KRAS mutant inhibitor, and pharmaceutical composition thereof, preparation method therefor, and use thereof

Abstract

A compound represented by formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition thereof, a preparation method therefor, and a use thereof. The compound has one or more of the following effects: (1) good KRAS G12C inhibitory activity; (2) good KRAS G12D inhibitory activity; (3) good KRAS G12V inhibitory activity; (4) optimal exposure dose; (5) good bioavailability; and (6) good in vivo efficacy.

Description

KRAS mutant inhibitors, pharmaceutical compositions thereof, methods of preparation and uses

[0001] This application claims priority to Chinese patent application 2024108384732 with filing date of 2024 / 6 / 26, Chinese patent application 2024110519672 with filing date of 2024 / 8 / 1, Chinese patent application 2024115188500 with filing date of 2024 / 10 / 29 and Chinese patent application 2024117246816 with filing date of 2024 / 11 / 28. This application incorporates the entire text of the above-mentioned Chinese patent applications. TECHNICAL FIELD

[0002] The present application relates to a novel compound that inhibits the activity of KRAS mutants, pharmaceutical compositions thereof, methods of preparation and uses. BACKGROUND

[0003] The RAS gene family mainly includes three genes, KRAS, NRAS and HRAS. RAS gene is a proto-oncogene, which becomes a cancer gene with carcinogenic activity after being activated. RAS encodes a group of monomeric globular proteins (21 kD) consisting of 188-189 amino acids, which are called p21 protein or RAS protein. RAS protein is a GDP / GTP binding protein, which can cycle between inactive GDP binding state and active GTP binding state, acting as a "molecular switch". The GDP / GTP cycle of RAS is activated by guanine nucleotide exchange factors (for example: SOS or RASGRP) and inactivated by GTPase activating proteins (GAPs, for example: p120GAP or neurofibromin). GAPs interacting with RAS can greatly accelerate the conversion of GTP to GDP, turn off the switch to inactivate RAS, affect the ability of RAS and GAP interaction or convert GTP back to GDP. Any mutation that affects the ability of RAS and GAP interaction or converts GTP back to GDP will cause RAS to be continuously activated, and thus produce a prolonged signal to the cell. Since RAS can regulate cell proliferation, differentiation and aging through multiple important signaling pathways, prolonged activation of downstream signaling pathways (for example: PI3K-AKT-mTOR, RAF-MEK-ERK, RALGDS-RAL) will eventually lead to the occurrence of cancer.

[0004] The RAS protein includes a highly conserved N-terminal G-binding domain, which also contains a p-loop and switch I (residues 30-40) and switch II (residues 60-76) that bind nucleotides. The p-loop is a rigid part of the binding domain with conserved amino acid residues (glycine 12, threonine 26 and lysine 16) that are essential for amino acid binding and hydrolysis. Threonine-35 and glycine-60 in switch I and switch II can form hydrogen bonds with the gamma-phosphate of GTP, respectively, to maintain the switch I and II regions in an active conformation. After GTP hydrolysis and phosphate release, both relax into the inactive GDP conformation. In addition, the RAS protein also includes a C-terminal extension called the CAAX box, which can be post-translationally modified and is responsible for targeting the protein to the cell membrane (Jonathan et al. Nature Reviews, 2016, 15: 771-785).

[0005] The RAS gene can be in a continuously activated state through point mutations, overexpression, and gene insertion and translocation, of which the most common is point mutation, about 30% of human malignant tumors have point mutations in the RAS gene. The most common is point mutation of KRAS, and the common mutation sites are 12, 13, 61 codons, of which the 12 codon mutation is the most common. These activated mutations increase the content of GTP-bound RAS protein by inactivating endogenous GTPase activity and causing GTPase-activating protein resistance (Zenker et al. J Med Genet, 2007, 44: 131-135).

[0006] Abnormal expression of KRAS accounts for 20% of all malignant tumors, of which G12C, G12D, G12V have an incidence of 2.7%, 5%, and 4% in malignant solid tumors, respectively. Among them, the incidence of G12C mutation in non-small cell lung cancer is about 11%, and the incidence of G12C mutation in colorectal cancer, pancreatic cancer and endometrial cancer is about 1%-4% (Hobbs et al. J Cell Sci, 2016, 129: 1287-1292; Prior et al. Cancer Res, 2012, 72: 2457-67). The incidence of G12D mutation in patients with pancreatic ductal adenocarcinoma is about 25%, the incidence of G12D mutation in patients with colorectal cancer is about 13.3%, the incidence of G12D mutation in patients with rectal cancer is about 10.1%, the incidence of G12D mutation in patients with non-small cell lung cancer is about 4.1%, and the incidence of G12D mutation in patients with small cell lung cancer is about 1.7% (Cancer Discovery, 2017, 7(8): 818-831).

[0007] Increasing number of studies have shown the key role of KRAS, especially mutants including KRAS G12C, KRAS G12D and G12V, in malignant tumors, making KRAS an important target in the pharmaceutical industry, and there is an urgent need to develop new KRAS mutant inhibitors. SUMMARY

[0008] The present application provides a compound as shown in formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof;

[0009] wherein,

[0010] A is a 5-6 membered heteroaryl substituted by 1-3 R8or R8', or a 5-6 membered heterocycloalkyl substituted by 1-3 R8or R8'; A is an independent substituent, or, A and R4are connected to each other to form a 6-9 membered heterocycloalkyl, which can further comprise 1 heteroatom selected from O or S; or, A and R9are connected to each other to form a 5-7 membered heterocycloalkyl; the 5-7 membered heterocycloalkyl comprises 1 N heteroatom; the 6-9 membered heterocycloalkyl or 5-7 membered heterocycloalkyl is unsubstituted, or further substituted by 1-3 R8or R8' at any position;

[0011] B is a 6-10 membered aryl or a 5-10 membered heteroaryl; the 6-10 membered aryl or 5-10 membered heteroaryl is unsubstituted, or optionally substituted by 1-4 R 10 at any position;

[0012] C is

[0013] Y is N, CH or C-CN;

[0014] U and V are any of the following combinations: 1) U is N or CR2, V is C; or 2) U is CH2, V is N;

[0015] L is a connecting bond, -O-, -NH- or -N(C 1-6 alkyl)-;

[0016] L' is a connecting bond, -O- or -NR 12 -;

[0017] R1, R2and R3are each independently H, halogen, cyano, C 1-3 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy or haloC 1-3 alkoxy or C 2-4 alkynyl;

[0018] R4is H, hydroxyl, C 1-6 alkyl, C1-6 Alkoxy; the C 1-6 Alkyl or C 1-6 The alkoxy group is unsubstituted, or selectively selected from 1-3 groups: hydroxyl, amino, halogen, deuterium, C. 1-4 Alkoxy and C 1-4 The substituents of the alkylamino group can be substituted at any position;

[0019] R5 and R6 are independently H, D, or C, respectively. 1-6 Alkyl; R5 and R6 are independent substituents, or R5 and R6 together with the carbon atom they are attached to form a C12 group. 3-6 cycloalkyl;

[0020] R7 is

[0021] R8 can be H, halogen, amino, cyano, or C. 1-6 Alkyl, Halogenated C 1-3 Alkyl, C 1-3 alkoxy or halogenated C 1-3 Alkoxy;

[0022] R8' represents H, halogen, cyano, or C. 1-6 Alkyl, Halogenated C 1-3 Alkyl, oxo, C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 2-6 alkenyl, halogenated C 2-6 alkynyl group, -OR a -N(R) a )2、-OC(O)R a -OC(O)OR a -NHC(O)R a -NHC(O)OR a -S(O) 0-2 R b -C(O)OR a -C(O)N(R) a )2 or -C(O)R a ;

[0023] R9 is H or C 1-6 alkyl;

[0024] R 10 H, halogen, oxo group, cyano group, -OR b -N(R) b )2、-OC(O)R b -OC(O)OR b -NHC(O)R b -NHC(O)OR b -NHP(O)(OR)b )2、-S(O) 0-2 R b -C(O)N(R) b )2、-C(O)R b C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 2-6 alkenyl, halogenated C 2-6 alkynyl group, C 3-6 Cycloalkyl groups;

[0025] R 11 C 3-8 Cycloalkyl or 3-8 membered heterocycloalkyl; the C 3-8 The cycloalkyl or 3-8 membered heterocyclic alkyl group is unsubstituted, or selectively substituted with 1-3 R groups. 13 Replace in any position;

[0026] R 11 'For H, halogen, hydroxyl, cyano, amino, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylene, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, Halogenated C 1-6 alkoxy or halogenated C 1-6 Alkylene;

[0027] R 12 R 12 'and R 12 "Each of the following groups can be independently represented as H, halogen, oxo group, cyano group, or -OR." b -N(R) b )2、-OC(O)R b -OC(O)OR b -NHC(O)R b -NHC(O)OR b -C(O)N(R) b )2、-C(O)R b -C(O)OR b C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-6 3-6 membered heterocyclic alkyl, C 3-6 Cycloalkyl C 1-4 Alkyl, 3-6 membered heterocyclic alkyl C 1-4alkyl, C 1-6 alkylene, haloC 1-6 alkylene; said C 1-6 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 membered heterocycloalkyl C 1-4 alkyl or 3-6 membered heterocycloalkyl C 1-4 alkyl is unsubstituted or optionally substituted with 1-3 R 13 substituted at any position;

[0028] R 13 is halogen, oxo, -OR b , -N(R b )2, -OC(O)R b , -OC(O)OR b , -NHC(O)R b , -NHC(O)OR b , -C(O)N(R b )2, -C(O)R b , -C(O)OR b , C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy, hydroxyC 1-6 alkyl, C 1-3 alkoxy C 1-6 alkyl, aminoC 1-6 alkyl or C 1-4 alkylamino C 1-6 alkyl;

[0029] R a is H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, haloC 1-6 alkyl, haloC 2-6 alkenyl or haloC 2-6 alkynyl;

[0030] R b is H, C 1-6 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl; said C 1-6 alkyl is unsubstituted or optionally substituted with 1-3 halogen, hydroxy, cyano, amino, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl at any position;

[0031] m is 0, 1, 2, 3, or 4.

[0032] The present application provides a compound as shown in formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof;

[0033] wherein,

[0034] A is A1, A2, A3, and A4 are each independently N or CR8';

[0035] B is a 6-10 membered aryl or a 5-10 membered heteroaryl; the 6-10 membered aryl or the 5-10 membered heteroaryl is unsubstituted or optionally substituted with 1-4 R 10 substituted at any position;

[0036] C is

[0037] Y is N, CH, or C-CN;

[0038] U and V are any of the following combinations: 1) U is N or CR2, V is C; or 2) U is CH2, V is N;

[0039] L is a linking bond, -O-, -NH-, or -N(C 1-6 alkyl)-;

[0040] L' is a linking bond, -O-, or -NR 12 -;

[0041] R1, R2, and R3 are each independently H, halogen, cyano, C 1-3 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy, or haloC 1-3 alkoxy, or C 2-4 alkynyl;

[0042] R4 is H, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy; the C 1-6 alkyl or C 1-6 alkoxy is unsubstituted or optionally substituted with 1-3 substituents selected from the group consisting of hydroxyl, amino, halogen, deuterium, C 1-4 alkoxy, and C 1-4 alkylamino substituted at any position;

[0043] R5 and R6 are each independently H, D, or C 1-6 alkyl; R5 and R6 are independent substituents, or R5 and R6 together with the carbon atom to which they are commonly attached form a C 3-6 cycloalkyl;

[0044] R7 is

[0045] R8and R8' are each independently H, halo, cyano, amino, C 1-6 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy, or haloC 1-3 alkyl;

[0046] R9is H or C 1-6 alkyl;

[0047] R 10 is H, halo, oxo, cyano, -OR b , -N(R b )2, -OC(O)R b , -OC(O)OR b , -NHC(O)R b , -NHC(O)OR b , -NHP(O)(OR b )2, -S(O) 0-2 R b , -C(O)N(R b )2, -C(O)R b , C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, haloC 2-6 alkenyl, haloC 2-6 alkynyl, C 3-6 membered cycloalkyl;

[0048] R 11 is C 3-8 cycloalkyl or 3-8 membered heterocycloalkyl; said C 3-8 cycloalkyl or 3-8 membered heterocycloalkyl is unsubstituted or optionally substituted with 1-3 R 13 substituents at any position;

[0049] R 11 ' is H, halo, hydroxyl, cyano, amino, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylene, haloC 1-6 alkyl, hydroxylC 1-6 alkyl, haloC 1-6 alkoxy, or haloC 1-6 alkylene;

[0050] R 12 , R12 'and R 12 "Each of the following groups can be independently represented as H, halogen, oxo group, cyano group, or -OR." b -N(R) b )2、-OC(O)R b -OC(O)OR b -NHC(O)R b -NHC(O)OR b -C(O)N(R) b )2、-C(O)R b -C(O)OR b C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-6 3-6 membered heterocyclic alkyl, C 3-6 Cycloalkyl C 1-4 Alkyl, 3-6 membered heterocyclic alkyl C 1-4 Alkyl, C 1-6 Alkylene, Halogenated C 1-6 Alkylene; the C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkyl C 1-4 Alkyl or 3-6 membered heterocyclic alkyl C 1-4 The alkyl group is unsubstituted, or selectively substituted with 1-3 R groups. 13 Replace in any position;

[0051] R 13 Halogen, oxo group, -OR b -N(R) b )2、-OC(O)R b -OC(O)OR b -NHC(O)R b -NHC(O)OR b -C(O)N(R) b )2、-C(O)R b -C(O)OR b C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, C 1-3 Alkoxy C 1-6 Alkyl, amino C 1-6 Alkyl or C 1-4 Alkylamino C 1-6 alkyl;

[0052] R b H, C 1-6 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl; said C 1-6 alkyl is unsubstituted or optionally substituted with 1-3 halogen, hydroxyl, cyano, amino, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl at any position;

[0053] m is 0, 1, 2, 3 or 4.

[0054] The present application provides a compound as shown in formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof;

[0055] A is A1, A2, A3and A4are each independently N or CR8';

[0056] B is 6-10 membered aryl or 5-10 membered heteroaryl; said 6-10 membered aryl or 5-10 membered heteroaryl is unsubstituted or optionally substituted with 1-4 R 10 substituted at any position;

[0057] C is

[0058] Y is N, CH or C-CN;

[0059] U and V are any of the following combinations: 1) U is N or CR2, V is C; or 2) U is CH2, V is N;

[0060] R1, R2and R3are each independently H, halogen, cyano, C 1-3 alkyl, halogenated C 1-3 alkyl, C 1-3 alkoxy or halogenated C 1-3 alkoxy or C 2-4 alkynyl;

[0061] R4is H, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy; said C 1-6 alkyl or C 1-6 alkoxy is unsubstituted or optionally substituted with 1-3 substituents selected from the group consisting of hydroxyl, amino, halogen, deuterium, C 1-4 alkoxy and C 1-4 alkylamino at any position;

[0062] R5and R6are each independently H, D or C 1-6 alkyl; R5and R6are independent substituents, or R5and R6together with the carbon atom to which they are commonly attached form a C 3-6 cycloalkyl;

[0063] R7is

[0064] R8and R8' are each independently H, halo, cyano, amino, C 1-6 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy, or haloC 1-3 alkyl;

[0065] R9is H or C 1-6 alkyl;

[0066] R 10 is H, halo, oxo, cyano, -OR b , -N(R b )2, -OC(O)R b , -OC(O)OR b , -NHC(O)R b , -NHC(O)OR b , -NHP(O)(OR b )2, -S(O) 0-2 R b , -C(O)N(R b )2, -C(O)R b , C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, haloC 2-6 alkenyl, haloC 2-6 alkynyl, C 3-6 membered cycloalkyl;

[0067] R 11 is C 3-8 cycloalkyl or 3-8 membered heterocycloalkyl; said C 3-8 cycloalkyl or 3-8 membered heterocycloalkyl is unsubstituted or optionally substituted with 1-3 R 13 substituted at any position;

[0068] R 11 ' is H, halo, hydroxyl, cyano, amino, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylene, haloC 1-6 alkyl, hydroxylC 1-6 alkyl, haloC 1-6 alkoxy, or haloC 1-6 alkylene;

[0069] R 13 halo, oxo, -OR b , -N(R b )2, -OC(O)R b , -OC(O)OR b , -NHC(O)R b , -NHC(O)OR b , -C(O)N(R b )2, -C(O)R b , -C(O)OR b , C 1-6 1-6 alkyl, C 1-6 1-6 alkoxy, haloC 1-6 1-6 alkyl, haloC 1-6 1-6 alkoxy, hydroxyC 1-6 1-6 alkyl, C 1-3 1-6 alkoxyC 1-6 1-6 alkyl, aminoC 1-6 1-6 alkyl or C 1-4 1-6 alkylaminoC 1-6 1-6 alkyl;

[0070] R b is H, C 1-6 1-6 alkyl, C 3-6 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl; said C 1-6 1-6 alkyl is unsubstituted or optionally substituted at any position with 1-3 halo, hydroxy, cyano, amino, C 3-6 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl.

[0071] The present application provides a compound as shown in formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof;

[0072] wherein,

[0073] A is 5-6 membered heteroaryl substituted with 1-3 R8or R8', or 5-6 membered heterocycloalkyl substituted with 1-3 R8or R8'; A is an independent substituent, or alternatively, A and R4are mutually connected to form a 6-9 membered heterocycloalkyl, which can further comprise 1 heteroatom selected from O or S; or alternatively, A and R9are mutually connected to form a 5-7 membered heterocycloalkyl; said 5-7 membered heterocycloalkyl comprises 1 N heteroatom; said 6-9 membered heterocycloalkyl or 5-7 membered heterocycloalkyl is unsubstituted or further substituted at any position with 1-3 R8or R8';

[0074] B is 6-10 membered aryl or 5-10 membered heteroaryl; said 6-10 membered aryl or 5-10 membered heteroaryl is unsubstituted or optionally substituted at any position with 1-4 R10 substituted at any position;

[0075] C is

[0076] Y is N, CH, or C-CN;

[0077] U and V are any combination of 1) U is N or CR2, V is C; or 2) U is CH2, V is N;

[0078] R1, R2, and R3are each independently H, halo, cyano, C 1-3 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy, or haloC 1-3 alkyl, C 2-4 alkyl, C

[0079] R4is H, hydroxy, C 1-6 alkyl, C 1-6 alkoxy; said C 1-6 alkyl, C 1-6 alkyl, C 1-4 alkyl, C 1-4 alkyl, C

[0080] R5and R6are each independently H, D, or C 1-6 alkyl; R5and R6are independent substituents, or R5and R6together with the carbon atom to which they are both attached form a C 3-6 cycloalkyl;

[0081] R7is

[0082] R8is H, halo, amino, cyano, C 1-6 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy, or haloC 1-3 alkyl, C

[0083] R8' is H, halo, cyano, C 1-6 alkyl, haloC 1-3 alkyl, oxo, C 2-6 alkyl, C 2-6 alkyl, C 2-6 alkyl, C 2-6 alkyl, -OR a , -N(R a )2, -OC(O)R a , -OC(O)OR a , -NHC(O)R a, -NHC(O)OR a , -S(O) 0-2 R b , -C(O)OR a , -C(O)N(R a )2or -C(O)R a ;

[0084] R9is H or C 1-6 alkyl;

[0085] R 10 is H, halogen, oxo, cyano, -OR b , -N(R b )2, -OC(O)R b , -OC(O)OR b , -NHC(O)R b , -NHC(O)OR b , -NHP(O)(OR b )2, -S(O) 0-2 R b , -C(O)N(R b )2, -C(O)R b , C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, haloC 2-6 alkenyl, haloC 2-6 alkynyl, C 3-6 membered cycloalkyl;

[0086] R 11 is C 3-8 cycloalkyl or 3-8 membered heterocycloalkyl; said C 3-8 cycloalkyl or 3-8 membered heterocycloalkyl is unsubstituted or optionally substituted with 1-3 R 13 substituted at any position;

[0087] R 11 ' is H, halogen, hydroxyl, cyano, amino, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylene, haloC 1-6 alkyl, hydroxyC 1-6 alkyl, haloC 1-6 alkoxy or haloC 1-6 alkylene;

[0088] R 13 is halogen, oxo, -ORb -N(R) b )2、-OC(O)R b -OC(O)OR b -NHC(O)R b -NHC(O)OR b -C(O)N(R) b )2、-C(O)R b -C(O)OR b C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, C 1-3 Alkoxy C 1-6 Alkyl, amino C 1-6 Alkyl or C 1-4 Alkylamino C 1-6 alkyl;

[0089] R a For H, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl, halogenated C 1-6 Alkyl, Halogenated C 2-6 alkenyl or halogenated C 2-6 alkynyl group;

[0090] R b For H, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, or 5-6 membered heteroaryl; the C 1-6 The alkyl group is unsubstituted, or selectively substituted with 1-3 halogens, hydroxyl groups, cyano groups, amino groups, or C groups. 3-6 Cycloalkyl, 3-6-membered heterocycloalkyl, phenyl, or 5-6-membered heteroaryl substitutions are made at any position.

[0091] The present invention provides a compound of formula (I), its stereoisomer or pharmaceutically acceptable salt;

[0092] Where A is A1 is N, A2 is CH, A3 is CH, A4 is CH;

[0093] B is a 5-10 membered heteroaryl group; the 5-10 membered heteroaryl group is unsubstituted, or selectively substituted by 1-4 R groups. 10 Replace in any position;

[0094] C is

[0095] Y is N;

[0096] U is N or CR2; V is C;

[0097] R1, R2and R3are each independently H, halo, C 1-3 alkyl or haloC 1-3 alkyl;

[0098] R4is C 1-6 alkyl; said C 1-6 alkyl is unsubstituted or optionally substituted with 1-3 substituents selected from the group consisting of hydroxy, amino, halo and deuterium at any position;

[0099] R5and R6are each independently H, D or C 1-6 alkyl;

[0100] R7is

[0101] R8is NH2;

[0102] R9is H or C 1-6 alkyl;

[0103] R 10 is H, halo, cyano, -N(R b )2, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy or C 3-6 membered cycloalkyl;

[0104] R 11 is C 3-8 cycloalkyl or 3-8 membered heterocycloalkyl; said C 3-8 cycloalkyl or 3-8 membered heterocycloalkyl is unsubstituted or optionally substituted with 1-3 R 13 substituents at any position;

[0105] R 11 ' is H, halo, C 1-6 alkyl, C 1-6 alkylene or haloC 1-6 alkylene;

[0106] R 13 is halo, oxo, -OR b , -N(R b )2, -OC(O)R b , -NHC(O)R b , -C(O)N(R b )2, -C(O)R b, -C(O)OR b , C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy, hydroxyC 1-6 alkyl or aminoC 1-6 alkyl;

[0107] R b is H or C 1-6 alkyl.

[0108] The present application provides a compound as shown in formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof;

[0109] wherein A is A1 is N, A2 is CH, A3 is CH, and A4 is CH;

[0110] B is a 5-10 membered heteroaryl; the 5-10 membered heteroaryl is unsubstituted or optionally substituted at any position with 1-4 R 10 substituents;

[0111] C is

[0112] Y is N;

[0113] U is N or CR2; V is C;

[0114] R1, R2 and R3 are each independently H, halogen, C 1-3 alkyl or haloC 1-3 alkyl;

[0115] R4 is C 1-6 alkyl; the C 1-6 alkyl is unsubstituted or optionally substituted at any position with 1-3 substituents selected from the group consisting of hydroxy, amino, halogen and deuterium;

[0116] R5 and R6 are each independently H, D or C 1-6 alkyl;

[0117] R7 is

[0118] R8 is NH2;

[0119] R9 is H or C 1-6 alkyl;

[0120] R 10 is H, halogen, cyano, -N(R b )2, C 1-6 alkyl, C 1-6alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy or C 3-6 membered heteroaryl;

[0121] R b is H or C 1-6 alkyl.

[0122] The present application provides a compound as shown in formula (II), a stereoisomer or a pharmaceutically acceptable salt thereof;

[0123] wherein, in the A ring, A1 is N, M - N + -L-R or N + -L-R', A2 is CH, A3 is CH, and A4 is CH;

[0124] B is

[0125] X is CR9R 9a ;

[0126] Y is N;

[0127] Z is N or C-CN;

[0128] L is C 1-4 alkylene;

[0129] M - is an anion;

[0130] R is H, -OC(O)R b , -OC(O)N(R b )2, -OC(O)OR b , 3-6 membered heterocycloalkyl substituted with 1-3 R c , or 3-6 membered heteroaryl substituted with 1-3 R c ;

[0131] R' is -OP(O)(OR b )O - ;

[0132] R1 and R2 are each independently H, halogen, C 1-3 alkyl, haloC 1-3 alkyl or C 1-3 alkoxy;

[0133] R3 is H or halogen;

[0134] R4 is C 1-6 alkyl; the C 1-6 alkyl is unsubstituted or optionally substituted with 1-3 groups selected from the group consisting of hydroxy, amino, halogen, deuterium, C1-4 alkoxy and C 1-4 substituted at any position by a substituent selected from the group consisting of halo, C

[0135] R5and R6are each independently H, deuterium or C 1-6 alkyl; R5and R6are independent substituents, or R5and R6together with the carbon atom to which they are commonly attached form a C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl or C 1-4 alkylene; said C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl or C 1-4 alkylene is unsubstituted or optionally substituted by 1 to 3 substituents selected from the group consisting of halo, C 1-3 alkyl and halo C 1-3 substituted at any position by a substituent selected from the group consisting of halo, C

[0136] R7is C 1-6 alkylamino, 4-10 membered heterocycloalkyl or 4-10 membered heterocycloalkyl substituted by 1 to 3 R 11 substituted 4-10 membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from N, O or S;

[0137] R8and R 8e are each independently -NH2, -NHC(O)R b , -NHC(O)OR b , -NHP(O)(OR b )2 or -NH-L-R;

[0138] R9is C 1-6 alkyl, halo C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl;

[0139] R 9a is H, deuterium or C 1-6 alkyl;

[0140] R 10 and R 10c are each independently H, halo, cyano, nitro, hydroxy, amino, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy or C 3-6 membered cycloalkyl;

[0141] R 10a is C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy or C3-6 cycloalkyl;

[0142] R 11 halogen, hydroxyl, cyano, amino, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylene, haloC 1-6 alkyl, hydroxylC 1-6 alkyl, haloC 1-6 alkoxy, haloC 1-6 alkylene, haloC 1-6 alkoxy-C 1-4 alkyl, C 3-8 cycloalkyl or 3-8 membered heterocycloalkyl;

[0143] R b H, C 1-6 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 3-6 cycloalkylC 1-4 alkyl, 3-6 membered heterocycloalkylC 1-4 alkyl, phenylC 1-4 alkyl or 5-6 membered heteroarylC 1-4 alkyl; said R b is unsubstituted or optionally substituted with 1-3 R c substituted at any position;

[0144] R c halogen, oxo, cyano, hydroxyl, nitro, C 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkyl, haloC 1-4 alkoxy or ester group;

[0145] t is 1, 2 or 3.

[0146] The present application provides a compound as shown in formula (II), a stereoisomer or a pharmaceutically acceptable salt thereof;

[0147] wherein, in the A ring, A1 is N, M - N + -L-R or N + -L-R', A2 is CH, A3 is CH, and A4 is CH;

[0148] B ring is

[0149] X is CR9R 9a ;

[0150] Y is N;

[0151] Z is N or C-CN;

[0152] L is C 1-4 alkylene;

[0153] M - is an anion;

[0154] R is H, -OC(O)R b , -OC(O)N(R b )2, -OC(O)OR b , 3-6 membered heterocycloalkyl substituted with 1 to 3 R c , or 3-6 membered heteroaryl substituted with 1 to 3 R c ;

[0155] R' is -OP(O)(OR b )O - ;

[0156] R1and R2are each independently H, halogen, C 1-3 alkyl, haloC 1-3 alkyl, or C 1-3 alkoxy;

[0157] R3is H or halogen;

[0158] R4is C 1-6 alkyl; said C 1-6 alkyl is unsubstituted or optionally substituted with 1 to 3 substituents selected from the group consisting of hydroxy, amino, halogen, deuterium, C 1-4 alkoxy, and C 1-4 alkylamino at any position;

[0159] R5and R6are each independently H, deuterium, or C 1-6 alkyl; R5and R6are independent substituents, or R5and R6together with the carbon atom to which they are both attached form a C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, or C 1-4 alkylene; said C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, or C 1-4 alkylene is unsubstituted or optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, cyclopropyl, C 1-3 alkyl, and haloC 1-3 alkyl at any position;

[0160] R7is 4-10 membered heterocycloalkyl substituted with 2 to 3 R 11 ; said 4-10 membered heterocycloalkyl comprises 1 to 3 heteroatoms selected from the group consisting of N, O, or S;

[0161] R8and R8e They are independently -NH2 and -NHC(O)R, respectively. b -NHC(O)OR b -NHP(O)(OR) b )2 or -NH-LR;

[0162] R9 is C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl or C 2-6 alkynyl group;

[0163] R 9a H, deuterium, or C 1-6 alkyl;

[0164] R 10 and R 10c Each can be independently represented by H, halogen, cyano, nitro, hydroxyl, amino, or C. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy or C 3-6 Cycloalkyl groups;

[0165] R 10a C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy or C 3-6 Cycloalkyl groups;

[0166] R 11 Halogen, hydroxyl, cyano, amino, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylene, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylene, Halogenated C 1-6 Alkoxy-C 1-4 Alkyl, C 3-8 Cycloalkyl or 3-8 membered heterocyclic alkyl; at least one R 11 C 1-6 Alkylene or halogenated C 1-6 alkylene, and at least one R 11 It is a 3-8 membered heterocyclic alkyl group;

[0167] R b For H, C 1-6 Alkyl, C 3-6cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 3-6 cycloalkyl 1-4 alkyl, 3-6 membered heterocycloalkyl 1-4 alkyl, phenyl 1-4 alkyl or 5-6 membered heteroaryl 1-4 alkyl; said R b is unsubstituted or optionally substituted with 1-3 R c substituted at any position;

[0168] R c is halogen, oxo, cyano, hydroxy, nitro, C 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkyl, haloC 1-4 alkoxy or ester;

[0169] t is 1, 2 or 3.

[0170] In some embodiments, the compound of Formula (II), stereoisomer or pharmaceutically acceptable salt thereof, is:

[0171] R 10a is C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy or C 3-6 membered cycloalkyl;

[0172] All embodiments of the compounds of Formula (I) or (II) and combinations of variables described below are included within the scope of the structural formula of Formula (I) or (II).

[0173] In some embodiments, the compound of Formula (I) or (II), stereoisomer or pharmaceutically acceptable salt thereof, wherein the definitions of moieties are as described below, and the definitions of the remaining moieties are as in any other aspect (hereinafter referred to as "in some embodiments").

[0174] In some embodiments, M - is a pharmaceutically acceptable anion, preferably a halide or an acid radical; including but not limited to chloride, bromide, fluoride, trifluoroacetate, acetate, sulfate, bisulfate, and the like.

[0175] In some embodiments, B is a 5-6 membered monocyclic heteroaryl or a 9-10 membered bicyclic heteroaryl, preferably a pyridyl, benzothienyl or benzothiazolyl; said B is unsubstituted or optionally substituted with 1-4 or 1-3 R 10 substituted at any position.

[0176] In some embodiments, B is pyridyl or benzothiophenyl; said B is unsubstituted or optionally substituted with 1-4 or 1-3 R 10 substituted at any position.

[0177] In some embodiments, B is pyridyl or benzothiophenyl; said B is substituted with 3 R 10 substituted at any position.

[0178] In some embodiments, each R 10 is independently halogen, cyano, -N(R b )2, C 1-6 alkyl or haloC 1-6 alkyl.

[0179] In some embodiments, each R 10 is independently F, Cl, -CN, -OH, -NH2, -CN, methyl, ethyl, isopropyl, methoxy, ethoxy, vinyl, ethynyl, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy or cyclopropyl.

[0180] In some embodiments, each R 10 is independently F, -NH2, -CN, methyl or trifluoromethyl.

[0181] In some embodiments, B is Z is N or C-CN.

[0182] In some embodiments, B is

[0183] In some embodiments, B is

[0184] In some embodiments, Z is C-CN.

[0185] In some embodiments, R8is -NH2.

[0186] In some embodiments, R 8e is -NH2.

[0187] In some embodiments, R 10 is H, F, Cl, -CN, -NO2, -OH, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy or cyclopropyl.

[0188] In some embodiments, R 10a and R 10cindependently H, F, Cl, -CN, -NO2, -OH, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, or cyclopropyl.

[0189] independently H, F, Cl, -CN, -NO2, -OH, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, or cyclopropyl. 10 H, halogen, cyano, -N(R b )2, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy, or C 3-6 membered cycloalkyl.

[0190] independently H, F, Cl, -CN, -NO2, -OH, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, or cyclopropyl. 10 halogen, cyano, or NH2.

[0191] independently H, F, Cl, -CN, -NO2, -OH, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, or cyclopropyl. 10 halogen, or C 1-6 alkyl.

[0192] independently H, F, Cl, -CN, -NO2, -OH, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, or cyclopropyl. 10 halogen.

[0193] independently H, F, Cl, -CN, -NO2, -OH, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, or cyclopropyl. 10 C 1-6 alkyl.

[0194] independently H, F, Cl, -CN, -NO2, -OH, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, or cyclopropyl. 10 F or methyl.

[0195] independently H, F, Cl, -CN, -NO2, -OH, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, or cyclopropyl. 10 F.

[0196] independently H, F, Cl, -CN, -NO2, -OH, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, or cyclopropyl. 10 methyl.

[0197] independently H, F, Cl, -CN, -NO2, -OH, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, or cyclopropyl. 10a haloC 1-6 alkyl.

[0198] independently H, F, Cl, -CN, -NO2, -OH, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, or cyclopropyl. 10a trifluoromethyl.

[0199] independently H, F, Cl, -CN, -NO2, -OH, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, or cyclopropyl. 10c H.

[0200] independently H, F, Cl, -CN, -NO2, -OH, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, or cyclopropyl. 10d H, methyl, ethyl, ethenyl, or ethynyl.

[0201] independently H, F, Cl, -CN, -NO2, -OH, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, or cyclopropyl. 11 H, halogen, C 1-6 alkyl, C 1-6 alkylene, or haloC 1-6alkylene.

[0202] In some embodiments, R 11 is H or methylene (=CH2).

[0203] In some embodiments, R 13 is halogen, oxo, -OR b , -N(R b )2, -OC(O)R b , -NHC(O)R b , -C(O)N(R b )2, -C(O)R b , -C(O)OR b , C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy, hydroxyC 1-6 alkyl, or aminoC 1-6 alkyl.

[0204] In some embodiments, R 13 is oxo or -OR b .

[0205] In some embodiments, R b is H or C 1-6 alkyl.

[0206] In some embodiments, B is R 10 is as previously described.

[0207] In some embodiments, B is R 10 is as previously described.

[0208] In some embodiments, B is R 10 is as previously described.

[0209] In some embodiments, B is R 10 is as previously described.

[0210] In some embodiments, B is R 10 is halogen (e.g., F).

[0211] In some embodiments, the B is any one of the following structures:

[0212] In some embodiments, B is

[0213] In some embodiments, B is

[0214] In some embodiments, B is

[0215] In some embodiments, R5and R6are each independently H, D, or methyl.

[0216] In some embodiments, R5and R6are H.

[0217] In some embodiments, R5and R6, together with the carbon atom to which they are both attached, form

[0218] In some embodiments, R7is R 11 is fluorine, methylene,

[0219] In some embodiments, R7is

[0220] In some embodiments, R7is

[0221] In some embodiments, R7is

[0222] In some embodiments, R7is

[0223] In some embodiments, R7is is preferably

[0224] In some embodiments, R7is is preferably

[0225] In some embodiments, in the compound of formula (I), R 11 is a 3-8 membered heterocycloalkyl, preferably a 5-6 membered monocyclic heterocycloalkyl, containing 1-2 heteroatoms selected from O, N, S.

[0226] In some embodiments, in the compound of formula (II), there are at least 2 R 11 wherein at least one R 11 is C 1-6 alkylene or haloC 1-6 alkylene and at least one R 11It is a 3-8 membered heterocyclic alkyl group (preferably a 5-6 membered monocyclic heterocyclic alkyl group containing 1-2 heteroatoms selected from O, N, and S).

[0227] In some embodiments, in the compound represented by formula (II), R7 is formed by 1 to 3 R groups. 11 The substituted 4-10-membered heterocyclic alkyl group, wherein the 4-10-membered heterocyclic alkyl group comprises 1 to 3 heteroatoms selected from N, O or S, preferably, R7 is a heteroatom surrounded by 2 R atoms. 11 Substituted 4-10 membered heterocyclic alkyl groups.

[0228] In some implementation schemes, R 12 For H, -N(R) b )2 or -OR b ;R 12 'For H, halogen, oxo group, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, C 1-3 Alkoxy C 1-4 Alkyl, amino C 1-4 Alkyl, C 1-4 Alkylamino C 1-4 Alkyl, Halogenated C 1-4 Alkoxy, C 3-6 3-6 membered heterocyclic alkyl, C 1-4 Alkylene, Halogenated C 1-4 Alkylene; the C 3-6 The cyclic alkyl group or 3-6-membered heterocyclic alkyl group is unsubstituted, or selectively substituted by 1-3 groups selected from halogens, C 1-4 Alkyl, -OH, -NH2, C 1-4 Alkoxy and C 1-4 The substituents of the alkylamino group can be substituted at any position.

[0229] In some implementation schemes, R 12 -N(R) b )2.

[0230] In some implementation schemes, R 12 'For C 1-4 Alkyl group.

[0231] In some implementation schemes, R b C 1-6 alkyl.

[0232] In some implementation schemes, R 12 -N(R) b )2;R 12 'For C 1-4 Alkyl group.

[0233] In some embodiments, R 12 is C 1-4 alkyl, C 3-6 cycloalkyl, or 3-6 membered heterocycloalkyl; said R 12 is unsubstituted or optionally substituted with 1-3 R 13 substituted at any position.

[0234] In some embodiments, R 12 is optionally substituted with 1-3 substituents selected from halo, oxo, -OH, -NH2, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, haloC 1-4 alkyl, haloC 1-4 alkoxy, hydroxyC 1-4 alkyl, C 1-3 alkoxyC 1-4 alkyl, aminoC 1-4 alkyl, and C 1-4 alkylaminoC 1-4 alkyl substituted at any position.

[0235] In some embodiments, L' is a bond, -O-, or -NR 12 ".

[0236] In some embodiments, L' is a bond.

[0237] In some embodiments, C is m is 0, 1, or 2.

[0238] In some embodiments, C is m is 0, 1, or 2.

[0239] In some embodiments, C is

[0240] In some embodiments, m is 1.

[0241] In some embodiments, C is m is 1.

[0242] In some embodiments, C is

[0243] In some embodiments, C is preferably

[0244] In some embodiments, C is

[0245] In some embodiments, C is

[0246] In some embodiments, C is

[0247] In some embodiments, C is preferably In some embodiments, R9is H or C 1-6 alkyl.

[0248] In some embodiments, in the compound of formula (I), R9is methyl, ethyl.

[0249] In some embodiments, in the compound of formula (II), R9is cyano, methyl, ethyl, trifluoromethyl, ethenyl, or ethynyl;

[0250] In some embodiments, R9is -CH3.

[0251] In some embodiments, is preferably

[0252] In some embodiments, A is A1, A2, A3, and A4are each independently N or CR8’.

[0253] In some embodiments, A is A1is N, A2is CH, A3is CH, and A4is CH.

[0254] In some embodiments, R8is NH2.

[0255] In some embodiments, R8is NH2; and A is A1is N, A2is CH, A3is CH, and A4is CH.

[0256] In some embodiments, A is

[0257] In some embodiments, A is

[0258] In some embodiments, A is

[0259] In some embodiments, A is R9is -CH3.

[0260] In some embodiments, A is u is 1 or 2.

[0261] In some embodiments, A is

[0262] In some embodiments, A is

[0263] In some embodiments, A and R9are taken together to form a 5-7 membered heterocycloalkyl; said 5-7 membered heterocycloalkyl contains 1-3 heteroatoms selected from N, O, S; said 5-7 membered heterocycloalkyl is unsubstituted or further substituted with 1-3 R8or R8’at any position.

[0264] In some embodiments, A and R9are taken together to form a 5-7 membered heterocycloalkyl; said 5-7 membered heterocycloalkyl contains 1-3 heteroatoms selected from N, O, S; said 5-7 membered heterocycloalkyl is unsubstituted or further substituted with 1-3 R8or R8’at any position. u is 1 or 2; R8’is H or C 1-4 alkyl.

[0265] In some embodiments, A and R9are taken together to form a 5-7 membered heterocycloalkyl; said 5-7 membered heterocycloalkyl contains 1-3 heteroatoms selected from N, O, S; said 5-7 membered heterocycloalkyl is unsubstituted or further substituted with 1-3 R8or R8’at any position.

[0266] In some embodiments, A and R4are taken together to form a 6-9 membered heterocycloalkyl; said 6-9 membered heterocycloalkyl contains 1-3 heteroatoms selected from N, O, S; said 6-9 membered heterocycloalkyl is unsubstituted or further substituted with 1-3 R8or R8’at any position.

[0267] In some embodiments, A and R4are taken together to form a 6-9 membered heterocycloalkyl; said 6-9 membered heterocycloalkyl contains 1-3 heteroatoms selected from N, O, S; said 6-9 membered heterocycloalkyl is unsubstituted or further substituted with 1-3 R8or R8’at any position. L” is a bond or -O-; R8and R8’are each independently H, C 1-4 alkyl or hydroxyl.

[0268] In some embodiments, A and R4are taken together to form a 6-9 membered heterocycloalkyl; said 6-9 membered heterocycloalkyl contains 1-3 heteroatoms selected from N, O, S; said 6-9 membered heterocycloalkyl is unsubstituted or further substituted with 1-3 R8or R8’at any position.

[0269] In some embodiments, R1is H, halogen, C 1-3 alkyl or haloC 1-3 alkyl.

[0270] In some embodiments, R2is H, halogen, C 1-3 alkyl or haloC 1-3 alkyl.

[0271] In some embodiments, R3is H, halogen, C 1-3 alkyl or haloC 1-3 alkyl.

[0272] In some embodiments, R1is halogen.

[0273] In some embodiments, R2is halogen.

[0274] In some embodiments, R1is F, R2is F, CI, or -CF3.

[0275] In some embodiments, R1is F.

[0276] In some embodiments, R2is F or CI.

[0277] In some embodiments, R3is H or -OCH3.

[0278] In some embodiments, R3is H.

[0279] In some embodiments, R4is C 1-6 alkyl; said C 1-6 alkyl is unsubstituted or optionally substituted with 1-3 substituents selected from the group consisting of hydroxyl, amino, halogen, and deuterium at any position.

[0280] In some embodiments, R4is C 1-6 alkyl.

[0281] In some embodiments, R4is H, -CH3, -CH2CH3, -OCH3, -CDH2, -CD2H, -CD3, -CHDCH3, -CD2CH3, or -OCD3; preferably, R4is -CH3, -CDH2, -CD2H, or -CD3.

[0282] In some embodiments, R4is -CH3.

[0283] In some embodiments, R5and R6are each independently H, D, or C 1-6 alkyl.

[0284] In some embodiments, R5and R6are each independently H, D, or methyl.

[0285] In some embodiments, the compound of Formula (I), stereoisomer or pharmaceutically acceptable salt thereof is a compound of Formula (I-1) or (I-2), stereoisomer or pharmaceutically acceptable salt thereof,

[0286] wherein R1, R3, R4, R5, R6, R9, R 11 , R 11 , R 12 , R 12 , L, L', m, B, and U are as previously described.

[0287] In some embodiments, the compound of Formula (I), a stereoisomer, or a pharmaceutically acceptable salt thereof is a compound of Formula (I-3) or (I-4), a stereoisomer, or a pharmaceutically acceptable salt thereof,

[0288] wherein R1, R2, R3, R4, R5, R6, R 10 , R 11 , R 11 , R 12 , R 12 and m are as defined above.

[0289] In some embodiments, the compound of Formula (I), a stereoisomer, or a pharmaceutically acceptable salt thereof is a compound of Formula (I-3-1) or (I-3-2), a stereoisomer, or a pharmaceutically acceptable salt thereof,

[0290] wherein R1, R2, R4, R5, R6, R 10 , R 11 and R 11 are as defined above.

[0291] In some embodiments, the compound of Formula (I), a stereoisomer, or a pharmaceutically acceptable salt thereof is a compound of Formula (I-3-3), a stereoisomer, or a pharmaceutically acceptable salt thereof,

[0292] wherein R1, R2, R4, R5, R6, R 10 , R 11 and R 11 are as defined above.

[0293] In some embodiments, the compound of Formula (I), a stereoisomer, or a pharmaceutically acceptable salt thereof is a compound of Formula (I-3-3A) or (I-3-3B), a stereoisomer, or a pharmaceutically acceptable salt thereof,

[0294] wherein R1, R2, R4, R5, R6, R 10 , R 11 and R 11 are as defined above.

[0295] In some embodiments, the compound of Formula (I-3), e.g., Formula (I-3-1), Formula (I-3-2), Formula (I-3-3), Formula (I-3-3A), or Formula (I-3-3B),

[0296] R1is H, halogen, C 1-3alkyl or haloC 1-3 alkyl;

[0297] R2is H, halogen, C 1-3 alkyl or haloC 1-3 alkyl;

[0298] R4is C 1-6 alkyl; said C 1-6 alkyl is unsubstituted or optionally substituted with 1-3 substituents selected from the group consisting of hydroxyl, amino, halogen, and deuterium at any position;

[0299] R5is H, D, or C 1-6 alkyl;

[0300] R6is H, D, or C 1-6 alkyl;

[0301] R 10 is H, halogen, cyano, -N(R b )2, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy, or C 3-6 membered cycloalkyl;

[0302] R 11 is C 3-8 cycloalkyl or 3-8 membered heterocycloalkyl (preferably 5-6 membered monocyclic heterocycloalkyl, containing 1-2 heteroatoms selected from O, N, S); said C 3-8 cycloalkyl or 3-8 membered heterocycloalkyl is unsubstituted or optionally substituted with 1-3 R 13 substituents at any position;

[0303] R 11 ' is H, halogen, C 1-6 alkyl, C 1-6 alkylene, or haloC 1-6 alkylene;

[0304] R 13 is halogen, oxo, -OR b , -N(R b )2, -OC(O)R b , -NHC(O)R b , -C(O)N(R b )2, -C(O)R b , -C(O)OR b , C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy, hydroxylC1-6 alkyl or amino C 1-6 alkyl;

[0305] R b is H or C 1-6 alkyl.

[0306] In some embodiments, the compound of Formula (I-3), e.g., Formula (I-3-1), Formula (I-3-2), Formula (I-3-3), Formula (I-3-3A), or Formula (I-3-3B), is a compound of Formula (I-3-4),

[0307] R1is halogen (e.g., F);

[0308] R2is halogen (e.g., F or Cl);

[0309] R4is C 1-6 alkyl (e.g., methyl);

[0310] R5is H;

[0311] R6is H;

[0312] R 10 is halogen (e.g., F);

[0313] R 11 is 3-8 membered heterocycloalkyl (preferably 5-6 membered monocyclic heterocycloalkyl, containing 1-2 heteroatoms selected from O, N, S); said 3-8 membered heterocycloalkyl is unsubstituted or optionally substituted with 1-3 R 13 substituted at any position;

[0314] R 11 is H, C 1-6 alkylene;

[0315] R 13 is oxo, -OR b ;

[0316] R b is H or C 1-6 alkyl (e.g., methyl).

[0317] In some embodiments, the compound of Formula (I), stereoisomer or pharmaceutically acceptable salt thereof, is a compound of Formula (I-3-4), stereoisomer or pharmaceutically acceptable salt thereof,

[0318] wherein R1, R2, R4, R5, R6, and R 10 are as previously described.

[0319] In some embodiments, the compound of Formula (I), a stereoisomer, or a pharmaceutically acceptable salt thereof is a compound of Formula (I-3-5), a stereoisomer, or a pharmaceutically acceptable salt thereof,

[0320] wherein R1, R2, R4, R5, R6, and R 10 are as previously described.

[0321] In some embodiments, the compound of Formula (I), a stereoisomer, or a pharmaceutically acceptable salt thereof is a compound of Formula (I-3-4A) or (I-3-4B), a stereoisomer, or a pharmaceutically acceptable salt thereof,

[0322] wherein R1, R2, R4, R5, R6, and R 10 are as previously described.

[0323] In some embodiments, the compound of Formula (I), a stereoisomer, or a pharmaceutically acceptable salt thereof is a compound of Formula (I-3-5A) or (I-3-5B), a stereoisomer, or a pharmaceutically acceptable salt thereof,

[0324] wherein R1, R2, R4, R5, R6, and R 10 are as previously described.

[0325] In some embodiments, the compound of Formula (I-3-4) and Formula (I-3-5), for example, Formula (I-3-4A), Formula (I-3-4B), Formula (I-3-5A), and Formula (I-3-5B),

[0326] R1is H, halogen, C 1-3 alkyl, or haloC 1-3 alkyl;

[0327] R2is H, halogen, C 1-3 alkyl, or haloC 1-3 alkyl;

[0328] R4is C 1-6 alkyl; the C 1-6 alkyl is unsubstituted or optionally substituted with 1-3 substituents selected from the group consisting of hydroxyl, amino, halogen, and deuterium at any position;

[0329] R5is H, D, or C 1-6 alkyl;

[0330] R6is H, D, or C 1-6 alkyl;

[0331] R 10H, halogen, cyano, -N(R b )2, C 1-6 1-6alkyl, C 1-6 1-6alkoxy, halogenated C 1-6 1-6alkyl, halogenated C 1-6 1-6alkoxy or C 3-6 1-6cycloalkyl;

[0332] R b is H or C 1-6 1-6alkyl.

[0333] In some embodiments, the compound of Formula (I-3-4) or Formula (I-3-5), e.g., Formula (I-3-4A), (I-3-4B), (I-3-5A), and Formula (I-3-5B), is a compound of Formula (I-3-4A), (I-3-4B), (I-3-5A), or Formula (I-3-5B), respectively:

[0334] R1is halogen (e.g., F);

[0335] R2is halogen (e.g., F or Cl);

[0336] R4is C 1-6 1-6alkyl (e.g., methyl);

[0337] R5is H;

[0338] R6is H;

[0339] R 10 is halogen (e.g., F).

[0340] In some embodiments, the compound of Formula (I), stereoisomer or pharmaceutically acceptable salt thereof, is any one of the following structures: or a pharmaceutically acceptable salt thereof.

[0341] In some embodiments, the compound of Formula (I), stereoisomer or pharmaceutically acceptable salt thereof, is any one of the following structures:

[0342] In some embodiments, the compound is a atropisomer of a compound of the following formula,

[0343] wherein the atropisomer is the compound with shorter retention time under the following analytical conditions: ultra performance liquid chromatography (UPLC) analysis using Waters ACQUITY Hclass; column Waters ACQUITY UPLC BEH Shield RP18, 2.1*100 mm; mobile phase A: 5 mM potassium dihydrogen phosphate buffer, pH 2.5 adjusted with phosphoric acid; mobile phase B: acetonitrile; gradient elution of mobile phase B from 10% to 40% in 5 min, from 40% to 90% in 2 min, 90% for 6 min, from 90% to 10% in 2 min; preferably, detection wavelength is 214 nm, and / or, column temperature is 40 °C, and / or, flow rate is 0.4 mL / min; further preferably, the compound with shorter retention time has a retention time of about 4.95-5.05 min, for example about 5.005 min.

[0344] In some embodiments, the compound is an atropisomer of a compound of the formula

[0345] wherein the atropisomer is the compound with longer retention time under the following analytical conditions: using Waters ACQUITY Hclass; column Waters ACQUITY UPLC BEH Shield RP18, 2.1*100 mm, mobile phase A: 5 mM potassium dihydrogen phosphate buffer, pH 2.5 adjusted with phosphoric acid; mobile phase B: acetonitrile; gradient elution of mobile phase B from 10% to 40% in 5 min, from 40% to 90% in 2 min, 90% for 6 min, from 90% to 10% in 2 min; preferably, injection volume is 1.7 μm, and / or, detection wavelength is 214 nm, and / or, column temperature is 40 °C, and / or, flow rate is 0.4 mL / min; further preferably, the compound with longer retention time has a retention time of about 5.21-5.31 min, for example about 5.262 min.

[0346] In some embodiments, the compound is a single stereoisomer of a compound of the following formula, which is resolved from a compound of the following formula by supercritical fluid chromatography (SFC) under the following resolution conditions: using SFC-150 (Waters); a chiral preparative column is OX 25*250mm, 10pm (Regis) (preferably, a flow rate is 100 mL / min, and / or, a column temperature is 35°C, and / or, an injection volume is 1 mL, and / or, a detection wavelength is 214 and / or 254 nm, and / or a cycle time is 8.1 minutes); a mobile phase is CO2 / [methanol (0.2% 7M ammonium methanol solution) / acetonitrile = 1 / 1] = 45:55;

[0347] Alternatively, the single stereoisomer is the compound with a shorter retention time under the following analytical conditions: using UPC®C (Waters), an analytical column is 6-OX 4.6*100mm, 5um (preferably, a flow rate is 3.0 mL / min, and / or, a column temperature is 40°C; and / or, an injection volume is 7.5 pL; and / or, a detection wavelength is 214 and / or 254 nm); a mobile phase is CO2 / [methanol (0.2% 7M ammonium methanol solution) / acetonitrile = 1 / 1] = 55:45; preferably, the compound with the shorter retention time has a retention time of about 3.23-3.33 min, for example, about 3.284 min);

[0348] the single stereoisomer is:

[0349] In some embodiments, the compound is a single stereoisomer of a compound of the following formula, which is resolved from a compound of the following formula by supercritical fluid chromatography (SFC) under the following resolution conditions: using SFC-150 (Waters); a chiral preparative column is OX 25*250mm, 10pm (Regis) (preferably, a flow rate is 100 mL / min, and / or, a column temperature is 35°C, and / or, an injection volume is 1 mL, and / or, a detection wavelength is 214 and / or 254 nm, and / or a cycle time is 8.1 minutes); a mobile phase is CO2 / [methanol (0.2% 7M ammonium methanol solution) / acetonitrile = 1 / 1] = 45:55;

[0350] Alternatively, the single stereoisomer is the compound with a longer retention time under the following analytical conditions: using a Waters ACQUITY Hclass; column: Waters ACQUITY UPLC BEH Shield RP18, 2.1*100 mm; mobile phase A: 5 mM potassium dihydrogen phosphate buffer, pH 2.5 with phosphoric acid; mobile phase B: acetonitrile; gradient elution of mobile phase B from 10% to 40% in 5 min, gradient elution of mobile phase B from 40% to 90% in 2 min, mobile phase B at 90% for 6 min, B from 90% to 10% in 2 min; preferably, detection wavelength is 214 nm, and / or column temperature is 40 °C, and / or flow rate is 0.4 mL / min; further preferably, the compound with a longer retention time has a retention time of about 4.93-5.06 min, for example about 4.983 min or 5.011 min.

[0351] The single stereoisomer is:

[0352] In some embodiments, the compound is a atropisomer of a compound of the formula

[0353] wherein the atropisomer is the compound with a shorter retention time under the following analytical conditions: using a Waters ACQUITY Hclass; column: Waters ACQUITY UPLC BEH Shield RP18, 2.1*100 mm; mobile phase A: 5 mM potassium dihydrogen phosphate buffer, pH 2.5 with phosphoric acid; mobile phase B: acetonitrile; gradient elution of mobile phase B from 10% to 40% in 5 min, gradient elution of mobile phase B from 40% to 90% in 2 min, mobile phase B at 90% for 6 min, B from 90% to 10% in 2 min; preferably, detection wavelength is 214 nm, and / or column temperature is 40 °C, and / or flow rate is 0.4 mL / min; further preferably, the compound with a shorter retention time has a retention time of about 4.93-5.06 min, for example about 4.983 min or 5.011 min.

[0354] In some embodiments, the compound is a single atropisomer of a compound of the formula

[0355] The atropisomer is a compound with a longer retention time under the following analytical conditions: Waters ACQUITY Hclass is used; the chromatographic column is Waters ACQUITY UPLC BEH Shield RP18, 2.1*100 mm; the mobile phase A is 5 mM potassium dihydrogen phosphate buffer, and the pH value is adjusted to 2.5 with phosphoric acid; the mobile phase B is acetonitrile; gradient elution of the mobile phase B from 10% to 40%, elution time 5 minutes, gradient elution of the mobile phase B from 40% to 90%, elution time 2 minutes, the mobile phase B is kept at 90% for 6 minutes, B from 90% to 10%, elution time 2 minutes; preferably, the detection wavelength is 214 nm, and / or, the column temperature is 40°C, and / or, the flow rate is 0.4 mL / min; further preferably, the retention time of the compound with a longer retention time is about 5.13-5.31 min, for example, 5.177 min or 5.256 min.

[0356] The present application provides a compound as shown in formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof.

[0357] wherein,

[0358] A is a 5-6 membered heteroaryl substituted by 1-3 R8or R8', or a 5-6 membered heterocycloalkyl substituted by 1-3 R8or R8'; A is an independent substituent, or A and R4are connected to each other to form a 6-9 membered heterocycloalkyl, which can further comprise 1 heteroatom selected from O or S; or A and R9are connected to each other to form a 5-7 membered heterocycloalkyl; the 5-7 membered heterocycloalkyl comprises 1 N heteroatom; the 6-9 membered heterocycloalkyl or 5-7 membered heterocycloalkyl is unsubstituted or further substituted at any position by 1-3 R8or R8';

[0359] B is a 6-10 membered aryl or a 5-10 membered heteroaryl; the 6-10 membered aryl or 5-10 membered heteroaryl is unsubstituted or optionally substituted at any position by 1-4 R 10 ;

[0360] C is

[0361] Y is N, CH or C-CN;

[0362] U and V are any of the following combinations: 1) U is N or CR2, V is C; or 2) U is CH2, V is N;

[0363] L is a connecting bond, -O-, -NH- or -N(C 1-6 alkyl)-;

[0364] L' is a connecting bond, -O- or -NR12

[0365] R1, R2and R3are each independently H, halo, cyano, C 1-3 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy or haloC 1-3 alkoxy or C 2-4 alkynyl;

[0366] R4is H, hydroxy, C 1-6 alkyl, C 1-6 alkoxy; said C 1-6 alkyl or C 1-6 alkoxy is unsubstituted or optionally substituted with 1-3 substituents selected from the group consisting of hydroxy, amino, halo, deuterium, C 1-4 alkoxy and C 1-4 alkylamino at any position;

[0367] R5and R6are each independently H, D or C 1-6 alkyl; R5and R6are independent substituents or R5and R6together with the carbon atom to which they are both attached form a C 3-6 cycloalkyl;

[0368] R7is

[0369] R8is H, halo, amino, cyano, C 1-6 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy or haloC 1-3 alkoxy;

[0370] R8' is H, halo, cyano, C 1-6 alkyl, haloC 1-3 alkyl, oxo, C 2-6 alkenyl, C 2-6 alkynyl, haloC 2-6 alkenyl, haloC 2-6 alkynyl, -OR a , -N(R a )2, -OC(O)R a , -OC(O)OR a , -NHC(O)R a , -NHC(O)OR a , -S(O) 0-2 R b , -C(O)OR a , -C(O)N(R a )2 or -C(O)R a ;

[0371] ​R9is H or C 1-6 alkyl;

[0372] R 10 is H, halogen, oxo, cyano, -OR b , -N(R b )2, -OC(O)R b , -OC(O)OR b , -NHC(O)R b , -NHC(O)OR b , -NHP(O)(OR b )2, -S(O) 0-2 R b , -C(O)N(R b )2, -C(O)R b , C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, haloC 2-6 alkenyl, haloC 2-6 alkynyl, C 3-6 membered cycloalkyl;

[0373] R 11 is C 3-8 cycloalkyl or 3-8 membered heterocycloalkyl; said C 3-8 cycloalkyl or 3-8 membered heterocycloalkyl is unsubstituted or optionally substituted with 1-3 R 13 substituted at any position;

[0374] R 11 ' is H, halogen, hydroxyl, cyano, amino, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylene, haloC 1-6 alkyl, hydroxyC 1-6 alkyl, haloC 1-6 alkoxy or haloC 1-6 alkylene;

[0375] R 12 , R 12 ' and R 12 " are each independently H, halogen, oxo, cyano, -OR b , -N(R b )2, -OC(O)R b , -OC(O)OR b , -NHC(O)R b , -NHC(O)ORb -C(O)N(R) b )2、-C(O)R b -C(O)OR b C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-6 3-6 membered heterocyclic alkyl, C 3-6 Cycloalkyl C 1-4 Alkyl, 3-6 membered heterocyclic alkyl C 1-4 Alkyl, C 1-6 Alkylene, Halogenated C 1-6 Alkylene; the C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkyl C 1-4 Alkyl or 3-6 membered heterocyclic alkyl C 1-4 The alkyl group is unsubstituted, or selectively substituted with 1-3 R groups. 13 Replace in any position;

[0376] R 13 Halogen, oxo group, -OR b -N(R) b )2、-OC(O)R b -OC(O)OR b -NHC(O)R b -NHC(O)OR b -C(O)N(R) b )2、-C(O)R b -C(O)OR b C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, C 1-3 Alkoxy C 1-6 Alkyl, amino C 1-6 Alkyl or C 1-4 Alkylamino C 1-6 alkyl;

[0377] R a For H, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl, halogenated C 1-6 Alkyl, Halogenated C 2-6 alkenyl or halogenated C 2-6 alkynyl group;

[0378] R b H, C 1-6 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl; said C 1-6 alkyl is unsubstituted or optionally substituted with 1-3 halogen, hydroxyl, cyano, amino, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl at any position;

[0379] m is 0, 1, 2, 3 or 4.

[0380] The present application provides a compound as shown in formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof;

[0381] wherein,

[0382] A is A1, A2, A3and A4are each independently N or CR8’;

[0383] B is 6-10 membered aryl or 5-10 membered heteroaryl; said 6-10 membered aryl or 5-10 membered heteroaryl is unsubstituted or optionally substituted with 1-4 R 10 at any position;

[0384] C is

[0385] Y is N, CH or C-CN;

[0386] U and V are any of the following combinations: 1) U is N or CR2, V is C; or 2) U is CH2, V is N;

[0387] L is a linking bond, -O-, -NH- or -N(C 1-6 alkyl)-;

[0388] L’ is a linking bond, -O- or -NR 12 ”-;

[0389] R1, R2and R3are each independently H, halogen, cyano, C 1-3 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy or haloC 1-3 alkoxy or C 2-4 alkynyl;

[0390] R4is H, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy; said C 1-6 alkyl or C 1-6The alkoxy group is unsubstituted, or selectively selected from 1-3 groups: hydroxyl, amino, halogen, deuterium, C. 1-4 Alkoxy and C 1-4 The substituents of the alkylamino group can be substituted at any position;

[0391] R5 and R6 are independently H, D, or C, respectively. 1-6 Alkyl; R5 and R6 are independent substituents, or R5 and R6 together with the carbon atom they are attached to form a C12 group. 3-6 cycloalkyl;

[0392] R7 is

[0393] R8 and R8' are independently H, halogen, cyano, amino, and C, respectively. 1-6 Alkyl, Halogenated C 1-3 Alkyl, C 1-3 alkoxy or halogenated C 1-3 Alkoxy;

[0394] R9 is H or C 1-6 alkyl;

[0395] R 10 H, halogen, oxo group, cyano group, -OR b -N(R) b )2、-OC(O)R b -OC(O)OR b -NHC(O)R b -NHC(O)OR b -NHP(O)(OR) b )2、-S(O) 0-2 R b -C(O)N(R) b )2、-C(O)R b C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 2-6 alkenyl, halogenated C 2-6 alkynyl group, C 3-6 Cycloalkyl groups;

[0396] R 11 C 3-8 Cycloalkyl or 3-8 membered heterocycloalkyl; the C 3-8 The cycloalkyl or 3-8 membered heterocyclic alkyl group is unsubstituted, or selectively substituted with 1-3 R groups. 13 Replace in any position;

[0397] R 11 'For H, halogen, hydroxyl, cyano, amino, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylene, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, Halogenated C 1-6 alkoxy or halogenated C 1-6 Alkylene;

[0398] R 12 R 12 'and R 12 "Each of the following groups can be independently represented as H, halogen, oxo group, cyano group, or -OR." b -N(R) b )2、-OC(O)R b -OC(O)OR b -NHC(O)R b -NHC(O)OR b -C(O)N(R) b )2、-C(O)R b -C(O)OR b C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-6 3-6 membered heterocyclic alkyl, C 3-6 Cycloalkyl C 1-4 Alkyl, 3-6 membered heterocyclic alkyl C 1-4 Alkyl, C 1-6 Alkylene, Halogenated C 1-6 Alkylene; the C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkyl C 1-4 Alkyl or 3-6 membered heterocyclic alkyl C 1-4 The alkyl group is unsubstituted, or selectively substituted with 1-3 R groups. 13 Replace in any position;

[0399] R 13 Halogen, oxo group, -OR b -N(R) b )2、-OC(O)R b -OC(O)OR b -NHC(O)R b -NHC(O)OR b -C(O)N(R) b )2、-C(O)R b, -C(O)OR b , C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy, hydroxyC 1-6 alkyl, C 1-3 alkoxyC 1-6 alkyl, aminoC 1-6 alkyl or C 1-4 alkylaminoC 1-6 alkyl;

[0400] R a is H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, haloC 1-6 alkyl, haloC 2-6 alkenyl or haloC 2-6 alkynyl;

[0401] R b is H, C 1-6 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl; said C 1-6 alkyl is unsubstituted or optionally substituted with 1-3 halogen, hydroxy, cyano, amino, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl at any position;

[0402] m is 0, 1, 2, 3 or 4.

[0403] The present application provides a compound as shown in formula (II), a stereoisomer or a pharmaceutically acceptable salt thereof;

[0404] wherein, in the A ring, A1 is N, M - N + -L-R or N + -L-R’, A2 is CH, A3 is CH, and A4 is CH;

[0405] B is

[0406] X is CR9R 9a ;

[0407] Y is N;

[0408] Z is N or C-CN;

[0409] L is C 1-4 alkylene;

[0410] M - is an anion;

[0411] R is H, -OC(O)R b , -OC(O)N(R b )2, -OC(O)OR b , 3-6 membered heterocycloalkyl substituted with 1 to 3 R c , or 3-6 membered heteroaryl substituted with 1 to 3 R c ;

[0412] R' is -OP(O)(OR b )O - ;

[0413] R1and R2are each independently H, halogen, C 1-3 alkyl, haloC 1-3 alkyl, or C 1-3 alkoxy;

[0414] R3is H or halogen;

[0415] R4is C 1-6 alkyl; said C 1-6 alkyl is unsubstituted or optionally substituted with 1 to 3 substituents selected from the group consisting of hydroxy, amino, halogen, deuterium, C 1-4 alkoxy, and C 1-4 alkylamino at any position;

[0416] R5and R6are each independently H, deuterium, or C 1-6 alkyl; R5and R6are independent substituents, or R5and R6together with the carbon atom to which they are commonly attached form a C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, or C 1-4 alkylene; said C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, or C 1-4 alkylene is unsubstituted or optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, cyclopropyl, C 1-3 alkyl, and haloC 1-3 alkyl at any position;

[0417] R7is C 1-6 alkylamino, 4-10 membered heterocycloalkyl, or 4-10 membered heterocycloalkyl substituted with 1 to 3 R 11 , said 4-10 membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from the group consisting of N, O, or S;

[0418] R8and R 8e are each independently -NH2, -NHC(O)R b , -NHC(O)OR b ;-NHP(O)(OR b )2or -NH-L-R;

[0419] R9is C 1-6 alkyl, haloC 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl;

[0420] R 9a is H, deuterium or C 1-6 alkyl;

[0421] R 10 and R 10c are each independently H, halogen, cyano, nitro, hydroxyl, amino, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy or C 3-6 membered cycloalkyl;

[0422] R 10a is C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy or C 3-6 membered cycloalkyl;

[0423] R 11 is halogen, hydroxyl, cyano, amino, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylene, haloC 1-6 alkyl, hydroxyC 1-6 alkyl, haloC 1-6 alkoxy, haloC 1-6 alkylene, haloC 1-6 alkoxy-C 1-4 alkyl, C 3-8 cycloalkyl or 3-8 membered heterocycloalkyl;

[0424] R b is H, C 1-6 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 3-6 cycloalkylC 1-4 alkyl, 3-6 membered heterocycloalkylC 1-4 alkyl, phenylC 1-4 alkyl or 5-6 membered heteroarylC 1-4 alkyl; said R b is unsubstituted or optionally substituted with 1 to 3 R c substituents at any position;

[0425] R c halogen, oxo, cyano, hydroxy, nitro, C 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkyl, haloC 1-4 alkoxy or ester;

[0426] t is 1, 2 or 3.

[0427] All embodiments of the compounds of formula (I) or (II) and combinations of the variables described below are included within the scope of the structural formula of formula (I) or (II).

[0428] In some embodiments, the compounds of formula (I) or (II), stereoisomers or pharmaceutically acceptable salts thereof, the definition of the moieties are as described below, and the definition of the remaining moieties are as described in any other aspect (hereinafter referred to as "in some embodiments").

[0429] In some embodiments, M - is a pharmaceutically acceptable anion, preferably a halide or an acid radical; including but not limited to chloride, bromide, fluoride, trifluoroacetate, acetate, sulfate, bisulfate, and the like.

[0430] In some embodiments, B is pyridyl, benzothienyl or benzothiazolyl; said B is unsubstituted or optionally substituted with 1-4 or 1-3 R 10 substituted at any position.

[0431] In some embodiments, each R 10 is independently F, Cl, -CN, -OH, -NH2, -CN, methyl, ethyl, isopropyl, methoxy, ethoxy, vinyl, ethynyl, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy or cyclopropyl.

[0432] In some embodiments, B is Z is N or C-CN.

[0433] In some embodiments, R 10 is H, F, Cl, -CN, -NO2, -OH, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy or cyclopropyl.

[0434] In some embodiments, R 10a and R 10cindependently H, F, Cl, -CN, -NO2, -OH, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, or cyclopropyl.

[0435] In some embodiments, R 10d is H, methyl, ethyl, vinyl, or ethynyl.

[0436] In some embodiments, B is R 10 is as previously described.

[0437] In some embodiments, B is R 10 is as previously described.

[0438] In some embodiments, B is R 10 is as previously described.

[0439] In some embodiments, the B is any one of the following structures:

[0440] In some embodiments, R5and R6are each independently H, D, or methyl.

[0441] In some embodiments, R5and R6together with the carbon atom to which they are both attached form

[0442] In some embodiments, R7is

[0443] In some embodiments, R7is

[0444] In some embodiments, R7is

[0445] In some embodiments, R 12 is H, -N(R b )2, or -OR b ; R 12 is H, halo, oxo, C 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkyl, hydroxyC 1-4 alkyl, C 1-3 alkoxyC 1-4 alkyl, aminoC 1-4Alkyl, C 1-4 Alkylamino C 1-4 Alkyl, Halogenated C 1-4 Alkoxy, C 3-6 3-6 membered heterocyclic alkyl, C 1-4 Alkylene, Halogenated C 1-4 Alkylene; the C 3-6 The cyclic alkyl group or 3-6-membered heterocyclic alkyl group is unsubstituted, or selectively substituted by 1-3 groups selected from halogens, C 1-4 Alkyl, -OH, -NH2, C 1-4 Alkoxy and C 1-4 The substituents of the alkylamino group can be substituted at any position.

[0446] In some implementation schemes, R 12 "for C" 1-4 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl; the R 12 "For non-replacement, or selectively replaced by 1-3 Rs" 13 Replace in any position.

[0447] In some implementation schemes, R 12 "Selectivity is achieved by selecting 1-3 groups from halogens, oxo groups, -OH, -NH2, C." 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, Halogenated C 1-4 Alkyl, Halogenated C 1-4 Alkoxy, hydroxy C 1-4 Alkyl, C 1-3 Alkoxy C 1-4 Alkyl, amino C 1-4 Alkyl and C 1-4 Alkylamino C 1-4 The alkyl substituents can be substituted at any position.

[0448] In some implementations, L' is a connector key, -O-, or -NR. 12 "-

[0449] In some implementations, C is m can be 0, 1, or 2.

[0450] In some implementations, C is m can be 0, 1, or 2.

[0451] In some implementations, C is

[0452] In some implementations, C is

[0453] In some embodiments, R9is cyano, methyl, ethyl, trifluoromethyl, ethenyl, or ethynyl.

[0454] In some embodiments, R9is -CH3.

[0455] In some embodiments, A is A1, A2, A3, and A4are each independently N or CR8’.

[0456] In some embodiments, R8is NH2; A1is N, A2is CH, A3is CH, and A4is CH.

[0457] In some embodiments, A is

[0458] In some embodiments, A is

[0459] In some embodiments, A is R9is -CH3.

[0460] In some embodiments, A is u is 1 or 2.

[0461] In some embodiments, A is In some embodiments, A is

[0462] In some embodiments, A and R9are taken together to form a 5-7 membered heterocycloalkyl; said 5-7 membered heterocycloalkyl comprises 1-3 heteroatoms selected from N, O, S; said 5-7 membered heterocycloalkyl is unsubstituted or further substituted with 1-3 R8or R8’at any position.

[0463] In some embodiments, A and R9are taken together to form a 5-7 membered heterocycloalkyl is u is 1 or 2; R8’is H or C 1-4 alkyl.

[0464] In some embodiments, A and R9are taken together to form a 5-7 membered heterocycloalkyl is

[0465] In some embodiments, A and R4are taken together to form a 6-9 membered heterocycloalkyl; said 6-9 membered heterocycloalkyl comprises 1-3 heteroatoms selected from N, O, S; said 6-9 membered heterocycloalkyl is unsubstituted or further substituted with 1-3 R8or R8’at any position.

[0466] In some embodiments, A and R4are connected to each other to form a 6-9 membered heterocycloalkyl group, which is L" is a bond or -O-; R8and R8' are each independently H, C 1-4 alkyl or hydroxyl.

[0467] In some embodiments, A and R4are connected to each other to form a 6-9 membered heterocycloalkyl group, which is

[0468] In some embodiments, R1is F, R2is F, Cl or -CF3.

[0469] In some embodiments, R3is H or -OCH3.

[0470] In some embodiments, R4is H, -CH3, -CH2CH3, -OCH3, -CDH2, -CD2H, -CD3, -CHDCH3, -CD2CH3or -OCD3; preferably, R4is -CH3, -CDH2, -CD2H or -CD3.

[0471] In some embodiments, R5and R6are each independently H, D or methyl.

[0472] In some embodiments, the compound of Formula (I), stereoisomer or pharmaceutically acceptable salt thereof is a compound of Formula (I-1) or (I-2), stereoisomer or pharmaceutically acceptable salt thereof,

[0473] wherein R1, R3, R4, R5, R6, R9, R 11 , R 11 , R 12 , R 12 , L, L', m, B and U are as defined above.

[0474] In some embodiments, the compound of Formula (I), stereoisomer or pharmaceutically acceptable salt thereof is a compound of Formula (I-3) or (I-4), stereoisomer or pharmaceutically acceptable salt thereof,

[0475] wherein R1, R2, R4, R5, R6, R 10 , R 11 , R 11 , R 12 , R 12 and m are as defined above.

[0476] The present application provides a compound of Formula (II), stereoisomer or pharmaceutically acceptable salt thereof;

[0477] wherein A ring is a 6-membered heteroaromatic ring, and A1is N, CR 8a , M - N + -L-R or N + -L-R', A2is N or CR 8b , A3is N or CR 8c , A4is N or CR 8d , A1, A2, A3and A4are not simultaneously N;

[0478] B ring is

[0479] X is O, NR9or CR9R 9a ;

[0480] Y is N, CH or C-CN;

[0481] Z is N or C-CN;

[0482] L is C 1-4 alkylene;

[0483] M is halogen;

[0484] R is H, -OC(O)R b , -OC(O)N(R b )2, -OC(O)OR b , or 3-6 membered heterocycloalkyl substituted with 1-3 R c ;

[0485] R' is -OP(O)(OR b )O - ;

[0486] R1and R2are each independently H, halogen, C 1-3 alkyl, haloC 1-3 alkyl or C 1-3 alkoxy;

[0487] R3is H, halogen, cyano, cyclopropyl, C 1-3 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 2-4 alkynyl or C 2-4 alkynyl substituted with 1 cyclopropyl;

[0488] R4is H, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy; said C 1-6alkyl or C 1-6 alkoxy is unsubstituted or optionally substituted with one or more substituents selected from the group consisting of hydroxy, amino, halogen, deuterium, C 1-4 alkoxy and C 1-4 alkylamino is substituted at any position;

[0489] R5and R6are each independently H, D or C 1-6 alkyl; R5and R6are independent substituents, or R5and R6together with the carbon atom to which they are commonly attached form a C 3-6 cycloalkyl;

[0490] R7is 4-10 membered heterocycloalkyl or 4-10 membered heterocycloalkyl substituted with 1-3 R 11 substituted 4-10 membered heterocycloalkyl comprising 1-3 heteroatoms selected from N, O or S;

[0491] R8, R 8a , R 8b , R 8c , R 8d and R 8e are each independently H, halogen, oxo, cyano, amino, hydroxy, -R a , -OR b , -OC(O)R b , -OC(O)OR b , -NR a R b , -NHC(O)R b , -NHC(O)OR b , -NHP(O)(OR b )2, -S(O) 0-2 R b , -C(O)N(R b )2, -C(O)R b or -NH-L-R;

[0492] R9is H, cyano, C 1-6 alkyl, haloC 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl;

[0493] R8and R9are each independent substituents, or, R8and R9are mutually linked to form C 5-8 cycloalkyl or 5-8 membered heterocycloalkyl; the 5-8 membered heterocycloalkyl comprises 1-3 heteroatoms selected from N, O or S; the 5-8 membered heterocycloalkyl is unsubstituted or further substituted with 1-3 substituents selected from halogen, oxo, cyano, hydroxy, -R a , -OR b , -NR a Rb -S(O) 0-2 R b -C(O)N(R) b )2 and -C(O)R b The substituents can be substituted at any position;

[0494] R 9a For H or C 1-6 Alkyl groups; or, R9 and R 9a Interconnected to form C 3-5 cycloalkyl;

[0495] R 10 R 10a R 10b and R 10c Each can be independently represented by H, halogen, cyano, nitro, hydroxyl, amino, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, 4-6 membered heterocyclic alkyl or C 3-6 Cycloalkyl; the 4-6 membered heterocycloalkyl or C 3-6 The cycloalkyl group is unsubstituted, or selectively substituted with 1 to 3 alkyl groups selected from halogens, C4, and C5. 1-3 Alkyl and Halogenated C 1-3 The alkyl substituents can be substituted at any position;

[0496] R 10d For H, C 1-6 Alkyl, C 2-6 alkenyl or C 2-6 alkynyl group;

[0497] R 11 Halogen, hydroxyl, cyano, amino, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylene, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylene, Halogenated C 1-6 Alkoxy-C 1-4 Alkyl, C 3-8 cycloalkyl or 3-8 membered heterocyclic alkyl;

[0498] R a and R b H and C are independent of each other. 1-6 Alkyl, C 3-6cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 3-6 cycloalkyl 1-4 alkyl, 3-6 membered heterocycloalkyl 1-4 alkyl, phenyl 1-4 alkyl or 5-6 membered heteroaryl 1-4 alkyl; said R a and R b are independently unsubstituted or optionally substituted with 1-3 R c substituted at any position;

[0499] R c is halogen, oxo, cyano, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy or ester group;

[0500] t is 1, 2 or 3.

[0501] The present application provides a compound as shown in formula (II), a stereoisomer or a pharmaceutically acceptable salt thereof;

[0502] wherein, A ring is 6-membered heteroaromatic ring, and A1 is N, CR 8a , M - N + -L-R or N + -L-R’, A2 is N or CR 8b , A3 is N or CR 8c , A4 is N or CR 8d , A1, A2, A3 and A4 are not simultaneously N;

[0503] B ring is

[0504] X is O, NR9 or CR9R 9a ;

[0505] Y is N, CH or C-CN;

[0506] Z is N or C-CN;

[0507] L is C 1-4 alkylene;

[0508] M is halogen;

[0509] R is H, -OC(O)R b , -OC(O)N(R b )2, -OC(O)OR b or 1-3 Rc substituted 3-6 membered heterocycloalkyl;

[0510] R' is -OP(O)(OR b )O - ;

[0511] R1and R2are each independently H, halo, C 1-3 alkyl, haloC 1-3 alkyl, or C 1-3 alkoxy;

[0512] R3is H, halo, cyano, cyclopropyl, C 1-3 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 2-4 alkynyl, or C 2-4 alkynyl substituted with 1 cyclopropyl;

[0513] R4is H, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy; said C 1-6 alkyl or C 1-6 alkoxy is unsubstituted or optionally substituted with one or more substituents selected from the group consisting of hydroxyl, amino, halo, deuterium, C 1-4 alkoxy, and C 1-4 alkylamino at any position;

[0514] R5and R6are each independently H, D, or C 1-6 alkyl; R5and R6are independent substituents, or R5and R6together with the carbon atom to which they are both attached form a C 3-6 cycloalkyl;

[0515] R7is 4-10 membered heterocycloalkyl or 4-10 membered heterocycloalkyl substituted with 1-3 R 11 substituents, said 4-10 membered heterocycloalkyl comprising 1-3 heteroatoms selected from the group consisting of N, O, or S;

[0516] R8, R 8a , R 8b , R 8c , R 8d , and R 8e are each independently H, halo, oxo, cyano, amino, hydroxyl, -R a , -OR b , -OC(O)R b , -OC(O)OR b , -NR a R b , -NHC(O)R b , -NHC(O)ORb -NHP(O)(OR b )2, -S(O) 0-2 R b , -C(O)N(R b )2, -C(O)R b or -NH-L-R;

[0517] R9is H, cyano, C 1-6 alkyl, haloC 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl;

[0518] R8and R9are each an independent substituent, or R8and R9are mutually connected to form a C 5-8 cycloalkyl or 5-8 membered heterocycloalkyl; the 5-8 membered heterocycloalkyl contains 1-3 heteroatoms selected from N, O or S; the 5-8 membered heterocycloalkyl is unsubstituted or further substituted at any position with 1-3 substituents selected from halogen, oxo, cyano, hydroxy, -R a , -OR b , -NR a R b , -S(O) 0-2 R b , -C(O)N(R b )2and -C(O)R b ;

[0519] R 9a is H or C 1-6 alkyl; or R9and R 9a are mutually connected to form a C 3-5 cycloalkyl;

[0520] R 10 , R 10a , R 10b and R 10c are each independently H, halogen, cyano, nitro, hydroxy, amino, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy or C 3-6 membered cycloalkyl;

[0521] R 10d is H, C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl;

[0522] R 11 is halogen, hydroxy, cyano, amino, oxo, C 1-6alkyl, C 1-6 alkylene or haloC 1-6 alkyl;

[0523] R a and R b are each independently H, C 1-6 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 3-6 cycloalkylC 1-4 alkyl, 3-6 membered heterocycloalkylC 1-4 alkyl, phenylC 1-4 alkyl or 5-6 membered heteroarylC 1-4 alkyl; said R a and R b are each unsubstituted or optionally substituted with 1-3 R c substituted at any position;

[0524] R c halo, oxo, cyano, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkyl, haloC 1-4 alkoxy or ester;

[0525] t is 1, 2 or 3.

[0526] The present application provides a compound as shown in formula (II), a stereoisomer or a pharmaceutically acceptable salt thereof;

[0527] wherein, A ring is a 6-membered heteroaromatic ring, and A1 is N, CR 8a , M - N + -L-R or N + -L-R', A2 is N or CR 8b , A3 is N or CR 8c , A4 is N or CR 8d , A1, A2, A3 and A4 are not simultaneously N;

[0528] B ring is

[0529] X is O, NR9 or CR9R 9a ;

[0530] Y is N, CH or C-CN;

[0531] Z is N or C-CN;

[0532] L is C 1-4 alkylene;

[0533] M is halogen;

[0534] R is H, -OC(O)R b , -OC(O)N(R b )2, -OC(O)OR b , or 3-6 membered heterocycloalkyl substituted with 1-3 R c ;

[0535] R' is -OP(O)(OR b )O - ;

[0536] R1and R2are each independently H, halogen, C 1-3 alkyl, haloC 1-3 alkyl, or C 1-3 alkoxy;

[0537] R3is H, halogen, cyano, cyclopropyl, C 1-3 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 2-4 alkynyl, or C 2-4 alkynyl substituted with 1 cyclopropyl;

[0538] R4is H, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy; said C 1-6 alkyl or C 1-6 alkoxy is unsubstituted or optionally substituted at any position with one or more substituents selected from the group consisting of hydroxyl, amino, halogen, deuterium, C 1-4 alkoxy, and C 1-4 alkylamino;

[0539] R5and R6are each independently H, D, or C 1-6 alkyl; R5and R6are independent substituents, or R5and R6together with the carbon atom to which they are both attached form a C 3-6 cycloalkyl;

[0540] R7is 4-10 membered heterocycloalkyl or 4-10 membered heterocycloalkyl substituted with 1-3 R 11 ; said 4-10 membered heterocycloalkyl contains 1-3 heteroatoms selected from the group consisting of N, O, or S;

[0541] R8, R 8a , R 8b , R 8c , R 8d , and R 8e are each independently H, halogen, oxo, cyano, amino, hydroxyl, -Ra b b b a b b b b 0-2 b b b

[0542] R9is H, cyano, C 1-6 alkyl, haloC 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl;

[0543] R8and R9are each an independent substituent, or R8and R9are mutually connected to form a C 5-8 cycloalkyl or 5-8 membered heterocycloalkyl; the 5-8 membered heterocycloalkyl contains 1-3 heteroatoms selected from N, O or S; the 5-8 membered heterocycloalkyl is unsubstituted, or further substituted at any position with 1-3 substituents selected from halogen, oxo, cyano, hydroxy, -R a b a b 0-2 b b b

[0544] R 9a is H or C 1-6 alkyl; or R9and R 9a are mutually connected to form a C 3-5 cycloalkyl;

[0545] R 10 , R 10a , R 10b and R 10c are each independently H, halogen, cyano, nitro, hydroxy, amino, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy or C 3-6 membered cycloalkyl;

[0546] R​​​​​​​​​​​​​​​​​​​​​10d H, C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl;

[0547] R 11 halogen, hydroxyl, cyano, amino, oxo, C 1-6 alkyl, C 1-6 alkylene or haloC 1-6 alkyl;

[0548] R a and R b are each independently H, C 1-6 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 3-6 cycloalkylC 1-4 alkyl, 3-6 membered heterocycloalkylC 1-4 alkyl, phenylC 1-4 alkyl or 5-6 membered heteroarylC 1-4 alkyl; said R a and R b are each unsubstituted or optionally substituted with 1-3 R c substituted at any position;

[0549] R c halogen, oxo, cyano, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkyl, haloC 1-4 alkoxy or ester;

[0550] t is 1, 2 or 3.

[0551] The present application provides a compound as shown in formula (II), a stereoisomer or a pharmaceutically acceptable salt thereof;

[0552] wherein, A ring is 6-membered heteroaromatic ring, and A1 is N or CR 8a , A2 is N or CR 8b , A3 is N or CR 8c , A4 is N or CR 8d , A1, A2, A3 and A4 are not simultaneously N;

[0553] B ring is

[0554] X is O, NR9 or CR9R 9a ;

[0555] Y is N, CH or C-CN;

[0556] Z is N or C-CN;

[0557] R1and R2are each independently H, halo, C 1-3 alkyl, haloC 1-3 alkyl or C 1-3 alkoxy;

[0558] R3is H, halo, cyano, cyclopropyl, C 1-3 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 2-4 alkynyl or C 2-4 alkynyl;

[0559] R4is H, hydroxy, C 1-6 alkyl or C 1-6 alkoxy;

[0560] R5and R6are each independently H, D or C 1-6 alkyl;

[0561] R7is 4-10 membered heterocycloalkyl or 4-10 membered heterocycloalkyl substituted with 1 to 3 R 11 substituted with 1 to 3 R

[0562] R8, R 8a , R 8b , R 8c and R 8d are each independently H, halo, oxo, cyano, amino, hydroxy, -R a , -OR b , -NR a R b , -S(O) 0-2 R b , -C(O)N(R b )2 or -C(O)R b ;

[0563] R9is H, cyano, C 1-6 alkyl, haloC 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl;

[0564] R8and R9are each an independent substituent, or alternatively, R8and R9are connected to each other to form C 5-8cycloalkyl or 5-8 membered heterocycloalkyl; said 5-8 membered heterocycloalkyl comprises 1 to 3 heteroatoms selected from N, O or S; said 5-8 membered heterocycloalkyl is unsubstituted or further substituted with 1 to 3 substituents selected from the group consisting of halogen, oxo, cyano, hydroxy, -R a , -OR b , -NR a R b , -S(O) 0-2 R b , -C(O)N(R b )2and -C(O)R b at any position;

[0565] R 9a is H or C 1-6 alkyl; or, R9and R 9a are mutually linked to form C 3-5 cycloalkyl;

[0566] R 10 , R 10a , R 10b and R 10c are each independently H, halogen, cyano, nitro, hydroxy, amino, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy or C 3-6 cycloalkyl;

[0567] R 10d is H, C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl;

[0568] R 11 is halogen, hydroxy, cyano, amino, oxo, C 1-6 alkyl, C 1-6 alkylene or haloC 1-6 alkyl;

[0569] R a and R b are each independently C 1-6 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 3-6 cycloalkylC 1-4 alkyl, 3-6 membered heterocycloalkylC 1-4 alkyl, phenylC 1-4 alkyl or 5-6 membered heteroarylC 1-4 alkyl; said R a and R bThey are either unsubstituted or selectively selected from 1 to 3 groups: halogen, oxo group, cyano group, hydroxyl group, C. 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl or halogenated C 1-4 The alkoxy group can be substituted at any position;

[0570] t can be 1, 2, or 3.

[0571] The present invention provides a compound of formula (II), its stereoisomer or pharmaceutically acceptable salt;

[0572] In ring A, A1 represents N and M. - N + -LR or N + -L-R', A2 is CH, A3 is CH, A4 is CH;

[0573] Ring B is

[0574] X is CR9R 9a ;

[0575] Y is N;

[0576] Z is either N or C-CN;

[0577] L is C 1-4 Alkylene;

[0578] M - It is an anion;

[0579] R is H, -OC(O)R b -OC(O)N(R) b 2. -OC(O)OR b , by 1 to 3 R c Substituted 3-6 membered heterocyclic alkyl groups or substituted with 1-3 R groups c Substituted 3-6 heteroaryl groups;

[0580] R' is -OP(O)(OR) b )O - ;

[0581] R1 and R2 are independently H, halogen, and C, respectively. 1-3 Alkyl, Halogenated C 1-3 Alkyl or C 1-3 Alkoxy;

[0582] R3 is H or a halogen;

[0583] R4 is C 1-6 Alkyl; the C 1-6alkyl is unsubstituted or optionally substituted with one to three substituents selected from the group consisting of hydroxy, amino, halogen, deuterium, C 1-4 alkoxy and C 1-4 alkyl; R5and R6are independent substituents or R5and R6together with the carbon atom to which they are both attached form a C

[0584] R5and R6are each independently H, deuterium or C 1-6 alkyl; R5and R6are independent substituents or R5and R6together with the carbon atom to which they are both attached form a C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl or C 1-4 alkylene; said C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl or C 1-4 alkyl is unsubstituted or optionally substituted with one to three substituents selected from the group consisting of halogen, cyclopropyl, C 1-3 alkyl and halogenated C 1-3 alkyl; R5and R6are independent substituents or R5and R6together with the carbon atom to which they are both attached form a C

[0585] R7is C 1-6 alkyl, 4-10 membered heterocycloalkyl or 1-3 R 11 substituted 4-10 membered heterocycloalkyl comprising 1-3 heteroatoms selected from N, O or S;

[0586] R8and R 8e are each independently -NH2, -NHC(O)R b , -NHC(O)OR b , -NHP(O)(OR b )2 or -NH-L-R;

[0587] R9is C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl;

[0588] R 9a is H, deuterium or C 1-6 alkyl;

[0589] R 10 and R 10c are each independently H, halogen, cyano, nitro, hydroxy, amino, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy or C 3-6 membered cycloalkyl;

[0590] R 10a is C 1-6 alkyl, C 1-6 alkoxy, halogenated C1-6 alkyl or C 3-6 cycloalkyl;

[0591] R 11 halogen, hydroxyl, cyano, amino, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylene, haloC 1-6 alkyl, hydroxylC 1-6 alkyl, haloC 1-6 alkoxy, haloC 1-6 alkylene, haloC 1-6 alkoxy-C 1-4 alkyl, C 3-8 cycloalkyl or 3-8 membered heterocycloalkyl;

[0592] R b H, C 1-6 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 3-6 cycloalkylC 1-4 alkyl, 3-6 membered heterocycloalkylC 1-4 alkyl, phenylC 1-4 alkyl or 5-6 membered heteroarylC 1-4 alkyl; said R b is unsubstituted or optionally substituted with 1-3 R c substituted at any position;

[0593] R c halogen, oxo, cyano, hydroxyl, nitro, C 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkyl, haloC 1-4 alkoxy or ester;

[0594] t is 1, 2 or 3.

[0595] The present application provides a compound as shown in formula (II), a stereoisomer or a pharmaceutically acceptable salt thereof;

[0596] wherein, in the A ring, A1 is N, A2 is CH, A3 is CH, and A4 is CH;

[0597] B ring is

[0598] X is CHR9;

[0599] Y is N;

[0600] R1 and R2 are each independently halogen, C 1-3alkyl, haloC 1-3 alkyl or C 1-3 alkoxy;

[0601] R3is H;

[0602] R4is methyl; said methyl is unsubstituted or optionally substituted with one to three substituents selected from the group consisting of hydroxy, amino, halogen, deuterium, C 1-4 alkoxy and C 1-4 alkylamino at any position;

[0603] R5and R6are each independently H, deuterium or C 1-6 alkyl; R5and R6are independent substituents or R5and R6together with the carbon atom to which they are both attached form a C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl;

[0604] R7is 8-10 membered heterocycloalkyl comprising one to three heteroatoms selected from N, O or S, optionally substituted with one to three R 11 substituents;

[0605] R9is C 1-6 alkyl, haloC 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl;

[0606] R 10 , R 10a and R 10c are each independently H, halogen, cyano, nitro, hydroxy, amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthio, haloC 1-6 alkyl, haloC 1-6 alkoxy, 3-6 membered heterocycloalkyl or C 3-6 cycloalkyl; said 3-6 membered heterocycloalkyl or C 3-6 cycloalkyl is unsubstituted or optionally substituted with one to three substituents selected from the group consisting of halogen, C 1-3 alkyl and haloC 1-3 alkyl at any position;

[0607] R 11 is halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylene, haloC 1-6 alkyl, haloC 1-6 alkylene, hydroxyC 1-6 alkyl, haloC 1-6alkoxy, halo-C 1-6 alkoxy-C 1-4 alkyl, C 3-8 cycloalkyl or 3-8 membered heterocycloalkyl;

[0608] t is 1, 2 or 3;

[0609] Also, the compounds of Formula (I) do not include any of the following structures:

[0610] All embodiments of the compounds of Formula (II) described below and combinations of the variables are included within the scope of the structural formula of Formula (II).

[0611] In some embodiments, the compounds of Formula (II), stereoisomers or pharmaceutically acceptable salts thereof, the definitions of the moieties are as described below, and the definitions of the remaining moieties are as described in any other aspect (hereinafter referred to as “in some embodiments”):

[0612] In some embodiments, A1is N, A2is N or CR 8b , A3is CR 8c , A4is CR 8d .

[0613] In some embodiments, A1is N, A2is CR 8b , A3is N or CR 8c , A4is CR 8d .

[0614] In some embodiments, A1is N, A2is CR 8b , A3is CR 8c , A4is N or CR 8d .

[0615] In some embodiments, R8is NH2; A1is N, A2is N or CH, A3is CH, A4is CH.

[0616] In some embodiments, R8is NH2; A1is N, A2is CH, A3is N or CH, A4is CH.

[0617] In some embodiments, R8is NH2; A1is N, A2is CH, A3is CH, A4is N or CH.

[0618] In some embodiments, R8is NH2; A1is N, A2is CH, A3is CH, A4is CH.

[0619] In some embodiments, R8is -NR a R b , -NHC(O)Rb -NHC(O)OR b -NHP(O)(OR b )2; A1is N, A2is CH, A3is CH, and A4is CH.

[0620] In some embodiments, M - is a pharmaceutically acceptable anion, preferably a halide or an acid radical; including but not limited to chloride, bromide, fluoride, trifluoroacetate, acetate, sulfate, bisulfate, and the like.

[0621] In some embodiments, M is chloride, fluoride, or bromide; preferably M is chloride.

[0622] In some embodiments, L is -CH2- or -CH(CH3)-; preferably L is -CH2-,

[0623] In some embodiments, R 10 , R 10a , R 10b , and R 10c are each independently H, F, Cl, -CN, -NO2, -OH, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, or cyclopropyl.

[0624] In some embodiments, R 10d is H, methyl, ethyl, ethenyl, or ethynyl.

[0625] In some embodiments, the B ring is R 10 is as previously described.

[0626] In some embodiments, the B ring is R 10 , R 10a , R 10b , and R 10c are as previously described.

[0627] In some embodiments, the B ring is R 10 is as previously described.

[0628] In some embodiments, the B ring is any one of the following structures:

[0629] In some embodiments, R5and R6are each independently H, D, or methyl.

[0630] In some embodiments, R5and R6together with the carbon atom to which they are both attached form

[0631] In some embodiments, R7is R7is unsubstituted or optionally substituted with 1-3 R 11 substituted at any position, R 11 is halogen, hydroxyl, cyano, amino, oxo, C 1-6 alkyl, C 1-6 alkylene, or halogenated C 1-6 alkyl.

[0632] In some embodiments, R7is R7is unsubstituted or optionally substituted with 1-3 R 11 substituted at any position, R 11 is fluorine, deuterium, methyl, or methylene.

[0633] In some embodiments, R7is R7is unsubstituted or optionally substituted with 1-3 R 11 substituted at any position, R 11 is fluorine, deuterium, methyl, or methylene.

[0634] In some embodiments, R7is R 11 is fluorine, methylene,

[0635] In some embodiments, R7is

[0636] In some embodiments, R7is

[0637] In some embodiments, X is CR9R 9a ; R9is cyano, methyl, ethyl, trifluoromethyl, vinyl, or ethynyl; R 9a is H.

[0638] In some embodiments, X is CHR9; R9is methyl.

[0639] In some embodiments, X is NR9; R9is methyl.

[0640] In some embodiments, X is O.

[0641] In some embodiments, R1is F, R2is Cl, and R3is F.

[0642] In some embodiments, R1is F, R2is Cl, and R3is H.

[0643] In some embodiments, R1is F, R2is CF3, and R3is H.

[0644] In some embodiments, R1is F, R2is Cl, and R3is F or H; the B ring is

[0645] In some embodiments, R1is F, R2is CF3, and R3is H; the B ring is

[0646] In some embodiments, R1is F, R2is Cl, and R3is H; R4is -CDH2, -CD2H, or -CD3; the B ring is

[0647] In some embodiments, R1is F, R2is Cl, and R3is H; the B ring is R7is

[0648] In some embodiments, R4is H, -CH3, -CH2CH3, -OCH3, -OH, -CDH2, -CD2H, -CD3, -CHDCH3, -CD2CH3, or -OCD3.

[0649] In some embodiments, R4is H or -CH3.

[0650] In some embodiments, R5and R6are each independently H, D, or methyl.

[0651] In some embodiments, the compound of Formula (II) does not include any of the following structures:

[0652] In some embodiments, the compound of Formula (II), stereoisomer, or pharmaceutically acceptable salt thereof, is a compound of Formula (IIA) or (IIB), stereoisomer, or pharmaceutically acceptable salt thereof;

[0653] wherein A1, the B ring, Y, R1, R2, R3, R4, R5, R6, R7, R8, and t are as previously described.

[0654] In some embodiments, the compound of Formula (II), stereoisomer, or pharmaceutically acceptable salt thereof, is a compound of Formula (III), (IV), (V), (VI), (VII), or (VIII), stereoisomer, or pharmaceutically acceptable salt thereof;

[0655] Among them, Y, A1, A2, A3, A4, R1, R2, R3, R4, R5, R6, R7, R8, R 8b R 8c R 8d The definitions of rings R9 and B are as described above.

[0656] In some implementations, R8 is -NH2.

[0657] In some implementations, A1 is N; R8 is -NH2.

[0658] In some implementation schemes, R 8b For H.

[0659] In some implementation schemes, R 8c For H.

[0660] In some implementation schemes, R 8d For H.

[0661] In some implementations, R8 is NH2; A1 is N, A2 is CH, A3 is CH, and A4 is CH.

[0662] In some embodiments, the compound shown in formula (I) is any one of the following compounds:

[0663] A transisomer of [the compound] has a short retention time under the following analytical conditions: Analytical column: Waters ACQUITY UPLC BEH Shield RP182.1*100 mm, 1.7 μm; flow rate: 0.4 mL / min; mobile phase A: 5 mM potassium dihydrogen phosphate buffer (pH = 2.5); mobile phase B: acetonitrile; gradient elution: mobile phase B from 10% to 40% for 5 min, mobile phase B from 40% to 90% for 2 min, mobile phase B held at 90% for 6 min, and mobile phase B from 90% to 10% for 2 min; preferably, under these analytical conditions, the short-retention compound has a retention time of 4.420 min.

[0664] A transisomer of [the compound] exhibits a longer retention time under the following analytical conditions: The analytical column is a Waters ACQUITY UPLC BEH Shield RP182.1*100 mm, 1.7 μm; the flow rate is 0.4 mL / min; mobile phase A is 5 mM potassium dihydrogen phosphate buffer (pH = 2.5), and mobile phase B is acetonitrile; gradient elution is performed with mobile phase B from 10% to 40% for 5 min, mobile phase B from 40% to 90% for 2 min, mobile phase B held at 90% for 6 min, and mobile phase B from 90% to 10% for 2 min; preferably, under these analytical conditions, the longer retention time of the compound is 5.020 min.

[0665] A transisomer of [the compound] has a short retention time under the following analytical conditions: the analytical column is a Waters ACQUITY UPLC BEH Shield RP182.1*100 mm, 1.7 μm; the flow rate is 0.4 mL / min; mobile phase A is 5 mM potassium dihydrogen phosphate buffer (pH = 2.5), and mobile phase B is acetonitrile; gradient elution is performed with mobile phase B from 10% to 40% for 5 min, mobile phase B from 40% to 90% for 2 min, mobile phase B held at 90% for 6 min, and mobile phase B from 90% to 10% for 2 min; preferably, under the analytical conditions, the retention time of the compound with the shortest retention time is 4.403 min;

[0666] A transisomer of [the compound] exhibits a longer retention time under the following analytical conditions: The analytical column is a Waters ACQUITY UPLC BEH Shield RP182.1*100 mm, 1.7 μm; the flow rate is 0.4 mL / min; mobile phase A is 5 mM potassium dihydrogen phosphate buffer (pH = 2.5), and mobile phase B is acetonitrile; gradient elution is performed with mobile phase B from 10% to 40% for 5 min, mobile phase B from 40% to 90% for 2 min, mobile phase B held at 90% for 6 min, and mobile phase B from 90% to 10% for 2 min; preferably, under these analytical conditions, the longer retention time of the compound is 5.012 min.

[0667] If the compound of formula (I) described in any embodiment of this invention contains a charged group, the suitable anion is selected from organic or inorganic acids. Such anions include halide ions (e.g., chloride, bromide, fluoride, iodide), sulfate, phosphate, acetate, succinate, citrate, lactate, maleate, fumarate, glutamate, glutarate, tartrate, salicylate, methanesulfonate, benzenesulfonate, sorbate, benzoate, etc.

[0668] The stereochemical definitions and rules used in this invention generally follow those of S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds,” John Wiley & Sons, Inc., New York, 1994. The term “stereoisomer” as used in this invention refers to optical isomers, geometric isomers, or inhibited isomers, and combinations thereof. These stereoisomers can be separated, purified, and enriched by asymmetric synthesis, chromatography, or chiral separation methods (including but not limited to thin-layer chromatography, rotational chromatography, column chromatography, gas chromatography, high-performance liquid chromatography, etc.), and can also be obtained through chiral resolution by bonding (chemical bonding, etc.) or salt formation (physical bonding, etc.) with other chiral compounds. The term “single stereoisomer” means that the mass content of one stereoisomer of the compound is not less than 90%, preferably not less than 95%, relative to all stereoisomers of the compound. Individual stereoisomers and mixtures thereof are included within the scope of this invention. This invention encompasses all combinations and subsets of stereoisomers of all specific groups defined above. The "stereoisomers" referred to in this invention are preferably optical isomers and / or transisomers.

[0669] The term "optical isomers" includes enantiomers, diastereomers, and mixtures thereof. For example, racemic mixtures. An enantiomer is a non-overlapping, mirror-image isomer of a compound. A diastereomer is a stereoisomer with two or more chiral, neutral molecules that are not mirror images of each other. Diastereomers typically possess different physical properties, such as melting point, boiling point, spectral properties, and reactivity.

[0670] The term "geometric isomers" includes cis-trans isomers. This is a stereoisomerism phenomenon present in certain double-bonded or cyclic compounds. Due to the presence of double bonds or rings, the free rotation of these molecules is hindered, resulting in two different stereoisomers, called cis and trans isomers, respectively.

[0671] The term "restricted rotation isomer" refers to stereoisomers resulting from impeded rotation around single bonds. These are conformational isomers that can be separated from each other due to energy differences caused by stereostrain or other contributing factors. For example, structures as shown in formula (IIIA) or (IIIB):

[0672] Among them, R1, R2, R3, R4, R9, R 10 The definitions of A, C and Y are as described above; when R1 and R2 are not H, the rotation of the α bond is hindered, resulting in the hindered rotation isomers shown in equations (IIIA) and (IIIB).

[0673] The present invention also provides a method for preparing the stereoisomer or pharmaceutically acceptable salt of the compound shown in formula (I), which is any of the following methods:

[0674] Method 1: In a solvent, the compound shown in formula (IA) and X-1 undergo a condensation reaction under basic conditions to obtain the compound shown in formula (I).

[0675] General Reaction Formula 1

[0676] The definitions of R1, R3, R4, R9, U, V, A, B, C, and Y are as described above. In Method 1, the solvent is preferably N,N-dimethylformamide or dimethyl sulfoxide; the base is preferably 4-dimethylaminopyridine or N,N-diisopropylethylamine; the condensing agent is preferably benzotriazol-1-yl-oxytripyrrolylphosphine hexafluorophosphate; the reaction temperature is preferably 0–35°C; and the reaction time is preferably 0.5–6 hours.

[0677] In some embodiments, in method 1, when B has an amino group, the amino group can be protected with a tert-butoxycarbonyl protecting group. If the above-mentioned amino protecting group is present, a further deprotection step is required to obtain the compound shown in formula (I). Preferably, the deprotection reaction is carried out in a dichloromethane / trifluoroacetic acid system.

[0678] Method 2: In a solvent, the compound shown in formula (IB) and X-2 or X-3 are coupled via a Suzuki coupling reaction to yield the compound shown in formula (I).

[0679] General Reaction Formula 2

[0680] Wherein, U is N or CR2, V is C; R1, R2, R3, R4, R9, A, B, C and Y are defined as described above. In Method 2, the conditions for the Suzuki coupling reaction are conventional Suzuki coupling reaction conditions in the art, preferably in a solvent under alkaline conditions, the compound shown in formula (IB) and X-2 or X-3 undergo a Suzuki coupling reaction in the presence of a catalyst to obtain the compound shown in formula (I). The solvent is preferably 1,4-dioxane, toluene, or N,N-dimethylformamide; the base is preferably cesium carbonate, sodium carbonate, potassium phosphate or cesium fluoride; the catalyst is preferably tetrakis(triphenylphosphine)palladium, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex, 1,1'-bis(di-tert-butylphosphine)ferrocene dichloropalladium or bis(diphenylphosphine phenyl ether)palladium dichloride (II); the reaction temperature is preferably 80-110°C; the reaction time is preferably 3-24 hours.

[0681] Method 3: In a solvent, the compound shown in formula (IC) and X-4 or X-5 are reacted under basic conditions via a nucleophilic substitution reaction to give the compound shown in formula (I).

[0682] General Reaction Formula 3

[0683] Among them, R1, R3, R4, R5, R6, R7, R9, R 12 R 12 The definitions of ', U, V, A, B, C, Y, and m are as described above. In Method 3, the reaction conditions for the nucleophilic substitution reaction are conventional nucleophilic substitution reaction conditions in the art. The solvent is preferably tetrahydrofuran, N,N-dimethylformamide, or dimethylacetamide; the base is preferably sodium hydrogen, potassium tert-butoxide, or N,N-diisopropylethylamine; the reaction temperature is preferably 0–80°C; and the reaction time is preferably 0.5–6 hours.

[0684] Method 4: In a solvent, the compound shown in formula (IB) and X-6 were reacted via a Negishi cross-coupling reaction to yield the compound shown in formula (I).

[0685] General Reaction Formula 4

[0686] Wherein, U is N or CR2, V is C; P is a leaving group, preferably a halogen (preferably I, Br or Cl) or a trifluoromethanesulfonate; R1, R2, R3, R4, R9, A, B, C and Y are defined as described above. In Method 4, the Negishi cross-coupling reaction is carried out under conventional Negishi cross-coupling reaction conditions in the art, preferably in a solvent, in the presence of a zinc reagent, the compound shown in formula (IB) is obtained by the Negishi cross-coupling reaction via an organozinc intermediate and X-6 in the presence of a catalyst to the compound shown in formula (I). The solvent is preferably tetrahydrofuran; the zinc reagent is preferably an isopropyl magnesium chloride-lithium chloride / zinc chloride system; the catalyst is preferably tetra(triphenylphosphine)palladium; the reaction temperature is preferably -70℃ to 85℃; the reaction time is preferably 0.5 to 5 hours.

[0687] In the above method, when an amino group, hydroxyl group, or carboxyl group is present in X-1 to X-6, the amino group, hydroxyl group, or carboxyl group can be protected by a protecting group to avoid any side reactions. If the above-mentioned amino protecting group, hydroxyl protecting group, or carboxyl protecting group is present, a subsequent deprotection step is required to obtain the compound shown in formula (I). Any suitable amino protecting group, such as tert-butyloxycarbonyl (Boc), can be used to protect the amino group. If Boc is used as the protecting group, the subsequent deprotection reaction can be carried out under standard conditions, such as a p-toluenesulfonic acid / methanol system, a dichloromethane / trifluoroacetic acid system, an organic solution system of hydrogen chloride (organic solutions include, but are not limited to, diethyl ether solution, 1,4-dioxane solution, methanol solution, ethanol solution, isopropanol solution), or a trimethylsilyl trifluoromethanesulfonate / 2,6-dimethylpyridine / dichloromethane system; any suitable hydroxyl protecting group, such as benzyl, methoxymethyl (MOM-), or organosilicon groups (including, but not limited to, tert-butyldimethyl) Silicon groups (TBS-), tert-butyldiphenylsilyl (TBDPS-), trimethylsilyl (TMS-), and triisopropylsilyl (TIPS-) can all be used to protect hydroxyl groups. Subsequent deprotection reactions can be performed under standard conditions. For example, benzyl groups can be deprotected using a palladium on carbon / hydrogen system; methoxymethyl groups can be deprotected using an organic solution system containing hydrogen chloride (organic solutions include, but are not limited to, diethyl ether, 1,4-dioxane, methanol, ethanol, and isopropanol); and organosilicon groups can be deprotected using a tetrabutylammonium fluoride / tetrahydrofuran system. Any suitable carboxyl protecting group, such as those forming carboxylic acid ester groups (e.g., methyl carboxylate, ethyl carboxylate), can be used to protect carboxyl groups. Subsequent deprotection reactions can be performed under standard conditions, such as using sodium hydroxide, potassium hydroxide, or lithium hydroxide in tetrahydrofuran, water, and / or methanol solvents. The above deprotection reaction is preferably carried out in the last step. For example, if the compound obtained by reaction formula 1 contains an amino protecting group, the final compound as shown in formula (I) can be obtained by further amino deprotection reaction.

[0688] The compounds shown in formula (I), their stereoisomers or pharmaceutically acceptable salts, can be synthesized by conventional chemical methods.

[0689] Generally, salts can be prepared by reacting a free base or acid with an equisional or excess amount of an acid (inorganic or organic) or a base (inorganic or organic) in a suitable solvent or solvent combination.

[0690] The present invention further provides an antibody-drug conjugate comprising a compound as shown in formula (I) or formula (II), wherein the stereoisomer or pharmaceutically acceptable salt thereof is the drug moiety.

[0691] The present invention further provides the use of compounds of formula (I) or formula (II), their stereoisomers or pharmaceutically acceptable salts, in the preparation of antibody-drug conjugates.

[0692] The present invention further provides the use of compounds of formula (I) or formula (II), the stereoisomers of which or pharmaceutically acceptable salts are used as pharmaceutical payloads in the preparation of antibody-drug conjugates.

[0693] In some embodiments, in the antibody-drug conjugate, the stereoisomer or pharmaceutically acceptable salt of the compound shown in formula (I) or (II) is conjugated to the antibody via a linker.

[0694] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of an active ingredient and a pharmaceutically acceptable excipient; said active ingredient comprising one or more of a compound as shown in formula (I) or formula (II), its stereoisomers, or a pharmaceutically acceptable salt.

[0695] The active ingredient in the pharmaceutical composition may also include other cancer therapeutic agents.

[0696] The present invention also provides the use of the compounds shown in formula (I) or formula (II), their stereoisomers or pharmaceutically acceptable salts, or the antibody-drug conjugates, or the pharmaceutical compositions, in the preparation of KRAS mutant inhibitors; wherein the KRAS mutants include, but are not limited to: KRAS G12A, G12C, G12D, G12V, G12R, G12S, G13D and / or Q61H; the KRAS mutants are preferably KRAS G12C, G12D, G12V and / or G12A.

[0697] The present invention also provides the use of the compounds shown in formula (I) or formula (II), their stereoisomers or pharmaceutically acceptable salts, or the antibody-drug conjugates, or the pharmaceutical compositions, in the preparation of medicaments for treating KRAS mutant-mediated diseases. The related diseases are cancer. Further, the cancer is cancer in which the tumor cell DNA contains a KRAS gene with a KRAS mutation; preferably, the cancer is cancer in which the tumor cell DNA contains a KRAS gene with KRAS G12C, G12D, G12V, and / or G12A mutations.

[0698] The present invention also provides the use of the compounds shown in formula (I) or formula (II), their stereoisomers or pharmaceutically acceptable salts, or the pharmaceutical compositions thereof in the preparation of therapeutic and / or alleviating cancer remedies.

[0699] The present invention also provides the use of the compounds shown in formula (I) or formula (II), their stereoisomers or pharmaceutically acceptable salts, or the pharmaceutical compositions thereof in the preparation of medicaments for treating and / or alleviating pancreatic cancer, endometrial cancer, lung cancer (e.g., small cell lung cancer, non-small cell lung cancer), rectal cancer and / or colorectal cancer.

[0700] The present invention also provides the use of the compounds shown in formula (I) or formula (II), their stereoisomers or pharmaceutically acceptable salts, or the pharmaceutical compositions thereof in the treatment of cancer.

[0701] The present invention also provides the use of the compounds shown in formula (I) or formula (II), their stereoisomers or pharmaceutically acceptable salts, or the pharmaceutical compositions thereof in the treatment and / or relief of pancreatic cancer, gastric cancer, ovarian cancer, breast cancer, head and neck cancer, liver cancer, malignant glioma, endometrial cancer, lung cancer (e.g., small cell lung cancer, non-small cell lung cancer), small bowel cancer, rectal cancer and / or colorectal cancer.

[0702] The present invention further provides a method of treating cancer with the compound of formula (I) or formula (II), its stereoisomer or pharmaceutically acceptable salt, or the pharmaceutical composition thereof, comprising: administering a therapeutically required dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof, to a mammal.

[0703] The mammal in question is preferably a human.

[0704] The present invention further provides compounds of formula (I) or formula (II), their stereoisomers or pharmaceutically acceptable salts, or pharmaceutical compositions thereof, which may be used in combination with one or more other types of therapeutic agents and / or treatments for the treatment and / or relief of diseases mediated by KRAS mutants. The KRAS mutant-mediated diseases are cancers. Further, the cancer is a cancer in which the tumor cell DNA contains a KRAS gene with a KRAS mutation; preferably, the cancer is a cancer in which the tumor cell DNA contains a KRAS gene with mutations in KRAS G12C, G12D, G12V, and / or G12A.

[0705] In this invention, the cancers include metastatic and non-metastatic cancers, as well as familial and incidental cancers, and may also include solid tumors and non-solid tumors.

[0706] Specific examples of the cancers mentioned may include, but are not limited to: eye cancer, bone cancer, lung cancer (including small cell lung cancer and non-small cell lung cancer), stomach cancer, pancreatic cancer, breast cancer, prostate cancer, brain cancer (including malignant glioma and medulloblastoma), ovarian cancer, bladder cancer, cervical cancer, endometrial cancer, fallopian tube cancer, peritoneal cancer, testicular cancer, kidney cancer (including adenocarcinoma and nephroblastoma), oral cancer (including squamous cell carcinoma), tongue cancer, laryngeal cancer, nasopharyngeal cancer, head and neck cancer, colon cancer, small intestine cancer, and rectal cancer. Cancer, appendix cancer, parathyroid cancer, thyroid cancer, esophageal cancer, gallbladder cancer, bile duct cancer, liver cancer, sarcoma, skin cancer, lymphocytic leukemia (including acute lymphoblastic leukemia, lymphoma, myeloma, chronic lymphocytic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, T-cell chronic lymphocytic leukemia, B-cell chronic lymphocytic leukemia), myeloid-associated leukemia (including acute myeloid leukemia, chronic myeloid leukemia), and AIDs-associated leukemia, one or more of these.

[0707] Unless otherwise stated, wedge-shaped solid lines are used in the specification and claims of this invention. and wedge-shaped dashed key The absolute configuration of the center of a solid is represented by a straight solid line key. and straight dashed key To indicate relative configurations, for example, using To indicate trans-3,4-disubstituted pyrrolidinyl groups, use It indicates a cis-3,4-disubstituted pyrroleyl group.

[0708] Unless otherwise stated, the following terms appearing in this specification and claims have the following meanings:

[0709] Term "C" t-q "" refers to the range from the starting point to the ending point, where t and q, and all points within the range, are integers representing the number of carbon atoms, for example, C. 1-4 This indicates that the number of carbon atoms is 1, 2, 3, or 4; C 1-6 This indicates that the number of carbon atoms is 1, 2, 3, 4, 5, or 6; C 3-8 This indicates that the number of carbon atoms is 3, 4, 5, 6, 7, or 8; C t-q It can be used in conjunction with any group containing carbon atoms to specify the number of carbon atoms, such as C. 1-6 Alkyl, C 1-4 Alkylene, C 3-8 cycloalkyl, C 6-10 Aryl, C 1-4 Alkoxy, C 3-8 cycloalkyl C 1-4 Alkyl groups, etc.

[0710] The term "alkyl" refers to a saturated straight-chain or branched hydrocarbon group containing 1-20 carbon atoms, preferably 1-10 carbon atoms, more preferably 1-8, 1-6, 1-4, or 1-3 carbon atoms. Representative examples of alkyl groups include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, n-pentyl, n-hexyl, n-heptyl, octyl, nonyl, decyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, 1-ethyl-2-methylpropyl, and 1,1,2-trimethylpropyl. 1,1-Dimethylbutyl, 1,2-Dimethylbutyl, 2,2-Dimethylbutyl, 1,3-Dimethylbutyl, 2,3-Dimethylbutyl, 2-Ethylbutyl, 2-Methylpentyl, 3-Methylpentyl, 4-Methylpentyl, 4,4-Dimethylpentyl, 2-Methylhexyl, 3-Methylhexyl, 4-Methylhexyl, 5-Methylhexyl, 2,3-Dimethylpentyl, 2,4-Dimethylpentyl, 2,2-Dimethylpentyl, 3,3-Dimethylpentyl, 2-Ethylpentyl, 3-Ethylpentyl, 2,2,4-Trimethylpentyl, Undecyl, Dodecyl, and their various isomers, etc.

[0711] The term "alkylene" refers to a saturated straight-chain or branched non-bridged divalent alkyl group containing 1-20 carbon atoms, preferably 1-6 carbon atoms, more preferably 1-4 or 1-3 carbon atoms. The alkylene group can be a substituent or a linking group. For example, when the alkylene group is a substituent, it includes, but is not limited to: =CH2, =CHCH3, =CHCH2CH3, etc.; when the alkylene group is a linking group, it includes, but is not limited to: -CH2-, -CH(CH3)-, -CH2CH2-, -CH2CH2CH2-, etc.

[0712] The term "cycloalkyl" refers to a monocyclic or polycyclic group containing 3-20 carbon atoms, either saturated or partially unsaturated (containing one or two double bonds). "Cycloalkyl" is preferably a 3-10 member monocyclic alkyl group, more preferably a 3-8 or 3-6 member monocyclic alkyl group. Representative examples of monocyclic cycloalkyl groups include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, 1,3-cyclohexadienyl, etc. "Polycyclic cycloalkyl" includes "bridged cycloalkyl," "fused cycloalkyl," and "spirocycloalkyl," such as tetrahydronaphthyl, 2,3-dihydroindenyl, etc. Monocyclic or polycyclic cycloalkyl groups can be linked to a parent molecule via any carbon atom on the ring.

[0713] The term "heterocyclic alkyl" refers to a non-aromatic cyclic group consisting of a carbon atom and heteroatoms selected from nitrogen, oxygen, sulfur, or boron, which is saturated or partially unsaturated (containing one or two double bonds). This cyclic group can be monocyclic or polycyclic, preferably monocyclic, bicyclic, or tricyclic. In this invention, the number of heteroatoms in the "heterocyclic" or "heterocyclic alkyl" is preferably 1, 2, 3, or 4, and the nitrogen, sulfur, or boron atom in the heterocyclic alkyl may optionally be oxidized (=O). The carbon atom may be further oxidized (=O) or thiolated (=S). The nitrogen atom may optionally be further substituted by other groups to form a tertiary amine or quaternary ammonium salt. "Heterocyclic alkyl" is preferably a 3-10 member monocyclic heterocyclic alkyl, more preferably a 3-8 member, 3-6 member, 4-8 member, 6-10 member, 6-8 member, 5-7 member, 5 member, 6 member, 7 member, or 8 member monocyclic heterocyclic alkyl. Representative examples include, but are not limited to: aziridinyl, aziridine, 2-oxoaziridine, tetrahydrofuran-2-yl, morpholinyl, 3-oxomorpholinyl, thiomorpholinyl, 3-oxothiomorpholinyl, thiomorpholin-S-oxide-4-yl, piperidinyl, 2-oxopiperidinyl, pyrrolyl, 2-oxopyrrolyl, piperazinyl, homopiperazinyl, 1,4-dioxanecycloyl, pyranyl, tetrahydropyranyl, tetrahydrothiopheneyl, dihydroimidazolyl, 2,3-dihydrofuranyl, 2,5-dihydrofuranyl, dihydropyrazolyl, 2,3-dihydro-1H-pyrrolyl, 2,5-dihydro-1H-pyrrolyl, 1,1-tetrahydro-2H-thiaranyl, 1-imino-1-tetrahydro-2H-thiaranyl, 1,1-tetrahydro-2H-thiaranyl Fenyl, 1-imino-1-tetrahydrothiopheneyl, 1,1-dioxo-3,4-dihydro-2H-thioranyl, 1-imino-1-dioxo-3,4-dihydro-2H-thioranyl, 1,1-dioxo-2,3-dihydrothiopheneyl, 1-imino-1-dioxo-2,3-dihydrothiopheneyl, 1,3-dioxopentyl, 1,3-dioxacyclopentenyl, 1 3-Oxythiapentyl, 1,3-Oxythiapentenyl, 1,4-Dioxa-2-hexenyl, 3,4-Dihydro-2H-pyranyl, 3,6-Dihydro-2H-pyranyl, 1,2,3,4-Tetrahydropyrazinyl, 1,2,3,4-Tetrahydropyridyl, 1,2,3,6-Tetrahydropyridyl, 2-Oxooxazolyl, 1,4-Oxazonylheptyl, etc. "Polycyclic heterocyclic alkyl" includes "fused heterocyclic groups," "spirocyclic groups," and "bridged heterocyclic groups." "Fused heterocyclic groups" include monocyclic heterocyclic alkyl groups fused to cycloalkyl or heterocyclic alkyl groups. "Fused heterocyclic groups" include, but are not limited to: "Spiroheterocyclic" refers to a polycyclic group formed by two heterocyclic alkyl groups or one cycloalkyl group and one heterocyclic alkyl group sharing a single carbon atom. "Spiroheterocyclic" includes, but is not limited to: "Bridged heterocyclic group" refers to a straight-chain group formed by 1 to 3 additional carbon atoms or heteroatoms bridging any two unlinked ring atoms of a heterocyclic alkyl group (the straight-chain group is selected from, but is not limited to: -CH2-, -O-, -NH-, -S-, -CH2CH2-, -CH2O-, -CH2S-, -CH2NH-, -CH2CH2CH2-, -CH2OCH2-, -CH2CH2O-, -CH2CH2NH-, -CH2NHCH2-, etc.), and bridged heterocyclic groups include, but are not limited to: The polycyclic heterocyclic alkyl group is preferably a bicyclic or tricyclic heterocyclic alkyl group. The monocyclic and polycyclic heterocyclic alkyl groups can be linked to the parent molecule via any ring atom. The aforementioned ring atom specifically refers to the carbon and / or nitrogen atoms that form the ring skeleton.

[0714] The term "cycloalkylalkyl" refers to a cycloalkyl group that is linked to the parent structure via an alkyl group. Therefore, "cycloalkylalkyl" encompasses the definitions of alkyl and cycloalkyl groups described above.

[0715] The term "heterocyclic alkyl alkyl" refers to a heterocyclic alkyl group that is linked to the parent structure via an alkyl group. Therefore, "heterocyclic alkyl alkyl" encompasses the definitions of alkyl and heterocyclic alkyl groups described above.

[0716] The term "alkenyl" refers to a straight or branched chain containing at least one carbon-carbon double bond. It may contain 1-3 carbon-carbon double bonds, preferably 1. The term "C"... 2-4 "Alkenyl" refers to an alkenyl group having 2-4 carbon atoms; the term "C" is used to indicate this. 2-6 "Alkenyl" refers to an alkenyl group having 2-6 carbon atoms, including vinyl, propenyl, butenyl, and 2-methylbutenyl. The alkenyl group can be substituted.

[0717] The term "alkynyl" refers to a straight or branched chain containing at least one carbon-carbon triple bond. It may contain 1-3 carbon-carbon triple bonds, preferably 1. The term "C"... 2-6 "Alynyl" refers to an alkynyl group with 2-6 carbon atoms, including ethynyl, propynyl, butynyl and 3-methylbutynyl.

[0718] The term "alkoxy" refers to a cyclic or acyclic alkyl group having the stated number of carbon atoms connected by an oxygen bridge, including alkyloxy, cycloalkyloxy, and heterocyclic alkyloxy groups. Thus, "alkoxy" encompasses the definitions of alkyl, heterocyclic alkyl, and cycloalkyl groups described above.

[0719] The term "aryl" refers to any stable 6-14 nucleotide aromatic group with a conjugated π-electron system, consisting of an all-carbon monocyclic or fused bicyclic ring. The aryl group is preferably 6-10 nucleotides, such as phenyl, naphthyl, etc.

[0720] The term "heteroaryl" refers to an aromatic ring group formed by replacing at least one carbon atom in a ring with a heteroatom selected from nitrogen, oxygen, or sulfur. The heteroaryl group can be a 5-6 membered monocyclic structure or a 7-12 membered bicyclic structure, preferably a 5-10 membered heteroaryl group; the heteroaryl group can also be an 11-13 membered tricyclic structure, preferably an 11-12 membered tricyclic structure. In this invention, the number of heteroatoms is preferably 1, 2, or 3, including but not limited to: pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyridazin-3(2H)-keto, furanyl, thiopheneyl, thiazolyl, isothiazolyl, pyrroleyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, 1H-indazoleyl. Isoinzolyl, 1H-indolyl Isoindolyl, benzofuranyl benzothiophene benzothiazolyl Benzisothiazolyl Benzoxazolyl Quinolinyl Isoquinoline Quinazolinyl Naphtho[2,3-b]furanyl, 1H-benzo[f]indolyl, 1H-benzo[f]indazoleyl, naphtho[2,1-b]furanyl, etc.

[0721] The term "arylalkyl" refers to an aryl group that is linked to the parent structure via an alkyl group. Therefore, "arylalkyl" encompasses the definitions of alkyl and aryl groups mentioned above.

[0722] The term "heteroarylalkyl" refers to a heteroaryl group that is linked to the parent structure via an alkyl group. Therefore, "heteroarylalkyl" encompasses the definitions of alkyl and heteroaryl groups mentioned above.

[0723] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0724] The term "halogenated alkyl" refers to an alkyl group that has been arbitrarily substituted with a halogen. Thus, "halogenated alkyl" encompasses the definitions of halogen and alkyl group mentioned above.

[0725] The term "haloalkoxy" refers to an alkoxy group that has been substituted with a halogen in any way. Therefore, "haloalkoxy" encompasses the definitions of halogen and alkoxy group mentioned above.

[0726] The term "ester group" refers to -C(O)O-alkyl; preferably -C(O)OC. 1-6 Alkyl group. The "ester group" includes, but is not limited to, -C(O)OCH3, -C(O)OCH2CH3, etc. Thus, "ester group" includes the above definition of alkyl group.

[0727] The term "amino" refers to -NH2.

[0728] The term "hydroxyl group" refers to -OH.

[0729] The term "oxo" refers to the =O group, such as the =O part in carbonyl (-CO-), nitrosyl (-N=O), sulfinyl (-SO-), or sulfonyl (-SO2-).

[0730] The term "cyano" refers to -CN.

[0731] The term "nitro" refers to -NO2.

[0732] The "room temperature" mentioned in this invention refers to 15-30℃.

[0733] In this invention, unless otherwise stated, the term "selective substitution by 1 to 3 groups at any position" means that one, two or three hydrogen atoms specified on the group are substituted by the specified group, provided that the substitution does not exceed the normal valence of the specified atom. All such substitutions are reasonable substitutions commonly used in the art, for example, =O cannot be substituted on a tertiary carbon.

[0734] In this invention, when the bonding with a substituent intersects with the bonding of two atoms in the connecting ring, then such a substituent can be bonded to any bondable ring atom on the ring.

[0735] In this invention, any combination of variables is permitted only if such a combination produces a stable compound.

[0736] The “pharmaceutically acceptable salts” described in this invention are discussed in Berge, et al., “Pharmaceutically acceptable salts”, J. Pharm. Sci., 66, 1-19 (1977), and are obvious to medicinal chemists that the salts are substantially nontoxic and provide the desired pharmacokinetic properties, palatability, absorption, distribution, metabolism or excretion, etc. The compounds described in this invention may have acidic, basic, or amphoteric groups. Typical pharmaceutically acceptable salts include those prepared by reacting the compounds of this invention with acids, such as: hydrochloride, hydrobromide, sulfate, pyrosulfate, hydrogen sulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, nitrate, acetate, propionate, decanoate, octanoate, formate, acrylate, isobutyrate, hexanoate, heptanoate, oxalate, malonate, succinate, octanoate, benzoate, methylbenzoate, phthalate, maleate, methanesulfonate, p-toluenesulfonate, (D,L)-tartaric acid, citric acid, maleic acid, (D,L)-malic acid, fumaric acid, succinic acid, succinate, lactate, trifluoromethanesulfonate, naphthalene-1-sulfonate, mandelate, pyruvate, stearate, ascorbate, and salicylate. When the compounds of the present invention contain acidic groups, their pharmaceutically acceptable salts may also include: alkali metal salts, such as sodium or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; organic base salts, such as salts formed with ammonia, alkylamines, hydroxyalkylamines, amino acids (lysine, arginine), N-methylglucosamine, etc.

[0737] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0738] The reagents and raw materials used in this invention are all commercially available.

[0739] The positive and progressive effects of the present invention are as follows: the compounds of the present invention have one or more of the following effects: (1) good KRAS G12C inhibitory activity; (2) good KRAS G12D inhibitory activity; (3) good KRAS G12V inhibitory activity; (4) good exposure level; (5) good bioavailability; (6) good in vivo efficacy. Detailed Implementation

[0740] The structures of all compounds in this invention can be determined by nuclear magnetic resonance (NMR). 1 Identification by 1H NMR and / or mass spectrometry (MS).

[0741] 1 HNMR chemical shifts (δ) were recorded in pPM (10 -6NMR was performed using a Bruker AVANCE-400 spectrometer. Suitable solvents were deuterated chloroform (CDCl3), deuterated methanol (CD3OD), deuterated dimethyl sulfoxide (DMSO-d6), and tetramethylsilane as an internal standard (TMS).

[0742] Liquid chromatography-mass spectrometry (LC-MS) was performed using an Agilent 1200 HPLC / 6120 mass spectrometer with an Ultimate C18 column (3.0 × 50 mm, 3 μm) at 40 °C; or a Thermo UltiMate 3000 HPLC / MSQ PLUS mass spectrometer with an XBridge C18 column (3.0 × 50 mm, 3.5 μm) at 30 °C. Agilent gradient elution conditions: 95-5% solvent A1 and 5-95% solvent B1 (0-2.0 min), then 95% solvent B1 and 5% solvent A1 (hold for 1.1 min). Percentages represent the volume percentage of a specific solvent in the total solvent volume. Solvent A1: 0.01% aqueous solution of trifluoroacetic acid (TFA); Solvent B1: 0.01% acetonitrile solution of trifluoroacetic acid; percentages represent the volume percentage of the solute in the solution. Thermo gradient elution condition 2: 95-5% solvent A2 and 5-95% solvent B2 (0-2 min), then 95% solvent B2 and 5% solvent A2 (hold for 1.8 min), where the percentage is the volume percentage of a particular solvent in the total solvent volume. Solvent A2: 10 mM ammonium bicarbonate aqueous solution; Solvent B2: acetonitrile.

[0743] All compounds of this invention can be separated by preparative high-performance liquid chromatography or rapid column chromatography.

[0744] Preparative high-performance liquid chromatography (prep-HPLC) was performed using a Shimadzu LC-20 preparative HPLC system. The chromatographic columns were either Welch Xtimate C18 (21.2 × 250 mm, 10 μm) or Welch Xtimate XB-C18 (30 × 250 mm, 10 μm). Alkaline conditions: Mobile phase A: 10 mmol / L ammonium bicarbonate aqueous solution; Mobile phase B: acetonitrile. Acidic conditions: Mobile phase A: trifluoroacetic acid aqueous solution; Mobile phase B: acetonitrile. Detection wavelengths: 214 nm & 254 nm; Flow rate: 15.0 mL / min.

[0745] The fast column chromatography (Flash system / Cheetah™) used an Agela Technologies MP200 system, with the accompanying normal phase separation column being a Flash column Silica-CS (25g, 40g, 80g, 120g, or 330g) manufactured by Tianjin Bona Agela, and the elution system being ethyl acetate / petroleum ether or dichloromethane / methanol; the reversed phase separation column was a C18 reversed phase column (12g, 20g, or 40g) manufactured by Changzhou Sante Technology, and the elution system being acetonitrile / 0.1% trifluoroacetic acid aqueous solution or acetonitrile / 10mmol / L ammonium bicarbonate aqueous solution.

[0746] The thin-layer silicone sheet (prep-TLC) is either Yantai Huanghai HSGF254 or Qingdao GF254 silicone sheet.

[0747] All compounds of this invention can be analyzed by ultra-high performance liquid chromatography or high performance liquid chromatography.

[0748] Ultra-high performance liquid chromatography (UPLC) was performed using a Waters ACQUITY H-class column: Waters ACQUITY UPLC BEH Shield RP182.1*100mm, 1.7μm. Mobile phase A: 5mM potassium dihydrogen phosphate buffer, adjusted to pH 2.5 with phosphoric acid; mobile phase B: acetonitrile. Gradient elution was performed with mobile phase B from 10% to 40% for 5 minutes, then from 40% to 90% for 2 minutes, holding mobile phase B at 90% for 6 minutes, and finally from 90% to 10% for 2 minutes. Detection wavelength: 214nm; column temperature: 40℃; flow rate: 0.4mL / min.

[0749] High-performance liquid chromatography (HPLC) was performed using a Waters e2695, 2498UV / VISDetector; the column was a Welch Xtimate C184.6mm*150mm, 5μm; mobile phase A: acetonitrile; mobile phase B: 10mm potassium dihydrogen phosphate buffer, adjusted to pH 8.0 with ammonia. Gradient elution was performed: mobile phase B held at 90% for 5 minutes; B eluted from 90% to 70% for 5 minutes; B eluted from 70% to 40% for 4 minutes; B eluted from 40% to 15% for 12 minutes; B eluted from 15% to 90% for 2 minutes; and B held at 90% for 2 minutes. Detection wavelengths: 214 & 262 nm; column temperature: 35℃; flow rate: 1 mL / min.

[0750] The chiral compounds or intermediates involved in this invention can be prepared by supercritical fluid chromatography (SFC).

[0751] This invention utilizes a supercritical fluid chromatograph (SFC-150, Waters) for chiral preparation. Method 1: Chiral preparation column: IC 20*250mm, 10μm (Daicel); flow rate: 120mL / min; column temperature: 35℃; sample concentration: 8mg / mL; injection volume: 3mL; detection wavelength: 214 and / or 254nM; cycle time: 4.45min; mobile phase: CO2 / [methanol (0.2% 7M ammonia methanol solution) / acetonitrile = 1 / 1] = 50:50; Method 2: Chiral preparation column: OX 25*250mm, 10μm (Regis); flow rate 100mL / min; column temperature 35℃; injection volume 1mL; detection wavelength 214 and / or 254nM; cycle time 8.1min; mobile phase CO2 / [methanol (0.2% 7M ammonia methanol solution) / acetonitrile = 1 / 1] = 45:55.

[0752] The chiral compounds or intermediates involved in this invention can be analyzed by high performance liquid chromatography (HPLC) or ultra-high performance phase chromatography (UPCC).

[0753] The chiral analysis of the compounds of this invention was performed using an ultra-high performance combined phase chromatograph (UPCC) (Waters). Method 1: Analytical column: IC 4.6*100mm, 5µm (Daicel), flow rate 3.0mL / min; column temperature 40℃, injection volume 5µL; detection wavelength 214 and / or 254nm; mobile phase CO2 / ethanol (0.2% 7M ammonia-methanol solution) = 55:45. Method 2: Analytical column: AD 4.6*100mm, 5µm (Daicel), flow rate 3.0mL / min; column temperature 40℃, injection volume 7.5µL; detection wavelength 214 and / or 254nm; mobile phase CO2 / methanol (0.2% 7M ammonia-methanol solution) = 90:10. Method 3: Analytical column: 6-OX 4.6*100mm, 5µm, flow rate 3.0mL / min; column temperature 40℃, injection volume 7.5µL; detection wavelength 214 and / or 254nm; mobile phase CO2 / [methanol (0.2% 7M ammonia methanol solution) / acetonitrile = 1 / 1] = 55:45.

[0754] The microwave reaction described in this embodiment of the invention uses Initiator+Microwave System EU(356006) type microwave reactor.

[0755] Unless otherwise specified, all reactions in the present invention can be carried out under a nitrogen or argon atmosphere; in the post-processing of all reactions in the present invention, the extracted organic phase can be dried using anhydrous sodium sulfate or anhydrous magnesium sulfate.

[0756] A hydrogen atmosphere can be achieved in the following ways: 1) Connect a hydrogen balloon with a volume of about 1L to the reaction system; 2) Continuously introduce hydrogen directly into the reaction system at atmospheric pressure; 3) Replace the hydrogen with a sealed tube and then seal it.

[0757] Synthesis of intermediates:

[0758] Intermediate 1: Synthesis of (R)-3-(1-(methylamino)ethyl)pyridine-2-amine

[0759] Step 1: To a solution of 1-(2-aminopyridin-3-yl)ethane-1-one (3.3 g, 24 mmol) in tetrahydrofuran (110 mL), S-tert-butylsulfinamide (3.9 g, 32 mmol), ethylene glycol dimethyl ether (2.4 g), and tetraethyl titanate (12 g) were added sequentially. The reaction system was stirred at 70 °C for 8 hours, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 4) to give (S,E)-N-(1-(2-aminopyridin-3-yl)ethylene)-2-methylpropane-2-sulfinamide (3.58 g) as a yellow solid. m / z: [M+H] + 240.1.

[0760] Step 2: A solution of (S,E)-N-(1-(2-aminopyridin-3-yl)ethylene)-2-methylpropane-2-sulfinamide (3.0 g, 12.6 mmol) in tetrahydrofuran (100 mL) was cooled to -60 °C. A solution of tri-sec-butylborohydride in tetrahydrofuran (L-selectride in THF, 1 M, 26 mL) was added to the above system. The reaction mixture was stirred at -60 °C for 2 hours. The reaction was quenched with saturated ammonium chloride aqueous solution. The aqueous phase was extracted with ethyl acetate. The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 1) to give (R)-N-((S)-1-(2-aminopyridin-3-yl)ethyl)-2-methylpropane-2-thioamide (920 mg) as a pale yellow oil. m / z: [M+H] + 242.1.

[0761] Step 3: Add a solution of 1,4-dioxane hydrochloride (4M, 10mL) to a methanol (25mL) solution of (R)-N-((S)-1-(2-aminopyridin-3-yl)ethyl)-2-methylpropane-2-thioamide (900mg, 3.7mmol). Stir the reaction mixture at room temperature for 3 hours, concentrate under reduced pressure, dissolve the residue in water, adjust the pH to 10 with 20% sodium hydroxide aqueous solution, extract the aqueous phase with dichloromethane, combine the organic phases, and concentrate under reduced pressure to obtain (R)-3-(1-aminoethyl)pyridin-2-amine (440mg) as a pale yellow oil. m / z: [M+H]+ 138.2.

[0762] Step 4: A solution of (R)-3-(1-aminoethyl)pyridine-2-amine (220 mg, 1.6 mmol) in ethyl formate (10 mL) was stirred at 60 °C for 10 minutes and concentrated under reduced pressure. The residue was redissolved in tetrahydrofuran (10 mL), and a tetrahydrofuran solution of lithium aluminum hydride (1 M, 10 mL) was added. The reaction mixture was heated under reflux and stirred for 5 minutes, cooled to 0 °C, and quenched with water (2 mL). The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 1 (270 mg) as a gray solid. m / z: [M+H] + 152.2.

[0763] Intermediate 2: Synthesis of (R)-3-(1-((methyl-d2)amino)ethyl)pyridine-2-amine

[0764] Using the synthetic method for intermediate 1, intermediate 2 was obtained by replacing the tetrahydrofuran solution of lithium aluminum hydride in step 4 with deuterated lithium aluminum hydride-d4 reaction. m / z: [M+H] + 154.2.

[0765] Intermediate 3: Synthesis of (R)-3-(1-((methyl-d)amino)ethyl)pyridine-2-amine

[0766] Step 1: 1) Add deuterated formic acid (920 mg, 19.6 mmol) to a solution of sodium bicarbonate (1.81 g, 21.5 mmol) in anhydrous acetonitrile (10 mL). Stir the reaction mixture at room temperature for 2 hours. At 0 °C, add acetyl chloride (1.38 g, 17.6 mmol) dropwise to the above reaction mixture and stir at room temperature for 2 hours. Filter the mixture, reserving the filtrate containing 1-ethyl acetate anhydride. 2) Add the filtrate containing 1-ethyl acetate anhydride (0.42 mL, 1.9 M) to a solution of (R)-3-(1-aminoethyl)pyridine-2-amine (110 mg, 0.8 mmol) in tetrahydrofuran (2 mL). Stir the reaction mixture overnight at room temperature and concentrate under reduced pressure. The residue was purified by prep-TLC (methanol / dichloromethane = 1 / 10) to give (R)-N-(1-(2-aminopyridin-3-yl)ethyl)formamide-1-d (11 mg) as a colorless oil. m / z: [M+H] + 167.2.

[0767] Step 2: Add a tetrahydrofuran solution (2.5 M, 0.1 mL) of lithium aluminum hydride in tetrahydrofuran to a solution of (R)-N-(1-(2-aminopyridin-3-yl)ethyl)formamide-1-d (11 mg, 0.07 mmol) in anhydrous tetrahydrofuran (2 mL). Stir the reaction mixture at 80 °C for 2 hours. Quench the reaction at 0 °C by adding 1 drop of water and 1 drop of 15% sodium hydroxide aqueous solution. Extract the aqueous phase with ethyl acetate, combine the organic phases, and concentrate under reduced pressure to obtain intermediate 3 (10 mg) as a colorless oil. m / z: [M+H] + 153.2.

[0768] Intermediate 4: Synthesis of (R)-3-(1-((methyl-d3)amino)ethyl)pyridine-2-amine

[0769] Step 1: A solution of (R)-3-(1-aminoethyl)pyridin-2-amine (300 mg, 2.19 mmol) and di-tert-butyl dicarbonate (478 mg, 2.19 mmol) in dichloromethane (5 mL) was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 1 / 50 to 1 / 25) to give (R)-(1-(2-aminopyridin-3-yl)ethyl)carbamate (480 mg) as a white solid. m / z: [M+H] + 238.2.

[0770] Step 2: Deuterated lithium aluminum hydride-d4 (212 mg, 5.05 mmol) was added to a tetrahydrofuran (10 mL) solution of (R)-(1-(2-aminopyridin-3-yl)ethyl)carbamate (240 mg, 1.01 mmol). The reaction mixture was stirred at 80 °C for 18 hours. After cooling to 0 °C, water (0.2 mL), 15% sodium hydroxide aqueous solution (0.2 mL), and water (0.6 mL) were added sequentially to quench the reaction. Anhydrous sodium sulfate was then added to the reaction system. The mixture was stirred at room temperature for 15 minutes, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 4 (270 mg) as a colorless oil. m / z: [M+H] + 155.2.

[0771] Synthesis of Intermediate 5: 6-Bromo-N,N-Di(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine

[0772] Under ice bath conditions, sodium hydroxide (470 mg, 11.8 mmol, 60%) was added to a DMF (20 mL) solution of 6-bromo-4-methyl-5-(trifluoromethyl)pyridine-2-amine (1 g, 3.92 mmol). The reaction mixture was stirred at 0 °C for 1 hour, followed by slow addition of 4-methoxybenzyl chloride (1.53 g, 9.8 mmol). The reaction mixture was stirred at 0 °C for another 1 hour. The reaction mixture was quenched in a saturated aqueous solution of ammonium chloride, and the aqueous phase was extracted with ethyl acetate. The organic layers were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 10) to give intermediate 5 (1.8 g) as a white solid. m / z: [M+H] + 495.2.

[0773] Intermediate 6: Synthesis of tert-butyl (3-cyano-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzo[b]thiophene-2-yl)carbamate

[0774] Step 1: Under ice bath conditions and nitrogen protection, sodium hydroxide (0.55 g, 60%) was added to a solution of 2-(2,6-dibromophenyl)acetonitrile (3.8 g, 13.8 mmol) in N,N-dimethylformamide (10 mL). The reaction system was stirred at 0 °C for 10 minutes, and then ethyl isothiocyanate (2.1 g, 15.2 mmol) was added. The reaction system was stirred at 95 °C for 4 hours, concentrated under reduced pressure, and then slurried with water and ethyl acetate. The mixture was filtered, and the filter cake was dried under vacuum to obtain ethyl (4-bromo-3-cyanobenzo[b]thiophene-2-yl)carbamate (1.7 g) as an orange solid.

[0775] Step 2: Sodium hydroxide (1.66 g, 41.6 mmol) was added to a solution of ethyl (4-bromo-3-cyanobenzo[b]thiophene-2-yl)carbamate (1.7 g, 5.2 mmol) in dimethyl sulfoxide (170 mL). The reaction mixture was stirred at 120 °C for 16 hours. After cooling the reaction solution to room temperature, it was poured directly into ice water, filtered, and the filter cake was dried under vacuum to obtain 0.79 g of 2-amino-4-bromobenzo[b]thiophene-3-onitrile as a yellow solid. m / z: [M+H] + 254.9.

[0776] Step 3: To a mixed solution of 2-amino-4-bromobenzo[b]thiophene-3-onitrile (0.77 g, 3.06 mmol) in N,N-dimethylformamide (10 mL) and tetrahydrofuran (2 mL), ditert-butyl dicarbonate (1 g, 4.59 mmol), 4-dimethylaminopyridine (75 mg, 0.61 mmol), and N,N-diisopropylethylamine (0.79 g, 6.12 mmol) were added sequentially. The reaction system was stirred at room temperature for 8 hours under nitrogen protection. The reaction solution was diluted with ethyl acetate and washed with water. The organic phase was separated and concentrated under reduced pressure to obtain (4-bromo-3-cyanobenzo[b]thiophene-2-yl)carbamate tert-butyl ester (700 mg) as a pale yellow solid.

[0777] Step 4: A solution of anhydrous 1,4-dioxane (46 mL) of (4-bromo-3-cyanobenzo[b]thiophene-2-yl)carbamate (2.5 g, 7.08 mmol), tris(dibenzylacetone)dipalladium (320 mg, 0.35 mmol), potassium acetate (2.08 g, 21.2 mmol), tricyclohexylphosphine (200 mg, 0.71 mmol), and pinacol borate (5.39 g, 21.2 mmol) was purged with nitrogen and stirred at 95 °C for 3 hours. After cooling to room temperature, the solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 10) to give intermediate 6 (2.5 g) as a pale yellow solid. m / z: [M+Na] + 423.0.

[0778] Intermediate 7: Synthesis of tert-butyl (3-cyano-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzo[b]thiophene-2-yl)carbamate

[0779] Intermediate 7 was obtained by reacting 2-(6-bromo-2,3-difluorophenyl)acetonitrile using the same method as intermediate 6. m / z: [M+Na] + 441.2.

[0780] Intermediate 8: Synthesis of (2-methylene-6-morpholinotetrahydro-1H-pyrrolazine-7a(5H)-yl)methanol

[0781] Step 1: Morpholine (1.04 g, 12 mmol) and tetraisopropyl titanate (2.56 g, 9 mmol) were added to a methanol (20 mL) solution of N-Boc-4-oxo-L-proline methyl ester (1.46 g, 6 mmol). The reaction mixture was stirred at room temperature for 1 hour, and sodium cyanoborohydride (1.12 g, 18 mmol) was added. The reaction mixture was stirred at room temperature for another 2 hours. A saturated sodium chloride aqueous solution was added, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / tetrahydrofuran = 5 / 1) to give 1-(tert-butyl)-2-methyl(2S)-4-morpholinopyrrolidine-1,2-dicarboxylic acid ester (1.5 g) as a pale yellow oil. m / z [M+H] + 315.1.

[0782] Step 2: Under nitrogen protection at -70°C, a tetrahydrofuran solution (1M, 10mL) of lithium bis(tert-butyl)-2-methyl(2S)-4-morpholinopyrrolidine-1,2-dicarboxylic acid ester (1.5g, 5mmol) in anhydrous tetrahydrofuran (20mL) was slowly added dropwise. The reaction mixture was stirred at this temperature for 0.5 hours, followed by the addition of 3-chloro-2-(chloromethyl)prop-1-ene (1.24g, 10mmol). After the addition was complete, the reaction mixture was stirred at this temperature for 2 hours. The reaction mixture was slowly poured into ice water, extracted with ethyl acetate, and the organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give 1-(tert-butyl)-2-methyl(2S)-2-(2-(chloromethyl)allyl)-4-morpholinopyrrolidine-1,2-dicarboxylic acid ester (1.78g) as a pale yellow oil. m / z[M+H] + 403.1.

[0783] Step 3: Add trifluoroacetic acid (3 mL) to a solution of 1-(tert-butyl)-2-methyl(2S)-2-(2-(chloromethyl)allyl)-4-morpholinopyrrolidine-1,2-dicarboxylic acid ester (1.78 g, 4.42 mmol) in dichloromethane (10 mL). Stir the reaction mixture at room temperature for 1 hour, concentrate under reduced pressure, dissolve the crude product in methanol (10 mL), and then slowly add ammonia methanol solution (17%) at 0 °C to adjust the pH to 8. Concentrate under reduced pressure. Purify the residue by silica gel column chromatography (dichloromethane / methanol = 20 / 1 / ) to obtain (7aS)-2-methyl-6-morpholinotetrahydro-1H-pyrrolazine-7a(5H)-carboxylic acid methyl ester (890 mg) as a pale yellow oil. m / z [M+H] + 267.2.

[0784] Step 4: Under ice bath conditions, a solution of lithium aluminum hydride in tetrahydrofuran (1M, 6 mL) was added to 15 mL of anhydrous tetrahydrofuran containing methyl (7aS)-2-methyl-6-morpholinotetrahydro-1H-pyrrolazine-7a(5H)-carboxylic acid (890 mg, 3.34 mmol). The reaction mixture was stirred at room temperature for 2 hours, then quenched by adding water (0.5 mL) at 0 °C. Anhydrous sodium sulfate was then added, and the mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give intermediate 8 (350 mg) as a pale yellow oily liquid. UPCC retention times were 1.984 and 3.027 min (Method 2); m / z [M+H] + 239.3.

[0785] Intermediate 9: Synthesis of ((6R)-2-methylene-6-morpholinotetrahydro-1H-pyrrolazine-7a(5H)-yl)methanol

[0786] Step 1: A solution of 1-(tert-butyl)-2-methyl(2S,4S)-4-hydroxypyrrolidine-1,2-dicarboxylic acid ester (25 g, 102 mmol), tert-butyldimethylchlorosilane (16.9 g, 112 mmol), and imidazole (10.4 g, 153 mmol) in dichloromethane (250 mL) was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 9 / 1) to give 1-(tert-butyl)-2-methyl(2S,4S)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1,2-dicarboxylic acid ester (36.4 g) as a colorless oil.

[0787] Step 2: At -60°C, a tetrahydrofuran solution (210 mL, 1 M) of lithium di(trimethylsilyl)aminoacetate (36.4 g, 101 mmol) in tetrahydrofuran (400 mL) was added. The reaction mixture was stirred at this temperature for 1 hour, and then 3-chloro-2-chloromethylpropene (15.2 g, 122 mmol) was added. The reaction mixture was stirred at room temperature for another 2 hours, and the reaction was quenched by adding a saturated aqueous solution of ammonium chloride. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 19 / 1) to give 1-(tert-butyl)-2-methyl(4S)-4-((tert-butyldimethylsilyl)oxy)-2-(2-(chloromethyl)allyl)pyrrolidine-1,2-dicarboxylic acid ester (45.6 g) as a pale yellow oil. m / z [M+Na] + 470.2.

[0788] Step 3: A hydrochloric acid-methanol solution (20 mL, 4 M) of 1-(tert-butyl)-2-methyl(4S)-4-((tert-butyldimethylsilyl)oxy)-2-(2-(chloromethyl)allyl)pyrrolidine-1,2-dicarboxylic acid ester (4 g, 8.39 mmol) was stirred at 60 °C for 3 hours. The reaction solution was then concentrated under reduced pressure to obtain (4S)-2-(2-(chloromethyl)allyl)-4-hydroxypyrrolidine-2-carboxylic acid methyl ester (3.3 g) as a pale yellow oil. m / z[M+H] + 234.1.

[0789] Step 4: A solution of (4S)-2-(2-(chloromethyl)allyl)-4-hydroxypyrrolidine-2-carboxylic acid methyl ester (1.96 g, 8.39 mmol) in ammonia-methanol (15 mL, 7 M) and methanol (20 mL) was stirred at room temperature for 2 hours. The solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane / tetrahydrofuran = 4 / 1 to 2 / 1) to obtain (2S)-2-hydroxy-6-methylenetetrahydro-1H-pyrrolazine-7a(5H)-carboxylic acid methyl ester (1.25 g) as a pale yellow oil. m / z [M+H] + 198.2.

[0790] Step 5: A solution of (2S)-2-hydroxy-6-methylenetetrahydro-1H-pyrrolizin-7a(5H)-carboxylic acid methyl ester (5.5 g, 27.9 mmol), p-toluenesulfonyl chloride (6.9 g, 36.3 mmol), 4-dimethylaminopyridine (340 mg, 2.79 mmol), and triethylamine (5.6 g, 55.8 mmol) in dichloromethane (100 mL) was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1 to 1 / 1) to give (6S)-2-methylene-6-(p-toluenesulfonyloxy)tetrahydro-1H-pyrrolizin-7a(5H)-carboxylic acid methyl ester (5.2 g) as a yellow oil. m / z [M+H] + 352.1.

[0791] Step 6: Add N,N-diisopropylethylamine (860 mg, 6.66 mmol) and morpholine (870 mg, 10 mmol) to a solution of (6S)-2-methylene-6-(p-toluenesulfonyloxy)tetrahydro-1H-pyrrolidine-7a(5H)-carboxylic acid methyl ester (1.17 g, 3.3 mmol) in acetonitrile (10 mL). Microwave the reaction mixture for 3 hours, concentrate under reduced pressure, and purify the residue by prep-HPLC (10%–65% acetonitrile in 10 mM ammonium bicarbonate aqueous solution, 20 min) to obtain (6R)-2-methylene-6-morpholinetetrahydro-1H-pyrrolidine-7a(5H)-carboxylic acid methyl ester (375 mg) as a yellow oil. m / z [M+H] + 267.2.

[0792] Step 7: Under ice bath conditions, a tetrahydrofuran solution (2.5 M, 1.1 mL) of lithium aluminum hydride (LCH) was added dropwise to a tetrahydrofuran solution (5 mL) of (6R)-2-methylene-6-morpholinotetrahydro-1H-pyrrolidine-7a(5H)-carboxylic acid methyl ester (371 mg, 1.39 mmol). The reaction mixture was slowly brought to room temperature and stirred for 2 hours. Then, at 0 °C, water (0.1 mL), sodium hydroxide aqueous solution (15%), and water (0.3 mL) were added sequentially. The reaction mixture was brought to room temperature, and tetrahydrofuran and anhydrous sodium sulfate were added, with stirring continued for 20 minutes. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain intermediate 9 (330 mg) as a pale yellow oil. m / z [M+H] + 239.2.

[0793] Synthesis of Intermediate 10: ((7aS)-2-morpholinotetrahydro-1H-pyrrolazine-7a(5H)-yl)methanol

[0794] Step 1: Under ice bath conditions, sodium cyanoborohydride (0.42 g, 6.62 mmol) was added to a solution of (S)-2,5-dioxotetrahydro-1H-pyrrolazin-7a(5H)-carboxylic acid ethyl ester (0.7 g, 3.31 mmol) and morpholine (0.30 g, 3.48 mmol) in dichloroethane (7 mL). The reaction mixture was stirred overnight at room temperature. Acetic acid (0.2 mL) was added, and the mixture was concentrated under reduced pressure. The residue was purified by Flash column chromatography to obtain (7aS)-2-morpholine-5-oxotetrahydro-1H-pyrrolazin-7a(5H)-carboxylic acid ethyl ester (0.72 g) as a pale yellow oil. m / z: [M+H] + 283.2.

[0795] Step 2: Under ice bath conditions, lithium aluminum hydride (0.13 g, 3.54 mmol) was added to a solution of (7aS)-2-morpholine-5-oxotetrahydro-1H-pyrrolazine-7a(5H)-carboxylic acid ethyl ester (0.5 g, 1.77 mmol) in tetrahydrofuran (5 mL). The reaction mixture was stirred at room temperature for half an hour and then refluxed for 2 hours. After cooling to 0°C, water was added dropwise until no bubbles were produced, followed by the addition of a 15% sodium hydroxide aqueous solution until the solid aggregated and precipitated. The mixture was filtered, and the filter cake was washed with tetrahydrofuran and ethyl acetate. The filtrate was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain intermediate 10 (0.26 g) as a yellow oily substance. m / z: [M+H] + 227.2.

[0796] Intermediate 11: Synthesis of 4-(7α-(hydroxymethyl)-6-methylenetetrahydro-1H-pyrrolazin-2-yl)morpholin-3-one

[0797] Step 1: To a solution of 21.4 g (88 mmol) of 1-tert-butyl-2-methyl(2S)-4-oxopyrrolidine-1,2-dicarboxylic acid ester (21.4 g, 88 mmol) in methanol (100 mL) and dichloromethane (50 mL), ethanolamine (6.5 g, 106 mmol) and trifluoroacetic acid (500 mg, 4.4 mmol) were added. The reaction mixture was stirred at room temperature for 30 minutes, and sodium cyanoborohydride (11.1 g, 176 mmol) was added. The mixture was stirred overnight. The reaction mixture was directly concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give 1-tert-butyl-2-methyl(2S)-4-((2-hydroxyethyl)amino)pyrrolidine-1,2-dicarboxylic acid ester (10 g) as a yellow oil. m / z [M+H] + 289.2.

[0798] Step 2: Under ice bath conditions, sodium bicarbonate (3.27 g, 38.9 mmol) and chloroacetyl chloride (2.1 g, 18.6 mmol) were added sequentially to a solution of 1-tert-butyl-2-methyl(2S)-4-(2-chloro-N-(2-hydroxyethyl)acetamido)pyrrolidine-1,2-dicarboxylic acid ester (5.1 g, 17.7 mmol) in 50 mL of 1,4-dioxane. The reaction system was stirred overnight at room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain crude 1-tert-butyl-2-methyl(2S)-4-(2-chloro-N-(2-hydroxyethyl)acetamido)pyrrolidine-1,2-dicarboxylic acid ester (6.5 g). m / z [M+H] + 365.2.

[0799] Step 3: Under ice bath conditions, a solution of potassium tert-butoxide in tetrahydrofuran (26.7 mL, 1 M) was slowly added to a solution of crude 1-tert-butyl-2-methyl(2S)-4-(2-chloro-N-(2-hydroxyethyl)acetamido)pyrrolidine-1,2-dicarboxylic acid ester (6.5 g, 17.8 mmol) in tetrahydrofuran (50 mL). The reaction mixture was stirred at room temperature for 2 hours, and the reaction was quenched by adding saturated ammonium chloride aqueous solution (2 mL). The mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0%-70%) to give 1-tert-butyl-2-methyl(2S)-4-(3-oxomorpholine)pyrrolidine-1,2-dicarboxylic acid ester (2.3 g) as a white solid. m / z [M+Na] + 351.2.

[0800] Step 4: At -60°C, a tetrahydrofuran solution (9.1 mL, 1 M) of potassium bis(trimethylsilyl)amino in tetrahydrofuran was added to a tetrahydrofuran solution of 1-tert-butyl-2-methyl(2S)-4-(3-oxomorpholine)pyrrolidine-1,2-dicarboxylate (1.5 g, 4.6 mmol) in 50 mL of tetrahydrofuran. The reaction mixture was stirred at this temperature for 30 minutes, and then 3-chloro-2-chloromethylpropene (690 mg, 5.5 mmol) was added. The reaction mixture was gradually brought to room temperature and stirred for 2 hours. The reaction was quenched by adding saturated ammonium chloride aqueous solution. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane) to give 1-tert-butyl-2-methyl-2-(2-(chloromethyl)allyl)-4-(3-oxomorpholine)pyrrolidine-1,2-dicarboxylate (1.7 g) as a white solid. m / z [M+Na] + 439.2.

[0801] Step 5: A solution of 1-tert-butyl-2-methyl-2-(2-(chloromethyl)allyl)-4-(3-oxomorpholine)pyrrolidine-1,2-dicarboxylic acid ester (1.7 g, 4.1 mmol) in 1,4-dioxane hydrochloride (5 mL, 4 M) was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in methanol (5 mL). The pH was adjusted to >7 by adding ammonia-methanol solution (7 M), and the solution was concentrated under reduced pressure to obtain methyl 2-methylene-6-(3-oxomorpholine)tetrahydro-1H-pyrrolidine-7a(5H)-carboxylic acid (800 mg) as a pale yellow solid. m / z: [M+Na] + 281.2.

[0802] Step 6: Under ice bath conditions, sodium borohydride (135 mg, 3.56 mmol) was added to a methanol (10 mL) solution of methyl 2-methylene-6-(3-oxomorpholine)tetrahydro-1H-pyrrolidine-7a(5H)-carboxylic acid (800 mg, 2.8 mmol) and calcium chloride (1 g). The reaction system was stirred at room temperature for 4 hours, the reaction was quenched with acetone, and the mixture was concentrated under reduced pressure. The residue was purified by Flash column chromatography (methanol / dichloromethane = 0%-15%) to give intermediate 11 (400 mg) as a pale yellow oil, m / z: [M+Na]. + 253.2.

[0803] Intermediate 12: Synthesis of 4-((2R)-(7a-(hydroxymethyl)-6-methylenetetrahydro-1H-pyrrolazin-2-yl)morpholin-3-one

[0804] Step 1: Under ice bath conditions, 2-((tert-butyl)-2-methyl(2S,4R)-4-aminopyrrolidine-1,2-dicarboxylic acid ester (25 g, 102 mmol) was added to a mixed solution of dichloromethane (200 mL) and methanol (50 mL). The reaction solution was stirred at room temperature for 1 hour. Then, sodium triacetoxyborohydride (26 g, 123 mmol) was added to the above reaction solution, and stirring was continued for 3 hours. The reaction was quenched with water, and the aqueous phase was extracted with dichloromethane. The organic phases were combined and concentrated under reduced pressure. The residue was purified by Flash column chromatography (ethyl acetate / petroleum ether = 0%-30%) to give 1-(tert-butyl)-2-methyl(2S,4R)-4-((2-((tert-butyldimethylsilyl)oxy)ethyl)amino)pyrrolidine-1,2-dicarboxylic acid ester (16 g) as a pale yellow oil. m / z: [M+H] + 403.2.

[0805] Step 2: Under ice bath conditions, chloroacetyl chloride (5.8 g, 51.7 mmol) was added to a dichloromethane (80 ml) solution of 1-(tert-butyl)-2-methyl(2S,4R)-4-(N-(2-((tert-butyldimethylsilyl)oxy)ethyl)amino)pyrrolidine-1,2-dicarboxylic acid ester (16 g, 39.7 mmol) and triethylamine (6 g, 39.7 mmol). The reaction solution was stirred at this temperature for 1 hour. The reaction was quenched by adding saturated sodium bicarbonate aqueous solution. The aqueous phase was extracted with dichloromethane. The organic phases were combined and concentrated under reduced pressure to obtain 1-(tert-butyl)-2-methyl(2S,4R)-4-(N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-chloroacetamido)pyrrolidine-1,2-dicarboxylic acid ester (16 g) as a pale yellow oil. m / z: [M+Na] + 501.2.

[0806] Step 3: Under ice bath conditions, tetrabutylammonium fluoride (5.5 g, 20.9 mmol) was added dropwise to a tetrahydrofuran (40 mL) solution of 1-(tert-butyl)2-methyl(2S,4R)-4-(N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-chloroacetamido)pyrrolidine-1,2-dicarboxylic acid ester (10 g, 20.9 mmol). The reaction mixture was stirred overnight at room temperature and concentrated under reduced pressure. The residue was purified by Flash column chromatography (ethyl acetate / petroleum ether = 0%-70%) to give 1-(tert-butyl)2-methyl(2S,4R)-4-(2-chloro-N-(2-hydroxyethyl)acetamido)pyrrolidine-1,2-dicarboxylic acid ester (2.3 g) as a yellow oil. m / z: [M+Na] + 387.2.

[0807] Step 4: Under ice bath conditions, sodium hydroxide (220 mg, 5.54 mmol) was added to a tetrahydrofuran (10 mL) solution of 1-(tert-butyl)-2-methyl(2S,4R)-4-(2-chloro-N-(2-hydroxyethyl)acetamido)pyrrolidine-1,2-dicarboxylic acid ester (2.3 g, 5.04 mmol). The reaction mixture was stirred at room temperature for 1 hour, and the reaction was quenched by adding saturated ammonium chloride aqueous solution. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined and concentrated under reduced pressure. The residue was purified by Flax column chromatography (ethyl acetate / petroleum ether = 0-60%) to give 1-(tert-butyl)-2-methyl(2S,4R)-4-(3-oxomorpholine)pyrrolidine-1,2-dicarboxylic acid ester (1.1 g) as a pale yellow oil. m / z: [M+Na] + 351.2.

[0808] Step 5: At -78°C, add dropwise a tetrahydrofuran solution (3.0 mL, 1.0 M) of potassium bis(trimethylsilyl)amino in 8 mL of a tetrahydrofuran solution of 1-(tert-butyl)-2-methyl(2S,4R)-4-(3-oxomorpholine)pyrrolidine-1,2-dicarboxylic acid ester (1.1 g, 3.35 mmol) to the above reaction solution. Stir the reaction solution at this temperature for 1 hour. Then add 3-chloro-2-chloromethylpropene (840 mg, 6.7 mmol) to the above reaction solution, and allow the reaction system to naturally warm to room temperature and stir overnight. The reaction was quenched by adding a saturated aqueous solution of ammonium chloride. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined and concentrated under reduced pressure. The residue was purified by Flash column chromatography (ethyl acetate / petroleum ether = 0%-35%) to give 1-(tert-butyl)-2-methyl(4R)-2-(2-(chloromethyl)allyl)-4-(3-oxomorpholine)pyrrolidine-1,2-dicarboxylic acid ester (630 mg) as a pale yellow oil. m / z: [M+Na] + 351.2.

[0809] Step 6: Under ice bath conditions, 1,4-dioxane hydrochloride (1.5 mL, 4 M) was added to a solution of 1-(tert-butyl)-2-methyl(4R)-2-(2-(chloromethyl)allyl)-4-(3-oxomorpholine)pyrrolidine-1,2-dicarboxylic acid ester (630 mg, 1.5 mmol) in dichloromethane (2 mL). The reaction mixture was stirred at room temperature for 3 hours and concentrated under reduced pressure. The residue was dissolved in methanol (2 mL), and the pH was adjusted to >7 with ammonia methanol solution (7 M). The resulting mixture was directly concentrated under reduced pressure to obtain (6R)-2-methylene-6-(3-oxomorpholine)tetrahydro-1H-pyrrolidine-7a(5H)-carboxylic acid methyl ester (0.6 g) as a pale yellow solid. m / z: [M+Na] + 281.2.

[0810] Methyl (6R,7aS)-2-methylene-6-(3-oxomorpholine)tetrahydro-1H-pyrrolidine-7a(5H)-carboxylate was prepared by prep-HPLC (elution with 0%–5% acetonitrile in 10 mM ammonium bicarbonate aqueous solution for 5 min; 5%–50% acetonitrile in 10 mM ammonium bicarbonate aqueous solution for 20 min). Both (6R,7aR)-2-methylene-6-(3-oxomorpholine)tetrahydro-1H-pyrrolidine-7a(5H)-carboxylate were pale yellow oily substances, m / z: [M+Na]. + 281.2.

[0811] Step 7: Under ice bath conditions, sodium borohydride (135 mg, 3.56 mmol) was added to (6R)-2-methylene-6-(3-oxomorpholine)tetrahydro-1H-pyrrolidine-7a(5H)-carboxylic acid methyl ester (0.5 g, 1.78 mmol) and calcium chloride (0.5 g, 5 mmol) in tetrahydrofuran (5 mL), and the mixture was stirred for 4 hours. The reaction was quenched with acetone and concentrated under reduced pressure. The residue was purified by Flash column chromatography (methanol / dichloromethane = 0%-15%) to give intermediate 12 (0.3 g) as a pale yellow oil, m / z: [M+Na]. + 253.2.

[0812] Using the synthetic method of intermediate 12, 4-((2R,7aS)-(7a-(hydroxymethyl)-6-methylenetetrahydro-1H-pyrrolidine-7a(5H)-carboxylic acid methyl ester was reacted to give 4-((2R,7aS)-(7a-(hydroxymethyl)-6-methylenetetrahydro-1H-pyrrolazin-2-yl)morpholin-3-one (intermediate 12-1 or 12-2).

[0813] Using the synthetic method of intermediate 12, 4-((2R,7aR)-(7a-(hydroxymethyl)-6-methylenetetrahydro-1H-pyrrolidine-7a(5H)-carboxylic acid methyl ester was reacted to give 4-((2R,7aR)-(7a-(hydroxymethyl)-6-methylenetetrahydro-1H-pyrrolazin-2-yl)morpholin-3-one (intermediate 12-1 or 12-2).

[0814] Intermediate 13: Synthesis of 3-((2R)-7a-(hydroxymethyl)-6-methylenetetrahydro-1H-pyrrolazin-2-yl)oxazolidin-2-one

[0815] Step 1: Under ice bath conditions, methyl chloroformate (5.37 g, 56.9 mmol) was added to a solution of 1-(tert-butyl)2-methyl(2S,4R)-4-((2-((tert-butyldimethylsilyl)oxy)ethyl)amino)pyrrolidine-1,2-dicarboxylic acid ester (32.7 g, 81.2 mmol) and triethylamine (8.2 g, 81.2 mmol) in dichloromethane (300 ml). The reaction mixture was brought to room temperature and stirred overnight. The reaction system was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain 1-(tert-butyl)2-methyl(2S,4R)-4-(N-(2-((tert-butyldimethylsilyl)oxy)ethyl)(methoxycarbonyl)amino)pyrrolidine-1,2-dicarboxylic acid ester (21.2 g) as a pale yellow oil. m / z: [M+Na] + 483.2.

[0816] Step 2: Under ice bath conditions, a tetrabutylammonium fluoride solution (1M, 6.5mL) in tetrahydrofuran was added dropwise to a toluene (10mL) solution of 1-(tert-butyl)2-methyl(2S,4R)-4-(N-(2-((tert-butyldimethylsilyl)oxy)ethyl)(methoxycarbonyl)amino)pyrrolidine-1,2-dicarboxylic acid ester (2g, 4.34mmol). The reaction mixture was stirred at room temperature for 3 days and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give 1-(tert-butyl)2-methyl(2S,4R)-4-(2-oxaoxazolidine-3-yl)pyrrolidine-1,2-dicarboxylic acid ester (750mg) as a colorless oil. m / z: [M+Na] + 337.2.

[0817] Step 3: At -65°C, a tetrahydrofuran solution (1M, 3.6mL) of potassium bis(trimethylsilyl)amino in tetrahydrofuran was added dropwise to an 8mL solution of (2S,4R)-4-(2-oxazolinone-3-yl)pyrrolidine-1,2-dicarboxylate (750mg, 2.39mmol). The reaction mixture was stirred at this temperature for 30 minutes. Then, 3-chloro-2-chloromethylpropene (600mg, 4.8mmol) was added to the above reaction mixture, and the reaction system was allowed to rise naturally to room temperature and stirred for 3 hours. The reaction was quenched with a saturated aqueous solution of ammonium chloride. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined and concentrated under reduced pressure to obtain 1-(tert-butyl)-2-methyl(4R)-2-(2-(chloromethyl)allyl)-4-(2-oxazolinone-3-yl)pyrrolidine-1,2-dicarboxylate (1.1g) as a yellow oil. m / z: [M+Na] + 425.2.

[0818] Step 4: Under ice bath conditions, trifluoroacetic acid (3 mL) was added to a solution of 1-(tert-butyl)-2-methyl(4R)-2-(2-(chloromethyl)allyl)-4-(2-oxaoxazolidine-3-yl)pyrrolidine-1,2-dicarboxylic acid ester (1.1 g, 2.7 mmol) in dichloromethane (5 mL). The reaction mixture was stirred overnight at room temperature and concentrated under reduced pressure. The residue was dissolved in methanol (2 mL), and the pH was adjusted to 8 with ammonia-methanol solution (7 M). The resulting mixture was directly concentrated under reduced pressure to obtain (6R)-2-methylene-6-(2-oxaoxazolidine-3-yl)tetrahydro-1H-pyrrolidine-7a(5H)-carboxylic acid methyl ester (0.5 g) as a colorless oil. m / z: [M+H] + 267.2.

[0819] Step 5: Sodium borohydride (190 mg, 5.07 mmol) was added to a solution of (6R)-2-methylene-6-(2-oxaoxazolidine-3-yl)tetrahydro-1H-pyrrolidine-7a(5H)-carboxylic acid methyl ester (190 mg, 5.07 mmol) and calcium chloride (0.5 g, 5 mmol) in tetrahydrofuran (5 mL). The reaction mixture was stirred at room temperature for 2 days. The reaction system was diluted with ethyl acetate and filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure, and the residue was purified by Flash column chromatography (methanol / dichloromethane = 0%-15%) to give intermediate 13 (209 mg) as a colorless oil, m / z: [M+H]. + 239.2.

[0820] Intermediate 17: Synthesis of 4-methoxy-N,N-methylpyrrolidine-3-amine (trans)

[0821] Step 1: To a methanol (5 mL) solution of tert-butyl 3-amino-4-methoxypyrrolidine-1-carboxylate (trans) (500 mg, 2.31 mmol), formaldehyde solution (37%, 0.94 g, 11.6 mmol) and acetic acid (28 mg, 0.46 mmol) were added. The reaction mixture was stirred at room temperature for 0.5 hours. Sodium cyanoborohydride (580 mg, 9.24 mmol) was added, and the reaction mixture was stirred overnight at room temperature. The solution was diluted with ethyl acetate, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was purified by Flash column chromatography (dichloromethane / methanol = 20 / 1) to give tert-butyl 3-(dimethylamino)-4-methoxypyrrolidine-1-carboxylate (trans) (499 mg) as a colorless oil. m / z: [M+H] + 245.2.

[0822] Step 2: A solution of tert-butyl 3-(dimethylamino)-4-methoxypyrrolidine-1-carboxylate (trans) (499 mg, 2.1 mmol) in 1,4-dioxane hydrogen chloride (4 M, 5 mL) was stirred at room temperature for 3 hours, concentrated under reduced pressure, and the residue was concentrated under reduced pressure with dichloromethane solution to obtain intermediate 17 (400 g) as an off-white solid. m / z: [M+H] + 145.2.

[0823] Intermediate 18: Synthesis of (3R,4S)-4-fluoro-N,N-dimethylpyrrolidine-3-amine

[0824] Step 1: A mixture of (3R,4S)-3-amino-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester (250 mg, 1.22 mmol), formaldehyde aqueous solution (37%, 325 mg, 4 mmol), palladium on carbon (10%, 50 mg), and methanol (5 mL) was purged with nitrogen and stirred at room temperature for 3 hours under a hydrogen atmosphere. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain (3R,4S)-3-(dimethylamino)-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester (280 mg) as a light brown gel. m / z: [M+H] + 233.2.

[0825] Step 2: A hydrogen chloride-methanol solution (4M, 5mL) of (3R,4S)-3-(dimethylamino)-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester (280 mg, 1.21 mmol) was stirred at 60 °C for 2 hours. The reaction system was cooled to room temperature and concentrated under reduced pressure to give intermediate 18 (150 mg, hydrochloride) as a light brown gel. m / z: [M+H] + 133.2.

[0826] Synthesis of Intermediate 24: 4'-Methoxy-1,3'-Dipyrrolidine (trans)

[0827] Step 1: Palladium on carbon (10%, 50 mg) was added to a methanol solution of 200 mg (0.92 mmol) and 1 mL (40%) of succinaldehyde aqueous solution in 5 mL of 3-amino-4-methoxypyrrolidine-1-carboxylic acid tert-butyl ester (trans) and 1 mL of succinaldehyde aqueous solution. The reaction system was stirred at room temperature for 2 hours under a hydrogen atmosphere. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain 385 mg (385 mg) of 4'-methoxy-[1,3'-dipyrrolidine]-1'-carboxylic acid tert-butyl ester as a yellow oily liquid. m / z: [M+H] + 271.1.

[0828] Step 2: A solution of 4'-methoxy-[1,3'-dipyrrolidine]-1'-carboxylic acid tert-butyl ester (285 mg, 1.42 mmol) in 1,4-dioxane hydrochloride (4 M, 5 mL) was stirred at 60 °C for 2 hours. After cooling, the solution was concentrated under reduced pressure to obtain intermediate 24 (330 mg) as a brown solid. m / z: [M+H] + 171.2.

[0829] Intermediate 25: Synthesis of N-((3R,4S)-4-fluoropyrrolidone-3-yl)-N-methylcyanamide

[0830] Step 1: Under ice bath conditions, benzyl chloroformate (620 mg, 3.66 mmol) was added to a mixed solution of (3R,4S)-3-amino-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester (250 mg, 1.22 mmol), sodium carbonate (650 mg, 6.1 mmol), tetrahydrofuran (4 mL), and water (4 mL). The reaction mixture was stirred at room temperature for 1 hour. The solution was concentrated under reduced pressure, and the residue was purified by Flash column chromatography (tetrahydrofuran / petroleum ether = 1 / 50-1 / 9) to give (3R,4S)-3-(((benzyloxy)carbonyl)amino)-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester (305 mg) as a colorless gel. m / z: [M+H] + 339.2.

[0831] Step 2: Under ice bath conditions, sodium hydrogen (180 mg, 4.5 mmol) was added to a tetrahydrofuran (4 mL) solution of (3R,4S)-3-(((benzyloxy)carbonyl)(methyl)amino)-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester (305 mg, 0.9 mmol). The reaction system was stirred at this temperature for 30 minutes, and iodomethane (260 mg, 1.8 mmol) was added. The reaction solution was stirred at room temperature for 1 hour, and the reaction was quenched with water. The aqueous phase was extracted with ethyl acetate, the organic phases were combined and concentrated under reduced pressure, and the residue was purified by Flash column chromatography (ethyl acetate / petroleum ether = 1 / 20-4 / 1) to obtain (3R,4S)-3-(((benzyloxy)carbonyl)(methyl)amino)-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester (275 mg) as a colorless gel. m / z: [M+H] + 353.2.

[0832] Step 3: Add palladium hydroxide / carbon (10%, 0.25 g) to a methanol (15 mL) solution of (3R,4S)-3-(((benzyloxy)carbonyl)(methyl)amino)-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester (275 mg, 0.78 mmol). After purging the reaction system with nitrogen, stir at room temperature for 16 hours under a hydrogen atmosphere, filter, and concentrate the filtrate under reduced pressure to obtain (3S,4R)-3-fluoro-4-(methylamino)pyrrolidine-1-carboxylic acid tert-butyl ester (155 mg) as a light brown gel. m / z: [M+H] + 219.2.

[0833] Step 4: Add sodium bicarbonate aqueous solution (1M, 20mL) and cyanogen bromide (0.25g, 2.37mmol) to a solution of (3S,4R)-3-fluoro-4-(N-methylcyanamido)pyrrolidine-1-carboxylic acid tert-butyl ester (0.28g, 1.28mmol) in dichloromethane (20mL). Stir the reaction solution at room temperature for 2 hours. Dilute the reaction solution with water, extract the aqueous phase with dichloromethane, combine the organic phases and concentrate under reduced pressure to obtain (3S,4R)-3-fluoro-4-(N-methylcyanamido)pyrrolidine-1-carboxylic acid tert-butyl ester (280mg) as a yellow gel.

[0834] Step 5: A solution of (3S,4R)-3-fluoro-4-(N-methylcyanamido)pyrrolidine-1-carboxylic acid tert-butyl ester (0.28 g, 1.15 mmol) in 1,4-dioxane-4-hydrochloride (4 M, 10 mL) was stirred at room temperature for 3 hours. The solution was then directly concentrated to give intermediate 25 (160 mg) as a brown gel.

[0835] Synthesis of Intermediate 26: 4-(dimethylamino)pyrrolidine-3-nitrile

[0836] Step 1: Under ice bath conditions, sodium borohydride (360 mg, 9.52 mmol) was added to a solution of tert-butyl 3-cyano-4-oxopyrrolidine-1-carboxylate (1 g, 4.76 mmol) in tetrahydrofuran (15 mL) and ethanol (3 mL). The reaction mixture was stirred at room temperature for 1 hour, then quenched in ice water. The aqueous phase was extracted with ethyl acetate. The organic phases were combined and concentrated under reduced pressure to obtain tert-butyl 3-cyano-4-hydroxypyrrolidine-1-carboxylate (1 g) as a yellow gel. m / z: [M+H] + 213.2.

[0837] Step 2: At -10℃, N,N-diisopropylethylamine (570 mg, 4.38 mmol) and methanesulfonic anhydride (509 mg, 2.92 mmol) were added sequentially to a dichloromethane (10 mL) solution of 3-cyano-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (310 mg, 1.46 mmol). The reaction system was stirred at this temperature for 1 hour. The reaction solution was then poured into a saturated sodium bicarbonate aqueous solution. The aqueous phase was extracted with dichloromethane. The organic phases were combined and concentrated under reduced pressure to obtain 3-cyano-4-((methanesulfonyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (424 mg) as a brown gel. m / z: [M+Na] + 313.1.

[0838] Step 3: A 2M, 5mL solution of tert-butyl 3-cyano-4-((methanesulfonyl)oxy)pyrrolidine-1-carboxylate (424 mg, 1.46 mmol) in tetrahydrofuran (2 M) was stirred overnight at room temperature. The solution was concentrated under reduced pressure, and the residue was purified by Flash column chromatography (dichloromethane / methanol / triethylamine = 100–100 / 10 / 1) to give tert-butyl 3-cyano-4-(dimethylamino)pyrrolidine-1-carboxylate (40 mg) as a yellow oil. m / z: [M+H] + 240.2.

[0839] Step 4: Add 1 mL of trifluoroacetic acid to a solution of 50 mg (0.21 mmol) of tert-butyl 3-cyano-4-(dimethylamino)pyrrolidine-1-carboxylate in 2 mL of dichloromethane. Stir the reaction mixture at room temperature for 1 hour, then concentrate under reduced pressure to obtain intermediate 26 (29.4 mg) as a yellow oil. m / z: [M+H] + 140.2.

[0840] Intermediate 27: Synthesis of (4-methoxypyrrolidone-3-yl)(methyl)carbamate benzyl ester

[0841] Step 1: Benzyl chloroformate (510 mg, 3 mmol) was added to a mixed solution of tert-butyl 3-amino-4-methoxypyrrolidine-1-carboxylate (226 mg, 1.05 mmol), sodium carbonate (318 mg, 3 mmol), tetrahydrofuran (15 mL), and water (15 mL). The reaction mixture was stirred at 20 °C for 2 hours. The reaction was quenched with water, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined and concentrated under reduced pressure. The residue was purified by Flash column chromatography (tetrahydrofuran / petroleum ether = 1 / 50-1 / 10) to give tert-butyl 3-(((benzyloxy)carbonyl)amino)-4-methoxypyrrolidine-1-carboxylate (350 mg) as a colorless gel. m / z: [M+H] + 351.1.

[0842] Step 2: A solution of tert-butyl 3-(((benzyloxy)carbonyl)amino)-4-methoxypyrrolidine-1-carboxylate (1.24 g, 3.5 mmol), methyl iodoform (710 mg, 5 mmol), and sodium hydroxide (60%, 200 mg, 5 mmol) in tetrahydrofuran (15 mL) was stirred at 0 °C for 1 hour. The reaction was quenched with water (50 mL). The aqueous phase was extracted with ethyl acetate. The organic phases were combined and concentrated under reduced pressure. The residue was purified by Flash column chromatography (ethyl acetate / petroleum ether = 1 / 20-4 / 1) to obtain tert-butyl 3-(((benzyloxy)carbonyl)(methyl)amino)-4-methoxypyrrolidine-1-carboxylate (340 mg) as a colorless gel. m / z: [M+H] + 365.2.

[0843] Step 3: Add trifluoroacetic acid (5 mL) to a solution of tert-butyl 3-(((benzyloxy)carbonyl)(methyl)amino)-4-methoxypyrrolidine-1-carboxylate (182 mg, 0.5 mmol) in dichloromethane (2 mL). Stir the reaction mixture at room temperature for 2 hours, concentrate under reduced pressure, add ethyl acetate (10 mL) to the residue, adjust the pH to approximately 10 with saturated sodium carbonate aqueous solution, separate the organic phase, and concentrate under reduced pressure to obtain intermediate 27 (180 mg) as a yellow oil. m / z: [M+H] + 265.2.

[0844] Intermediate 28: Synthesis of 1-(4-methoxypyrrolidone-3-yl)azacyclobut-3-ol

[0845] Step 1: To a solution of tert-butyl 3-methoxy-4-((methanesulfonyl)oxy)pyrrolidine-1-carboxylate (660 mg, 2.23 mmol) in N,N-dimethylformamide (10 mL), aziridine-3-ol (327 mg, 4.47 mmol) and potassium carbonate (1.54 g, 11.2 mmol) were added sequentially. The reaction mixture was stirred at 120 °C for 16 hours. The reaction solution was then poured into water, and the pH was adjusted to >10 with sodium hydroxide aqueous solution (1 M). The aqueous phase was extracted with ethyl acetate, and the organic phases were combined and concentrated under reduced pressure. The residue was purified by Flash column chromatography (dichloromethane / methanol / triethylamine = 10 / 1 / 0.1) to obtain tert-butyl 3-(3-hydroxyaziridine-1-yl)-4-methoxypyrrolidine-1-carboxylate (160 mg). m / z: [M+H] + 273.2.

[0846] Step 2: Add trifluoroacetic acid (1 mL) to a solution of tert-butyl 3-(3-hydroxyazacyclobut-1-yl)-4-methoxypyrrolidine-1-carboxylate (160 mg, 0.59 mmol) in dichloromethane (2 mL). Stir the reaction mixture at room temperature for 1 hour, then concentrate under reduced pressure to obtain intermediate 28 (100 mg). m / z: [M+H] + 173.2.

[0847] Using the synthesis methods of intermediate 9, intermediate 17, or intermediate 18, the intermediates shown in Table 1 below were synthesized:

[0848] Table 1

[0849] Compound synthesis:

[0850] Example 1: Synthesis of 2-amino-4-((7R)-4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-8-fluoro-2-(((6R)-2-methylene-6-morpholinotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolino-7-yl)benzo[b]thiophene-3-onitrile (compound 1-1-1) and 2-amino-4-((7S)-4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-8-fluoro-2-(((6R)-2-methylene-6-morpholinotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolino-7-yl)benzo[b]thiophene-3-onitrile (compound 1-1-2)

[0851] Step 1: A mixture of 7-bromo-2,6-dichloro-8-fluoroquinazoline-4-ol (1.09 g, 3.49 mmol), intermediate 7 (2.92 g, 6.98 mmol), potassium phosphate (2.22 g, 10.5 mmol), and 1,1'-bis(di-tert-butylphosphine)ferrocene dichloropalladium (230 mg, 0.35 mmol) in 1,4-dioxane (25 mL) was purged three times with nitrogen. The reaction system was stirred at 90 °C for 2 hours under nitrogen protection. After cooling the reaction solution to room temperature, the reaction was quenched in water. The aqueous phase was extracted with ethyl acetate, the combined organic layers were washed with saturated brine, the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Flash column chromatography (C18, eluent: 0%–75% acetonitrile in 0.1% trifluoroacetic acid aqueous solution) to give compound 1A (650 mg, yield: 36%) as a pale yellow solid. m / z: [M+H] + 523.0.

[0852] Step 2: Under ice bath conditions, sodium hydroxide (380 mg, 9.6 mmol, 60%) was added to a solution of intermediate 9 (400 mg, 1.7 mmol) in N,N-dimethylformamide (10 mL). The reaction system was stirred at room temperature for 1 hour. Compound 1A (500 mg, 0.96 mmol) was added to the above reaction system, and the reaction solution was stirred at 90 °C for 0.5 hours. The reaction solution was poured into a saturated ammonium chloride aqueous solution to quench the reaction. Citric acid solid was added to adjust the pH to 6-7. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated brine. The organic phase was separated and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Flash column chromatography (C18, eluent: 0%-80% acetonitrile in 10 mM ammonium bicarbonate aqueous solution) to give compound 1B (450 mg, yield: 65%) as a pale yellow solid. m / z: [M+H] + 725.2.

[0853] Step 3: A solution of compound 1B (150 mg, 0.18 mmol), 1H-benzotriazol-1-yloxytripyrrolyl hexafluorophosphate (PyBOP) (190 mg, 0.36 mmol), and N,N-diisopropylethylamine (120 mg, 0.9 mmol) in dimethyl sulfoxide (3 mL) was stirred at room temperature for 30 minutes. Intermediate 1 (54 mg, 0.36 mmol) was added to the above reaction solution, and the reaction system was stirred at room temperature for another 2 hours. The reaction solution was directly purified by Flash column chromatography (C18, eluent: 0%–95% acetonitrile in 10 mM ammonium bicarbonate aqueous solution) to give compound 1C (85 mg, yield: 56%) as an off-white solid. m / z: [M+H] + 858.4.

[0854] Step 4: Add 1 mL of trifluoroacetic acid to a 3 mL solution of compound 1C (85 mg, 0.1 mmol) in dichloromethane. Stir the reaction mixture at room temperature for 2 hours. Concentrate the reaction mixture directly under reduced pressure and adjust the pH to neutral with ammonia-methanol solution (7 M). Purify the residue by prep-HPLC (elution of 15%–60% acetonitrile in 10 mM ammonium bicarbonate aqueous solution for 20 min) to obtain compounds 1-1-1 (19.7 mg, yield: 25%) and 1-1-2 (19.2 mg, yield: 25%), both of which are off-white solids.

[0855] Compound 1-1-1: UPLC retention time 5.005 min; m / z [M+H] + 758.2; 1H NMR (400MHz, CD3OD): δ8.09(s,1H),7.96-7.92(m,1H),7.79-7.73(m,1H),7.24-7.18(m,1H),7.05-7.01(m,1H),6.80-6.76(m,1H),6.25-6. 17(m,1H),4.96(s,2H),4.60(s,3H),4.33(s,1H),3.76-3.70(m,1H), 3.69-3.61(m,4H),3.38-3.32(m,1H),3.25-3.17(m,3H),3.09-2.97(m 2H),2.82-2.68(m,1H),2.59-2.41(m,5H),2.26-2.17(m,1H),2.04-1.94(m,1H),1.76-1.68(m,3H).

[0856] Compound 1-1-2: UPLC retention time 5.262 min; m / z [M+H] + 758.2; 1 H NMR (400MHz, CD3OD): δ8.01(s,1H),7.89-7.85(m,1H),7.70-7.66(m,1H),7.16-7.10(m,1H) ,7.01-6.95(m,1H),6.72-6.66(m,1H),6.15-6.11(m,1H),4.90(s,2H),4.54(s,2H),4.42-4 .18(m,2H),3.72-3.54(m,5H),3.36-3.28(m,1H),3.18-3.12(m,3H),2.97-2.93(m,2H),2.7 4-2.66(m,1H),2.58-2.29(m,5H),2.15-2.11(m,1H),1.94-1.87(m,1H),1.67-1.60(m,3H).

[0857] Compound 1-1-1 (28 mg) was resolved by SFC (Method 2) to obtain compounds 1-1-3 (14 mg, a single stereoisomer, UPLC retention time of 5.064 min, UPCC retention time of 3.284 min (Method 3)) and 1-1-4 (10 mg, a single stereoisomer, UPLC retention time of 5.075 min, UPCC retention time of 4.547 min (Method 3)), both of which were white solids.

[0858] Example 2: Synthesis of 7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-N-((R)-1-(2-aminopyridin-3-yl)ethyl)-6-chloro-8-fluoro-N-methyl-2-(((6R)-2-methylene-6-morpholinotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolino-4-amine (1-4-1 or 1-4-2)

[0859] Step 1: Under ice bath conditions, an aqueous solution of sodium methanethiol (20%, 2.54 g, 7.26 mmol) was added to a tetrahydrofuran (20 mL) solution of 7-bromo-2,4,6-trichloro-8-fluoroquinoline (1.6 g, 4.84 mmol). The reaction mixture was stirred at 0 °C for 5 hours, water was added to precipitate the solid, which was filtered and the filter cake was dried under vacuum to give compound 2A (1.66 g, yield: 100%) as a white solid. m / z: [M+H] + 341.0.

[0860] Step 2: A solution of compound 2A (600 mg, 1.75 mmol), triethylenediamine (12 mg, 0.1 mmol), methanesulfonic acid (10 mg, 0.1 mmol), and potassium fluoride (339 mg, 5.84 mmol) in dimethyl sulfoxide (6 mL) was stirred at 65 °C for 13 hours. The reaction mixture was poured into ice water, filtered, and the filter cake was slurried with a small amount of ethyl acetate, filtered again, and vacuum dried to give compound 2B (400 mg, yield: 70%) as a yellow solid. m / z: [M+H] + 325.0.

[0861] Step 3: At -70°C, a 2-methyltetrahydrofuran solution (1.3M, 1.86mL) of magnesium isopropyl chloride-lithium chloride in 15mL of isopropyl magnesium chloride was added to the anhydrous tetrahydrofuran solution of compound 2B (750mg, 2.3mmol). The reaction mixture was stirred at this temperature for 30 minutes, followed by the addition of a 2-methyltetrahydrofuran solution of zinc chloride (1.9M, 941mg). The reaction mixture was gradually brought to room temperature and stirred for 1 hour, then intermediate 5 (750mg, 1.51mmol) and tetra(triphenylphosphine)palladium (870mg, 0.76mmol) were added. The reaction system was purged with nitrogen three times, stirred at 85°C for 1.5 hours under a nitrogen atmosphere, cooled to room temperature, and quenched with dilute hydrochloric acid (1M). The aqueous phase was extracted with ethyl acetate, and the organic phases were combined and concentrated under reduced pressure. The residue was purified by Flash column chromatography (ethyl acetate / petroleum ether = 1 / 8) to give compound 2C (240mg, yield: 16%) as a yellow solid. m / z:[M+H] + 661.2.

[0862] Step 4: Under ice bath conditions, a tetrahydrofuran solution of potassium tert-butoxide (1.8 mL, 1 M) and intermediate 9 (317 mg, 1.33 mmol) were added to a tetrahydrofuran solution of compound 2C (800 mg, 1.21 mmol) (5 mL). The reaction mixture was stirred at room temperature for 1 hour, and the reaction was quenched with a saturated aqueous solution of ammonium chloride. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined and concentrated under reduced pressure. The residue was purified by prep-TLC (methanol / dichloromethane = 1 / 20) to give compound 2D (340 mg, yield: 32%) as an off-white solid. m / z: [M+H] + 879.2.

[0863] Step 5: Lithium hydroxide monohydrate (82 mg, 1.95 mmol) was added to a mixed solution of compound 2D (340 mg, 0.39 mmol) in tetrahydrofuran (5 mL) and water (1.2 mL). The reaction mixture was stirred at 65 °C for 18 hours, and the pH was adjusted to 7 with dilute hydrochloric acid (1.3 M). The solution was then concentrated under reduced pressure. The residue was purified by prep-TLC (methanol / dichloromethane = 1 / 20) to give compound 2E (50 mg, yield: 15%) as an off-white solid. m / z: [M+H] + 849.2.

[0864] Step 6: A solution of compound 2E (100 mg, 0.12 mmol), PyBOP (94 mg, 0.18 mmol), and N,N-diisopropylethylamine (46.5 mg, 0.36 mmol) in dimethyl sulfoxide (3 mL) was stirred at room temperature for 30 minutes. Intermediate 1 (54.4 mg, 0.36 mmol) was added to the above reaction solution, and the reaction system was stirred at room temperature for another 2 days. The reaction solution was directly purified by prep-HPLC (5%–45% acetonitrile in 10 mM ammonium bicarbonate aqueous solution, elution time 20 min) to give compound 2F (60 mg, yield: 52%) as a yellow solid. m / z: [M+H] + 982.4.

[0865] Step 7: Add 1.5 mL of trifluoroacetic acid to a 1 mL solution of compound 2F (50 mg, 0.051 mmol) in dichloromethane. Heat the reaction mixture under reflux and stir overnight. Concentrate the reaction mixture directly under reduced pressure. Purify the residue by prep-HPLC (elution with 15%–85% acetonitrile in 10 mM ammonium bicarbonate aqueous solution for 20 min) to obtain compounds 1-2-1 (transisomer 1, 10 mg, yield: 25%) and 1-2-2 (transisomer 2, 2.3 mg, yield: 6%), both of which are off-white solids.

[0866] Compound 1-4-1: Short UPLC retention time, 4.403 min; m / z [M+H] + 742.4.

[0867] Compound 1-4-2: Short UPLC retention time, 5.012 min; m / z [M+H] + 742.4.

[0868] Example 3: 4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-8-fluoro-2-((((6R)-2-methylene-6-morpholinotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthyl-2-ol . Synthesis of trifluoroacetate (1-8)

[0869] Step 1: At -60°C, trifluoroethanol (1.98 g, 19.8 mmol) and a tetrahydrofuran solution of potassium tert-butoxide (1 M, 19.8 mL) were added sequentially to a tetrahydrofuran solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (5 g, 19.8 mmol) (50 mL). The reaction mixture was stirred at this temperature for 2 hours, the reaction was quenched with water, the aqueous phase was extracted with ethyl acetate, the organic phases were combined and concentrated under reduced pressure, the residue was slurried with petroleum ether, filtered, and the filter cake was dried under vacuum to give compound 3A (4.68 g, yield: 75%) as a pale yellow solid. m / z[M+H] + 346.2.

[0870] Step 2: A solution of compound 3A (500 mg, 1.58 mmol), intermediate 9 (414 mg, 1.74 mmol), and N,N-diisopropylethylamine (612 mg, 4.74 mmol) in 1,4-dioxane (15 mL) was stirred at 65 °C for 16 hours. The reaction mixture was poured into ice water, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined and concentrated under reduced pressure. The residue was purified by Flash column chromatography (petroleum ether / ethyl acetate = 4 / 1 to 1 / 1) to give compound 3B (410 mg, yield: 50%) as a yellow solid. m / z [M+H] + 518.2.

[0871] Step 3: A solution of compound 3B (160 mg, 0.31 mmol), 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxoborane (168 mg, 0.46 mmol), methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (cataCXiumA Pd G3) (34 mg, 0.05 mmol), and tripotassium phosphate (197 mg, 0.93 mmol) in tetrahydrofuran (6 mL) was purged three times with nitrogen, and then stirred at 60 °C for 6 hours under a nitrogen atmosphere. The reaction system was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the residue was purified by prep-TLC (dichloromethane / methanol = 1 / 20) to give compound 3C (160 mg, yield: 72%) as a yellow solid. m / z[M+H] + 716.4.

[0872] Step 4: A mixed solution of compound 3C (160 mg, 0.22 mmol) and lithium hydroxide monohydrate (28 mg, 0.66 mmol) in water (0.5 mL) and tetrahydrofuran (3 mL) was stirred at 65 °C for 4 hours. The reaction system was cooled to room temperature, extracted with ethyl acetate, and the organic phases were combined and concentrated under reduced pressure to give compound 3D (100 mg, yield: 71%) as a yellow solid. m / z [M+H] + 634.4.

[0873] Step 5: A solution of compound 3D (80 mg, 0.13 mmol), 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (101 mg, 0.2 mmol), and N,N-diisopropylethylamine (50.4 mg, 0.39 mmol) in dimethyl sulfoxide (3 mL) was stirred at room temperature for 30 minutes. Intermediate 1 (59 mg, 0.39 mmol) was added to the above system. The reaction mixture was stirred at room temperature for another 16 hours. The mixture was then purified directly by Flash column chromatography (C18, eluent: 0%–65% acetonitrile in 10 mM ammonium bicarbonate aqueous solution) to give compound 3E (60 mg, yield: 62%) as a white solid. m / z [M+H] + 767.4.

[0874] Step 6: Add 1 mL of trifluoroacetic acid to a 3 mL solution of compound 3E (80 mg, 0.1 mmol) in dichloromethane. Stir the reaction mixture at 0 °C for 2 hours. Concentrate the reaction mixture directly under reduced pressure. Purify the residue by prep-HPLC (elution with 10%–75% acetonitrile in 0.05% aqueous trifluoroacetic acid for 20 min) to give compounds 1-8 (4.5 mg, yield: 6%) as a white solid. UPLC retention time: 4.547 min; m / z [M+H] + 723.4.

[0875] Example 4: Synthesis of 2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-8-fluoro-2-(((6R)-2-methylene-6-(2-oxooxazolidine-3-yl)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-onitrile (1-9)

[0876] Step 1: Sodium hydroxide (116 mg, 2.9 mmol, 60%) was added to a solution of intermediate 13 (173 mg, 0.72 mmol) in N,N-dimethylformamide (10 mL). The reaction mixture was stirred at room temperature for 1 hour. Compound 1A (150 mg, 0.29 mmol) was added to the above reaction mixture, and the reaction solution was stirred at 90 °C for 1 hour. The reaction solution was poured into a saturated ammonium chloride aqueous solution to quench the reaction. Citric acid solid was added to adjust the pH to 6–7. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated brine. The organic phase was separated and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Flash column chromatography (C18, eluent: 0%–85% acetonitrile in 10 mM ammonium bicarbonate aqueous solution) to give compound 4A (60 mg, yield: 30%) as a pale yellow solid. m / z: [M+H] + 699.2.

[0877] Step 2: N,N-diisopropylethylamine (67 mg, 0.52 mmol) and N,N'-carbonyldiimidazole (70 mg, 0.43 mmol) were added to a solution of compound 4A (60 mg, 0.086 mmol) in N,N-dimethylformamide (2 mL). The reaction system was microwaved at 70 °C for 1 hour. The reaction solution was then purified directly by Flash column chromatography (C18, eluent: 0%–85% acetonitrile in 10 mM ammonium bicarbonate aqueous solution) to obtain compound 4B (35 mg, yield: 56%) as a pale yellow solid. m / z: [M+H] + 725.2.

[0878] Step 3: A solution of compound 4B (35 mg, 0.05 mmol), PyBOP (38 mg, 0.07 mmol), and N,N-diisopropylethylamine (19 mg, 0.14 mmol) in dimethyl sulfoxide (2 mL) was stirred at room temperature for 30 minutes. Intermediate 1 (22 mg, 0.14 mmol) was added to the above reaction solution, and the reaction system was stirred at room temperature for another 2 hours. The reaction solution was directly purified by Flash column chromatography (C18, eluent: 0%–85% acetonitrile in 0.1% trifluoroacetic acid aqueous solution) to give compound 4C (20 mg, yield: 48%) as a yellow solid. m / z: [M+H] + 858.2.

[0879] Step 4: Add 1 mL of trifluoroacetic acid to a 3 mL solution of compound 4C (20 mg, 0.023 mmol) in dichloromethane. Stir the reaction mixture at room temperature for 2 hours. Concentrate the reaction mixture directly under reduced pressure and adjust the pH to neutral with ammonia-methanol solution (7 M). Purify the residue by Flash column chromatography (C18, eluent: 0%–65% acetonitrile in 0.1% trifluoroacetic acid aqueous solution) to give compounds 1-9 (9 mg, yield: 51%) as a yellow solid. m / z: [M+H] + 758.3.

[0880] Example 5: Synthesis of 2-amino-4-((7R)-4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-2-(3-(dimethylamino)-4-methoxypyrrolidine-1-yl)-8-fluoroquinazoline-7-yl)-7-fluorobenzo[b]thiophene-3-onitrile (trans) (1-12-1) and 2-amino-4-((7S)-4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-2-(3-(dimethylamino)-4-methoxypyrrolidine-1-yl)-8-fluoroquinazoline-7-yl)-7-fluorobenzo[b]thiophene-3-onitrile (trans) (1-12-2)

[0881] Step 1: N,N-diisopropylethylamine (248 mg, 1.92 mmol) and intermediate 17 (125 mg, 0.58 mmol) were added to a solution of compound 1A (250 mg, 0.48 mmol) in N,N-dimethylacetamide (10 mL). The reaction system was microwaved at 80 °C for 1 hour. After cooling to room temperature, the system was purified directly by Flash column chromatography (C18, eluent: 0%–85% acetonitrile in 10 mM ammonium bicarbonate aqueous solution) to obtain compound 5A (223 mg, yield: 74%) as a pale yellow solid. m / z: [M+H] + 631.0.

[0882] Step 2: A solution of compound 5A (223 mg, 0.35 mmol), PyBOP (273 mg, 0.52 mmol), and N,N-diisopropylethylamine (1360 mg, 1.1 mmol) in dimethyl sulfoxide (5 mL) was stirred at room temperature for 30 minutes. Intermediate 1 (159 mg, 1.1 mmol) was added to the above reaction solution, and the reaction system was stirred at room temperature for another 20 hours. The reaction solution was directly purified by Flash column chromatography (C18, eluent: 0%–85% acetonitrile in 10 mM ammonium bicarbonate aqueous solution) to give compound 5B (250 mg, yield: 93%) as an off-white solid. m / z: [M+H] + 764.2.

[0883] Step 3: Trifluoroacetic acid (1 mL) was added to a solution of compound 1C (250 mg, 0.33 mmol) in dichloromethane (3 mL), and the reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was then concentrated under reduced pressure and the pH was adjusted to neutral with ammonia-methanol solution (7 M). The residue was purified by prep-HPLC (15%–60% acetonitrile in 10 mM ammonium bicarbonate aqueous solution, elution time 20 min) to give compounds 1-12-1 (30 mg, yield: 14%) and 1-12-2 (24 mg, yield: 11%), both white solids. Compound 1-12-1: Short UPLC retention time, 5.382 min; m / z [M+H] + 664.2; Compound 1-12-2: Short UPLC retention time, 5.683 min; m / z [M+H] + 664.2.

[0884] Example 6: Resolution of 2-amino-4-((R)-4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-2-((3R,4R)-3-(dimethylamino)-4-methoxypyrrolidine-1-yl)-8-fluoroquinazoline-7-yl)-7-fluorobenzo[b]thiophene-3-onitrile (compound 1-12-3) and 2-amino-4-((R)-4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-2-((3S,4S)-3-(dimethylamino)-4-methoxypyrrolidine-1-yl)-8-fluoroquinazoline-7-yl)-7-fluorobenzo[b]thiophene-3-onitrile (compound 1-12-4)

[0885] 1-12-1 was resolved by SFC (Method 1) to obtain compounds 1-12-3 and 1-12-4, both of which were white solids.

[0886] Compound 1-12-3: UPCC retention time: 1.951 min (Method 1); m / z [M+H] + 664.2; 1 H NMR (400MHz, DMSO-d6): δ8.24(s,2H),8.12(s,2H),8.03(dd,J=14.0,10.2Hz,3H),7.24-7.12(m,2H),6.95(dd,J=13.2,6.4Hz,1H) ,5.83(s,1H),4.34(s,1H),3.96-3.90(m,4H),3.53(d,J=13.2Hz,1H),3.39(d,J=16.4Hz,6H),2.88(s,6H),1.67(d,J=6.8Hz,3H).

[0887] Compound 1-12-4: UPCC retention time: 1.196 min (Method 1); m / z [M+H] + 664.2.

[0888] Example 7: Synthesis of 2-amino-4-((R)-4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-2-(3-(dimethylamino)-4-methoxypyrrolidine-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-7-yl)-7-fluorobenzo[b]thiophene-3-onitrile (trans) (compounds 1-21)

[0889] Step 1: A mixture of compound 3A (200 mg, 0.63 mmol), intermediate 17 (109 mg, 0.76 mmol), N,N-diisopropylethylamine (244 mg, 1.89 mmol) in tetrahydrofuran (10 mL) and N,N-dimethylacetamide (3 mL) was stirred at room temperature for 4 hours. The reaction was quenched with water (10 mL), and the aqueous phase was extracted with ethyl acetate. The organic phases were combined and concentrated under reduced pressure. The residue was purified by Flash column chromatography (ethyl acetate / petroleum ether = 0–100%) to give compound 6A (120 mg, yield: 45%) as a white solid. m / z: [M+H] + 424.1.

[0890] Step 2: A mixture of compound 6A (110 mg, 0.26 mmol), intermediate 7 (217 mg, 0.52 mmol), potassium phosphate (165 mg, 0.78 mmol), 1,1'-bis(di-tert-butylphosphine)ferrocene dichloropalladium (51 mg, 0.08 mmol), 1,4-dioxane (10 mL), and water (0.5 mL) was purged three times with argon. The reaction mixture was stirred at 80 °C for 2 hours. The reaction mixture was cooled to room temperature, and water (5 mL) and ethyl acetate (15 mL) were added. The organic phase was separated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0–100%) to give compound 6B (120 mg, yield: 68%) as a brown gel. m / z: [M+H] + 680.0.

[0891] Step 3: A mixed solution of compound 6B (50 mg, 0.07 mmol) and lithium hydroxide monohydrate (31 mg, 0.74 mmol) in tetrahydrofuran (5 mL) and water (1.5 mL) was stirred at 50 °C for 2 hours. The reaction solution was diluted with ethyl acetate (10 mL), adjusted to pH ~4 with hydrochloric acid (2 M), the organic phase was separated, and the solution was concentrated under reduced pressure to give compound 6C (40 mg, yield: 90%) as a yellow solid. m / z: [M+H] + 598.2.

[0892] Step 4: A solution of compound 6C (50 mg, 0.08 mmol), intermediate 1 (38 mg, 0.25 mmol), PyBOP (87 mg, 0.17 mmol), and N,N-diisopropylethylamine (65 mg, 0.5 mmol) in dimethyl sulfoxide (1 mL) was stirred at room temperature for 20 hours. Water (4 mL) and ethyl acetate (10 mL) were added. The organic phase was separated and concentrated under reduced pressure. The residue was purified by Flash silica gel column chromatography (methanol / dichloromethane = 0–60%) to give 6D (50 mg, yield: 82%) as a brown oil. m / z: [M+H] + 731.3.

[0893] Step 5: A solution of compound 6D (50 mg, 0.07 mmol) and trifluoroacetic acid (1 mL) in dichloromethane (3 mL) was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by prep-HPLC (20%–70% acetonitrile in 0.05% trifluoroacetic acid aqueous solution, elution time 20 min) to give 1-21 (10 mg, yield: 23%) as a yellow solid. UPLC retention time was 3.999 min; m / z [M+H] + 631.3; 1HNMR (400MHz, CD3OD): δ9.06(d,J=2.6Hz,1H),8.10(t,J=6.8Hz,1H),7.84(dd,J=6.4,1.2Hz,1H),7.31(dd,J=8.4,5.2Hz,1H),7.03-6.88(m,2H),6 .27-6.13(m,1H),4.47-4.05(m,4H),3.90(dd,J=13.8,7.4Hz,2H),3.40(d ,J=1.6Hz,3H),3.31(d,J=6.4Hz,3H),2.93(s,6H),1.70(d,J=6.8Hz,3H).

[0894] Example 8: Synthesis of 7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-N-((R)-1-(2-aminopyridin-3-yl)ethyl)-6-chloro-2-(3-(dimethylamino)-4-methoxypyrrolidine-1-yl)-8-fluoro-N-methylquinazoline-4-amine (trans, stereoisomer 1) and 7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-N-((R)-1-(2-aminopyridin-3-yl)ethyl)-6-chloro-2-(3-(dimethylamino)-4-methoxypyrrolidine-1-yl)-8-fluoro-N-methylquinazoline-4-amine (trans, stereoisomer 2) (compound 1-22-2)

[0895] Step 1: A mixed solution of compound 2C (100 mg, 0.15 mmol), intermediate 17 (26 mg, 0.18 mmol), N,N-diisopropylethylamine (58 mg, 0.45 mmol), N,N-dimethylacetamide (1.5 mL), and tetrahydrofuran (5 mL) was stirred at room temperature for 4 hours. Water (10 mL) and ethyl acetate (20 mL) were added, the organic phase was separated, and the mixture was concentrated under reduced pressure. The residue was purified by Flash column chromatography (ethyl acetate / petroleum ether = 0–100%) to give compound 7A (75 mg, yield: 63%) as a brown gel. m / z: [M+H] + 785.3.

[0896] Step 2: A mixed solution of compound 7A (75 mg, 0.1 mmol), lithium hydroxide monohydrate (80 mg, 1.92 mmol), methanol (1 mL), tetrahydrofuran (1 mL), and water (1 mL) was placed in a sealed tube and stirred at 85 °C for 16 hours. The reaction solution was cooled to room temperature, the pH was adjusted to approximately 3 with acetic acid, and water (5 mL) and ethyl acetate (20 mL) were added. The organic phase was separated and concentrated under reduced pressure. The residue was purified by Flash column chromatography (methanol / dichloromethane = 0–80%) to give compound 7B (60 mg, yield: 83%) as a light brown solid. m / z: [M+H] + 755.3.

[0897] Step 3: A solution of compound 7B (60 mg, 0.08 mmol), intermediate 1 (36 mg, 0.24 mmol), PyBOP (82 mg, 0.16 mmol), and N,N-diisopropylethylamine (61.3 mg, 0.47 mmol) in dimethyl sulfoxide (2 mL) was stirred at room temperature for 40 hours. Water (6 mL) and ethyl acetate (20 mL) were added, the organic phase was separated, and the solution was concentrated under reduced pressure. The residue was purified by Flash column chromatography (methanol / dichloromethane = 0–60%) to give compound 7C (40 mg, yield: 57%) as a yellow gel. m / z: [M+H] + 888.4.

[0898] Step 4: A solution of compound 7C (40 mg, 0.05 mmol) and trifluoroacetic acid (3 mL) in dichloromethane (1 mL) was stirred at 80 °C for 3 hours and concentrated under reduced pressure. The residue was purified by prep-HPLC (elution with 20%–70% acetonitrile in 0.05% trifluoroacetic acid aqueous solution for 20 min) to give 1-22-1 (7.72 mg) and 1-22-1 (12.2 mg), both white solids.

[0899] Compound 1-22-1: UPLC retention time 4.526 min; m / z [M+H] + 648.3; 1H NMR (400MHz, CD3OD): δ8.20(t,J=7.8Hz,1H),8.06(t,J=1.8Hz,1H),7.95(d,J=6 .2Hz,1H),7.11-7.00(m,1H),6.69(s,1H),6.20-6.05(m,1H),4.32(ddd,J=35.4, 20.2,9.2Hz,3H),4.04-3.83(m,2H),3.67(dd,J=11.6,5.8Hz,1H),3.51(d,J=1. 8Hz,3H),3.37(s,3H),3.04(s,6H),2.48(d,J=1.6Hz,3H),1.80(d,J=6.8Hz,3H);

[0900] Compound 1-22-2: UPLC retention times 5.034, 5.096 min; m / z [M+H] + 648.3; 1 H NMR (400MHz, CD3OD): δ8.19(t,J=8.2Hz,1H),8.08(t,J=1.8Hz,1H),7.97-7.92(m,1H),7.09-7. 02(m,1H),6.72(d,J=10.0Hz,1H),6.17(dd,J=16.8,6.8Hz,1H),4.43(d,J=6.2Hz,1H),4.33-4.1 9(m,2H),3.94(ddd,J=12.0,11.2,5.6Hz,2H),3.64(ddd,J=10.8,9.8,5.2Hz,1H),3.52-3.48(m, 3H), 3.37 (d, J = 11.8Hz, 3H), 3.04 (d, J = 1.6Hz, 6H), 2.49 (d, J = 1.8Hz, 3H), 1.81 (d, J = 6.8Hz, 3H).

[0901] Example 9: Synthesis of 2-amino-4-((7R)-4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-8-fluoro-2-(3-methoxy-4-(methylamino)pyrrolidine-1-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-onitrile (1-31-1) and 2-amino-4-((7S)-4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-8-fluoro-2-(3-methoxy-4-(methylamino)pyrrolidine-1-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-onitrile (1-31-2)

[0902] Steps 1-2: Using the synthetic method of compound 5B in Example 5, compound 1A and intermediate 27 were reacted to obtain compound 8B as a yellow solid. m / z: [M+H] + 884.2.

[0903] Step 3: Under ice bath conditions, trimethyliodosilane (100 mg, 0.5 mmol) was added to a 10 mL solution of compound 8B (140 mg, 0.16 mmol) in acetonitrile. The reaction mixture was stirred at this temperature for 1 hour. The reaction was quenched with methanol and concentrated under reduced pressure. The residue was purified by prep-HPLC (elution of 15%–70% acetonitrile in 10 mM ammonium bicarbonate aqueous solution for 20 min) to give compounds 1-31-1 (2.3 mg, yield: 2%) and 1-31-2 (2.7 mg, yield: 2%), both white solids.

[0904] Compound 1-31-1: UPLC retention time 5.246 min; m / z [M+H] + 650.2; 1 H NMR (400MHz, CD3CN): δ7.97(dd,J=4.8,1.6Hz,1H),7.91(d,J=1.6Hz,1H),7.63(d,J=7.4Hz,1H ),7.25(dd,J=8.4,5.2Hz,1H),7.07(dd,J=9.6,8.4Hz,1H),6.70(dd,J=7.4,5.0Hz,1H),6.31(s ,2H),6.12(dt,J=13.0,6.6Hz,1H),5.30(s,1H),5.22(s,1H),3.91–3.60(m,5H),3.57-3.51(m, 1H), 3.35 (s, 3H), 3.23-3.17 (m, 1H), 3.05 (s, 3H), 2.39 (d, J = 1.4Hz, 3H), 1.65 (d, J = 6.8Hz, 3H).

[0905] Compound 1-31-2: UPLC retention time 4.891 min; m / z [M+H] + 650.3; 1H NMR (400MHz, CD3CN): δ7.98(dd,J=4.8,1.6Hz,1H),7.92(s,1H),7.63(d,J=7.4Hz,1H ),7.24(dd,J=8.4,5.2Hz,1H),7.07(dd,J=9.6,8.4Hz,1H),6.70(dd,J=7.4,5.2Hz,1H ),6.34(s,2H),6.17(dt,J=13.0,6.4Hz,1H),5.39(s,1H),5.32(s,1H),4.15-3.46(m, 6H), 3.36 (s, 3H), 3.25-3.16 (m, 1H), 3.06 (s, 3H), 2.40 (s, 3H), 1.63 (d, J = 6.8Hz, 3H).

[0906] Example 10: Synthesis of 2-amino-4-((R)-4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-onitrile (1-32-1) and 2-amino-4-((S)-4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-onitrile (1-32-2)

[0907] Synthesis of compound 9A: Using the same synthetic method as compound 1B, 9A was obtained by reacting intermediate 1A with ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol as a pale yellow solid. m / z: [M+H] + 646.1; 1 H NMR (400MHz, DMSO-d6): δ12.08(br.s,2H),7.95-7.90(m,1H),7.40-7.18(m,2H),5.50-5.30(m,1H),4.4 2-4.22(m,2H),3.47-3.27(m,3H),3.07-2.95(m,1H),2.39-2.07(m,3H),2.04-1.82(m,3H),1.48(s,9H).

[0908] Step 1: A solution of compound 9A (50 mg, 0.08 mmol), PyBOP (60 mg, 0.12 mmol), and N,N-diisopropylethylamine (30 mg, 0.23 mmol) in dimethyl sulfoxide (1 mL) was stirred at room temperature for 30 minutes. Intermediate 1 (21.1 mg, 0.15 mmol) was added to the above reaction solution. The reaction system was stirred at room temperature for another 3 days. The elution was then performed directly by prep-HPLC (5%–15% acetonitrile in 10 mM ammonium bicarbonate aqueous solution, elution time 5 min; 15%–45% acetonitrile in 10 mM ammonium bicarbonate aqueous solution, elution time 15 min) to obtain compounds 9B-1 (10 mg, yield: 16%) and 9B-2 (13 mg, yield: 21%), both as yellow solids. m / z: [M+H] + 779.0.

[0909] Step 2: Trifluoroacetic acid (1 mL) was added to a solution of compound 9B-1 (10 mg, 0.013 mmol) in dichloromethane (2 mL), and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was then concentrated directly under reduced pressure. The residue was purified by prep-HPLC (5%–15% acetonitrile in 10 mM ammonium bicarbonate aqueous solution, elution time 5 min; 15%–45% acetonitrile in 10 mM ammonium bicarbonate aqueous solution, elution time 15 min) to give compound 1-32-1 (7.8 mg, yield: 90%) as a white solid. UPLC retention time was short, 5.265 min, m / z: [M+H] + 679.1.

[0910] Using the synthetic method for 1-32-1, 1-32-2 (8.1 mg) was reacted with 9B-2 to give 1-32-2 as a white solid. The UPLC retention time was relatively long, 5.574 minutes, m / z: [M+H]. + 679.1.

[0911] Example 11: Single crystal diffraction experiment of compound 9B-1

[0912] 1. Single crystal culture: Dissolve compound 9B-1 (30mg) in anhydrous ethanol (0.5mL), place it in a 2mL round-bottom PE tube, seal and let stand for 5 days, collect the single crystals for single crystal diffraction test.

[0913] 2. The test parameters are shown in Table 1 below:

[0914] Table 1

[0915] 3. Test results: The stereostructure of compound 9B-1 is as follows:

[0916] The compounds shown in Table 2 can be synthesized by any of the methods shown in general formulas 1-4 or Examples 1-4, or by synthetic methods commonly used in the art:

[0917] Table 2

[0918] The compounds shown in Table 3 can be synthesized by any of the methods shown in general formulas 1-4 or Examples 5-8, or by synthetic methods commonly used in the art:

[0919] Table 3

[0920] The compounds shown in Table 4 can be synthesized by any of the methods shown in Formulas 1-4 or Example 10, or by synthetic methods commonly used in the art:

[0921] Table 4

[0922] Biological Example:

[0923] Example 1: KRAS-RAF1 protein interaction (PPI) experiment

[0924] This experiment used a homogeneous time-resolved fluorescence (HTRF) kit (PerkinElmer) to detect the inhibitory activity of small molecule compounds on the interaction between GTP-activated KRAS protein and downstream RAF1 protein. GTP powder (Sigma, V900868) was dissolved in ddh2O and diluted to a 100 μM stock solution with Diluent Buffer. A 1-fold mixture was prepared by adding 500-fold Tag1-RAF1 protein stock solution, 500-fold Tag2-KRAS-G12C, Tag1-KRAS-G12D, or Tag2-KRAS-G12V protein stock solutions, and the aforementioned 100-fold diluted GTP stock solution to Diluent Buffer.

[0925] The test compound was serially diluted with DMSO solution to control the final concentration of DMSO at 0.25%. 1 μL of the test compound was added to a 384-well white shallow-well plate (PerkinElmer) and centrifuged at 1000 rpm for 1 minute. Add 4 μL of a mixture of G12C (Tag1-RAF1, Tag2-KRAS-G12C and GTP), G12D (Tag2-RAF1, Tag1-KRAS-G12D and GTP), or G12V (Tag1-RAF1, Tag2-KRAS-G12V and GTP) to the 384-well plate described above. Centrifuge at 1000 rpm for 1 minute and pre-incubate at 4°C for 15 minutes. Suitable controls (wells without compound and wells with positive compounds) are also included in the 384-well plate. Then, add 5 μL of labeled antibody mixture diluted with HTRF detection buffer (G12C and G12V use a mixture of Anti-Tag1-Eu3+ and Anti-Tag2-XL665 labeled antibodies, and G12D uses a mixture of Anti-Tag1-Tb3+ and Anti-Tag2-d2 labeled antibodies) to initiate the reaction. Seal the plate and incubate at 4°C in the dark for 1 hour. Then, use a microplate. TR-FRET signal values ​​were measured using a reader-based microplate reader (Tecan, Infinite M1000 Pro) (excitation wavelength: 320 nm, emission wavelengths: 615 nm and 665 nm). The fluorescence signal ratio (RLU) was calculated as (665 nm signal / 615 nm signal). The percentage inhibition rate of the compound was calculated using the signals from the wells with 0% and 100% inhibition rates, representing the wells with the maximum signal (wells without compound, DMSO control) and the wells with the minimum signal (wells containing a mixture of KRAS, RAF1 protein, and GTP).

[0926] Compound inhibition rate (%) = (RLU 0% inhibition - RLU compound) / (RLU 0% inhibition - RLU 100% inhibition) * 100%. The IC50 is calculated by fitting the compound gradient dilution concentrations and corresponding inhibition rates using a four-parameter method. 50 Value. The IC50 value was used to test the inhibitory activity of the compound against the interaction between KRAS G12C, G12D, G12V and RAF1 protein. 50 The values ​​are shown in Table 5 below.

[0927] Table 5

[0928] The compounds of this invention can effectively inhibit the binding activity of KRAS G12C, G12D or G12V to RAF1 protein.

[0929] Example 2: Cell proliferation inhibition experiment

[0930] On the first day, the density of the suspensions of KRAS G12C-mutated human pancreatic cancer cells MIA PaCa-2 (Nanjing Kebai), KRAS G12D-mutated human colon cancer cells GP2D (Nanjing Kebai), human pancreatic cancer cells HPAC (Nanjing Kebai), human uterine adenocarcinoma cells HEC-1-B (Nanjing Kebai), KRAS G12V-mutated human colon cancer cells SW480 (Nanjing Kebai), KRAS G12A-mutated human myeloma cells RPMI8226 (Nanjing Kebai), KRAS wild-type human melanoma cells A375 (ATCC), KRAS G12V-mutated human colon adenocarcinoma cells SW620 (Nanjing Kebai), KRAS G12C-mutated human non-small cell lung cancer cells H358 (ATCC), or KRAS-amplified human gastric cancer cells MKN1 (Nanjing Kebai) was adjusted to 3.2 × 10⁻⁶. 4 Cells / mL were seeded at 95 μL / well in a 96-well plate, resulting in 3000 cells per well. The cell culture plates were incubated overnight at 37°C with 5% CO2. The next day, the test compound was serially diluted with 100% DMSO, and then further diluted with complete culture medium (DMDM + 10% FBS + 1% P / S) to prepare the working solution. 5 μL / well of the working solution was added to each well of the 96-well cell culture plate, with a concentration range of 0.15 nM to 10 μM. The plates were incubated at 37°C with 5% CO2 for 72 hours. Cell Titer-Glo (Cell Titer-glo, Promega) assay reagent was added to each well, and the plates were incubated in the dark for 5 minutes. After standing, luminescence was detected using a Microplate reader (Tecan, Infinite M1000 Pro). The data were analyzed using Graphpad software, and a four-parameter equation was used to fit the curve and calculate the IC50 of the inhibitor. 50 Values. The results are shown in Table 6 below:

[0931] Table 6

[0932] The compounds of this invention exhibit good inhibitory activity against tumor cells containing KRAS G12C, KRAS G12V, or KRAS G12D mutations.

[0933] Example 3: Pharmacokinetic Experiment

[0934] The test compound was administered orally and intravenously to male ICR mice. Blood samples were collected via the submandibular vein, approximately 0.10 mL per sample, anticoagulated with EDTA-K2. Blood collection time points were as follows: Intravenous administration group: before administration, 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h post-administration. Oral administration group: before administration, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h post-administration. After collection, blood samples were placed on ice and centrifuged to separate plasma (centrifugation conditions: 8000 rpm, 6 minutes, 2-8℃). Collected plasma was stored at -80℃ before analysis. Plasma samples were analyzed using LC-MS / MS (API5500). Based on the drug's blood concentration data, various pharmacokinetic parameters were calculated using the WinNonlin 5.2 non-compartmental model. The pharmacokinetic parameters of mice are shown in Tables 7 and 8 below:

[0935] Table 7

[0936] Table 8

[0937] The compounds of this invention have good pharmacokinetic properties, such as good exposure levels and / or oral bioavailability.

[0938] Example 4: In vivo efficacy experiment

[0939] Cell culture: Human pancreatic cancer cells MIA PaCa-2, human non-small cell lung cancer cells NCI-H358, human colon cancer cells GP2D, or human colon cancer cells SW620 were cultured in a monolayer at 37°C in an incubator containing 5% CO2 in RPMI 1640 medium containing 10% fetal bovine serum. Tumor cells were passaged twice a week. Cells in the exponential growth phase were harvested and counted for seeding.

[0940] Experimental animals: BALB / c nude mice, 6-8 weeks old, 18-22g, purchased from Jiangsu Jicui Yaokang Biomedical Technology Co., Ltd.

[0941] Experimental method: Cell lines (5.0 × 10⁻⁶) 6 ~1.0×10 7 (0.1 mL / mouse) was injected subcutaneously into the right back of each experimental mouse. The tumor growth was observed regularly until it grew to approximately 100 mm. 3 Mice were randomly grouped according to tumor size and body weight, and administered medication according to the dosing schedule. Throughout the experiment, mouse body weight and tumor size were measured twice a week.

[0942] Formula for calculating tumor size: Tumor volume (mm) 3 = 0.5 × (tumor long diameter × tumor short diameter) 2 ).

[0943] The efficacy model data for MIAPaCa-2 are shown in Table 7 below:

[0944] Table 7

[0945] The compounds of this invention have good in vivo efficacy.

[0946] Note: Ref. A refers to compound 600 in WO2024030633A1.

Claims

1. A compound of formula (I), its stereoisomer or pharmaceutically acceptable salt; in, A is a 5-6 membered heteroaryl group substituted with 1-3 R8 or R8' or a 5-6 membered heterocyclic alkyl group substituted with 1-3 R8 or R8'; A is an independent substituent, or A is connected to R4 to form a 6-9 membered heterocyclic alkyl group, which may further contain one heteroatom selected from O or S; or A is connected to R9 to form a 5-7 membered heterocyclic alkyl group; the 5-7 membered heterocyclic alkyl group contains one N heteroatom; the 6-9 membered heterocyclic alkyl group or the 5-7 membered heterocyclic alkyl group is unsubstituted, or is further substituted with 1-3 R8 or R8' at any position; B is a 6-10 aryl or a 5-10 heteroaryl; the 6-10 aryl or 5-10 heteroaryl is unsubstituted, or selectively substituted by 1-4 R groups. 10 Replace in any position; C is Y represents N, CH, or C-CN; U and V can be any of the following combinations: 1) U is N or CR2, V is C; or 2) U is CH2, V is N; L represents a connecting bond, -O-, -NH-, or -N(C) 1-6 alkyl)-; L' is a connector, -O-, or -NR. 12 "-; R1, R2, and R3 are independently H, halogen, cyano, and C, respectively. 1-3 Alkyl, Halogenated C 1-3 Alkyl, C 1-3 alkoxy or halogenated C 1-3 Alkoxy or C 2-4 alkynyl group; R4 represents H, hydroxyl group, and C. 1-6 Alkyl, C 1-6 Alkoxy; the C 1-6 Alkyl or C 1-6 The alkoxy group is unsubstituted, or selectively selected from 1-3 groups: hydroxyl, amino, halogen, deuterium, C. 1-4 Alkoxy and C 1-4 The substituents of the alkylamino group can be substituted at any position; R5 and R6 are independently H, D, or C, respectively. 1-6 Alkyl; R5 and R6 are independent substituents, or R5 and R6 together with the carbon atom they are attached to form a C12 group. 3-6 cycloalkyl; R7 is R8 can be H, halogen, amino, cyano, or C. 1-6 Alkyl, Halogenated C 1-3 Alkyl, C 1-3 alkoxy or halogenated C 1-3 Alkoxy; R8' represents H, halogen, cyano, or C. 1-6 Alkyl, Halogenated C 1-3 Alkyl, oxo, C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 2-6 alkenyl, halogenated C 2-6 Alkyne group, -OR a -N(R) a )2、-OC(O)R a -OC(O)OR a -NHC(O)R a -NHC(O)OR a -S(O) 0-2 R b -C(O)OR a -C(O)N(R) a )2 or -C(O)R a ; R9 is H or C 1-6 alkyl; R 10 H, halogen, oxo group, cyano group, -OR b -N(R) b )2、-OC(O)R b -OC(O)OR b -NHC(O)R b -NHC(O)OR b -NHP(O)(OR) b )2、-S(O) 0-2 R b -C(O)N(R) b )2、-C(O)R b C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 2-6 alkenyl, halogenated C 2-6 alkynyl group, C 3-6 Cycloalkyl groups; R 11 C 3-8 Cycloalkyl or 3-8 membered heterocycloalkyl; the C 3-8 The cycloalkyl or 3-8 membered heterocyclic alkyl group is unsubstituted, or selectively substituted with 1-3 R groups. 13 Replace in any position; R 11 'For H, halogen, hydroxyl, cyano, amino, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylene, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, Halogenated C 1-6 alkoxy or halogenated C 1-6 Alkylene; R 12 R 12 'and R 12 "Each of the following groups can be independently represented as H, halogen, oxo group, cyano group, or -OR." b -N(R) b )2、-OC(O)R b -OC(O)OR b -NHC(O)R b -NHC(O)OR b -C(O)N(R) b )2、-C(O)R b -C(O)OR b C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-6 3-6 membered heterocyclic alkyl, C 3-6 Cycloalkyl C 1-4 Alkyl, 3-6 membered heterocyclic alkyl C 1-4 Alkyl, C 1-6 Alkylene, Halogenated C 1-6 Alkylene; the C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkyl C 1-4 Alkyl or 3-6 membered heterocyclic alkyl C 1-4 The alkyl group is unsubstituted, or selectively substituted with 1-3 R groups. 13 Replace in any position; R 13 Halogen, oxo group, -OR b -N(R) b )2、-OC(O)R b -OC(O)OR b -NHC(O)R b -NHC(O)OR b -C(O)N(R) b )2、-C(O)R b -C(O)OR b C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, C 1-3 Alkoxy C 1-6 Alkyl, amino C 1-6 Alkyl or C 1-4 Alkylamino C 1-6 alkyl; R a For H, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl, halogenated C 1-6 Alkyl, Halogenated C 2-6 alkenyl or halogenated C 2-6 alkynyl group; R b For H, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, or 5-6 membered heteroaryl; the C 1-6 The alkyl group is unsubstituted, or selectively substituted with 1-3 halogens, hydroxyl groups, cyano groups, amino groups, or C groups. 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl substitutions are in any position; m can be 0, 1, 2, 3, or 4.

2. The compound of claim 1, its stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the compound satisfies one of the following conditions: (1) A is a 5-6 membered heteroaryl group substituted with 1-3 R8 or R8' or a 5-6 membered heterocyclic alkyl group substituted with 1-3 R8 or R8'; A is an independent substituent, or A is connected to R4 to form a 6-9 membered heterocyclic alkyl group, which may further contain one heteroatom selected from O or S; or A is connected to R9 to form a 5-7 membered heterocyclic alkyl group; which contains one N heteroatom; the 6-9 membered heterocyclic alkyl group or the 5-7 membered heterocyclic alkyl group is unsubstituted, or is further substituted with 1-3 R8 or R8' at any position; B is a 6-10 aryl or a 5-10 heteroaryl; the 6-10 aryl or 5-10 heteroaryl is unsubstituted, or selectively substituted by 1-4 R groups. 10 Replace in any position; C is Y represents N, CH, or C-CN; U and V can be any of the following combinations: 1) U is N or CR2, V is C; or 2) U is CH2, V is N; R1, R2, and R3 are independently H, halogen, cyano, and C, respectively. 1-3 Alkyl, Halogenated C 1-3 Alkyl, C 1-3 alkoxy or halogenated C 1-3 Alkoxy or C 2-4 alkynyl group; R4 represents H, hydroxyl group, and C. 1-6 Alkyl, C 1-6 Alkoxy; the C 1-6 Alkyl or C 1-6 The alkoxy group is unsubstituted, or selectively selected from 1-3 groups: hydroxyl, amino, halogen, deuterium, C. 1-4 Alkoxy and C 1-4 The substituents of the alkylamino group can be substituted at any position; R5 and R6 are independently H, D, or C, respectively. 1-6 Alkyl; R5 and R6 are independent substituents, or R5 and R6 together with the carbon atom they are attached to form a C12 group. 3-6 cycloalkyl; R7 is R8 can be H, halogen, amino, cyano, or C. 1-6 Alkyl, Halogenated C 1-3 Alkyl, C 1-3 alkoxy or halogenated C 1-3 Alkoxy; R8' represents H, halogen, cyano, or C. 1-6 Alkyl, Halogenated C 1-3 Alkyl, oxo, C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 2-6 alkenyl, halogenated C 2-6 Alkyne group, -OR a -N(R) a )2、-OC(O)R a -OC(O)OR a -NHC(O)R a -NHC(O)OR a -S(O) 0-2 R b -C(O)OR a -C(O)N(R) a )2 or -C(O)R a ; R9 is H or C 1-6 alkyl; R 10 H, halogen, oxo group, cyano group, -OR b -N(R) b )2、-OC(O)R b -OC(O)OR b -NHC(O)R b -NHC(O)OR b -NHP(O)(OR) b )2、-S(O) 0-2 R b -C(O)N(R) b )2、-C(O)R b C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 2-6 alkenyl, halogenated C 2-6 alkynyl group, C 3-6 Cycloalkyl groups; R 11 C 3-8 Cycloalkyl or 3-8 membered heterocycloalkyl; the C 3-8 The cycloalkyl or 3-8 membered heterocyclic alkyl group is unsubstituted, or selectively substituted with 1-3 R groups. 13 Replace in any position; R 11 'For H, halogen, hydroxyl, cyano, amino, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylene, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, Halogenated C 1-6 alkoxy or halogenated C 1-6 Alkylene; R 13 Halogen, oxo group, -OR b -N(R) b )2、-OC(O)R b -OC(O)OR b -NHC(O)R b -NHC(O)OR b -C(O)N(R) b )2、-C(O)R b -C(O)OR b C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, C 1-3 Alkoxy C 1-6 Alkyl, amino C 1-6 Alkyl or C 1-4 Alkylamino C 1-6 alkyl; R a For H, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl, halogenated C 1-6 Alkyl, Halogenated C 2-6 alkenyl or halogenated C 2-6 alkynyl group; R b For H, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, or 5-6 membered heteroaryl; the C 1-6 The alkyl group is unsubstituted, or selectively substituted with 1-3 halogens, hydroxyl groups, cyano groups, amino groups, or C groups. 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl substitutions are in any position; (2) A is A1, A2, A3, and A4 are each independently N or CR8'; B is a 6-10 aryl or a 5-10 heteroaryl; the 6-10 aryl or 5-10 heteroaryl is unsubstituted, or selectively substituted by 1-4 R groups. 10 Replace in any position; C is Y represents N, CH, or C-CN; U and V can be any of the following combinations: 1) U is N or CR2, V is C; or 2) U is CH2, V is N; R1, R2, and R3 are independently H, halogen, cyano, and C, respectively. 1-3 Alkyl, Halogenated C 1-3 Alkyl, C 1-3 alkoxy or halogenated C 1-3 Alkoxy or C 2-4 alkynyl group; R4 represents H, hydroxyl group, and C. 1-6 Alkyl, C 1-6 Alkoxy; the C 1-6 Alkyl or C 1-6 The alkoxy group is unsubstituted, or selectively selected from 1-3 groups: hydroxyl, amino, halogen, deuterium, C. 1-4 Alkoxy and C 1-4 The substituents of the alkylamino group can be substituted at any position; R5 and R6 are independently H, D, or C, respectively. 1-6 Alkyl; R5 and R6 are independent substituents, or R5 and R6 together with the carbon atom they are attached to form a C12 group. 3-6 cycloalkyl; R7 is R8 and R8' are independently H, halogen, cyano, amino, and C, respectively. 1-6 Alkyl, Halogenated C 1-3 Alkyl, C 1-3 alkoxy or halogenated C 1-3 Alkoxy; R9 is H or C 1-6 alkyl; R 10 H, halogen, oxo group, cyano group, -OR b -N(R) b )2、-OC(O)R b -OC(O)OR b -NHC(O)R b -NHC(O)OR b -NHP(O)(OR) b )2、-S(O) 0-2 R b -C(O)N(R) b )2、-C(O)R b C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 2-6 alkenyl, halogenated C 2-6 alkynyl group, C 3-6 Cycloalkyl groups; R 11 C 3-8 Cycloalkyl or 3-8 membered heterocycloalkyl; the C 3-8 The cycloalkyl or 3-8 membered heterocyclic alkyl group is unsubstituted, or selectively substituted with 1-3 R groups. 13 Replace in any position; R 11 'For H, halogen, hydroxyl, cyano, amino, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylene, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, Halogenated C 1-6 alkoxy or halogenated C 1-6 Alkylene; R 13 Halogen, oxo group, -OR b -N(R) b )2、-OC(O)R b -OC(O)OR b -NHC(O)R b -NHC(O)OR b -C(O)N(R) b )2、-C(O)R b -C(O)OR b C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, C 1-3 Alkoxy C 1-6 Alkyl, amino C 1-6 Alkyl or C 1-4 Alkylamino C 1-6 alkyl; R b For H, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, or 5-6 membered heteroaryl; the C 1-6 The alkyl group is unsubstituted, or selectively substituted with 1-3 halogens, hydroxyl groups, cyano groups, amino groups, or C groups. 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl substitutions are in any position; (3) A is A1 is N, A2 is CH, A3 is CH, A4 is CH; B is a 5-10 membered heteroaryl group; the 5-10 membered heteroaryl group is unsubstituted, or selectively substituted by 1-4 R groups. 10 Replace in any position; C is Y is N; U is N or CR2; V is C; R1, R2, and R3 are independently H, halogen, and C, respectively. 1-3 Alkyl or halogenated C 1-3 alkyl; R4 is C 1-6 Alkyl; the C 1-6 The alkyl group is unsubstituted or selectively substituted at any position by 1-3 substituents selected from hydroxyl, amino, halogen and deuterium; R5 and R6 are independently H, D, or C, respectively. 1-6 alkyl; R7 is R8 is NH2; R9 is H or C 1-6 alkyl; R 10 H, halogen, cyano, -N(R) b 2. C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy or C 3-6 Cycloalkyl groups; R 11 C 3-8 Cycloalkyl or 3-8 membered heterocycloalkyl; the C 3-8 The cycloalkyl or 3-8 membered heterocyclic alkyl group is unsubstituted, or selectively substituted with 1-3 R groups. 13 Replace in any position; R 11 'For H, halogen, C 1-6 Alkyl, C 1-6 Alkylene or halogenated C 1-6 Alkylene; R 13 Halogen, oxo group, -OR b -N(R) b )2、-OC(O)R b -NHC(O)R b -C(O)N(R) b )2、-C(O)R b -C(O)OR b C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl or amino C 1-6 alkyl; R b For H or C 1-6 alkyl; (4) A is A1 is N, A2 is CH, A3 is CH, A4 is CH; B is a 5-10 membered heteroaryl group; the 5-10 membered heteroaryl group is unsubstituted, or selectively substituted by 1-4 R groups. 10 Replace in any position; C is Y is N; U is N or CR2; V is C; R1, R2, and R3 are independently H, halogen, and C, respectively. 1-3 Alkyl or halogenated C 1-3 alkyl; R4 is C 1-6 Alkyl; the C 1-6 The alkyl group is unsubstituted or selectively substituted at any position by 1-3 substituents selected from hydroxyl, amino, halogen and deuterium; R5 and R6 are independently H, D, or C, respectively. 1-6 alkyl; R7 is R8 is NH2; R9 is H or C 1-6 alkyl; R 10 H, halogen, cyano, -N(R) b 2. C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy or C 3-6 Cycloalkyl groups; R b For H or C 1-6 alkyl.

3. A compound of formula (II), its stereoisomer or pharmaceutically acceptable salt; in, In ring A, A1 represents N and M. - N + -LR or N + -L-R', A2 is CH, A3 is CH, A4 is CH; B is X is CR9R 9a ; Y is N; Z is either N or C-CN; L is C 1-4 Alkylene; M - It is an anion; R is H, -OC(O)R b -OC(O)N(R) b 2. -OC(O)OR b , by 1 to 3 R c Substituted 3-6 membered heterocyclic alkyl groups or substituted with 1-3 R groups c Substituted 3-6 heteroaryl groups; R’ is -OP(O)(OR b )O - ; R1 and R2 are independently H, halogen, and C, respectively. 1-3 Alkyl, Halogenated C 1-3 Alkyl or C 1-3 Alkoxy; R3 is H or a halogen; R4 is C 1-6 Alkyl; the C 1-6 The alkyl group is unsubstituted, or selectively replaced by 1 to 3 groups selected from hydroxyl, amino, halogen, deuterium, C. 1-4 Alkoxy and C 1-4 The substituents of the alkylamino group can be substituted at any position; R5 and R6 are independently H, deuterium, or C, respectively. 1-6 Alkyl; R5 and R6 are independent substituents, or R5 and R6 together with the carbon atom they are attached to form a C12 group. 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl or C 1-4 Alkylene; the C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl or C 1-4 The alkylene group is unsubstituted, or selectively substituted with 1 to 3 groups selected from halogen, cyclopropyl, C. 1-3 Alkyl and Halogenated C 1-3 The alkyl substituents can be substituted at any position; R7 is C 1-6 Alkylamino, 4-10 membered heterocyclic alkyl, or with 1-3 R 11 Substituted 4-10-membered heterocyclic alkyl groups, wherein the 4-10-membered heterocyclic alkyl groups contain 1 to 3 heteroatoms selected from N, O or S; R8 and R 8e They are independently -NH2 and -NHC(O)R, respectively. b -NHC(O)OR b -NHP(O)(OR) b )2 or -NH-LR; R9 is C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl or C 2-6 alkynyl group; R 9a H, deuterium, or C 1-6 alkyl; R 10 and R 10c Each can be independently represented by H, halogen, cyano, nitro, hydroxyl, amino, or C. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy or C 3-6 Cycloalkyl groups; R 10a C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy or C 3-6 Cycloalkyl groups; R 11 Halogen, hydroxyl, cyano, amino, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylene, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylene, Halogenated C 1-6 Alkoxy-C 1-4 Alkyl, C 3-8 cycloalkyl or 3-8 membered heterocyclic alkyl; R b For H, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 3-6 cycloalkyl C 1-4 Alkyl, 3-6 membered heterocyclic alkyl C 1-4 Alkyl, phenyl C 1-4 Alkyl or 5-6-membered heteroaryl C 1-4 Alkyl; the R b For non-replacement, or selectively replaced by 1 to 3 Rs c Replace in any position; R c Halogen, oxo, cyano, hydroxyl, nitro, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, Halogenated C 1-4 alkoxy or ester group; t can be 1, 2, or 3.

4. A compound of formula (II), its stereoisomer or pharmaceutically acceptable salt; in, In ring A, A1 represents N and M. - N + -LR or N + -L-R', A2 is CH, A3 is CH, A4 is CH; B is X is CR9R 9a ; Y is N; Z is either N or C-CN; L is C 1-4 Alkylene; M - It is an anion; R is H, -OC(O)R b -OC(O)N(R) b 2. -OC(O)OR b , by 1 to 3 R c Substituted 3-6 membered heterocyclic alkyl groups or substituted with 1-3 R groups c Substituted 3-6 heteroaryl groups; R’ is -OP(O)(OR b )O - ; R1 and R2 are independently H, halogen, and C, respectively. 1-3 Alkyl, Halogenated C 1-3 Alkyl or C 1-3 Alkoxy; R3 is H or a halogen; R4 is C 1-6 Alkyl; the C 1-6 The alkyl group is unsubstituted, or selectively replaced by 1 to 3 groups selected from hydroxyl, amino, halogen, deuterium, C. 1-4 Alkoxy and C 1-4 The substituents of the alkylamino group can be substituted at any position; R5 and R6 are independently H, deuterium, or C, respectively. 1-6 Alkyl; R5 and R6 are independent substituents, or R5 and R6 together with the carbon atom they are attached to form a C12 group. 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl or C 1-4 Alkylene; the C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl or C 1-4 The alkylene group is unsubstituted, or selectively substituted with 1 to 3 groups selected from halogen, cyclopropyl, C. 1-3 Alkyl and Halogenated C 1-3 The alkyl substituents can be substituted at any position; R7 is the result of 2-3 Rs 11 Substituted 4-10-membered heterocyclic alkyl groups, wherein the 4-10-membered heterocyclic alkyl groups contain 1 to 3 heteroatoms selected from N, O or S; R8 and R 8e They are independently -NH2 and -NHC(O)R, respectively. b -NHC(O)OR b -NHP(O)(OR) b )2 or -NH-LR; R9 is C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl or C 2-6 alkynyl group; R 9a H, deuterium, or C 1-6 alkyl; R 10 and R 10c Each can be independently represented by H, halogen, cyano, nitro, hydroxyl, amino, or C. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy or C 3-6 Cycloalkyl groups; R 10a C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy or C 3-6 Cycloalkyl groups; R 11 Halogen, hydroxyl, cyano, amino, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylene, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylene, Halogenated C 1-6 Alkoxy-C 1-4 Alkyl, C 3-8 Cycloalkyl or 3-8 membered heterocyclic alkyl; and at least one R 11 C 1-6 Alkylene or halogenated C 1-6 alkylene, and at least one R 11 It is a 3-8 membered heterocyclic alkyl group; R b For H, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 3-6 cycloalkyl C 1-4 Alkyl, 3-6 membered heterocyclic alkyl C 1-4 Alkyl, phenyl C 1-4 Alkyl or 5-6-membered heteroaryl C 1-4 Alkyl; the R b For non-replacement, or selectively replaced by 1 to 3 Rs c Replace in any position; R c Halogen, oxo, cyano, hydroxyl, nitro, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, Halogenated C 1-4 alkoxy or ester group; t can be 1, 2, or 3.

5. The compound, its stereoisomer, or a pharmaceutically acceptable salt according to any one of claims 1-4, wherein the compound satisfies one or more of the following conditions: (1)M - These are pharmaceutically acceptable anions, such as halide ions or acid radicals. (2) B is a 5-6 membered monocyclic heteroaryl or a 9-10 membered bicyclic heteroaryl, preferably pyridyl, benzothiophene, or benzothiazolyl, for example pyridyl or benzothiazolyl; wherein B is unsubstituted, or selectively substituted with 1-4 or 1-3 R groups. 10 Replace in any position, for example, B is replaced by 3 Rs 10 Replace in any position; (3) Each R 10 Independently H, halogen, cyano, -N(R) b 2. C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy or C 3-6 Cycloalkyl groups, preferably halogenated, cyano, or -N(R) b 2. C 1-6 Alkyl or halogenated C 1-6 Alkyl groups, such as halogens, cyano groups, NH2, more preferably halogens or C 1-6 alkyl; (4)R 10a C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy or C 3-6 Cycloalkyl groups; (5)R 11 'For H, halogen, C 1-6 Alkyl, C 1-6 Alkylene or halogenated C 1-6 Alkyl groups, such as H, methylene (=CH2); (6)R 13 Halogen, oxo group, -OR b -N(R) b )2、-OC(O)R b -NHC(O)R b -C(O)N(R) b )2、-C(O)R b -C(O)OR b C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl or amino C 1-6 Alkyl groups, such as oxo groups, -OR b ; (7)R b For H or C 1-6 Alkyl, such as C 1-6 alkyl; (8) R7 is the result of 1 to 3 Rs 11 The substituted 4-10-membered heterocyclic alkyl group, wherein the 4-10-membered heterocyclic alkyl group comprises 1 to 3 heteroatoms selected from N, O or S, preferably, R7 is a heteroatom surrounded by 2 R atoms. 11 Substituted 4-10 membered heterocyclic alkyl groups; (9) In compound I, R 11 It is a 3-8 membered heterocyclic alkyl group, preferably a 5-6 membered monocyclic heterocyclic alkyl group, containing 1-2 heteroatoms selected from O, N, and S; in the compound of formula II, it contains at least 2 R atoms. 11 , of which at least one R 11 C 1-6 Alkylene or halogenated C 1-6 alkylene and at least one R 11 It is a 3-8 membered heterocyclic alkyl group (preferably a 5-6 membered monocyclic heterocyclic alkyl group containing 1-2 heteroatoms selected from O, N, and S); (10)R 12 For H, -N(R) b )2 or -OR b For example, -N(R) b )2; (11)R 12 'For H, halogen, oxo group, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, C 1-3 Alkoxy C 1-4 Alkyl, amino C 1-4 Alkyl, C 1-4 Alkylamino C 1-4 Alkyl, Halogenated C 1-4 Alkoxy, C 3-6 3-6 membered heterocyclic alkyl, C 1-4 Alkylene, Halogenated C 1-4 Alkylene; the C 3-6 The cyclic alkyl group or 3-6-membered heterocyclic alkyl group is unsubstituted, or selectively substituted by 1-3 groups selected from halogens, C 1-4 Alkyl, -OH, -NH2, C 1-4 Alkoxy and C 1-4 The substituents of the alkylamino group can be substituted at any position; for example, R 12 'For C 1-4 Alkoxy; (12)R 12 "for C" 1-4 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic alkyl; the R 12 "For non-replacement, or selectively replaced by 1-3 Rs" 13 Replace in any position; for example, R 12 "Selectivity is achieved by selecting 1-3 groups from halogens, oxo groups, -OH, -NH2, C." 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, Halogenated C 1-4 Alkyl, Halogenated C 1-4 Alkoxy, hydroxy C 1-4 Alkyl, C 1-3 Alkoxy C 1-4 Alkyl, amino C 1-4 Alkyl and C 1-4 Alkylamino C 1-4 The alkyl substituents can be substituted at any position; (13) L' is a connector, -O- or -NR 12 "-, for example, a link key; (14) C is For example Preferred m can be 0, 1, or 2, for example, 1; (15) R9 is C 1-6 alkyl; (16) A is A1, A2, A3, and A4 are each independently N or CR8'; preferably A is... A1 is N, A2 is CH, A3 is CH, A4 is CH; (17) R1 is H, halogen, C 1-3 Alkyl or halogenated C 1-3 Alkyl groups, such as halogens; (18) R2 is H, halogen, C 1-3 Alkyl or halogenated C 1-3 Alkyl groups, such as halogens; (19) R3 is H, halogen, C 1-3 Alkyl or halogenated C 1-3 alkyl; (20) R4 is C 1-6 Alkyl, the C 1-6 The alkyl group is unsubstituted, or selectively substituted at any position by 1-3 substituents selected from hydroxyl, amino, halogen, and deuterium; for example, R4 is C. 1-6 alkyl; (21) R5 and R6 are independently H, D or C, respectively. 1-6 alkyl.

6. The compound, its stereoisomer, or a pharmaceutically acceptable salt according to any one of claims 1-5, wherein the compound satisfies one or more of the following conditions: (1)M - It consists of chloride ions, bromide ions, fluoride ions, trifluoroacetate ions, acetate ions, sulfate ions, or hydrogen sulfate ions; (2) B is Preferred (For example ) in, Z is either N or C-CN; B is preferred. Alternatively, B is preferred. For example Alternatively, B is preferred. B is more preferably any of the following structures: For example (3) Z is C-CN; (4) R8 is -NH2; (5)R 8e It is -NH2; (6)R 10 The derivative is H, F, Cl, -CN, -NO2, -OH, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, or cyclopropyl, preferably F or methyl, for example F; (7)R 10a The following are possible values: H, F, Cl, -CN, -NO2, -OH, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, or cyclopropyl, such as trifluoromethyl. (8)R 10c Each can be independently H, F, Cl, -CN, -NO2, -OH, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, or cyclopropyl, for example, H; (9)R 10d It can be H, methyl, ethyl, vinyl, or ethynyl; (10) R5 and R6 are independently H, D or methyl, for example H; or, R5 and R6 together with the carbon atom they are attached to form (11) R7 is For example Preferably, R7 is For example Or, R7 is For example Preferred Or, R7 is Preferred (12)C is For example Preferred (13) In Formula I, R9 is methyl or ethyl; in Formula II, R9 is cyano, methyl, ethyl, trifluoromethyl, vinyl or ethynyl, for example, methyl; (14) for Preferred (15) R8 is NH2; (16) A1 is N, A2 is CH, A3 is CH, A4 is CH; (17) A is Preferred For example Or, A is u is 1 or 2; A is preferably... Or, A is Alternatively, A and R9 can be interconnected to form a 5-7 membered heterocyclic alkyl group. u is 1 or 2; R8' is H or C. 1-4 Alkyl; the 5-7 membered heterocyclic alkyl group is Alternatively, A and R4 can be interconnected to form a 6-9 membered heterocyclic alkyl group. "L" is a connector or -O-; R8 and R8' are independently H and C, respectively. 1-4 Alkyl or hydroxyl; the 6-9 membered heterocyclic alkyl group is (18) R1 is F, R2 is F, Cl or -CF3, for example F; (18) R2 is either F or Cl; (19) R3 is H or -OCH3, for example, H; (20) R4 is H, -CH3, -CH2CH3, -OCH3, -CDH2, -CD2H, -CD3, -CHDCH3, -CD2CH3 or -OCD3, preferably -CH3, -CDH2, -CD2H or -CD, for example -CH3; (21) R5 and R6 are independently H, D or methyl.

7. The compound, its stereoisomer, or a pharmaceutically acceptable salt according to any one of claims 1-6, wherein the compound satisfies one of the following conditions: (1) The compound, its stereoisomer or pharmaceutically acceptable salt being a compound of formula (I-1) or (I-2), its stereoisomer or pharmaceutically acceptable salt, in, R1, R3, R4, R5, R6, R9, R 11 R 11 '、R 12 R 12 ', L, L', m, B and U are as defined in any one of claims 1-6; (2) The compound, its stereoisomer or pharmaceutically acceptable salt being a compound of formula (I-3) or (I-4), its stereoisomer or pharmaceutically acceptable salt, Among them, R1, R2, R3, R4, R5, R6, R 10 R 11 R 11 '、R 12 R 12 'and m are as defined in any one of claims 1-6; (3) The compound, its stereoisomer or pharmaceutically acceptable salt being a compound of formula (I-3-1) or (I-3-2), its stereoisomer or pharmaceutically acceptable salt, Among them, R1, R2, R4, R5, R6, R 10 R 11 and R 11 'As defined in any one of claims 1-6; (4) The stereoisomer or pharmaceutically acceptable salt of the compound is a compound of formula (I-3-3), or a stereoisomer or pharmaceutically acceptable salt thereof. Among them, R1, R2, R4, R5, R6, R 10 R 11 and R 11 'As defined in any one of claims 1-6 (5) The compound, its stereoisomer or pharmaceutically acceptable salt being a compound of formula (I-3-3A) or (I-3-3B), its stereoisomer or pharmaceutically acceptable salt, Among them, R1, R2, R4, R5, R6, R 10 R 11 and R 11 'As defined in any one of claims 1-6; (6) The compound, its stereoisomer or pharmaceutically acceptable salt being a compound of formula (I-3-4) (e.g., compounds of formulas (I-3-4A) and (I-3-4B)), its stereoisomer or pharmaceutically acceptable salt, For example Among them, R1, R2, R4, R5, R6 and R 10 As defined in any one of claims 1-6; (7) The compound, its stereoisomer or pharmaceutically acceptable salt being a compound of formula (I-3-5) (e.g., compounds of (I-3-5A) and (I-3-5B)), its stereoisomer or pharmaceutically acceptable salt, For example, Among them, R1, R2, R4, R5, R6 and R 10 As defined in any one of claims 1-6.

8. The compound of claim 7, its stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the compound satisfies one of the following conditions: (1) Equation (I-3), such as Equation (I-3-1), Equation (I-3-2), Equation (I-3-3), Equation (I-3-3A) or Equation (I-3-3B), R1 is H, halogen, or C. 1-3 Alkyl or halogenated C 1-3 alkyl; R2 is H, halogen, or C. 1-3 Alkyl or halogenated C 1-3 alkyl; R4 is C 1-6 Alkyl; the C 1-6 The alkyl group is unsubstituted or selectively substituted at any position by 1-3 substituents selected from hydroxyl, amino, halogen and deuterium; R5 is H, D, or C. 1-6 alkyl; R6 is H, D, or C. 1-6 alkyl; R 10 H, halogen, cyano, -N(R) b 2. C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy or C 3-6 Cycloalkyl groups; R 11 C 3-8 Cycloalkyl or 3-8 membered heterocyclic alkyl (preferably 5-6 membered monocyclic heterocyclic alkyl, containing 1-2 heteroatoms selected from O, N, and S); the C 3-8 The cycloalkyl or 3-8 membered heterocyclic alkyl group is unsubstituted, or selectively substituted with 1-3 R groups. 13 Replace in any position; R 11 'For H, halogen, C 1-6 Alkyl, C 1-6 Alkylene or halogenated C 1-6 Alkylene; R 13 Halogen, oxo group, -OR b -N(R) b )2、-OC(O)R b -NHC(O)R b -C(O)N(R) b )2、-C(O)R b -C(O)OR b C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl or amino C 1-6 alkyl; R b For H or C 1-6 alkyl; (2) Equation (I-3), such as equation (I-3-1), equation (I-3-2), equation (I-3-3), equation (I-3-3A), or equation (I-3-3B), R1 is a halogen (e.g., F); R2 is a halogen (e.g., F or Cl); R4 is C 1-6 Alkyl groups (e.g., methyl groups); R5 is H; R6 is H; R 10 Halogens (e.g., F); R 11 It is a 3-8 membered heterocyclic alkyl group (preferably a 5-6 membered monocyclic heterocyclic alkyl group containing 1-2 heteroatoms selected from O, N, and S); the 3-8 membered heterocyclic alkyl group is unsubstituted, or selectively substituted with 1-3 R atoms. 13 Replace in any position; R 11 'For H, C 1-6 Alkylene; R 13 Oxide group, -OR b ; R b For H or C 1-6 Alkyl groups (e.g., methyl groups); (3) Equation (I-3-4) or Equation (I-3-5), for example, Equation (I-3-4A), Equation (I-3-4B), Equation (I-3-5A) or (I-3-5B), R1 is H, halogen, or C. 1-3 Alkyl or halogenated C 1-3 alkyl; R2 is H, halogen, or C. 1-3 Alkyl or halogenated C 1-3 alkyl; R4 is C 1-6 Alkyl; the C 1-6 The alkyl group is unsubstituted or selectively substituted at any position by 1-3 substituents selected from hydroxyl, amino, halogen and deuterium; R5 is H, D, or C. 1-6 alkyl; R6 is H, D, or C. 1-6 alkyl; R 10 H, halogen, cyano, -N(R) b 2. C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy or C 3-6 Cycloalkyl groups; R b For H or C 1-6 alkyl; (4) Equation (I-3-4) or Equation (I-3-5), for example, Equation (I-3-4A), (I-3-4B), (I-3-5A) or (I-3-5B), R1 is a halogen (e.g., F); R2 is a halogen (e.g., F or Cl); R4 is C 1-6 Alkyl groups (e.g., methyl groups); R5 is H; R6 is H; R 10 It is a halogen (e.g., F).

9. The compound, its stereoisomer, or a pharmaceutically acceptable salt according to any one of claims 1-8, wherein the compound satisfies one of the following conditions: (1) The compound has any of the following structures: (2) The compound has any of the following structures: (3) The compound is a single stereoisomer of the following formula. The single stereoisomer is a compound with a short retention time under the following analytical conditions: using a UPCC (Waters) with a 6-OX 4.6*100mm, 5µm column (preferably, a flow rate of 3.0mL / min and / or a column temperature of 40°C; and / or an injection volume of 7.5µL; and / or a detection wavelength of 214 and / or 254nm); and a mobile phase of CO2 / [methanol (0.2% 7M ammonia methanol solution) / acetonitrile = 1 / 1] = 55:45; preferably, the short-retention compound has a retention time of approximately 3.23-3.33 min, for example, approximately 3.284 min; The single stereoisomer is: (4) The compound is a single stereoisomer of the following formula. The single stereoisomer is a compound with a long retention time under the following analytical conditions: using a UPCC (Waters) with a 6-OX 4.6*100mm, 5µm column (preferably, a flow rate of 3.0mL / min and / or a column temperature of 40℃; and / or an injection volume of 7.5µL; and / or a detection wavelength of 214 and / or 254nm); and a mobile phase of CO2 / [methanol (0.2% 7M ammonia methanol solution) / acetonitrile = 1 / 1] = 55:45; preferably, the long retention time of the compound is approximately 4.49-4.59 min, for example, approximately 4.547 min; The single stereoisomer is:

10. A method for preparing a compound, its stereoisomer, or a pharmaceutically acceptable salt according to any one of claims 1-9, comprising the following steps: In a solvent, the compound shown in formula (IA) and X-1 undergo a condensation reaction under basic conditions to give the compound shown in formula (I). Wherein, R1, R3, R4, R9, U, V, A, B, C, and Y are as defined in any one of claims 1-9; the solvent is preferably N,N-dimethylformamide or dimethyl sulfoxide; the base is preferably 4-dimethylaminopyridine or N,N-diisopropylethylamine; the condensing agent is preferably benzotriazol-1-yl-oxytripyrrolylphosphine hexafluorophosphate; the reaction temperature is preferably 0–35°C; and the reaction time is preferably 0.5–6 hours. When B contains an amino group, the amino group can be protected by a tert-butoxycarbonyl protecting group. If the above-mentioned amino protecting group is present, a further deprotection step is required to obtain the compound shown in formula (I). Preferably, the deprotection reaction is carried out in a dichloromethane / trifluoroacetic acid system.

11. An antibody-drug conjugate comprising one or more of the compounds, stereoisomers thereof, and pharmaceutically acceptable salts as the drug component, as any one of claims 1-9.

12. The use of the compound, its stereoisomer, and pharmaceutically acceptable salt as described in any one of claims 1-9 in the preparation of antibody-drug conjugates.

13. A pharmaceutical composition comprising (i) one or more of the compounds, stereoisomers thereof, and pharmaceutically acceptable salts as claimed in any one of claims 1-9, or the antibody-drug conjugate as claimed in claim 11; and (ii) a pharmaceutically acceptable excipient.

14. The use of the compound, its stereoisomer, and pharmaceutically acceptable salt as claimed in any one of claims 1-9, the antibody-drug conjugate as claimed in claim 11, or the pharmaceutical composition as claimed in claim 13 in the preparation of a KRAS mutant inhibitor.

15. The use of the compound, its stereoisomer, and pharmaceutically acceptable salt of any one of claims 1-9, the antibody-drug conjugate of claim 11, or the pharmaceutical composition of claim 13 in the preparation of a medicament for treating and / or alleviating KRAS mutant-mediated related diseases; wherein the related diseases are preferably cancer, and the cancer is preferably cancer in which the tumor cell DNA contains a KRAS gene with a KRAS mutation; the cancer is further preferably cancer in which the tumor cell DNA contains a KRAS gene with a KRAS G12C, G12D, G12V, and / or G12A mutation; And / or, the cancer is pancreatic cancer, gastric cancer, ovarian cancer, breast cancer, head and neck cancer, liver cancer, malignant glioma, endometrial cancer, lung cancer (e.g., small cell lung cancer, non-small cell lung cancer), small bowel cancer, rectal cancer and / or colorectal cancer.

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