituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 1-4 alkylene, halosubstituted 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 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-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; 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 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, 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 2b and R 2c Together with the nitrogen atom directly attached thereto, a 4-6 membered heterocyclic group or a 5-8 membered heteroaryl group is formed, wherein the 4-6 membered heterocyclic group or the 5-8 membered heteroaryl group is optionally further surrounded by one or more elements selected from deuterium, halogen, hydroxyl, =O, C. 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, halogenated C 1-4 Alkyl, deuterated 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 group, C 6- 8-aryl, C 6-8 Aryloxy group, 5-8 membered heteroaryl group, 5-8 membered heteroaryloxy group, amino group, mono-C group 1-4 Alkylamino, diC 1-4 Alkylamino and C 1-4 The alkyl acyl group is replaced by a substituent; R3 and R4 are each independently selected from hydrogen, deuterium, hydroxyl, 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, -S(O)2R 15 -C(O)OR 16 -C(O)SR 16 -C(O)R 17 -NR 18 R 19 -C(=NR) 18 )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 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 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)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; Alternatively, R3 and R4 together with the carbon atom directly attached to them form a 3-10 membered heterocyclic group or a 5-8 membered heteroaryl group, wherein the above groups are independently and optionally further surrounded by one or more elements selected from deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, 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- 4alkyl-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 substituted by substituents selected from the group consisting of p is 0, 1, 2, or 3; each R 5a and each R 5b is 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- 4alkyl-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 , or, R 5a and R 5b together with the carbon atom to which they are attached form a C(O), C 3-6 cycloalkyl or 3-6 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, 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, =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- 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 substituted by substituents selected from the group consisting of q is 0, 1, 2, or 3; each R 6a and each R 6b is independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 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- 4alkyl-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 , or, R 6a and R 6b together with the carbon atom to which they are attached form a C(O), C 3- 6 cycloalkyl or 3-6 membered heterocyclyl, each of the above groups being independently optionally further substituted by one or more, preferably 1, 2 or 3, more preferably 1 or 2, even more preferably 1, 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 substituents selected from the group consisting of R7is selected from hydrogen, deuterium, hydroxyl, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-10 cycloalkyl, 3-10 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 , -NR 18 R 19 , -C(=NR 18 )R 17 , and -C(O)NR 18 R 19 , the aforementioned groups are independently further optionally 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, =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 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)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; 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. The compound of formula (I), stereoisomer thereof, or pharmaceutically acceptable salt thereof according to claim 1, 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- 4alkyl-C(O)OR 16 , -C 0-4 alkyl-C(O)R 17 , -C 0-4 alkyl-C(O)NR 18 R 19 , -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 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 2-4 alkynyl, 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, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, and -NR 18 R 19 , the aforementioned groups are independently optionally further substituted by one or more substituents selected from deuterium, halogen, hydroxyl, nitro, cyano, =0, 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, and -NR 18 R 19 ; Each R 16 Each is independently selected from hydrogen, deuterium, and C. 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-8 aryl and 5-8 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 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group, C 6-8 Aryl, C 6-8 aryloxy, 5-8 heteroaryl, 5-8 heteroaryloxy and -NR 18 R 19 The substituents are replaced; Each R 17 Each is independently selected from hydrogen, deuterium, hydroxyl, and C. 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2- 4-chain ynyl group, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group, C 6-8 Aryl, C 6- 8-aryloxy, 5-8-membered heteroaryl, 5-8-membered heteroaryloxy 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 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group, C 6-8 Aryl, C 6-8 aryloxy, 5-8 heteroaryl, 5-8 heteroaryloxy 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 1-4 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, 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 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- 4alkyl, 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 18 and R 19 Together with the nitrogen atom directly attached thereto, a 4-6 membered heterocyclic group or a 5-8 membered heteroaryl group is formed, wherein the 4-6 membered heterocyclic group or the 5-8 membered heteroaryl group is optionally further surrounded by one or more elements selected from deuterium, halogen, hydroxyl, =O, C. 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, halogenated C 1-4 Alkyl, deuterated 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 group, C 6- 8-aryl, C 6-8 Aryloxy group, 5-8 membered heteroaryl group, 5-8 membered heteroaryloxy group, amino group, mono-C group 1-4 Alkylamino, diC 1-4 Alkylamino and C 1-4 The alkyl acyl group is substituted by a substituent; and each r is independently 0, 1, or 2. The compound of formula (I), stereoisomer thereof, or pharmaceutically acceptable salt thereof according to claim 1, characterized in that, The structure of the compound of formula (I) selected from the group consisting of: wherein R 5a , R 5b , R 6a , R 6b , R7, X1, X2, X3and X4are as described in claim 1. The compound of formula (I), stereoisomer thereof, or pharmaceutically acceptable salt thereof according to claim 1, characterized in that, The compound of formula (I) is a compound of formula (II) wherein, is a single or double bond, when R is a substituent on the carbon atom directly attached to the double bond when the double bond is present 5b and R 6b is absent; Y is a bond, O, S, or N(R7); X3is CR 10 or N; X4is N or CR 11 ; 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 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 Alternatively, when m≥2, two adjacent R1s together with their directly connected portions 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, -SF5, -S(O)(=NR) 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 ; R2 is selected from hydrogen, halogens, and -(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 The aryl or 5-8 heteroaryl group is 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 ; 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, C 1-4 alkylene, C 3-6 cycloalkylene or 3-6 membered heterocyclylene is independently optionally further substituted with 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- 4alkynyl, 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 2a each independently is 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 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 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, 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 directly attached thereto, a 4-6 membered heterocyclic group or a 5-8 membered heteroaryl group is formed, wherein the 4-6 membered heterocyclic group or the 5-8 membered heteroaryl group is optionally further surrounded by one or more elements selected from deuterium, halogen, hydroxyl, =O, C. 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, halogenated C 1-4 Alkyl, deuterated 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 group, C 6- 8-aryl, C 6-8 aryloxy group, 5-8 membered heteroaryl group, 5-8 membered heteroaryloxy group, amino group, mono-C group 1-4 Alkylamino, diC 1-4 Alkylamino and C 1-4 The alkyl acyl group is replaced by a substituent; R3and R4are each independently selected from hydrogen, deuterium, hydroxyl, 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(O)OR 16 , -C(O)R 17 , -NR 18 R 19 and -C(O)NR 18 R 19 , the aforementioned 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, 3-6 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 , the aforementioned groups are 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.alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -SF5, =0, -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 R3and R4together with the carbon atom to which they are directly attached form a 3-10 membered heterocyclyl or 5-8 membered heteroaryl, each of which is independently optionally further substituted with one or more substituents selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C1-6alkyl, C1-6alkyl substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, deuterium, hydroxy, C1-6alkoxy, C1-6alkylthio, C1-6alkylsulfinyl, C1-6alkylsulfonyl, C3-6cycloalkyl, 3-6 membered heterocyclyl, aryl, 5-6 membered heteroaryl, -OR, -SR, -N(R)2, -N=C(R)2, -N(R)-C(=N-R)2, -C(=N-R)2, -C(=O)R, -C(=S)R, -C(=O)OR, -C(=O)SR, -C(=S)OR, -C(=S)SR, -C(=O)N(R)2, -C(=S)N(R)2, -S(O)R, -S(O)2R, -S(O)(=N-R)R, -O-R, -P(O)(R)2, -NR-C(=NR)R, -C(=NR)R, -N(R)-C(=NR)R, -C(O)NR2, and -N(R)-C(O)R; 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, =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 ; p is 0, 1, or 2; each R 5a and each R 5b is independently selected from hydrogen, deuterium, halogen, cyano, C 1- 4alkyl, C 2-4 2-6alkenyl, C 2-4 2-6alkynyl, C 3-6 3-6cycloalkyl, 3-6heterocyclyl, C 6-8 6 aryl, 5-8heteroaryl, =0, =S, -SF5, -S(O)(=N-R 12 )R 13 , -N=S(O)R 13 R 14 , -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, R 5a and R 5b , together with the carbon atom to which they are directly attached, form a C(O), C 3-6 3-6cycloalkyl, or 3-6heterocyclyl, each of which is independently optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, C 1-4 1-6alkyl, halosubstituted C 1-4 1-6alkyl, deuterium- substituted C 1-4 1-6alkyl, C 2-4 2-6alkenyl, C 2-4 2-6alkynyl, C 3-6 3-6cycloalkyl, 3-6heterocyclyl, C 6-8 6 aryl, 5-8heteroaryl, =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; q is 0, 1, or 2; each R 6a and each R 6b is independently selected from hydrogen, deuterium, halogen, cyano, C 1- 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 , or, R 6a and R 6b together 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 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, =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 18 R 19 -C(=NR 18 )R 17 -N(R 18 )-C(=NR 19 )R 17 -C(O)NR 18 R 19 -N(R 18 )-C(O)R 17 ; R7is selected from hydrogen, deuterium, hydroxyl, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -C(O)OR 16 , -C(O)R 17 , -NR 18 R 19 and -C(O)NR 18 R 19 , the aforementioned groups are independently optionally further substituted by one or more substituents selected from 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, =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 , the aforementioned groups are 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, 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 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, -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. The compound of formula (I), stereoisomer, or pharmaceutically acceptable salt thereof according to claim 5, characterized in that, The structure of the compound of formula (I) selected from the group consisting of: wherein R 5a , R 5b , R 6a , R 6b , R7, R 10 and R 11 are as described in claim 5. The compound of formula (I), stereoisomer thereof, or pharmaceutically acceptable salt thereof according to claim 1, characterized in that, The compound of formula (I) is a compound of formula (III1), a compound of formula (III2), a compound of formula (III3), a compound of formula (III4), a compound of formula (III5), or a compound of formula (III6): wherein ring A, R1, R2, R3, R4, R 5a , R 5b , R 6a , R 6b , R7, R 10 and m are as described in claim 1. The compound of formula (I), stereoisomer thereof, or pharmaceutically acceptable salt thereof according to claim 1, characterized in that, The compound of formula (I) is a compound of formula (IV1) or a compound of formula (IV2): wherein each R2is 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 and 3-6 membered heterocyclyl, and each -(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 or 3-6 membered heterocyclyl 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, deuterosubstituted C 1-4 alkyl, C 1-10 alkylene, halosubstituted C 1-10 alkylene, deuterosubstituted C 1-10 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 , -C(O)OR 16 , -C(O)R 17 , -O-C(O)R 17 , -P(O)(R 17 )2, -NR 18 R 19 , -C(O)NR 18 R 19 and -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, which are 1-4 alkylene, C 3-6 cycloalkylene or 3-6 membered heterocycloalkylene, independently and 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, =0, =S, -SF5, -O-R 16 , -C(O)OR 16 , -C(O)R 17 , -O-C(O)R 17 , -P(O)(R 17 )2, -NR 18 R 19 , -C(O)NR 18 R 19 and -N(R 18 )-C(O)R 17 ; 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 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 arylene, 5-8 membered heteroarylene, =0, =S, -SF5, -S(O) r R 15 , -O-R 16 , -C(O)OR 16 , -C(O)R 17 , -O-C(O)R 17 , -P(O)(R 17 )2, -NR 18 R 19 , -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)R 17 , and -C(O)NR 18 R 19 , the aforementioned groups are independently 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- 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 R3and each R4is each 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, -C(O)R 17 and -C(O)NR 18 R 19 , the foregoing groups are independently optionally further substituted by one or more substituents selected from 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) 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 , the foregoing groups are 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, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -SF5, =O, -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 ; In the compounds of formula (IV1), R 5a is 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, -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 , are each independently optionally further substituted with 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 heterocyclyl, =O, =S, -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 ; In the compounds of formula (IV1), R 6a is 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, =0, =S, -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 , 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 heterocyclyl, =0, =S, -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 R 10 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 groups, -OR 16 -C(O)R 17 -OC(O)R 17 -NR 18 R 19 -C(O)NR 18 R 19 and -N(R) 18 )-C(O)R 17 ; wherein ring A, R1, R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , m and r are as described in claim 1. The compound of formula (I), stereoisomer thereof, or pharmaceutically acceptable salt thereof according to claim 1, characterized in that, in the compound of formula (I) selected from the group consisting of: 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; 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 halo-substituted C1-6alkyl, 1-4 deuterium-substituted C1-6alkyl, 1-4 C1-6alkyl, C1-6haloalkyl, 2-4 C2-6alkenyl, C2-6haloalkenyl, 2-4 C2-6alkynyl, C2-6haloalkynyl, 3-6 C3-6cycloalkyl, 3-6 membered heterocyclyl, 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 ; wherein R 15 , R 16 , R 17 , R 18 , R 19 and r are as described in claim 1. The compound of formula (I), stereoisomer, or pharmaceutically acceptable salt thereof according to claim 9, 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; 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. The compound of formula (I), stereoisomer thereof, or pharmaceutically acceptable salt thereof according to claim 1, characterized in that, R3and R4are 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, and 5-8 membered heteroaryl, said groups being independently and 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, -S(O) r R 15 , -O-R 16 , -C(O)OR 16 , -C(O)R 17 , -O-C(O)R 17 , -P(O)(R 18 )2, -NR 19 R 18 , -C(O)NR 19 R 18 , and -N(R 17 )-C(O)R 1- ; said groups being independently and optionally further substituted by one or more substituents selected from the group consisting of deuterium, halogen, cyano, C 1-4 4alkyl, halosubstituted C 1-4 alkyl, deuterium-substituted C 2-4 alkyl, C 2-4 alkenyl, C 3-6 alkynyl, C 6-8 cycloalkyl, 3-6 membered heterocyclyl, C r aryl, 5-8 membered heteroaryl, =O, -S(O) 15 R 16 , -O-R 16 , -C(O)OR 17 , -C(O)R 17 , -O-C(O)R 17 , -P(O)(R 18 )2, -NR 19 R 18 , -C(O)NR 19 R 18 , and -N(R 17 )-C(O)R ; each R 5a and each R 5b is 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, -O-R 16 and -NR 18 R 19 , or, R 5a and R 5b together with the carbon atom to which they are directly attached form a C(O), C 3-6 cycloalkyl or 3-6 membered heterocyclyl; each R 6a and each R 6b is 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, -O-R 16 and -NR 18 R 19 , or, R 6a and R 6b together with the carbon atom to which they are directly attached form a C(O), C 3-6 cycloalkyl or 3-6 membered heterocyclyl; R 10 and R 11 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 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, C 6-8 aryl, 5- to 8-membered heteroaryl, -SF5, -O-R 16 and -NR 18 R 19 ; wherein R 15 , R 16 , R 17 , R 18 , R 19 and r are as described in claim 1. The compound of formula (I), stereoisomer thereof, or pharmaceutically acceptable salt thereof according to claim 1, characterized in that, R3is selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, and 5-8 membered heteroaryl, each of which is independently and optionally further substituted with 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 heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -S(O) r R 15 , -O-R 16 , -C(O)OR 16 , -C(O)R 17 , -O-C(O)R 17 , -P(O)(R 17 )2, -NR 18 R 19 , -C(O)NR 18 R 19 , and -N(R 18 )-C(O)R 17 ; R4is selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, and 5- to 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, 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, 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, -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 ; 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 ; Preferably, R3 is selected from hydrogen, deuterium, hydroxyl, C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6-membered heterocyclic, phenyl, and 5-8-membered heteroaryl groups, wherein the above groups are independently 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 groups, -OR 16 and -NR 18 R 19 The substituents are replaced; R4 is selected from hydrogen, deuterium, hydroxyl group, and C. 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6-membered heterocyclic, phenyl, and 5-8-membered heteroaryl groups, wherein the above groups are independently 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, 5-8 membered heteroaryl, -OR 16 -NR 18 R 19 -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, C 2-4 Alkenyl, C 2-4 Alkyne group, C 3-6 Cycloalkyl, 3-6 membered heterocyclic groups, =O, -OR 16 -C(O)R 17 and -NR 18 R 19 The substituents are replaced; wherein R 16 , R 17 , R 18 and R 19 are as in claim 1. The compound of formula (I), stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, characterized in that, R7is selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 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, -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 , 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 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 , -0-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, -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 ; R7is selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl, each of the aforementioned groups being independently and 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, -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. The compound of formula (I), stereoisomer thereof, or pharmaceutically acceptable salt thereof according to claim 1, characterized in that, R2is selected from hydrogen, halogen, -(L) s -O-(L) s -R 2a s -O-(L) s -NR 2b R 2c and 3-6 membered heterocyclyl, the above -(L) s -O-(L) s -R 2a s -O-(L) s -NR 2b R 2c or 3-6 membered heterocyclyl is independently optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, C 1-4 alkyl, halosubstituted C 1-4 alkyl, deuterosubstituted C 1-4 alkyl, C 1-4 alkylene, halosubstituted C 1-4 alkylene, deuterosubstituted 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 independently selected from C 1-4 alkylene, C 3-6 cycloalkylene or 3-6 membered heterocyclyl, said C 1-4 alkylene, C 3-6 cycloalkylene or 3-6 membered heterocyclyl 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 heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, =0, =S, -SF5, -O-R 16 and -NR 18 R 19 substituted; 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 heteroaryl, =0, =S, -SF5, -O-R 16 and -NR 18 R 19 ; R 2b and R 2c are 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, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, and C 1-4 alkanoyl, each of the above 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 directly attached thereto, a 4-6 membered heterocyclic group or a 5-8 membered heteroaryl group is formed, wherein the 4-6 membered heterocyclic group or the 5-8 membered heteroaryl group is optionally further surrounded by one or more elements selected from deuterium, halogen, hydroxyl, =O, C. 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkyne group, halogenated C 1-4 Alkyl, deuterated 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 group, C 6- 8-aryl, C 6-8 Aryloxy group, 5-8 membered heteroaryl group, 5-8 membered heteroaryloxy group, amino group, mono-C group 1-4 Alkylamino, diC 1-4 Alkylamino and C 1-4 The alkyl acyl group is replaced by a substituent; wherein R 16 , R 18 and R 19 are as defined in claim 1. The compound of formula (I), stereoisomer thereof, or pharmaceutically acceptable salt thereof according to claim 1, characterized in that, R2 is selected from -(L) s -O-(L) s -R 2a Or 3-6 membered heterocyclic groups, the above-mentioned -(L) s -O-(L) s -R 2a Alternatively, 3-6 membered heterocyclic groups may be independently and optionally further selected from one or more groups chosen from deuterium, halogen, cyano, hydroxyl, C 1-4 Alkyl, C 1- 4-alkoxy, halosubstituted C 1-4 Alkyl, halogenated C 1-4 Alkoxy, deuterated C 1-4 Alkyl, deuterated C 1-4 Alkoxy, 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, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group, =O, =S, -SF5, amino, mono-C 1-4 Alkylamino and diC 1-4 Substituents of alkylamino groups; 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 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, hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, deuterated C 1-4 Alkyl, deuterated C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkyne group, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group, =O, =S, -SF5, amino, mono-C 1- 4-alkylamino and diC 1-4 Substituents of alkylamino groups; R 2a selected from hydrogen, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl, The above groups may optionally be further divided by one or more radicals selected from deuterium, halogen, cyano, hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, deuterated C 1-4 Alkyl, deuterated C 1-4 Alkoxy, 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, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group, =O, =S, -SF5, amino, mono-C 1-4 Alkylamino and diC 1-4 Substituents of alkylamino groups; each s is independently 0, 1, 2, or 3. The compound of formula (I), stereoisomer thereof, or pharmaceutically acceptable salt thereof according to claim 1, characterized in that, R2is selected from each R is independently selected from hydrogen, deuterium, hydroxyl, amino, methylamino, dimethylamino, fluorine, chlorine, methyl, ethyl, isopropyl, ethenyl, allyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, 2a1 each R is independently selected from hydrogen, deuterium, hydroxyl, amino, methylamino, dimethylamino, fluorine, chlorine, methyl, ethyl, isopropyl, ethenyl, allyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, The above groups 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, halogen-substituted C 1-4 alkylene, deuterium-substituted C 1-4 alkylene, vinyl, ethynyl, cyclopropyl, cyclobutyl, oxetanyl, azetanyl, =0, =S, -SF5, amino, methylamino and dimethylamino; R 2a2 selected from hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, C 1-4 alkylene, halogen-substituted C 1-4 alkylene, deuterium-substituted C 1-4 alkylene, vinyl, allyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, and azetanyl; R 2a3 selected from hydrogen, deuterium, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, The above groups 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, halogen-substituted C 1-4 alkylene, deuterium-substituted C 1-4 alkylene, vinyl, ethynyl, cyclopropyl, cyclobutyl, oxetanyl, azetanyl, =0, =S, -SF5, amino, methylamino and dimethylamino; each R 2a4 and each R 2a5 is each independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, and cyclopropyl; R 2b1 selected from hydrogen, deuterium, methyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, ethyl, isopropyl, ethenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, and azetidinyl. The compound of formula (I), stereoisomer thereof, or pharmaceutically acceptable salt thereof according to claim 1, characterized in that, Each R 5a 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 3-6 cycloalkyl groups and 3-6 membered heterocyclic groups; each R is independently selected from hydrogen, deuterium, halogen, cyano, C1-6alkyl, 6a each R is independently selected from hydrogen, deuterium, halogen, cyano, C1-6alkyl, 1-4 C1-6alkyl, deuterium-substituted C1-6alkyl, halogen-substituted C1-6alkyl, 1-4 C1-6alkyl, deuterium-substituted C1-6alkyl, halogen-substituted C1-6alkyl, 1-4 C1-6alkyl, deuterium-substituted C1-6alkyl, halogen-substituted C1-6alkyl, 3-6 cycloalkyl, and 3-6 The compound of formula (I), stereoisomer thereof, or pharmaceutically acceptable salt thereof according to claim 1, characterized in that, R 10 selected from hydrogen, deuterium, halogen, hydroxyl, cyano, C 1-4 alkyl, halosubstituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, amino, methylamino, and dimethylamino. The compound of formula (I), stereoisomer thereof, or pharmaceutically acceptable salt thereof according to claim 1, characterized in that, The compound of formula (I) is a compound of formula (V 1-1 ), a compound of formula (V 1-2 ), a compound of formula (V 1-3 ), a compound of formula (V 2-1 ), a compound of formula (V 2-2 ), a compound of formula (V 2-3 ), or a compound of formula (V wherein, in the compound of formula (V 1-1 ) or the compound of formula (V 2-1 ), each R 1i , each R 1j , and each R 1k is 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, -O-R 16 , and -NR 18 R 19 ; In the compound of formula (V 1-2 ) or the compound of formula (V 2-2 ), each Z1 is independently O, S, or NH; each Z2 is independently CR 1a or N; each Z3 is independently CR 1b or N; and each Z6 is independently CR 1e or N. each R 1a , each R 1b , each R 1c , each R 1d and each R 1e is 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, -O-R 16 and -NR 18 R 19 ; In the compound of formula (V 1-3 ) or the compound of formula (V 2-3 ), each Z7is independently CR 1f or N; each Z9is independently CR 1h or N. each R 1f , each R 1g , and each R 1h 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, -O-R 16 , and -NR 18 R 19 ; each R 1L and each R 1m is 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, -O-R 16 and -NR 18 R 19 ; each R2is independently selected from the group consisting of each R is independently selected from hydrogen, deuterium, hydroxyl, amino, methylamino, dimethylamino, fluorine, chlorine, methyl, ethyl, isopropyl, ethenyl, allyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, 2a1 each R is independently selected from hydrogen, deuterium, hydroxyl, amino, methylamino, dimethylamino, fluorine, chlorine, methyl, ethyl, isopropyl, ethenyl, allyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, The above groups 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, halogen-substituted C 1-4 alkylene, deuterium-substituted C 1-4 alkylene, vinyl, ethynyl, cyclopropyl, cyclobutyl, oxetanyl, azetanyl, =0, =S, -SF5, amino, methylamino and dimethylamino; each R is independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, C 2a2 each R is independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, C 1-4 alkylene, halo-substituted C 1-4 alkylene, deuterium-substituted C 1-4 alkylene, vinyl, allyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, and azetanyl; each R is independently selected from hydrogen, deuterium, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, 2a3 each R is independently selected from hydrogen, deuterium, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, The above groups 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, halogen-substituted C 1-4 alkylene, deuterium-substituted C 1-4 alkylene, vinyl, ethynyl, cyclopropyl, cyclobutyl, oxetanyl, azetanyl, =0, =S, -SF5, amino, methylamino and dimethylamino; each R 2a4 and each R 2a5 each independently is selected from hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, and cyclopropyl; Each R 2b1 Each is independently selected from hydrogen, deuterium, methyl, trifluoromethyl, difluoromethyl, trideuterium methyl, dideuterium methyl, ethyl, isopropyl, vinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl or aziridine; each R3is independently selected from hydrogen, deuterium, hydroxyl, C1-6alkyl, 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, and 5-8 membered heteroaryl, each of which is independently and optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, C1-6alkyl, 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, 3-6 membered heterocyclyl, -O-R 16 and -NR 18 R 19 ; each R4is independently selected from hydrogen, deuterium, hydroxyl, C1-C6alkyl, 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, and 5-8 membered heteroaryl, each of which is independently and optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, C1-C6alkyl, 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, 5-8 membered heteroaryl, -O-R 16 , -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, C1-C6alkyl, 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, =O, -O-R 16 , -C(O)R 17 , and -NR 18 R 19 ; Each R 10 Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, and C. 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic groups, amino, methylamino and dimethylamino; wherein R 16 , R 17 , R 18 and R 19 are as defined in claim 1. The compound of formula (I), stereoisomer thereof, or pharmaceutically acceptable salt thereof according to claim 1, characterized in that, said compound of formula (I) is a compound of formula (VI 1-1 ), a compound of formula (VI 1-2 ), a compound of formula (VI 1-3 ), a compound of formula (VI 1-4 ), a compound of formula (VI 1-5 ), a compound of formula (VI 1-6 ), a compound of formula (VI 1-7 ), a compound of formula (VI 1-8 ), a compound of formula (VI 1-9 ), a compound of formula (VI 1-10 ), a compound of formula (VI 1-11 ), a compound of formula (VI 1-12 ), a compound of formula (VI 1-13 ), a compound of formula (VI 1-14 ) or a compound of formula (VI wherein each Q1 is independently CH or N; each Q2 is independently CR 3b or N; each Q3 is independently CH or N; Each R 3b Each is independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, trideutermethyl, dideutermethyl, methoxy, trifluoromethoxy, difluoromethoxy, trideutermethoxy, and dideutermethoxy; In the compound of Formula (VI 1-1 ), the compound of Formula (VI 1-2 ), the compound of Formula (VI 1-3 ), the compound of Formula (VI 1-4 ), the compound of Formula (VI 1-5 ), or the compound of Formula (VI 1-6 ), 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 compounds of Formula (VI 1-7 ), Formula (VI 1-8 ), Formula (VI 1-9 ), Formula (VI 1-10 ), Formula (VI 1-11 ), or Formula (VI 1-12 ), each Z7is independently CR 1f or N; each Z9is independently CR 1h or N. each R 1f , each R 1g , and each R 1h is 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; each R 1L and each R 1m 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 (VI 1-13 ) or the compound of formula (VI 1-14 ), each Z1is independently O, S, or NH; each Z2is independently CR 1a or N; each Z3is independently CR 1b or N; and each Z6is independently CR 1e or N. each R 1a , each R 1b , each R 1c , each R 1d and each R 1e 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; each M1is independently a bond, O, CHR 2a10 or CR 2a11 ; M2is N or CH; M3is N or CR 2a11 ; In the compound of formula (VI 1-3 ) or the compound of formula (VI 1-12 ), each R 2a1 is independently selected from hydrogen, deuterium, fluorine, chlorine, 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, allyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinylamino, methylamino, and dimethylamino; in a compound of Formula (VI 1-1 ), a compound of Formula (VI 1-4 ), a compound of Formula (VI 1-5 ), a compound of Formula (VI 1-6 ), a compound of Formula (VI 1-7 ), a compound of Formula (VI 1-8 ), a compound of Formula (VI 1-9 ), or a compound of Formula (VI 1-13 ), each R 2a2 is independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, C 1- 4alkylene, halo-substituted C 1-4 4alkylene, deuterium-substituted C 1-4 4alkylene, vinyl, allyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetanyl, amino, methylamino, and dimethylamino; in a compound of Formula (VI 1-1 ), a compound of Formula (VI 1-2 ), a compound of Formula (VI 1-4 ), a compound of Formula (VI 1-5 ), a compound of Formula (VI 1-6 ), a compound of Formula (VI 1-7 ), a compound of Formula (VI 1-8 ), a compound of Formula (VI 1-10 ), a compound of Formula (VI 1-11 ), a compound of Formula (VI 1-13 ), or a compound of Formula (VI 1-14 ), each R 2a6 is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, methylene, monofluoromethylene, difluoromethylene, deuterium- substituted C 1-4 alkylene, ethenyl, ethynyl, cyclopropyl, cyclobutyl, oxetanyl, azetanyl, =0, =S, -SF5, amino, methylamino, and dimethylamino; In the compound of formula (VI 1-1 ), the compound of formula (VI 1-2 ), the compound of formula (VI 1-7 ), the compound of formula (VI 1-10 ), the compound of formula (VI 1-11 ), the compound of formula (VI 1-13 ), or the compound of formula (VI 1-14 ), each R 2a7 is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, methylene, monofluoromethylene, difluoromethylene, deuterium- substituted C 1-4 alkylene, ethenyl, ethynyl, cyclopropyl, cyclobutyl, oxetanyl, azetanyl, =0, =S, -SF5, amino, methylamino, and dimethylamino; in the compound of Formula (VI 1-4 ), the compound of Formula (VI 1-8 ), or the compound of Formula (VI 1-9 ), each R 2a8 is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, ethenyl, ethynyl, cyclopropyl, cyclobutyl, oxetanyl, azetanyl, -SF5, amino, methylamino, and dimethylamino; in the compound of Formula (VI 1-4 ), the compound of Formula (VI 1-8 ), or the compound of Formula (VI 1-9 ), each R 2a9 is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy, ethenyl, ethynyl, cyclopropyl, cyclobutyl, oxetanyl, azetanyl, -SF5, amino, methylamino, and dimethylamino; Each R 2a10 Each is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideutermethyl, dideutermethyl, methoxy, trifluoromethoxy, difluoromethoxy, trideutermethoxy, dideutermethoxy, vinyl, ethynyl, cyclopropyl, cyclobutyl, oxetyl, aziridine, -SF5, amino, methylamino, and dimethylamino; Each R 2a11 Each is independently selected from monofluoromethylene, difluoromethylene, and deuterated C. 1-4 Alkylene, =O or =S; Each R 2a12 Each is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideutermethyl, dideutermethyl, methoxy, trifluoromethoxy, difluoromethoxy, trideutermethoxy, dideutermethoxy, vinyl, ethynyl, cyclopropyl, cyclobutyl, oxetyl, aziridine, -SF5, amino, methylamino, and dimethylamino; In the compound of formula (VI 1-12 ) R 2b1 is selected from hydrogen, deuterium, methyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, ethyl, isopropyl, ethenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, or azetidinyl; In the compound of formula (VI 1-6 ) or the compound of formula (VI 1-9 ), each R 2b2 is independently selected from hydrogen, deuterium, methyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, ethyl, isopropyl, ethenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, or azetidinyl; each R4is independently selected from hydrogen, 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 independently selected from deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2- 4alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, 5-8 membered heteroaryl, -O-R 16 , -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 independently 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, =O, -O-R 16 , -C(O)R 17 , and -NR 18 R 19 ; wherein R 16 , R 17 , R 18 and R 19 are as defined in claim 1. The compound of formula (I), stereoisomer thereof, or pharmaceutically acceptable salt thereof according to claim 1, characterized in that, said compound of formula (I) is a compound of formula (VI 2-1 ), a compound of formula (VI 2-2 ), or a compound of formula (VI 2-3 ): wherein each Q1 is independently CH or N; each Q2 is independently CR 3b or N; each Q3 is independently CH or N; Each R 3b Each is independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, trideutermethyl, dideutermethyl, methoxy, trifluoromethoxy, difluoromethoxy, trideutermethoxy, and dideutermethoxy; In the compound of formula (VI 2-1 ) R 1i , R 1j and R 1k 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 compounds of formula (VI 2-2 ) Z7 is CR 1f or N; Z9 is CR 1h or N; 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; In compounds of formula (VI 2-3 ) Z1 is O, S or NH; Z2 is CR 1a or N; Z6 is CR 1e or N; R 1a 2, R 1c 3, R 1d 4and R 1e 5are 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; Each R 2a2 Each is independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideutermethyl, dideutermethyl, methoxy, trifluoromethoxy, difluoromethoxy, trideutermethoxy, dideutermethoxy, C 1-4 Alkylene, halogenated C 1-4 Alkylene, deuterated C 1-4 Alkylene, vinyl, allyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetyl, and aziridine; Each R 2a6 Each is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideutermethyl, dideutermethyl, methoxy, trifluoromethoxy, difluoromethoxy, trideutermethoxy, dideutermethoxy, C 1-4 Alkylene, halogenated C 1-4 Alkylene, deuterated C 1-4 Alkylene, vinyl, ethynyl, cyclopropyl, cyclobutyl, oxetyl, aziridine, =O, =S, -SF5, amino, methylamino and dimethylamino; Each R 2a7 Each is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideutermethyl, dideutermethyl, methoxy, trifluoromethoxy, difluoromethoxy, trideutermethoxy, dideutermethoxy, C 1-4 Alkylene, halogenated C 1-4 Alkylene, deuterated C 1-4 Alkylene, vinyl, ethynyl, cyclopropyl, cyclobutyl, oxetyl, aziridine, =O, =S, -SF5, amino, methylamino and dimethylamino; each R4is independently selected from hydrogen, 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 independently selected from deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2- alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, 5-8 membered heteroaryl, -O-R 16 , -C(O)R 18 R 19 , -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 independently 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, =O, -O-R 16 , -C(O)R 17 , and -NR 18 R 19 ; wherein R 16 , R 17 , R 18 and R 19 are as in claim 1. The compound of formula (I), stereoisomer thereof, or pharmaceutically acceptable salt thereof according to claim 1, characterized in that, selected from the group consisting of: A pharmaceutical composition comprising an effective amount of a compound of any one of claims 1-22, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, for administration to a patient in need thereof. Use of a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1-22, for the manufacture of a medicament for the treatment and / or prevention of a tumor associated with KRAS. A compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1-22, for use in the treatment and / or prevention of a tumor associated with KRAS. Use according to claim 25, 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. Use according to claim 26, characterized 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, 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 skull cancer, a brain cancer, a glioma, a uterine cancer, a vulvar cancer, a vaginal 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. A compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1-22, 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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