Use of heterocyclic Anti-tumor compound

Abstract

The invention relates to the technical field of medicines, and provides a use of a heterocyclic anti-tumor compound, in particular a use of the heterocyclic anti-tumor compound in the preparation of a medicine for preventing and / or treating tumors or cancers. The compound has a tri-heterocyclic structure (for example, a structure as shown in formula (B)), has a novel structure, and provides a new direction for the development of SOS1 inhibitor drugs.

Description

Use of a heterocyclic antitumor compound

[0001] Citation of Related Applications

[0002] The present invention claims priority to invention patent application No. 202310707871.6, entitled “Use of a Heterocyclic Antitumor Compound”, filed in China on June 15, 2023. The entire contents of the patent application are incorporated herein by reference. Technical Field

[0003] The present invention relates to the field of medical technology, and in particular to the use of a heterocyclic compound in treating tumor diseases. Background Art

[0004] Currently, there are three known RAS family genes: KRAS (Kirsten rat sarcoma viral oncogene homolog), NRAS (neuroblastoma RAS viral oncogene homolog), and HRAS (Harvey rat sarcoma viral oncogene homolog). RAS family proteins are a class of small GTPases and were the first oncogenes identified in human tumors. RAS family proteins have weak intrinsic GTPase activity and slow nucleotide exchange rates. Binding of GTPase-activating proteins (GAPs), such as NF1, increases the GTPase activity of RAS family proteins.

[0005] Mutations in RAS enzymes are closely associated with tumorigenesis, and the types of RAS mutations vary across different tumor types. In human tumors, KRAS mutations (e.g., amino acids G12, G13, Q61, A146) are the most common, accounting for approximately 85%. NRAS (e.g., amino acids G12, G13, Q61, A146) and HRAS (e.g., amino acids G12, G13, Q61) account for 12% and 3%, respectively. Alterations in RAS family proteins (e.g., mutations, overexpression, gene amplification) have also been described as mechanisms of resistance to cancer drugs such as the EGFR antibodies cetuximab and panitumumab, and the EGFR tyrosine kinase inhibitor osimertinib. In oncogenic RAS mutants, GAP activity is impaired or greatly reduced, leading to permanent activation, which underlies oncogenic RAS signaling. Direct inhibition of RAS has proven challenging and elusive due to the picomolar affinity of GTP for its binding site, the lack of other well-defined pockets, and the extended and flat protein-protein interactions that RAS interacts with GEFs, GAPs, and effectors. Therefore, there may be new hope for inhibiting RAS activation by targeting the upstream guanine nucleotide exchange factor protein SOS.

[0006] SOS has two human isoforms, SOS1 and SOS2, but most studies have focused on SOS1. Human SOS1 comprises 1333 amino acids (15 kDa) and is composed of an N-terminal histone-like domain, a Dbl homology (DH) domain, a pleckstrin homology (PH) domain, a helical linker (HL), a Ras exchanger motif (Rem) domain, a Cdc25 domain, and a C-terminal region. PH, Rem, and Cdc25 are components of the core catalytic domain of SOScat.

[0007] Over the past few decades, the RAS family protein-SOS1 protein interaction has gained increasing recognition. Recently, research has been conducted to combine rational design and screening platforms to screen and identify small molecule inhibitors of SOS1, that is, compounds that bind to SOS1 and inhibit protein-protein interactions with RAS family proteins. For example, WO2021105960A1 describes a variety of cyclic SOS1 inhibitors.

[0008] Although some small molecules of SOS1 inhibitors have been disclosed, such as MRTX0902 and BI-3406, no SOS1 inhibitors have been developed and marketed yet. Therefore, there is an urgent need to develop new compounds with potential for marketing and better efficacy and pharmacokinetic results.

[0009] Summary of the Invention

[0010] In a first aspect, the present invention provides a compound or its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates or isotopic derivatives for use in the preparation of a medicament for preventing and / or treating tumors or cancer, wherein the compound has a structure as shown in formula (B):

[0011] Among them, R 1 Select from -OR A 、-N(R D )R B or R C ;

[0012] When R 1 For-OR A , R A Selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl are each optionally substituted by 1-3 identical or different R a1 replace;

[0013] If present, each R a1 Each is independently selected from halogen, hydroxy, cyano, amino, nitro, oxo, formyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -COC 1-6 Alkyl, -CH2COC 1-6 Alkyl, -CH2CON(C 1-6 Alkyl)2, -CH2CONHC 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 3-10 Cycloalkyl, C 6-10 aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl;

[0014] When R 1 -N(R D )R B , R B Selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl are each optionally substituted by 1-3 identical or different R b1 replace;

[0015] If present, each R b1 Each is independently selected from halogen, hydroxy, cyano, amino, nitro, oxo, formyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -COC 1-6 Alkyl, -CH2COC 1-6Alkyl, -CH2CON(C 1-6 Alkyl)2, -CH2CONHC 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 3-10 Cycloalkyl, C 6-10 aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl;

[0016] R D Selected from hydrogen, halogen, hydroxy, cyano, amino, nitro, oxo, formyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -COC 1-6 Alkyl, -CH2COC 1-6 Alkyl, -CH2CON(C 1-6 Alkyl)2, -CH2CONHC 1-6 Alkyl, -NHC 1-6 Alkyl or -N(C 1-6 Alkyl)2;

[0017] When R 1 R C , R C Selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl are each optionally substituted by 1-4 identical or different R c1 replace;

[0018] If present, each R c1 Each is independently selected from halogen, hydroxy, cyano, amino, nitro, oxo, formyl, methylsulfonyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -COC 1-6 Alkyl, -COC 3-6 Cycloalkyl, -CH2COC 1-6Alkyl, -CH2CON(C 1-6 Alkyl)2, -CH2CONHC 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 3-10 Cycloalkyl, C 6-10 aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -COC 1-6 Alkyl, -COC 3-6 Cycloalkyl, -CH2COC 1-6 Alkyl, -CH2CON(C 1-6 Alkyl)2, -CH2CONHC 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl are optionally substituted by one or more selected from deuterium, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Alkoxy or halogen substituents;

[0019] R 2 is 1 or 2, each of which is independently selected from hydrogen, halogen, hydroxy, cyano, amino, nitro, formyl, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 alkoxy;

[0020] R 3 Selected from hydrogen, halogen, hydroxy, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl and 3-6 membered heterocyclyl are optionally substituted with one or more hydroxyl or halogen;

[0021] Ring B is selected from C 4-12 Cycloalkyl, C 4-12 Cycloalkenyl, C 4-12 Heterocyclic group, C 6-12 Aryl, C 5-12 Heteroaryl, C6-12 Aryl C 4-12 Cycloalkyl, C 6-12 Aryl C 4-12 Heterocyclic or C 6-12 Aryl C 4-12 cycloalkenyl;

[0022] If present, each R 4 Each is independently selected from hydrogen, cyano, halogen, amino, hydroxy, oxo, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, -C 0-6 Alkyl-NH-C 1-6 Alkyl, -C 0-6 Alkyl-N(C 1-6 Alkyl)(C 1-6 Alkyl), C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl or 3-6 membered heterocyclic group, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, -C 0-6 Alkyl-NH-C 1-6 Alkyl, -C 0-6 Alkyl-N(C 1-6 Alkyl)(C 1-6 Alkyl), C 3-6 Cycloalkyl, C 3-6 The halocycloalkyl and 3-6 membered heterocyclic groups are optionally substituted with one or more of the following substituents: halogen, hydroxy, amino, -SO2-C 1-4 Alkyl or oxo; w is 0, 1, 2, 3 or 4;

[0023] Unless otherwise specified, the heteroatoms in the above heteroaryl and heterocyclic groups are each independently selected from O, N or S, and the number of heteroatoms is 1, 2, 3 or 4.

[0024] In a preferred embodiment of the present invention, R 1 For-OR A , R A Selected from C 1-6 Alkyl, C 3-10 Cycloalkyl, C 6-10 aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl are each optionally substituted by 1-3 identical or different R a1 replace;

[0025] If present, each R a1 Each is independently selected from halogen, hydroxy, cyano, amino, nitro, oxo, formyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -COC 1-6 Alkyl, -CH2COC 1-6 Alkyl, -CH2CON(C 1-6 Alkyl)2, -CH2CONHC 1-6 Alkyl, -NHC 1-6 Alkyl or -N(C 1-6 Alkyl)2.

[0026] More preferably, R A Selected from C 3-6 Cycloalkyl, C 6-10 aryl, 3-6 membered heterocyclic group or 5-6 membered heteroaryl, wherein the C 3-6 Cycloalkyl, C 6-10 Aryl, 3-6 membered heterocyclyl and 5-6 membered heteroaryl are optionally substituted by 1-3 identical or different R a1 replace;

[0027] If present, each R a1 Each independently selected from halogen, hydroxy, cyano, amino, oxo, formyl, C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl or -COC 1-6 alkyl.

[0028] More preferably, R A is selected from 5-6 membered heterocyclyl or 5-6 membered heteroaryl, wherein the 5-6 membered heterocyclyl and 5-6 membered heteroaryl are optionally substituted by 1-3 identical or different R a1 replace;

[0029] If present, each R a1 Each independently selected from halogen, hydroxy, cyano, amino, oxo, formyl, C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl or -COC 1-4 alkyl.

[0030] More preferably, R A is selected from 5-6 membered heterocyclic groups, wherein the 5-6 membered heterocyclic groups are optionally substituted by 1-2 identical or different R a1 replace;

[0031] If present, each R a1 Each is independently selected from halogen, oxo, formyl, acetyl, methyl, ethyl, n-propyl, isopropyl or methoxy.

[0032] More preferably, R A is selected from 5-6 membered monocyclic heterocyclic groups, wherein the 5-6 membered monocyclic heterocyclic groups are optionally substituted by 1-2 identical or different R a1 Substitution; the heteroatoms in the 5-6 membered monocyclic heterocyclic group are each independently selected from O, N or S, and the number of heteroatoms is 1;

[0033] If present, each R a1 Each is independently selected from halogen, oxo, formyl, acetyl, methyl, ethyl, n-propyl, isopropyl or methoxy.

[0034] More preferably, R A is selected from tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl or tetrahydrothiopyranyl, wherein the tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl and tetrahydrothiopyranyl are optionally substituted by 1-2 identical or different R a1 replace;

[0035] If present, each R a1 Each is independently selected from halogen, oxo, formyl, acetyl, methyl, ethyl, n-propyl, isopropyl or methoxy.

[0036] More preferably, R A Selected from the following groups:

[0037] In a preferred embodiment of the present invention, R 1 -N(R D )R B , R B Selected from C 1-6 Alkyl, C 3-10 Cycloalkyl, C 6-10 aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl are each optionally substituted by 1-3 identical or different R b1 replace;

[0038] If present, each R b1 Each is independently selected from halogen, hydroxy, cyano, amino, nitro, oxo, formyl, C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl or -COC 1-6 alkyl.

[0039] More preferably, R B Selected from C 1-6 alkyl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl are each optionally substituted by 1-3 identical or different R b1 replace;

[0040] If present, each R b1 Each is independently selected from halogen, hydroxy, cyano, amino, nitro, oxo, formyl, C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl or -COC 1-6 alkyl.

[0041] More preferably, R B Selected from C 1-6 Alkyl or 5-6 membered monocyclic heterocyclic group, wherein the C 1-6 The alkyl group and the 5-6 membered monocyclic heterocyclic group are each optionally substituted by 1-2 identical or different R b1 Substitution; the heteroatoms in the 5-6 membered monocyclic heterocyclic group are each independently selected from O, N or S, and the number of heteroatoms is 1;

[0042] If present, each R b1 Each independently selected from halogen, oxo, formyl, C 1-4 Alkyl, -OC 1-4 Alkyl or -COC 1-4 alkyl.

[0043] More preferably, R B is selected from methyl, ethyl, n-propyl, isopropyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl or tetrahydrothiopyranyl, wherein the methyl, ethyl, n-propyl, isopropyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl and tetrahydrothiopyranyl are optionally substituted by 1-2 identical or different R b1 replace;

[0044] If present, each R b1Each is independently selected from oxo, formyl, acetyl, methyl, ethyl, methoxy or ethoxy.

[0045] More preferably, R B Selected from the following groups:

[0046] In a preferred embodiment of the present invention, R 1 -N(R D )R B , R D Selected from hydrogen, C 1-6 Alkyl or -OC 1-6 Alkyl; further preferably, R D Selected from hydrogen or C 1-3 Alkyl; More preferably, R D is selected from hydrogen or methyl; most preferably, R D For hydrogen.

[0047] In a preferred embodiment of the present invention, R 1 R C , R C Selected from C 3-10 Cycloalkyl, C 6-10 aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl, wherein the C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl are each optionally substituted by 1-4 identical or different R c1 replace;

[0048] If present, each R c1 Each is independently selected from halogen, hydroxy, cyano, amino, nitro, oxo, formyl, methylsulfonyl, C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -COC 1-6 Alkyl, -COC 3-6 Cycloalkyl, -CH2COC 1-6 Alkyl, -CH2CON(C 1-6 Alkyl)2, -CH2CONHC 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -COC 1-6 Alkyl, -COC 3-6 Cycloalkyl, -CH2COC1-6 Alkyl, -CH2CON(C 1-6 Alkyl)2, -CH2CONHC 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 3-10 The cycloalkyl and 3-10 membered heterocyclic groups are optionally substituted with one or more radicals selected from deuterium, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 The substituent is substituted with an alkoxy group or a halogen group.

[0049] More preferably, R C Selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl, wherein the C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl are each optionally substituted by 1-4 identical or different R c1 replace;

[0050] If present, each R c1 Each is independently selected from halogen, hydroxy, cyano, amino, nitro, oxo, formyl, methylsulfonyl, C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -COC 1-4 Alkyl, -COC 3-6 Cycloalkyl, -CH2COC 1-4 Alkyl, -CH2CON(C 1-4 Alkyl)2, -CH2CONHC 1-4 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, wherein the C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -COC 1-4 Alkyl, -COC 3-6 Cycloalkyl, -CH2COC 1-4 Alkyl, -CH2CON(C 1-4 Alkyl)2, -CH2CONHC 1-4 Alkyl, C 3-6 The cycloalkyl and 3-6 membered heterocyclic groups are optionally substituted with one or more radicals selected from deuterium, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 The substituent is substituted with an alkoxy group or a halogen group.

[0051] More preferably, R C is selected from 3-10 membered heterocyclyl or 5-10 membered heteroaryl, wherein the 3-10 membered heterocyclyl and 5-10 membered heteroaryl are optionally substituted by 1-4 identical or different Rc1 replace;

[0052] If present, each R c1 Each is independently selected from halogen, hydroxy, cyano, amino, oxo, formyl, methylsulfonyl, C 1-4 Alkyl, -OC 1-4 Alkyl, -COC 1-4 Alkyl, -COC 3-6 Cycloalkyl, -CH2CON(C 1-4 alkyl) 2 or 3-6 membered heterocyclic group, wherein the C 1-4 Alkyl, -OC 1-4 Alkyl, -COC 1-4 Alkyl, -COC 3-6 Cycloalkyl, -CH2CON(C 1-4 alkyl) 2 and 3-6 membered heterocyclyl are each optionally substituted with one or more substituents selected from deuterium, hydroxy, cyano, methyl, methoxy or halogen.

[0053] More preferably, R C is selected from 5-6 membered monocyclic heterocyclic radical, 6-10 membered spiro heterocyclic radical, 6-8 membered bridged heterocyclic radical, 8-10 membered fused heterocyclic radical or 5-6 membered monocyclic heteroaryl, wherein the 5-6 membered monocyclic heterocyclic radical, 6-10 membered spiro heterocyclic radical, 6-8 membered bridged heterocyclic radical, 8-10 membered fused heterocyclic radical and 5-6 membered monocyclic heteroaryl are optionally substituted by 1-4 identical or different R c1 replace;

[0054] If present, each R c1 Each is independently selected from halogen, hydroxy, cyano, amino, oxo, formyl, acetyl, propionyl, methylsulfonyl, methoxy, ethoxy, methyl, ethyl, n-propyl, isopropyl, -CH2CON(CH3)2, -CO-cyclopropyl, -CO-cyclobutyl, 4-membered heterocyclyl, 5-membered heterocyclyl or 6-membered heterocyclyl, wherein the acetyl, propionyl, methylsulfonyl, methoxy, ethoxy, methyl, ethyl, n-propyl, isopropyl, -CH2CON(CH3)2, -CO-cyclopropyl, -CO-cyclobutyl, 4-membered heterocyclyl, 5-membered heterocyclyl and 6-membered heterocyclyl are optionally substituted with one or more substituents selected from deuterium, hydroxy, cyano, methyl, methoxy or halogen.

[0055] More preferably, R C is selected from 6-membered monocyclic heterocyclic radical, 4-membered / 6-membered spiro heterocyclic radical, 4-membered / 4-membered spiro heterocyclic radical, 6-membered / 5-membered fused heterocyclic radical, 7-membered bridged heterocyclic radical or 6-membered monocyclic heteroaryl, wherein the 6-membered monocyclic heterocyclic radical, 4-membered / 6-membered spiro heterocyclic radical, 4-membered / 4-membered spiro heterocyclic radical, 6-membered / 4-membered fused heterocyclic radical, 7-membered bridged heterocyclic radical and 6-membered monocyclic heteroaryl are optionally substituted by 1-4 identical or different Rc1 replace;

[0056] If present, each R c1 Each is independently selected from halogen, hydroxy, cyano, amino, oxo, formyl, acetyl, propionyl, methylsulfonyl, methoxy, ethoxy, methyl, ethyl, n-propyl, isopropyl, -CH2CON(CH3)2, -CO-cyclopropyl, 4-membered heterocyclyl, 5-membered heterocyclyl or 6-membered heterocyclyl, wherein the acetyl, propionyl, methylsulfonyl, methoxy, ethoxy, methyl, ethyl, n-propyl, isopropyl, -CH2CON(CH3)2, -CO-cyclopropyl, 4-membered heterocyclyl, 5-membered heterocyclyl and 6-membered heterocyclyl are optionally substituted with one or more substituents selected from deuterium, hydroxy, cyano, methyl, methoxy or halogen.

[0057] More preferably, R C Selected from The R C are optionally replaced by 1-4 identical or different R c1 replace;

[0058] If present, each R c1 Each is independently selected from F, Cl, Br, hydroxy, cyano, amino, oxo, methylsulfonyl, acetyl, -COCH2CH3, -COCH2OH, -COCH2CN, -CH(OH)(CH3)2, hydroxymethyl, hydroxyethyl, -CH2OCH3, -CH2CH2OCH3, methoxy, methyl, CD3, ethyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, -CH2CON(CH3)2 or morpholinyl.

[0059] Still more preferably, optionally R c1 Replaced R C Selected from the following groups:

[0060] In a preferred embodiment of the present invention, R 2 is 1 or 2, each of which, when present, is independently selected from hydrogen, halogen, hydroxy, cyano, amino, nitro, formyl, oxo, methoxy, methyl, ethyl, n-propyl or isopropyl.

[0061] More preferably, R 2 is 1 or 2, each of which, when present, is independently selected from hydrogen, halogen, hydroxy, cyano, amino, nitro, methoxy or methyl.

[0062] More preferably, R 2 is 1 or 2, each of which, when present, is independently selected from hydrogen or methyl.

[0063] More preferably, R 2 For hydrogen.

[0064] In a preferred embodiment of the present invention, R 3 is selected from hydrogen, halogen, hydroxy, amino, cyano, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or methoxy.

[0065] More preferably, R 3 is selected from hydrogen, halogen, hydroxy, amino, cyano, methyl, ethyl, n-propyl, isopropyl or cyclopropyl.

[0066] More preferably, R 3 is selected from hydrogen, F, Cl, Br, amino, methyl, ethyl or cyclopropyl.

[0067] In a preferred embodiment of the present invention, ring B is selected from C 4-12 Cycloalkenyl, 4-12 membered heterocyclic group, C 6-12 Aryl, C 6-8 Aryl C 4-6 Cycloalkyl, C 6-8 aryl and a 4- to 6-membered heterocyclic group or a 5- to 12-membered heteroaryl group.

[0068] More preferably, ring B is selected from C 6-10 Aryl, 5-10 membered heteroaryl or C 6-8 Aryl and 4-6 membered heterocyclic group.

[0069] More preferably, ring B is selected from phenyl, pyridyl or benzotetrahydrofuranyl.

[0070] In a preferred embodiment of the present invention, each R 4 are independently selected from hydrogen, cyano, halogen, amino, nitro, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Hydroxyalkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl or 3-6 membered heterocyclic group, wherein the C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Hydroxyalkyl, C 3-6 Cycloalkyl, C 3-6 The halocycloalkyl and 3-6 membered heterocyclic groups are optionally substituted with one or more of the following substituents: halogen, hydroxy, amino, -SO2-C 1-4alkyl or oxo; w is 0, 1, 2 or 3.

[0071] More preferably, each R 4 are independently selected from hydrogen, cyano, halogen, amino, nitro, C 1-4 Alkyl, C 1-4 Haloalkyl or C 1-4 Hydroxyalkyl, wherein the C 1-4 Alkyl, C 1-4 Haloalkyl and C 1-4 The hydroxyalkyl groups are optionally substituted with one or more of the following substituents: halogen, hydroxy or amino; and w is 1, 2 or 3.

[0072] More preferably, each R 4 Each is independently selected from hydrogen, cyano, halogen, amino, nitro, methyl, ethyl, n-propyl or isopropyl, wherein the methyl, ethyl, n-propyl and isopropyl are optionally substituted with one or more of the following substituents: halogen or hydroxy; w is 1, 2 or 3.

[0073] More preferably, each R 4 Each is independently selected from hydrogen, halogen, amino, cyano, methyl, ethyl or isopropyl, wherein the methyl, ethyl and isopropyl are optionally substituted with one or more of the following substituents: halogen or hydroxy; w is 1, 2 or 3.

[0074] More preferably, each R 4 Each is independently selected from hydrogen, fluorine, amino, cyano, methyl, trifluoromethyl, difluoromethyl, monofluoromethyl, -CF2CH2OH, -C(CH3)2OH, -CF2CH3 or -CH2CHF2; w is 1, 2 or 3.

[0075] In a second aspect, the present invention further provides a use of a compound or its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates or isotopic derivatives in the preparation of a medicament for preventing and / or treating tumors or cancer, wherein the compound has a structure as shown in formula (C):

[0076] The substituents in formula (C) are as defined in formula (B).

[0077] In a third aspect, the present invention further provides a compound or its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates or isotopic derivatives for use in the preparation of a medicament for preventing and / or treating tumors or cancer, wherein the compound has a structure as shown in formula (D):

[0078] Among them, R 1 、R 4, w are defined as described in formula (B) or (C).

[0079] Preferably, each R 4 Each independently selected from cyano, halogen, amino, C 1-6 Alkyl or C 1-6 haloalkyl, wherein the C 1-6 Alkyl and C 1-6 The haloalkyl groups are optionally substituted with one or more hydroxyl groups; w is 1 or 2;

[0080] R 1 Select from -OR A 、-N(R D )R B or R C ;

[0081] When R 1 For-OR A , R A is selected from 3-10 membered heterocyclic groups, wherein the 3-10 membered heterocyclic groups are optionally substituted by 1-3 identical or different R a1 replace;

[0082] If present, each R a1 Each independently selected from C 1-6 Alkyl or -COC 1-6 alkyl;

[0083] When R 1 -N(R D )R B , R B Selected from C 1-6 Alkyl or 3-10 membered heterocyclic group, wherein the C 1-6 The alkyl group and the 3-10 membered heterocyclic group are each optionally substituted by 1-3 identical or different R b1 replace;

[0084] If present, each R b1 Each independently selected from -OC 1-6 alkyl;

[0085] R D selected from hydrogen;

[0086] When R 1 R C , R C is selected from 3-10 membered heterocyclyl or 5-10 membered heteroaryl, wherein the 3-10 membered heterocyclyl and 5-10 membered heteroaryl are optionally substituted by 1-4 identical or different R c1 replace;

[0087] If present, each R c1Each independently selected from halogen, hydroxy, cyano, amino, methylsulfonyl, C 1-6 Alkyl, -OC 1-6 Alkyl, -COC 1-6 Alkyl, -COC 3-6 Cycloalkyl, -CH2CON(C 1-6 alkyl) 2 or 3-10 membered heterocyclic group, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl, -COC 1-6 Alkyl, -COC 3-6 Cycloalkyl, -CH2CON(C 1-6 alkyl) 2 and 3-10 membered heterocyclic groups are optionally substituted by one or more groups selected from deuterium, hydroxyl, cyano, C 1-3 The substituent is substituted with an alkoxy group or a halogen group.

[0088] Unless otherwise specified, the heteroatoms in the above heteroaryl and heterocyclic groups are each independently selected from O, N or S, and the number of heteroatoms is 1, 2, 3 or 4.

[0089] In a preferred embodiment of the present invention, R 1 For-OR A , R A is selected from 3-6 membered heterocyclic groups, wherein the 3-6 membered heterocyclic groups are optionally substituted by 1-3 identical or different R a1 replace;

[0090] If present, each R a1 Each independently selected from C 1-6 Alkyl or -COC 1-6 alkyl.

[0091] More preferably, R A is selected from 5-6 membered heterocyclic groups, wherein the 5-6 membered heterocyclic groups are optionally substituted by 1-2 identical or different R a1 replace;

[0092] If present, each R a1 Each is independently selected from acetyl, methyl, ethyl, n-propyl or isopropyl.

[0093] More preferably, R A is selected from 5-6 membered monocyclic heterocyclic groups, wherein the 5-6 membered monocyclic heterocyclic groups are optionally substituted by 1-2 identical or different R a1 Substitution; the heteroatoms in the 5-6 membered monocyclic heterocyclic group are each independently selected from O, N or S, and the number of heteroatoms is 1;

[0094] If present, each R a1 Each is independently selected from acetyl, methyl or ethyl.

[0095] More preferably, R A is selected from tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl or tetrahydrothiopyranyl, wherein the tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl and tetrahydrothiopyranyl are optionally substituted by 1-2 identical or different R a1 replace;

[0096] If present, each R a1 Each is independently selected from acetyl, methyl or ethyl.

[0097] More preferably, R A Selected from the following groups:

[0098] In a preferred embodiment of the present invention, R 1 -N(R D )R B (e.g. NHR B ), R B Selected from C 1-6 Alkyl or 3-6 membered monocyclic heterocyclic group, wherein the C 1-6 The alkyl group and the 3-6 membered monocyclic heterocyclic group are each optionally substituted by 1-2 identical or different R b1 Substitution; the heteroatoms in the 3-6 membered monocyclic heterocyclic group are each independently selected from O, N or S, and the number of heteroatoms is 1;

[0099] If present, each R b1 Each independently selected from -OC 1-4 alkyl.

[0100] More preferably, R B is selected from methyl, ethyl, n-propyl, isopropyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl or tetrahydrothiopyranyl, wherein the methyl, ethyl, n-propyl, isopropyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl and tetrahydrothiopyranyl are optionally substituted by 1-2 identical or different R b1 replace;

[0101] If present, each R b1 Each is independently selected from methoxy or ethoxy.

[0102] More preferably, R B Selected from the following groups:

[0103] In a preferred embodiment of the present invention, R 1 R C , RC is selected from 3-10 membered heterocyclyl or 5-10 membered heteroaryl, wherein the 3-10 membered heterocyclyl and 5-10 membered heteroaryl are optionally substituted by 1-4 identical or different R c1 replace;

[0104] If present, each R c1 Each independently selected from halogen, hydroxy, cyano, amino, methylsulfonyl, C 1-4 Alkyl, -OC 1-4 Alkyl, -COC 1-4 Alkyl, -COC 3-6 Cycloalkyl, -CH2CON(C 1-4 alkyl) 2 or 3-6 membered heterocyclic group, wherein the C 1-4 Alkyl, -OC 1-4 Alkyl, -COC 1-4 Alkyl, -COC 3-6 Cycloalkyl, -CH2CON(C 1-4 alkyl) 2 and 3-6 membered heterocyclyl are each optionally substituted with one or more substituents selected from deuterium, hydroxy, cyano, methoxy or halogen.

[0105] More preferably, R C is selected from 5-6 membered monocyclic heterocyclic radical, 6-10 membered spiro heterocyclic radical, 6-8 membered bridged heterocyclic radical, 8-10 membered fused heterocyclic radical or 5-6 membered monocyclic heteroaryl, wherein the 5-6 membered monocyclic heterocyclic radical, 6-10 membered spiro heterocyclic radical, 6-8 membered bridged heterocyclic radical, 8-10 membered fused heterocyclic radical and 5-6 membered monocyclic heteroaryl are optionally substituted by 1-4 identical or different R c1 replace;

[0106] If present, each R c1 Each is independently selected from halogen, hydroxy, cyano, amino, methanesulfonyl, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, acetyl, propionyl, -CO-cyclopropyl, -CO-cyclobutyl, -CH2CON(CH3)2, a 4-membered heterocyclyl, a 5-membered heterocyclyl or a 6-membered heterocyclyl, wherein the methanesulfonyl, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, acetyl, propionyl, -CO-cyclopropyl, -CO-cyclobutyl, -CH2CON(CH3)2, a 4-membered heterocyclyl, a 5-membered heterocyclyl and a 6-membered heterocyclyl are optionally substituted with one or more substituents selected from deuterium, hydroxy, cyano, methoxy or halogen.

[0107] More preferably, R Cis selected from 6-membered monocyclic heterocyclic radical, 4-membered / 6-membered spiro heterocyclic radical, 4-membered / 4-membered spiro heterocyclic radical, 7-membered bridged heterocyclic radical, 6-membered / 5-membered fused heterocyclic radical or 6-membered monocyclic heteroaryl, wherein the 6-membered monocyclic heterocyclic radical, 4-membered / 6-membered spiro heterocyclic radical, 4-membered / 4-membered spiro heterocyclic radical, 7-membered bridged heterocyclic radical, 6-membered / 4-membered fused heterocyclic radical and 6-membered monocyclic heteroaryl are optionally substituted by 1-4 identical or different R c1 replace;

[0108] If present, each R c1 Each is independently selected from halogen, hydroxy, cyano, amino, methanesulfonyl, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, acetyl, propionyl, -CO-cyclopropyl, -CH2CON(CH3)2, a 4-membered heterocyclyl, a 5-membered heterocyclyl or a 6-membered heterocyclyl, wherein the methanesulfonyl, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, acetyl, propionyl, -CO-cyclopropyl, a 4-membered heterocyclyl, a 5-membered heterocyclyl and a 6-membered heterocyclyl are optionally substituted with one or more substituents selected from deuterium, hydroxy, cyano, methoxy or halogen.

[0109] More preferably, R C Selected from The R C are optionally replaced by 1-4 identical or different R c1 replace;

[0110] If present, each R c1 Each is independently selected from F, Cl, Br, hydroxy, cyano, amino, methanesulfonyl, methyl, ethyl, isopropyl, CD3, hydroxymethyl, hydroxyethyl (e.g., 2-hydroxyethyl), -CH(OH)(CH3)2, -CHOCH3, -CH2CH2OCH3, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl (e.g., 2-fluoroethyl), difluoroethyl (e.g., 2,2-difluoroethyl), trifluoroethyl (e.g., 2,2,2-trifluoroethyl), methoxy, acetyl, -COCH2CH3, -COCH2OH, -COCH2CN, -CH2CON(CH3)2, oxadiazine (e.g., ) or morpholinyl (e.g., morpholin-4-yl).

[0111] Still more preferably, optionally R c1 Replaced R C Selected from the following groups:

[0112] In a preferred embodiment of the present invention, each R4 Each independently selected from cyano, halogen, amino, C 1-4 Alkyl or C 1-4 haloalkyl, wherein the C 1-4 Alkyl and C 1-4 The haloalkyl groups are each optionally substituted with one or more hydroxy groups; w is 1 or 2.

[0113] More preferably, each R 4 Each is independently selected from cyano, fluoro, amino, methyl, trifluoromethyl, difluoromethyl, monofluoromethyl, -CF2CH2OH, -CF2C(CH3)2OH, -CF2CH3 or -CH2CHF2; w is 1 or 2.

[0114] In a fourth aspect, the present invention further provides a compound or its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates or isotopic derivatives for use in the preparation of a medicament for preventing and / or treating tumors or cancer, wherein the compound has a structure as shown in formula (E):

[0115] The substituents in formula (E) are as defined in formula (D).

[0116] In a fifth aspect, the present invention further provides a compound or its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates or isotopic derivatives for use in the preparation of a medicament for preventing and / or treating tumors or cancer, wherein the compound has a structure as shown in Formula (F) or Formula (F'):

[0117] Among them, R c1 、R 4 , w is defined as described in formula (D) or (E); v is 0 or 1, when v is 1, preferably R c1 Connected to the N atom.

[0118] Preferably, R c1 is selected from methyl, ethyl, isopropyl, CD3, hydroxymethyl, hydroxyethyl (e.g., 2-hydroxyethyl), monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl (e.g., 2-fluoroethyl), difluoroethyl (e.g., 2,2-difluoroethyl), trifluoroethyl (e.g., 2,2,2-trifluoroethyl), -CH2CON(CH3)2 or oxadiazolyl (e.g., ).

[0119] More preferably, Selected from the following groups:

[0120] In a sixth aspect, the present invention further provides a compound or its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates or isotopic derivatives for use in the preparation of a medicament for preventing and / or treating tumors or cancer, wherein the compound has a structure as shown in Formula (G) or Formula (G'):

[0121] Among them, R c1 、R 4 , w is defined as described in formula (D) or (E); v is 0 or 1, when v is 1, preferably R c1 Connected to the N atom.

[0122] Preferably, R c1 is selected from methyl, ethyl, isopropyl, hydroxymethyl, hydroxyethyl (e.g., 2-hydroxyethyl), -CH2OCH3, -CH2CH2OCH3, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl (e.g., 2-fluoroethyl), difluoroethyl (e.g., 2,2-difluoroethyl), trifluoroethyl (e.g., 2,2,2-trifluoroethyl), or -CH2CON(CH3)2.

[0123] More preferably, Selected from the following groups:

[0124] In a seventh aspect, the present invention further provides a use of a compound or its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates or isotopic derivatives in the preparation of a medicament for preventing and / or treating tumors or cancer, wherein the compound is selected from compounds having the following structure:

[0125] Preferably, the compound is selected from compounds having the following structure:

[0126] In an eighth aspect, the present invention also provides a use of a pharmaceutical composition in the preparation of a drug for preventing and / or treating tumors or cancer, wherein the pharmaceutical composition comprises the compound described in any one of the first to seventh aspects or its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates or isotope derivatives.

[0127] In a preferred embodiment of the present invention, the pharmaceutical composition comprises the compound described in any one of the first to seventh aspects or its stereoisomer, optical isomer, pharmaceutically acceptable salt, prodrug, solvate or isotope derivative, and pharmaceutically acceptable excipients.

[0128] Preferably, in any one of the first aspect to the eighth aspect, the tumor or cancer is pancreatic cancer, colorectal cancer or bladder cancer (such as bladder transitional cell carcinoma).

[0129] Preferably, in any one of the first aspect to the eighth aspect, the tumor or cancer is a tumor or cancer caused by a RAS mutation; more preferably, the tumor or cancer caused by a RAS mutation is pancreatic cancer, colorectal cancer or bladder cancer (such as bladder transitional cell carcinoma), that is, pancreatic cancer, colorectal cancer or bladder cancer (such as bladder transitional cell carcinoma) caused by a RAS mutation.

[0130] Preferably, in any one of the first to eighth aspects, the tumor or cancer is a tumor or cancer caused by a KRAS mutation; more preferably, the tumor or cancer caused by the KRAS mutation is lung cancer (such as non-small cell lung cancer), pancreatic cancer, colorectal cancer or bladder cancer (such as bladder transitional cell carcinoma), and the lung cancer (such as non-small cell lung cancer) is lung cancer (non-small cell lung cancer) caused by a non-KRAS G12C mutation, that is, lung cancer (such as non-small cell lung cancer), pancreatic cancer, colorectal cancer or bladder cancer (such as bladder transitional cell carcinoma) caused by a KRAS mutation, and the lung cancer (such as non-small cell lung cancer) is lung cancer (non-small cell lung cancer) caused by a non-KRAS G12C mutation.

[0131] Preferably, in any one of the first to eighth aspects, the tumor or cancer is a tumor or cancer caused by KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12S or KRAS G13D mutation; more preferably, the tumor or cancer caused by KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12S or KRAS G13D mutation is lung cancer (such as non-small cell lung cancer), pancreatic cancer, colorectal cancer or bladder cancer (such as bladder transitional cell carcinoma), and the lung cancer (such as non-small cell lung cancer) is lung cancer (non-small cell lung cancer) caused by a non-KRAS G12C mutation, that is, KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12S or KRAS Lung cancer (such as non-small cell lung cancer), pancreatic cancer, colorectal cancer or bladder cancer (such as bladder transitional cell carcinoma) caused by G13D mutation, wherein the lung cancer (such as non-small cell lung cancer) is not lung cancer (non-small cell lung cancer) caused by KRAS G12C mutation.

[0132] Preferably, in any one of the first to eighth aspects, the tumor or cancer is pancreatic cancer caused by KRAS G12C mutation, bladder cancer (such as bladder transitional cell carcinoma) caused by KRAS G12C mutation, colorectal cancer caused by KRAS G12D mutation, lung cancer (such as non-small cell lung cancer) with KRAS G12V mutation, lung cancer (such as non-small cell lung cancer) with KRAS G12S mutation or colorectal cancer caused by KRAS G13D mutation.

[0133] In the ninth aspect, the present invention further provides the compound described in any one of the first to seventh aspects or its stereoisomer, optical isomer, pharmaceutically acceptable salt, prodrug, solvate or isotope derivative, or the pharmaceutical composition described in the eighth aspect, for use in preventing and / or treating tumors or cancer.

[0134] Preferably, in the ninth aspect, the tumor or cancer is pancreatic cancer, colorectal cancer or bladder cancer (such as bladder transitional cell carcinoma).

[0135] Preferably, in the ninth aspect, the tumor or cancer is a tumor or cancer caused by RAS mutation; more preferably, the tumor or cancer caused by RAS mutation is pancreatic cancer, colorectal cancer or bladder cancer (such as bladder transitional cell carcinoma), that is, pancreatic cancer, colorectal cancer or bladder cancer (such as bladder transitional cell carcinoma) caused by RAS mutation.

[0136] Preferably, in the ninth aspect, the tumor or cancer is a tumor or cancer caused by a KRAS mutation; more preferably, the tumor or cancer caused by the KRAS mutation is lung cancer (such as non-small cell lung cancer), pancreatic cancer, colorectal cancer or bladder cancer (such as bladder transitional cell carcinoma), and the lung cancer (such as non-small cell lung cancer) is lung cancer (non-small cell lung cancer) caused by a non-KRAS G12C mutation, that is, lung cancer (such as non-small cell lung cancer), pancreatic cancer, colorectal cancer or bladder cancer (such as bladder transitional cell carcinoma) caused by a KRAS mutation, and the lung cancer (such as non-small cell lung cancer) is lung cancer (non-small cell lung cancer) caused by a non-KRAS G12C mutation.

[0137] Preferably, in the ninth aspect, the tumor or cancer is a tumor or cancer caused by KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12S or KRAS G13D mutation; more preferably, the tumor or cancer caused by KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12S or KRAS G13D mutation is lung cancer (such as non-small cell lung cancer), pancreatic cancer, colorectal cancer or bladder cancer (such as bladder transitional cell carcinoma), and the lung cancer (such as non-small cell lung cancer) is lung cancer (non-small cell lung cancer) caused by non-KRAS G12C mutation, that is, KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12S or KRAS Lung cancer (such as non-small cell lung cancer), pancreatic cancer, colorectal cancer or bladder cancer (such as bladder transitional cell carcinoma) caused by G13D mutation, wherein the lung cancer (such as non-small cell lung cancer) is not lung cancer (non-small cell lung cancer) caused by KRAS G12C mutation.

[0138] Preferably, in the ninth aspect, the tumor or cancer is pancreatic cancer caused by KRAS G12C mutation, bladder cancer (such as bladder transitional cell carcinoma) caused by KRAS G12C mutation, colorectal cancer caused by KRAS G12D mutation, lung cancer (such as non-small cell lung cancer) caused by KRAS G12V mutation, lung cancer (such as non-small cell lung cancer) caused by KRAS G12S mutation or colorectal cancer caused by KRAS G13D mutation.

[0139] In the tenth aspect, the present invention also provides a method for preventing and / or treating pancreatic cancer, colorectal cancer or bladder cancer (such as bladder transitional cell carcinoma), which comprises administering to an individual a preventively and / or therapeutically effective amount of the compound described in any one of the first to seventh aspects or its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates or isotope derivatives, or the pharmaceutical composition described in the eighth aspect.

[0140] Preferably, in the tenth aspect, the pancreatic cancer, colorectal cancer or bladder cancer (such as bladder transitional cell carcinoma) is pancreatic cancer, colorectal cancer or bladder cancer (such as bladder transitional cell carcinoma) caused by RAS mutation.

[0141] In the eleventh aspect, the present invention also provides a method for preventing and / or treating tumors or cancers caused by KRAS mutations, comprising administering to an individual a preventively and / or therapeutically effective amount of the compound described in any one of the first to seventh aspects, or its stereoisomer, optical isomer, pharmaceutically acceptable salt, prodrug, solvate or isotope derivative, or the pharmaceutical composition described in the eighth aspect; preferably, the tumor or cancer caused by the KRAS mutation is lung cancer (such as non-small cell lung cancer), pancreatic cancer, colorectal cancer or bladder cancer (such as bladder transitional cell carcinoma), and the lung cancer (such as non-small cell lung cancer) is lung cancer (non-small cell lung cancer) with a non-KRAS G12C mutation, that is, lung cancer (such as non-small cell lung cancer), pancreatic cancer, colorectal cancer or bladder cancer (such as bladder transitional cell carcinoma) caused by KRAS mutation, and the lung cancer (such as non-small cell lung cancer) is lung cancer (non-small cell lung cancer) with a non-KRAS G12C mutation.

[0142] In a twelfth aspect, the present invention also provides a method for preventing and / or treating tumors or cancers caused by KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12S or KRAS G13D mutations, comprising administering to an individual a preventively and / or therapeutically effective amount of the compound described in any one of the first to seventh aspects or its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates or isotopic derivatives, or the pharmaceutical composition described in the eighth aspect.

[0143] Preferably, the tumor or cancer caused by the KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12S or KRAS G13D mutation is lung cancer (such as non-small cell lung cancer), pancreatic cancer, colorectal cancer or bladder cancer (such as bladder transitional cell carcinoma), and the lung cancer (such as non-small cell lung cancer) is lung cancer (non-small cell lung cancer) caused by a non-KRAS G12C mutation, that is, lung cancer (such as non-small cell lung cancer), pancreatic cancer, colorectal cancer or bladder cancer (such as bladder transitional cell carcinoma) caused by a KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12S or KRAS G13D mutation, and the lung cancer (such as non-small cell lung cancer) is lung cancer (non-small cell lung cancer) caused by a non-KRAS G12C mutation.

[0144] In the thirteenth aspect, the present invention also provides a method for preventing and / or treating pancreatic cancer caused by KRAS G12C mutation, bladder cancer (such as bladder transitional cell carcinoma) caused by KRAS G12C mutation, colorectal cancer caused by KRAS G12D mutation, lung cancer (such as non-small cell lung cancer) caused by KRAS G12V mutation, lung cancer (such as non-small cell lung cancer) caused by KRAS G12S mutation or colorectal cancer caused by KRAS G13D mutation, which comprises administering to an individual a preventive and / or therapeutically effective amount of the compound or its stereoisomer, optical isomer, pharmaceutically acceptable salt, prodrug, solvate or isotope derivative described in any one of the first to seventh aspects, or the pharmaceutical composition described in the eighth aspect.

[0145] The beneficial effects of the present invention are as follows:

[0146] In vitro enzyme inhibition studies have shown that the novel compounds designed by this invention have a strong inhibitory effect on SOS1 and can effectively inhibit the interaction between KRAS (KRAS G12D) and SOS1 protein. In addition, in vitro cell proliferation inhibition studies have shown that these compounds exhibit significant inhibitory activity against the proliferation of KRAS mutant NCI-H358 cells, MIA-PaCa-2 cells, GP2d cells, NCI-H441 cells, NCI-H1373 cells, DLD-1 cells, A549 cells, and UM-UC-3 cells, while having no proliferation activity against wild-type KRAS cells, demonstrating good selectivity. DETAILED DESCRIPTION

[0147] [Definition of terms]

[0148] The terms "optional," "optionally," "optionally," or "optionally" mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0149] Unless otherwise specified, the term "alkyl" refers to a linear or branched monovalent saturated aliphatic hydrocarbon group, typically containing 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms (i.e., C 1-10 Alkyl), further preferably containing 1-8 carbon atoms (ie C 1-8 Alkyl), more preferably containing 1-6 carbon atoms (ie C 1-6 Alkyl), such as "C 1-6The term "alkyl" means that the group is an alkyl group and the number of carbon atoms in the carbon chain is between 1 and 6 (specifically, 1, 2, 3, 4, 5 or 6). Non-limiting examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl and n-octyl.

[0150] Unless otherwise specified, the term "alkenyl" refers to a linear or branched monovalent unsaturated aliphatic hydrocarbon group having at least one double bond and generally containing 2 to 20 carbon atoms, preferably 2 to 10 carbon atoms (i.e., C 2-10 alkenyl), further preferably containing 2-8 carbon atoms (ie C 2-8 alkenyl), more preferably containing 2 to 6 carbon atoms (ie, C 2-6 alkenyl), such as "C 2-6 The term "alkenyl" refers to an alkenyl group, and the number of carbon atoms in the carbon chain is between 2 and 6 (specifically 2, 3, 4, 5 or 6). Non-limiting examples of alkenyl include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl and 1,3-butadienyl.

[0151] Unless otherwise specified, the term "alkynyl" refers to a straight or branched monovalent unsaturated aliphatic hydrocarbon group having at least one triple bond and generally containing 2 to 20 carbon atoms, preferably 2 to 10 carbon atoms (i.e., C 2-10 Alkynyl), further preferably containing 2-8 carbon atoms (ie C 2-8 Alkynyl), more preferably containing 2-6 carbon atoms (ie, C 2-6 Alkynyl), such as "C 2-6 "Alkynyl" means that the group is an alkynyl group, and the number of carbon atoms in the carbon chain is between 2 and 6 (specifically 2, 3, 4, 5 or 6). Non-limiting examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl and 1-butynyl.

[0152] Unless otherwise specified, the term "cycloalkyl" refers to a monovalent aliphatic hydrocarbon group that is monocyclic or polycyclic (e.g., fused, bridged, or spiro) and contains no unsaturated bonds and typically contains 3 to 12 carbon atoms (i.e., C 3-12 cycloalkyl), more preferably containing 3 to 10 carbon atoms (ie, C 3-10 Cycloalkyl), further preferably 3-6 carbon atoms (ie C 3-6 Cycloalkyl), 4-6 carbon atoms (ie C 4-6 Cycloalkyl), 5-6 carbon atoms (ie C 5-6Non-limiting examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, 2-ethylcyclopentyl, and dimethylcyclobutyl. Non-limiting examples of fused-ring cycloalkyl groups include, but are not limited to, decahydronaphthyl, octahydroindenyl, and octahydropentalenyl. Non-limiting examples of bridged-ring cycloalkyl groups include, but are not limited to, Non-limiting examples of spirocyclic cycloalkyls include, but are not limited to wait.

[0153] Unless otherwise specified, the term "cycloalkenyl" refers to a monocyclic or polycyclic monovalent aliphatic hydrocarbon group having at least one double bond and generally containing 3 to 12 carbon atoms (i.e., C 3-12 cycloalkenyl), more preferably containing 4 to 12 carbon atoms (ie, C 4-12 Cycloalkenyl), or 3-10 carbon atoms (ie C 3-10 Cycloalkenyl), further preferably 3-6 carbon atoms (ie C 3-6 Cycloalkenyl), 4-6 carbon atoms (ie C 4-6 Cycloalkenyl), 5-6 carbon atoms (ie C 5-6 Non-limiting examples of monocyclic cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclopentadienyl, cyclohexadienyl, cycloheptatrienyl, cyclooctatrienyl, and the like.

[0154] Unless otherwise specified, the term "alkoxy" refers to an "-O-alkyl" group, wherein the alkyl group is as defined above, i.e., containing 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 8 carbon atoms, and more preferably 1 to 6 carbon atoms (specifically 1, 2, 3, 4, 5 or 6). Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, tert-butoxy, pentyloxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, and the like.

[0155] Unless otherwise specified, the term "halogen" or "halo" refers to F, Cl, Br, I. The term "haloalkyl" refers to an alkyl group as defined above in which one, two or more hydrogen atoms or all hydrogen atoms are replaced by halogen. Representative examples of haloalkyl groups include CCl3, CF3, CHCl2, CH2Cl, CH2Br, CH2I, CH2CF3, CF2CF3, etc. Different expressions can be used for haloalkyl groups, for example, "C 1-6 "Haloalkyl" can also be expressed as "halogenated C 1-6Alkyl". The term "haloalkoxy" means that one, two or more hydrogen atoms or all hydrogen atoms in the alkoxy group as defined above are replaced by halogen. Representative examples of haloalkoxy include OCCl3, OCF3, OCHCl2, OCH2Cl, OCH2Br, OCH2I, OCH2CF3, OCF2CF3, etc. For haloalkoxy, different expressions can also be used, for example, "C 1-6 "Haloalkoxy" can also be expressed as "halogenated C 1-6 Alkoxy". The term "halocycloalkyl" refers to a cycloalkyl group as defined above in which one, two or more hydrogen atoms or all hydrogen atoms are replaced by halogen.

[0156] Unless otherwise specified, the term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic (e.g., fused ring, bridged ring or spiro) monovalent aliphatic ring system, which is a non-aromatic structure as a whole, generally containing 3-20 ring atoms, of which 1, 2, 3 or more ring atoms are selected from N, O or S, and the remaining ring atoms are C, preferably containing 3-12 ring atoms, further preferably containing 4-12 ring atoms, or 5-12 ring atoms, or 3-10 ring atoms, or 3-8 ring atoms, or 3-6 ring atoms, or 4-6 ring atoms, or 5-6 ring atoms. The number of heteroatoms is preferably 1-4, more preferably 1-3 (i.e., 1, 2 or 3). Non-limiting examples of monocyclic heterocyclyls include, but are not limited to, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyranyl, 2,5-dihydrofuranyl, pyridonyl, etc. Polycyclic heterocyclic groups include spirocyclic, fused ring and bridged ring heterocyclic groups. Non-limiting examples of fused ring heterocyclic groups include, but are not limited to, decahydroquinolinyl, octahydroindolyl, etc. Non-limiting examples of bridged ring heterocyclic groups include, but are not limited to Non-limiting examples of spirocyclic heterocyclyls include, but are not limited to wait.

[0157] Unless otherwise specified, the term "aryl" refers to a monovalent aromatic ring system of monocyclic or polycyclic (e.g., fused rings), typically containing 6-16 carbon atoms, or 6-14 carbon atoms, or 6-12 carbon atoms, preferably 6-10 carbon atoms. The term "aryl" can be used interchangeably with the term "aromatic ring". Non-limiting examples of aryl include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, or pyrenyl.

[0158] Unless otherwise specified, the term "heteroaryl" refers to a monovalent, monocyclic or polycyclic (e.g., fused) aromatic ring system, typically containing 5-12 members, or preferably 5-10 members, 5-8 members, and more preferably 5-6 members, wherein 1, 2, 3 or more ring atoms are heteroatoms and the remaining atoms are carbon, each heteroatom being independently selected from O, N or S, and the number of heteroatoms is preferably 1, 2 or 3. The term "heteroaryl" can be used interchangeably with the term "heteroaromatic ring." Non-limiting examples of heteroaryl groups include, but are not limited to, furanyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiodiazolyl, triazinyl, phthalazinyl, quinolyl, isoquinolyl, pteridinyl, purinyl, indolyl, isoindolyl, indazolyl, benzofuranyl, benzothiophenyl, benzopyridinyl, benzopyrimidinyl, Benzopyrazinyl, benzimidazolyl, benzophthalazinyl, pyrrolo[2,3-b]pyridinyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridinyl, etc.

[0159] Unless otherwise specified, the term "hydroxy" refers to a "-OH" group.

[0160] Unless otherwise specified, the term "cyano" refers to a "-CN" group.

[0161] Unless otherwise specified, the term "amino" refers to a "-NH2" group. In some cases, the term "amino" also refers to a group in which one or both hydrogen atoms are replaced by an alkyl group (e.g., C 1-6 Alkyl, preferably C 1-4 The group obtained after substitution with an alkyl group.

[0162] Unless otherwise specified, the term "nitro" refers to a "-NO2" group.

[0163] Unless otherwise specified, the term "formyl" or "aldehyde" refers to a "-C(=O)H" group.

[0164] Unless otherwise specified, the term "oxo" refers to a "=O" group attached to a carbon atom, and the term "oxido" refers to a "=O" group attached to a heteroatom (eg, a sulfur atom).

[0165] Unless otherwise specified, the term "pharmaceutically acceptable salt," "pharmaceutically acceptable salt," or "pharmaceutically acceptable salt" refers to a salt that is suitable for use in contact with mammalian tissues, particularly human tissues, without undue toxicity, irritation, allergic response, or the like, and is commensurate with a reasonable benefit / risk ratio, within the scope of sound medical judgment. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting a free base or free acid with a suitable reagent. For example, a free base can be reacted with a suitable acid.

[0166] Unless otherwise specified, the term "solvate" or "solvate" refers to a physical association of a compound of the invention with one or more solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. In certain circumstances, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate will be capable of isolation. The solvent molecules in the solvate may exist in a regular and / or disordered arrangement. The solvate may contain stoichiometric or non-stoichiometric amounts of solvent molecules. "Solvate" encompasses solution-phase and isolatable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.

[0167] Unless otherwise specified, the compounds of the present invention also include their "isotopic derivatives" (such as deuterated forms). The term "isotopic derivative" means that the compounds of the present invention may exist in an isotopically labeled or enriched form, containing one or more atoms whose atomic mass or mass number is different from the atomic mass or mass number of the largest atom found in nature. Isotopes can be radioactive or non-radioactive isotopes. Isotopes commonly used as isotopic labels are: Hydrogen isotopes: 2 H(D) and 3 H(T); Carbon isotope: 13 C and 14 C; Chlorine isotope: 35 Cl and 37 Cl; Fluorine isotope: 18 F; Iodine isotope: 123 I and 125 I; Nitrogen isotopes: 13 N and 15 N; oxygen isotopes: 15 O. 17 O and 18 O; and sulfur isotopes: 35 These isotope-labeled compounds can be used to study the distribution of pharmaceutical molecules in tissues. 3 H and 13 C, because they are easy to label and detect, they are more widely used. Some heavy isotopes, such as deuterium ( 2H), substitution can enhance metabolic stability and prolong half-life, thereby achieving the goal of reducing dosage and providing therapeutic advantages. Isotope-labeled compounds are generally synthesized from labeled starting materials using known synthetic techniques similar to those used for synthesizing non-isotope-labeled compounds.

[0168] Unless otherwise specified, the term "prodrug" refers to a drug that is converted into the parent drug in vivo. Prodrugs are often useful because, in certain circumstances, they may be easier to administer than the parent drug. For example, they may be bioavailable by oral administration, whereas the parent drug is not. Prodrugs may also have improved solubility in pharmaceutical compositions compared to the parent drug.

[0169] Unless otherwise specified, the term "optical isomers" refers to substances with identical molecular structures, similar physical and chemical properties, but different optical rotations.

[0170] Unless otherwise specified, the term "stereoisomer" refers to compounds that have the same chemical constitution but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis / trans) isomers, atropisomers, etc. Any resulting mixture of stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on the differences in the physicochemical properties of the components, for example, by chromatography and / or fractional crystallization.

[0171] Unless otherwise indicated, the structural formulas described herein include all isomeric forms (e.g., enantiomers, diastereomers, and geometric isomers (or conformers)): for example, R and S configurations containing asymmetric centers, (Z) and (E) isomers of double bonds, and (Z) and (E) conformers. Therefore, individual stereochemical isomers of the compounds of the present invention or mixtures of their enantiomers, diastereomers, or geometric isomers (or conformers) are within the scope of the present invention.

[0172] Unless otherwise specified, the terms "optionally substituted", "optionally substituted by", "optionally substituted by" mean that the hydrogen at the substitutable position of the group is not replaced or is replaced by one or more substituents, the substituents being preferably selected from the group consisting of halogen, hydroxy, thiol, cyano, nitro, amino, azido, oxo, carboxyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14 Aryl or 5-10 membered heteroaromatic ring group, wherein the C 2-6 Alkenyl, C 2-6Alkynyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14 Aryl and 5-10 membered heteroaromatic ring groups can be optionally selected from halogen, hydroxy, amino, cyano, C 1-6 Alkyl or C 1-6 The alkoxy group is substituted with one or more substituents.

[0173] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the present invention. Experimental methods in the following examples where specific conditions are not specified are generally performed under conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to professionals in the field. In addition, any methods and materials similar or equivalent to those described herein can be applied to the present invention. The preferred embodiments and materials shown herein are for demonstration purposes only.

[0174] The structures of the compounds of the present invention were determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS) and / or liquid chromatography (HPLC). NMR measurements were performed using a Bruker AVANCE III 600 MHz instrument, LC-MS using a WATERS ACQUITY UPLC H-Class PLUS or / and SQD2 instrument, and HPLC using a WATERS e2695-2998 or / and an Agilent 1100 instrument.

[0175] The starting materials in the examples of the present invention are known and commercially available, or can be synthesized according to methods known in the art.

[0176] Preparation Example 1: Synthesis of Intermediate A

[0177] Synthesis of intermediate A-2

[0178] 1-(3-Nitro-5-trifluoromethyl-phenyl)-ethanone (10.00 g, 43.0 mmol) was dissolved in ethanol (200 mL), followed by the addition of iron powder (7.22 g, 129.0 mmol) and concentrated hydrochloric acid (50 mL). The reaction was continued at 80°C for 2 h. LC-MS analysis confirmed the absence of residual starting material. The mixture was cooled and filtered, and the solvent was evaporated from the filtrate under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol = 50:1-20:1) to afford A-2 (8.12 g, 40.0 mmol, 92%). ESI-MS: m / z 204.12 [M+H] + .

[0179] Synthesis of intermediate A-3

[0180] A-2 (27.02 g, 133.0 mmol) was dissolved in tetrahydrofuran (50 mL), followed by the addition of (R)-(+)-2-methyl-2-propanesulfenamide (24.24 g, 200.0 mmol) and Ti(OEt)4 (91.02 g, 399 mmol). The system was reacted at 80 ° C for 2 h. LC-MS monitoring showed that no starting material remained. The reaction solution was quenched with ice water, and the precipitate was dissolved in ethyl acetate and filtered. The filtrate was evaporated under reduced pressure to remove the solvent, and the residue was separated and purified by column chromatography (dichloromethane: methanol = 50: 1-20: 1) to obtain product A-3 (34.65 g, 113.1 mmol, 85%). ESI-MS: m / z 307.12 [M+H] + .

[0181] Synthesis of intermediate A-4

[0182] A-3 (34.65 g, 113.1 mmol) was dissolved in tetrahydrofuran (50 mL) and sodium borohydride (6.42 g, 169.7 mmol) was added at -78 °C. The reaction system was slowly heated to room temperature and no starting material remained after LC-MS monitoring. The reaction solution was quenched with ice water and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated sodium chloride (100 mL × 2), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was separated and purified by column chromatography (dichloromethane:methanol=50:1-20:1) to obtain A-4 (28.43 g, 92.2 mmol, 82%). ESI-MS: m / z 309.10 [M+H] + .

[0183] Synthesis of intermediate A

[0184] A-4 (28.43 g, 92.2 mmol) was dissolved in a dioxane hydrochloride solution (50 mL). The system was reacted at room temperature for 2 h. LC-MS monitoring confirmed that no starting material remained. The solvent was evaporated under reduced pressure to obtain intermediate A, which was directly used in the next reaction as the hydrochloride salt. ESI-MS: m / z 205.22 [M+H] + .

[0185] The following intermediates can be obtained by referring to the synthesis method of intermediate A or the related synthesis method in CN110167928A. If necessary, the crude product is purified by chromatography.

[0186] Example 1: Synthesis of Compound 1

[0187] Synthesis of intermediate 1-1

[0188] 2-Amino-6-chloronicotinic acid (5.00 g, 29.0 mmol) was dissolved in 80 mL of methanol, the system was cooled to 0°C, and then 16 mL of concentrated sulfuric acid was added. The system was reacted at 80°C for 5 h. LC-MS monitoring showed that no raw material remained. The reaction solution was added with 100 mL of water and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated sodium chloride (100 mL × 2), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was separated and purified by column chromatography (petroleum ether:ethyl acetate = 5:1-1:1) to obtain 1-1 (5.03 g, yield 93%). ESI-MS: m / z 187.02 [M+H] + .

[0189] Synthesis of intermediate 1-2

[0190] 1-1 (5.03 g, 26.9 mmol) was dissolved in acetonitrile (80 mL), followed by the addition of N-bromosuccinimide (7.17 g, 40.3 mmol). The reaction was allowed to proceed at room temperature for 1.5 h. LC-MS analysis revealed no residual starting material. The reaction solution was quenched with ice water and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated sodium chloride (100 mL × 2), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 5:1-1:3) to afford 1-2 (6.85 g, yield 96%). ESI-MS: m / z 265.10 / 267.13 [M+H] + .

[0191] Synthesis of intermediates 1-3

[0192] 1-2 (6.85 g, 25.8 mmol) was dissolved in 80 mL of acetonitrile, followed by the addition of 15 mL of methanesulfonic acid. The reaction was allowed to proceed at 130°C for 8 h. LC-MS analysis indicated no residual starting material. The reaction solution was quenched with ice water and extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated sodium chloride (100 mL x 2) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 5:1 to 1:3) to afford 1-3 (1.51 g, 21% yield). ESI-MS: m / z 274.02 / 275.98 [M+H] + .

[0193] Synthesis of intermediates 1-4

[0194] 1-3 (1.51 g, 5.50 mmol) was dissolved in 50 mL of ethanol, followed by the addition of hydrazine hydrate (1.76 g, 55.0 mmol). The reaction was continued at 80°C for 2 h. LC-MS analysis confirmed no residual starting material. The solvent was evaporated under reduced pressure, and the residue was directly used for the next reaction. ESI-MS: m / z 270.01 / 272.03 [M+H] + .

[0195] Synthesis of intermediates 1-5

[0196] 1-4 was dissolved in 30 mL of chloroform, followed by the addition of 10 mL of triethyl orthoformate. The reaction was allowed to proceed at 80°C for 2 h. LC-MS monitoring revealed no residual starting material. The reaction solution was quenched with ice water and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated sodium chloride (100 mL × 2), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 5:1-1:3) to afford 1-5 (1.00 g, 65% yield over two steps). ESI-MS: m / z 280.00 / 282.02 [M+H] + .

[0197] Synthesis of intermediates 1-6

[0198] 1-5 (1.00 g, 3.60 mmol) was dissolved in 50 mL of toluene, followed by the addition of diisopropylethylamine (464 mg, 3.60 mmol) and phosphorus oxychloride (2.76 g, 18.0 mmol). The system was reacted at 100 ° C for 2 h. LC-MS monitoring showed that there was no residual raw material. The reaction solution was quenched with ice water and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated sodium chloride (100 mL × 2), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was separated and purified by column chromatography (petroleum ether: ethyl acetate = 5:1-1:1) to obtain 1-6 (800 mg, yield 75%). ESI-MS: m / z 298.03 / 300.02 [M+H] + .

[0199] Synthesis of intermediates 1-7

[0200] 1-6 (800 mg, 2.68 mmol) was dissolved in 30 mL of N,N-dimethylformamide, followed by diisopropylethylamine (697 mg, 5.40 mmol) and intermediate B (612 mg, 3.24 mmol). The system was reacted at 120 ° C for 2 h. LC-MS monitoring showed that there was no residual starting material. The reaction solution was quenched with ice water and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated sodium chloride (100 mL × 2), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was separated and purified by column chromatography (petroleum ether: ethyl acetate = 5:1-1:2) to obtain 1-7 (798 mg, yield 66%). ESI-MS: m / z 451.02 / 453.07 [M+H] + .

[0201] Synthesis of intermediates 1-8

[0202] 1-7 (100 mg, 0.22 mmol) was dissolved in dioxane (40 mL) and water (10 mL). Potassium hydroxide (25 mg, 0.44 mmol), tris(dibenzylideneacetone)dipalladium (18 mg, 0.02 mmol), and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (10 mg, 0.02 mmol) were then added. The reaction mixture was stirred at 100°C for 3 h. TLC confirmed the absence of residual starting material. 50 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride (50 mL × 2), dried over anhydrous sodium sulfate, and the solvent removed under reduced pressure. The mixture was separated and purified by column chromatography (dichloromethane:methanol = 60:1 to 20:1) to afford 1-8 (40 mg, 47% yield). ESI-MS: m / z 389.15 [M+H] + .

[0203] Synthesis of compound 1

[0204] 1-8 (40 mg, 0.10 mmol) was dissolved in N,N-dimethylformamide (15 mL), followed by the addition of (R)-3-hydroxytetrahydrofuran p-toluenesulfonate (30 mg, 0.12 mmol) and cesium carbonate (65 mg, 0.20 mmol). The entire system was stirred at 80°C for 3 h. TLC confirmed the absence of residual starting material. 30 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride (50 mL × 2), dried over anhydrous sodium sulfate, and the solvent removed under reduced pressure. The mixture was separated and purified by column chromatography (dichloromethane:methanol = 60:1-20:1) to obtain compound 1 (30 mg, yield 65%). ESI-MS: m / z 459.25 [M+H] + . 1H NMR (600MHz, DMSO-d6): δ9.59(s,1H),8.40(d,J=7.2Hz,1H),7.82(s,1H),7.77(d,J=7.2Hz,1H),7.63-7.58(m,2H),7.46(s,1H),5.71-5.64 (m,1H),5.47-5.45(m,1H),4.05-4.03(m,1H),3.98-3.94(m,2H),3.88-3.84(m,1H),2.46(s,3H),2.42-2.37(m,2H),1.66(d,J=7.2Hz,3H).

[0205] Example 2: Synthesis of Compound 2

[0206] Synthesis of intermediate 2-1

[0207] 1-7 (100 mg, 0.22 mmol) was dissolved in dioxane (30 mL), followed by the addition of N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (84 mg, 0.27 mmol), tetrakis(triphenylphosphine)palladium (23 mg, 0.02 mmol), and cesium carbonate (143 mg, 0.44 mmol). The reaction mixture was stirred at 100°C for 3 h. TLC confirmed the absence of residual starting material. 50 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride (50 mL × 2), dried over anhydrous sodium sulfate, and the solvent removed under reduced pressure. The mixture was separated and purified by column chromatography (dichloromethane:methanol = 60:1 to 20:1) to afford 2-1 (100 mg, 82% yield). ESI-MS: m / z 554.19 [M+H] + .

[0208] Synthesis of intermediate 2-2

[0209] 2-1 (100 mg, 0.18 mmol) was dissolved in 4 M hydrochloric acid ethyl acetate solution (10 mL) and stirred at room temperature for 2 h. TLC showed that no starting material remained. The solvent was removed under reduced pressure to obtain the residue 2-2, which was directly used for the next step. ESI-MS: m / z 454.16 [M+H] + .

[0210] Synthesis of compound 2

[0211] 2-2 was dissolved in dichloromethane (10 mL), followed by the addition of triethylamine (36 mg, 0.36 mmol) and acetic anhydride (22 mg, 0.22 mmol). The reaction was stirred at room temperature for 2 h. TLC confirmed the absence of residual starting material. The reaction solution was quenched with water and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride (50 mL × 2), dried over anhydrous sodium sulfate, and the solvent removed under reduced pressure. The product was separated and purified by column chromatography (dichloromethane:methanol = 60:1-15:1) to obtain compound 2 (50 mg, yield 56%). ESI-MS: m / z 496.17 [M+H] + . 1 H NMR (600MHz, DMSO-d6): δ9.59 (d, J=3.6Hz, 1H), 8.75 (dd, J=7.8Hz, J=7.8Hz, 1H),8.03(d,J=5.4Hz,1H),7.83(s,1H),7.78(d,J=7.2Hz,1H),7.63-7.58(m, 2H),7.49-7.47(m,1H),5.72-5.68(m,1H),4.33-4.26(m,2H),3.77-3.73(m,2 H), 2.87-2.63 (m, 2H), 2.48 (s, 3H), 2.13-2.08 (m, 3H), 1.66 (d, J = 7.2Hz, 3H).

[0212] Example 3: Synthesis of Compound 3

[0213] 1-7 (100 mg, 0.22 mmol) was dissolved in N-methylpyrrolidone (30 mL), followed by the addition of N-methylpiperazine (27 mg, 0.27 mmol), tris(dibenzylideneacetone)dipalladium (18 mg, 0.02 mmol), and sodium tert-butoxide (42 mg, 0.44 mmol). The entire system was stirred at 120°C for 3 h. TLC confirmed the absence of residual starting material. 50 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride (50 mL × 2), dried over anhydrous sodium sulfate, and the solvent removed under reduced pressure. The product was separated and purified by column chromatography (dichloromethane:methanol = 60:1-20:1) to obtain compound 3 (41 mg, 40% yield). ESI-MS: m / z 471.18 [M+H] + . 1H NMR (600MHz, DMSO-d6): δ9.53(s,1H),8.42(d,J=7.8Hz,1H),7.82(s,1H),7.77(d,J=7.2Hz,1H),7.61-7.57(m,2H),7 .10(s,1H),5.68-5.65(m,1H),3.65-3.60(m,4H),2.63-2.59(m,4H),2.43(s,3H),2.30(s,3H),1.65(d,J=7.2Hz,3H).

[0214] Example 4: Synthesis of Compound 4

[0215] 1-7 (100 mg, 0.22 mmol) was dissolved in N-methylpyrrolidone (30 mL), followed by the addition of morpholine (24 mg, 0.27 mmol), tris(dibenzylideneacetone)dipalladium (18 mg, 0.02 mmol), and sodium tert-butoxide (42 mg, 0.44 mmol). The reaction mixture was stirred at 120°C for 3 h. TLC confirmed the absence of residual starting material. 50 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride (50 mL × 2), dried over anhydrous sodium sulfate, and the solvent removed under reduced pressure. The mixture was separated and purified by column chromatography (dichloromethane:methanol = 60:1-20:1) to obtain compound 4 (50 mg, 50% yield). ESI-MS: m / z 458.16 [M+H] + . 1 H NMR (600MHz, DMSO-d6): δ9.53(s,1H),8.43(d,J=7.8Hz,1H),7.82(s,1H),7.77(d,J=6.6Hz,1H),7.62-7.58(m, 2H),7.13(s,1H),5.70-5.65(m,1H),3.88-3.87(m,4H),3.61-3.59(m,4H),2.43(s,3H),1.65(d,J=7.2Hz,3H).

[0216] Example 5: Synthesis of Compound 5

[0217] Synthesis of intermediate 5-1

[0218] 4,6-Dichloro-2-methylpyrimidine-5-carbaldehyde (2.00 g, 10.47 mmol) was dissolved in tetrahydrofuran (20 mL), followed by the addition of ethoxycarbonylmethylenetriphenylphosphine (5.47 g, 15.71 mmol) and triethylamine (2.12 g, 20.94 mmol). The reaction was continued at 80°C for 6 h. LC-MS monitoring revealed no residual starting material. The reaction system was directly separated and purified by column chromatography (n-hexane:ethyl acetate = 20:1-10:1) to afford 5-1 (1.71 g, 6.54 mmol, 63% yield). ESI-MS: m / z 260.85 [M+H] + .

[0219] Synthesis of intermediate 5-2

[0220] 5-1 (1.71 g, 6.54 mmol) was dissolved in N,N-dimethylformamide (20 mL), followed by the addition of tert-butyl (2-aminoethyl)carbamate (1.26 g, 7.85 mmol) and triethylamine (1.32 g, 13.08 mmol). The reaction was allowed to react at room temperature for 12 h. LC-MS analysis indicated no residual starting material. Water (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride (30 mL × 2), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by thin-layer chromatography (n-hexane:ethyl acetate = 10:1 to 3:1) to afford 5-2 (2.30 g, 5.99 mmol, 92% yield). ESI-MS: m / z 385.15 [M+H] + .

[0221] Synthesis of intermediate 5-3

[0222] 5-2 (2.30 g, 5.99 mmol) was dissolved in methanol (30 mL), and then sodium methoxide (3.6 mL, 17.97 mmol, 30% w / w in methanol) was added. The system was reacted at room temperature for 12 h. A solid precipitated from the reaction solution. LC-MS monitoring showed that no raw material remained. Water (10 mL) was added to the reaction solution, and the solution was filtered to give a white solid 5-3 (1.60 g, 4.79 mmol, yield 80%), ESI-MS: m / z 335.07 [M+H] +.

[0223] Synthesis of intermediate 5-4

[0224] 5-3 (1.60 g, 4.79 mmol) was dissolved in dichloromethane (30 mL), followed by the addition of bromine (1.15 g, 7.19 mmol). The reaction was allowed to react at room temperature for 12 h. LC-MS analysis revealed no residual starting material. The reaction system was directly separated and purified by column chromatography (n-hexane:ethyl acetate = 5:1 to 3:1) to afford 5-4 (1.80 g, 4.36 mmol, 91% yield). ESI-MS: m / z 412.98 / 415.00 [M+H] + .

[0225] Synthesis of intermediate 5-5

[0226] 5-4 (1.80 g, 4.36 mmol) was dissolved in dichloromethane (20 mL), followed by the addition of 5 mL of trifluoroacetic acid. The system was reacted at room temperature for 4 h. LC-MS monitoring revealed no residual starting material. The solvent was evaporated under reduced pressure, and the residue was added with 15 mL of water. The pH was adjusted to 8-9 with saturated aqueous sodium carbonate solution, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride (20 mL × 2), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 5-5 (0.90 g, 2.88 mmol, yield 66%). ESI-MS: m / z 312.92 / 314.91 [M+H] + .

[0227] Synthesis of intermediate 5-6

[0228] 5-5 (0.90 g, 2.88 mmol) was dissolved in toluene (20 mL), followed by the slow addition of trimethylaluminum (1.9 mL, 3.75 mmol, 2.0 M in toluene). The system was reacted at 120 ° C for 5 h. LC-MS monitoring revealed no residual starting material. The reaction solution was quenched with saturated aqueous ammonium chloride solution, and the toluene was evaporated under reduced pressure. 15 mL of water was added to the residue, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride (20 mL × 2), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 5-6 (0.59 g, 2.01 mmol, 70% yield). ESI-MS: m / z 294.87 / 296.83 [M+H] + .

[0229] Synthesis of intermediate 5-7

[0230] 5-6 (0.59 g, 2.01 mmol) was dissolved in dichloromethane (10 mL) and boron tribromide (2.52 g, 10.05 mmol) was slowly added under ice-cooling. The ice-cooling bath was removed and the system was allowed to react at room temperature for 72 h. LC-MS analysis revealed no residual starting material. Sodium carbonate solution was slowly added under ice-cooling to quench the reaction. A solid precipitated and was filtered to obtain 5-7 (0.46 g, 1.64 mmol, 82% yield). ESI-MS: m / z 280.82 / 282.84 [M+H]+.

[0231] Synthesis of intermediate 5-8

[0232] 5-7 (50 mg, 0.18 mmol) was dissolved in N,N-dimethylformamide (15 mL), followed by the addition of (R)-1-(3-(trifluoromethyl)phenyl)ethanamine hydrochloride (61 mg, 0.27 mmol), benzotriazole-1-oxytris(dimethylamino)phosphine hexafluorophosphate (102 mg, 0.23 mmol), and 1,8-diazabicycloundec-7-ene (82 mg, 0.54 mmol). The reaction was allowed to react at room temperature for 8 h. LC-MS analysis confirmed the absence of residual starting material. Water (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated sodium chloride (30 mL × 2), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by thin-layer chromatography (dichloromethane:methanol = 20:1) to afford 5-8 (40 mg, 0.089 mmol, 49% yield). ESI-MS: m / z 451.94 / 453.94[M+H] + .

[0233] Synthesis of compound 5

[0234] 5-8 (40 mg, 0.089 mmol) was dissolved in dioxane (10 mL) and water (2 mL), followed by the addition of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (31 mg, 0.133 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (13 mg, 0.018 mmol), and cesium carbonate (58 mg, 0.178 mmol). The system was reacted at 100°C for 4 h. LC-MS monitoring revealed no residual starting material. The solvent was evaporated under reduced pressure, and the residue was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride (10 mL × 2), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by thin-layer chromatography (dichloromethane:methanol:triethylamine=100:2:1) to give compound 5 (17 mg, 0.035 mmol, yield 40%). ESI-MS: m / z 481.11 [M+H] + . 1H NMR (600MHz, DMSO-d6): δ8.37(s,1H),8.32(s,1H),7.78-7.73(m,3H),7.60-7.59(m,2H),7.21(s,1H),6.81(d,J=12.0H z,1H),5.61-5.59(m,1H),4.12(t,J=6.0Hz,2H),3.97(t,J=6.0Hz,2H),3.46(s,3H),2.31(s,3H),1.59(d,J=6.0Hz,3H).

[0235] Example 6: Synthesis of Compound 6

[0236] Synthesis of intermediate 6-1

[0237] 5-7 (100 mg, 0.36 mmol) was dissolved in N,N-dimethylformamide (15 mL), followed by the addition of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline (110 mg, 0.54 mmol), benzotriazole-1-oxytris(dimethylamino)phosphine hexafluorophosphate (207 mg, 0.47 mmol), and 1,8-diazabicycloundec-7-ene (164 mg, 1.08 mmol). The reaction was allowed to react at room temperature for 8 h. LC-MS analysis confirmed the absence of residual starting material. Water (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated sodium chloride (30 mL × 2), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by thin-layer chromatography (dichloromethane:methanol = 20:1) to afford 6-1 (60 mg, 36% yield). ESI-MS: m / z 466.91 / 469.12[M+H] + .

[0238] Synthesis of compound 6

[0239] 6-1 (60 mg, 0.128 mmol) was dissolved in dioxane (10 mL) and water (2 mL), followed by the addition of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (45 mg, 0.191 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (19 mg, 0.026 mmol), and cesium carbonate (84 mg, 0.258 mmol). The system was reacted at 100°C for 4 h. LC-MS monitoring revealed no residual starting material. The solvent was evaporated under reduced pressure, and the residue was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride (10 mL × 2), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by thin-layer chromatography (dichloromethane:methanol:triethylamine=50:2:1) to give compound 6 (20 mg, yield 31%). ESI-MS: m / z 496.08 [M+H] + . 1 H NMR (600MHz, DMSO-d6): δ8.30(s,1H),8.13(d,J=6.0Hz,1H),7.72(d,J=6.0Hz,1H),7.32(s,1H),6.88(d,J=6.0Hz,1H),6.84-6.82(m,2 H), 6.71 (s, 1H), 5.57 (s, 2H), 5.50-5.47 (m, 1H), 4.07-4.05 (m, 2H), 3.98-3.95 (m, 2H), 3.45 (s, 3H), 2.31 (s, 3H), 1.52 (d, J = 6.0Hz, 3H).

[0240] Example 7: Synthesis of Compound 7

[0241] Synthesis of intermediate 7-1

[0242] 5-7 (100 mg, 0.36 mmol) was dissolved in N,N-dimethylformamide (15 mL), followed by the addition of (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine hydrochloride (121 mg, 0.54 mmol), benzotriazole-1-oxytris(dimethylamino)phosphine hexafluorophosphate (205 mg, 0.47 mmol), and 1,8-diazabicycloundec-7-ene (163 mg, 1.08 mmol). The reaction was allowed to react at room temperature for 8 h. LC-MS analysis confirmed the absence of residual starting material. Water (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated sodium chloride (30 mL × 2), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by thin-layer chromatography (dichloromethane:methanol = 20:1) to afford 7-1 (110 mg, 68% yield). ESI-MS: m / z 451.93 / 453.93[M+H] + .

[0243] Synthesis of compound 7

[0244] 7-1 (110 mg, 0.243 mmol) was dissolved in dioxane (10 mL) and water (2 mL), followed by the addition of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (86 mg, 0.366 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (36 mg, 0.049 mmol), and cesium carbonate (159 mg, 0.488 mmol). The system was reacted at 100°C for 4 h. LC-MS monitoring revealed no residual starting material. The solvent was evaporated under reduced pressure, and the residue was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride (10 mL × 2), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by thin-layer chromatography (dichloromethane:methanol:triethylamine=100:2:1) to give compound 7 (50 mg, yield 43%). ESI-MS: m / z 481.09 [M+H] + . 1 H NMR (600MHz, DMSO-d6): δ8.33(s,1H),8.18(d,J=6.0Hz,1H),7.72(d,J=6.0Hz,1H),7.66-7.64(m,1H),7.52-7.50(m,1H),7.33-7.32(m ,2H),7.24(t,J=54.0Hz,1H),6.91-6.89(m,1H),5.75-5.70(m,1H),4.02-3.95(m,4H),3.45(s,3H),3.25(s,3H),1.58(d,J=6.0Hz,3H).

[0245] Example 8: Synthesis of Compound 8

[0246] Synthesis of intermediate 8-1

[0247] 5-7 (100 mg, 0.36 mmol) was dissolved in N,N-dimethylformamide (15 mL), followed by the addition of Intermediate G (112 mg, 0.54 mmol), benzotriazole-1-oxytris(dimethylamino)phosphine hexafluorophosphate (205 mg, 0.47 mmol), and 1,8-diazabicycloundec-7-ene (163 mg, 1.08 mmol). The reaction was allowed to react at room temperature for 8 h. LC-MS analysis confirmed the absence of residual starting material. Water (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride (30 mL × 2), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by thin-layer chromatography (dichloromethane:methanol = 20:1) to afford 8-1 (127 mg, 75% yield). ESI-MS: m / z 470.98 / 472.98 [M+H] + .

[0248] Synthesis of compound 8

[0249] 8-1 (113 mg, 0.24 mmol) was dissolved in dioxane (10 mL) and water (2 mL), followed by the addition of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (86 mg, 0.366 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (36 mg, 0.049 mmol), and cesium carbonate (159 mg, 0.488 mmol). The system was reacted at 100°C for 4 h. LC-MS monitoring revealed no residual starting material. The solvent was evaporated under reduced pressure, and the residue was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride (10 mL × 2), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by thin-layer chromatography (dichloromethane:methanol:triethylamine=100:2:1) to give compound 8 (55 mg, yield 46%). ESI-MS: m / z 499.11 [M+H] + . 1H NMR (600MHz, DMSO-d6): δ8.95(s,1H),8.80(s,1H),7.87-7.85(m,2H),7.67(dd,J=6.6Hz,J=6.6Hz,1H),7.39(dd,J=7.8Hz,J=7.8H z,1H),6.91(s,1H),6.65(d,J=6.6Hz,1H),5.77-5.71(m,1H),4.41-4.34(m,4H),3.50(s,3H),2.34(s,3H),1.62(d,J=6.0Hz,3H).

[0250] Example 9: Synthesis of Compound 9

[0251] Synthesis of intermediate 9-1

[0252] 3-Amino-2-chloroisonicotinic acid (5.00 g, 29.0 mmol) was dissolved in methanol (80 mL). The system was cooled to 0°C, and concentrated sulfuric acid (16 mL) was added. The system was reacted at 80°C for 5 h. LC-MS monitoring showed no residual starting material. The reaction solution was added with water (100 mL), extracted with ethyl acetate (100 mL × 3), and the organic phases were combined, washed with saturated sodium chloride (100 mL × 2), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was separated and purified by column chromatography (petroleum ether:ethyl acetate = 5:1-1:1) to obtain 9-1 (5.00 g, yield 92%). ESI-MS: m / z 187.02 [M+H] + .

[0253] Synthesis of intermediate 9-2

[0254] 9-1 (5.00 g, 26.8 mmol) was dissolved in acetonitrile (80 mL), followed by the addition of N-bromosuccinimide (7.17 g, 40.3 mmol). The reaction was allowed to proceed at room temperature for 1.5 h. LC-MS analysis revealed no residual starting material. The reaction solution was quenched with ice water and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated sodium chloride (100 mL × 2), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 5:1-1:3) to obtain 9-2 (6.85 g, yield 96%). ESI-MS: m / z 265.10 / 267.12 [M+H] + .

[0255] Synthesis of intermediate 9-3

[0256] 9-2 (6.85 g, 25.8 mmol) was dissolved in acetonitrile (80 mL), followed by the addition of methanesulfonic acid (15 mL). The reaction was allowed to proceed at 130°C for 8 h. LC-MS analysis indicated no residual starting material. The reaction solution was quenched with ice water and extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated sodium chloride (100 mL × 2) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 5:1-1:3) to afford 9-3 (1.51 g, 21% yield). ESI-MS: m / z 274.02 / 276.11 [M+H] + .

[0257] Synthesis of intermediate 9-4

[0258] 9-3 (1.51 g, 5.50 mmol) was dissolved in ethanol (50 mL), followed by the addition of hydrazine hydrate (1.76 g, 55.0 mmol). The reaction was continued at 80°C for 2 h. LC-MS analysis revealed no residual starting material. The solvent was evaporated under reduced pressure, and the residue was directly used for the next reaction. ESI-MS: m / z 270.02 / 271.06 [M+H] + .

[0259] Synthesis of intermediate 9-5

[0260] 9-4 was dissolved in chloroform (30 mL), followed by the addition of triethyl orthoformate (10 mL). The reaction mixture was allowed to react at 80°C for 2 h. LC-MS analysis revealed no residual starting material. The reaction solution was quenched with ice water and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated sodium chloride (100 mL × 2), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 5:1-1:3) to obtain 9-5 (1.00 g, yield 65%). ESI-MS: m / z 280.02 / 282.14 [M+H] + .

[0261] Synthesis of intermediate 9-6

[0262] 9-5 (1.00 g, 3.60 mmol) was dissolved in toluene (50 mL), followed by diisopropylethylamine (465 mg, 3.60 mmol) and phosphorus oxychloride (2.76 g, 18.0 mmol). The system was reacted at 100 ° C for 2 h. LC-MS monitoring showed that there was no residual starting material. The reaction solution was quenched with ice water and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated sodium chloride (100 mL × 2), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was separated and purified by column chromatography (petroleum ether: ethyl acetate = 5:1-1:1) to obtain 9-6 (800 mg, yield 74%). ESI-MS: m / z 298.02 / 300.20 [M+H] + .

[0263] Synthesis of intermediate 9-7

[0264] 9-6 (400 mg, 1.34 mmol) was dissolved in N,N-dimethylformamide (30 mL), followed by diisopropylethylamine (349 mg, 2.70 mmol) and intermediate D (384 mg, 2.02 mmol). The system was reacted at 120 ° C for 2 h. LC-MS monitoring showed that there was no residual starting material. The reaction solution was quenched with ice water and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated sodium chloride (100 mL × 2), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was separated and purified by column chromatography (petroleum ether: ethyl acetate = 5:1-1:2) to obtain 9-7 (397 mg, yield 66%). ESI-MS: m / z 451.02 / 453.09 [M+H] + .

[0265] Synthesis of compound 9

[0266] 9-7 (397 mg, 0.88 mmol) was dissolved in dioxane (30 mL), followed by the addition of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (249 mg, 1.06 mmol), tetrakis(triphenylphosphine)palladium (104 mg, 0.09 mmol), and cesium carbonate (574 mg, 1.76 mmol). The entire system was stirred at 100 ° C for 3 h. TLC monitoring showed that no raw material remained. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride (50 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The product was separated and purified by column chromatography (dichloromethane: methanol = 60: 1-20: 1) to give compound 9 (253 mg, yield 60%). ESI-MS: m / z 480.11[M+H] + . 1H NMR (600MHz, DMSO-d6): δ9.34(s,1H),8.58(d,J=7.2Hz,1H),7.98(d,J=6.6Hz,1H),7.94(s,1H),7.70(dd,J=7.2Hz,J=7.2Hz,1H),7 .53(dd,J=6.6Hz,J=7.2Hz,1H),7.32(dd,J=7.8Hz,J=7.8Hz,1H),7.26(t,J=54.6Hz,1H),6.87(d,J=1.8Hz,1H),6.66(dd,J=1.8Hz, J=2.4Hz,1H),5.81-5.79(m,1H),3.56(s,3H),2.49(s,3H),1.63(d,J=6.6Hz,3H).

[0267] Example 10: Synthesis of Compound 10

[0268] Synthesis of Intermediate 10-1

[0269] 9-6 (400 mg, 1.34 mmol) was dissolved in N,N-dimethylformamide (30 mL), followed by diisopropylethylamine (349 mg, 2.70 mmol) and intermediate G (418 mg, 2.02 mmol). The system was reacted at 120 ° C for 2 h. LC-MS monitoring showed that there was no residual starting material. The reaction solution was quenched with ice water and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated sodium chloride (100 mL × 2), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was separated and purified by column chromatography (petroleum ether: ethyl acetate = 5:1-1:2) to obtain 10-1 (415 mg, yield 66%). ESI-MS: m / z 469.02 / 471.09 [M+H] + .

[0270] Synthesis of compound 10

[0271] 10-1 (415 mg, 0.88 mmol) was dissolved in dioxane (30 mL), followed by the addition of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (249 mg, 1.06 mmol), tetrakis(triphenylphosphine)palladium (104 mg, 0.09 mmol), and cesium carbonate (574 mg, 1.76 mmol). The entire system was stirred at 100 ° C for 3 h. TLC monitoring showed that there was no residual starting material. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride (50 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The mixture was separated and purified by column chromatography (dichloromethane: methanol = 60: 1-20: 1) to give compound 10 (250 mg, yield 57%). ESI-MS: m / z 498.11[M+H] + . 1 H NMR (600MHz, DMSO-d6): δ9.34(s,1H),8.64(d,J=6.6Hz,1H),7.98(d,J=6.6Hz,1 H),7.94(s,1H),7.83(dd,J=7.2Hz,J=7.2Hz,1H),7.67(dd,J=6.6Hz,J=7.2Hz,1 H),7.38(dd,J=7.8Hz,J=7.8Hz,1H),6.87(d,J=1.8Hz,1H),6.67(dd,J=1.8Hz,J =1.8Hz,1H),5.78-5.74(m,1H),3.56(s,3H),2.47(s,3H),1.64(d,J=6.6Hz,3H).

[0272] Example 11: Synthesis of Compound 11

[0273] Synthesis of Intermediate 11-1

[0274] Intermediate 1-3 (0.68 g, 2.48 mmol) was dissolved in anhydrous ethanol (10 mL), and aminoacetaldehyde diethyl acetal (0.49 g, 3.72 mmol) and N,N-diisopropylethylamine (0.64 g, 4.96 mmol) were added. The reaction was refluxed for 5 h. LC-MS monitoring showed that no starting material remained. The reaction system was cooled, saturated brine was added, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 11-1 (0.83 g, yield 90%). ESI-MS: m / z 371.58 / 373.32 [M+H] + .

[0275] Synthesis of intermediate 11-2

[0276] Intermediate 11-1 (0.83 g, 2.24 mmol) was dissolved in concentrated sulfuric acid and heated to 65°C for 2 h. LC-MS monitoring confirmed that no starting material remained. The reaction solution was slowly added dropwise to a saturated sodium bicarbonate solution to quench the reaction. Ethyl acetate was added for extraction, and the mixture was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 11-2 (0.40 g, yield 63%). ESI-MS: m / z 279.10 / 301.14 [M+H] + .

[0277] Synthesis of intermediate 11-3

[0278] Intermediate 11-2 (0.26 g, 0.94 mmol) was dissolved in N,N-dimethylformamide (5 mL), and intermediate B (0.27 g, 1.22 mmol) and benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (0.74 g, 1.41 mmol) were added. The mixture was allowed to react at room temperature for 2 h. LC-MS monitoring confirmed that no residual starting material remained. Saturated brine was added to the reaction system, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 11-3 (0.18 g, yield 43%). ESI-MS: m / z 449.90 / 451.91 [M+H] + .

[0279] Synthesis of intermediate 11-4

[0280] 11-3 (180 mg, 0.40 mmol) was dissolved in dioxane (40 mL) and water (10 mL), followed by the addition of potassium hydroxide (67 mg, 1.2 mmol), tris(dibenzylideneacetone)dipalladium (18 mg, 0.02 mmol), and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (10 mg, 0.02 mmol). The whole system was stirred at 100°C for 3 h. TLC confirmed that no starting material remained. 50 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride (50 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The product was separated and purified by column chromatography (dichloromethane:methanol=60:1-20:1) to obtain 11-4 (71 mg, yield 46%). ESI-MS: m / z 388.07 [M+H] + .

[0281] Synthesis of compound 11

[0282] 11-4 (71 mg, 0.16 mmol) was dissolved in N,N-dimethylformamide (15 mL), followed by the addition of (R)-3-hydroxytetrahydrofuran p-toluenesulfonate (47 mg, 0.19 mmol) and cesium carbonate (104 mg, 0.32 mmol). The entire system was stirred at 80°C for 3 h. TLC confirmed the absence of residual starting material. 30 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride (50 mL × 2), dried over anhydrous sodium sulfate, and the solvent removed under reduced pressure. Compound 11 was isolated and purified by column chromatography (dichloromethane:methanol = 60:1-20:1) to obtain compound 11 (48 mg, yield 66%). ESI-MS: m / z 458.32 [M+H] + . 1 H NMR (600MHz, DMSO-d6): δ8.29(s,1H),7.87(d,J=4.8Hz,1H),7.82(d,J=6.3Hz,1H),7.67-7.53(m,4H),5.69(p,J=7.2Hz,1H),5.51(d,J=6 .5Hz,1H),4.05(dt,J=10.8,3.6Hz,1H),3.97-3.91(m,2H),3.84(td,J=8.3,4.5Hz,1H),2.45(s,3H),1.68(d,J=7.1Hz,3H),1.23(m,2H).

[0283] Example 12-30:

[0284] The compounds of the following Examples 12-30 can be obtained by referring to the synthesis methods of Examples 1-11.

[0285] Example 31: Synthesis of Compound 31

[0286] Synthesis of compound 31

[0287] Intermediate 7-1 (99 mg, 0.22 mmol) from Example 7 was dissolved in dioxane (30 mL), followed by the addition of 1-acetyl-5,6-dihydro-2H-pyridine-4-boronic acid pinacol ester (68 mg, 0.27 mmol), tetrakis(triphenylphosphine)palladium (23 mg, 0.02 mmol), and cesium carbonate (143 mg, 0.44 mmol). The entire system was stirred at 100°C for 3 h. TLC confirmed the absence of residual starting material. 50 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride (50 mL × 2), dried over anhydrous sodium sulfate, and the solvent removed under reduced pressure. The mixture was separated and purified by column chromatography (dichloromethane:methanol = 60:1-15:1) to obtain compound 31 (69 mg, 0.14 mmol, yield 64%). ESI-MS: m / z 497.24 [M+H] + . 1 H NMR (600MHz, DMSO-d6): δ8.23(s,1H),8.00(s,1H),7.64(dd,J=7.2Hz,J=7.2Hz,1H) ,7.50(dd,J=7.2Hz,J=7.2Hz,1H),7.32-7.29(m,1H),7.23(t,J=54.0Hz,1H),6.82( d,J=87.6Hz,1H),5.75-5.70(m,1H),4.22-4.02(m,4H),3.95-3.92(m,2H),3.67-3. 62(m,2H),2.50(s,3H),2.26(s,3H),2.06(d,J=24.6Hz,2H),1.56(d,J=6.6Hz,3H).

[0288] Example 32-92:

[0289] The compounds of the following Examples 32-92 can be obtained by referring to the synthesis methods of Examples 1-11.

[0290] Example 93: Synthesis of Compound 93

[0291] Synthesis of compound 93

[0292] Intermediate 5-8 from Example 5 (40 mg, 0.089 mmol) was dissolved in dioxane (10 mL) and water (2 mL). 1-Acetyl-5,6-dihydro-2H-pyridine-4-boronic acid pinacol ester (34 mg, 0.133 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (13 mg, 0.018 mmol), and cesium carbonate (58 mg, 0.178 mmol) were added. The system was reacted at 100°C for 4 h. LC-MS analysis revealed no residual starting material. The solvent was evaporated under reduced pressure, and the residue was extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated sodium chloride (10 mL x 2), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by thin-layer chromatography (dichloromethane:methanol:triethylamine = 100:2:1) to afford compound 93 (29 mg, 0.058 mmol, 65% yield). ESI-MS: m / z 497.27[M+H] + . 1 H NMR (600MHz, DMSO-d6): δ7.97(s,1H),7.76(s,1H),7.72-7.71(m,2H),7.62-7.56(m,2H),7.06(d,J=96.0Hz,1H),5.60-5.55(m,1 H),4.16-4.10(m,2H),4.03-3.90(m,4H),3.66-3.62(m,2H),2.51(s,3H),2.27(s,3H),2.08-2.04(m,2H),1.57(d,J=6.6Hz,3H).

[0293] Examples 94-108:

[0294] The compounds of the following Examples 94-108 can be obtained by referring to the synthesis method of Example 93.

[0295] Example 109: Synthesis of Compound 109

[0296] Intermediate 5-8 (40 mg, 0.089 mmol) from Example 5 was dissolved in dioxane (10 mL) and water (2 mL). 1-(Methyl-d3)-pyridin-2-one-4-boronic acid pinacol ester (32 mg, 0.133 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (13 mg, 0.018 mmol), and cesium carbonate (58 mg, 0.178 mmol) were added. The system was reacted at 100°C for 4 h. LC-MS analysis revealed no residual starting material. The solvent was evaporated under reduced pressure, and the residue was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated sodium chloride (10 mL × 2), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by thin-layer chromatography (dichloromethane:methanol:triethylamine = 100:2:1) to afford compound 109 (25 mg, 0.051 mmol, 57% yield). ESI-MS: m / z 484.24[M+H] + . 1 H NMR (600MHz, DMSO-d6): δ8.29(s,1H),8.22(d,J=7.2Hz,1H),7.77(s,1H),7.76-7.68(m,2H),7.65-7.54(m,2H) ,7.28(s,1H),6.86(d,J=7.0Hz,1H),5.65-5.53(m,1H),4.22-3.87(m,4H),2.29(s,3H),1.59(d,J=7.0Hz,3H).

[0297] Examples 110-121:

[0298] The compounds of the following Examples 110-121 can be obtained by referring to the synthesis method of Example 93.

[0299] Example 122: Synthesis of Compound 122

[0300] Synthesis of Intermediate 122-1

[0301] 7-1 (99 mg, 0.22 mmol) was dissolved in dioxane (30 mL), followed by the addition of N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (84 mg, 0.27 mmol), tetrakis(triphenylphosphine)palladium (23 mg, 0.02 mmol), and cesium carbonate (143 mg, 0.44 mmol). The entire system was stirred at 100°C for 3 h. TLC confirmed the absence of residual starting material. 50 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride (50 mL × 2), dried over anhydrous sodium sulfate, and the solvent removed under reduced pressure. The mixture was separated and purified by column chromatography (dichloromethane:methanol = 60:1-20:1) to obtain 122-1 (100 mg, yield 82%). ESI-MS: m / z 555.19 [M+H] + .

[0302] Synthesis of Intermediate 122-2

[0303] 122-1 (100 mg, 0.18 mmol) was dissolved in 4 M hydrochloric acid ethyl acetate solution (10 mL) and stirred at room temperature for 2 h. TLC showed that no starting material remained. The solvent was removed under reduced pressure to obtain the residue 122-2, which was directly used for the next step. ESI-MS: m / z 455.18 [M+H] + .

[0304] Synthesis of compound 122

[0305] Compound 122-2 was dissolved in dichloromethane (10 mL), followed by the addition of triethylamine (36 mg, 0.36 mmol) and methanesulfonyl chloride (25 mg, 0.22 mmol). The reaction was stirred at room temperature for 2 h. TLC confirmed the absence of residual starting material. The reaction solution was quenched with water and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride (50 mL × 2), dried over anhydrous sodium sulfate, and the solvent removed under reduced pressure. The product was separated and purified by column chromatography (dichloromethane:methanol = 60:1-15:1) to obtain compound 122 (50 mg, 52% yield). ESI-MS: m / z 533.20 [M+H] + . 1H NMR (600MHz, DMSO-d6): δ8.00(s,1H),7.80(s,1H),7.64(dd,J=7.2Hz,J=7.2Hz,1H),7.50(dd,J=7.2Hz,J=7.2Hz,1H),7.32-7.30(m,1H),7.24(t,J=5 4.0Hz,1H),7.11(s,1H),5.75-5.70(m,1H),4.00-3.88(m,6H),3.40-3.37( m,2H),2.95(s,3H),2.72-2.63(m,2H),2.24(s,3H),1.56(d,J=6.6Hz,3H).

[0306] Examples 123-124:

[0307] The compounds of the following Examples 123-124 can be obtained by referring to the synthesis method of Example 93.

[0308] Example 125: Synthesis of Compound 125

[0309] Compound 124 (100 mg, 0.18 mmol) was dissolved in dichloromethane / isopropanol (22 mL, V1 / V2 = 1 / 10), and phenylsilane (19.5 mg, 0.18 mmol) and tris(2,2,6,6-tetramethyl-3,5-heptenoate)manganese (7.6 mg, 0.01 mmol) were added sequentially at room temperature. The reaction solution was replaced three times under an oxygen atmosphere and stirred at room temperature under an oxygen balloon atmosphere for 16 h. LC-MS showed that the raw material reaction was complete. The reaction solution was filtered to obtain a filtrate, which was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (dichloromethane:methanol=60:1-15:1) to obtain compound 125 (28 mg, yield 28%). ESI-MS: m / z 559.24 [M+H] + . 1 H NMR (400MHz, CD3OD): δ8.32(d,J=16.0Hz,1H),7.57(t,J=7.2Hz,1H),7.47(t,J=7.2Hz,1H),7.23(t,J=8.0Hz,1H),6.99(t,J=54.8Hz,1H),5.82-5. 73(m,1H),4.56-4.24(m,4H),4.10(t,J=10.0Hz,2H),3.85-3.45(m,2H), 2.39(s,3H),2.10-2.06(m,4H),1.64(d,J=7.2Hz,3H),1.28-1.24(m,4H).

[0310] Biological activity assay experiment 1:

[0311] 1.K-Ras G12D Binding analysis with hSOS1

[0312] This assay can be used to examine the potency of compounds to inhibit the protein-protein interaction between SOS1 and KRAS G12D. GST-KRas bound by anti-GSK-Europium (FRET donor) was detected by homogeneous time-resolved fluorescence (HTRF). G12D The binding of compounds to K-Ras was determined by His-tagged hSOS1 (FRET donor) conjugated to anti-6His-XL665. G12D Inhibitory effect on hSOS1.

[0313] 1.1 Reagents

[0314] Buffer (5 mM HEPES pH 7.4, 150 mM NaCl, 10 mM EDTA, 1 mM DTT, 0.05% BAS pH 7.0, 0.0025% Igepal and 100 mM KF);

[0315] GST-tagged hK-RasG12D (produced in-house);

[0316] His-tagged hSOS1 (produced in-house);

[0317] Preparation of Ras mixed solution

[0318] GST-hK-RasG12D 10 nM (final concentration) and anti-GSK-Europium 2 nM (final concentration) were mixed in the assay buffer and placed at room temperature until use.

[0319] Preparation of SOS mixed solution

[0320] His-tag hSOS1 20 nM (final concentration) and anti-6His-XL665 10 nM (final concentration) were mixed in the assay buffer and placed at room temperature until use.

[0321] Dissolve the test compound in DMSO at a concentration of 100 times the experimental concentration. Using a Hummingbird liquid handler or an Echo acoustic system, pipette 50 nL of the solution into a black microplate.

[0322] 1.2 Experimental steps

[0323] All experimental steps were completed at 20°C. During the experiment, 2.5 μL of Ras mixture was added to all wells of the test plate via a multidrop dispenser. After a 2-minute preincubation, 2.5 μL of SOS mixture was added to all wells except the edge wells, and 2.5 μL of compound control solution was added to the edge wells. After a 60-minute incubation, the cells were analyzed using the Pheraster HTRF module (excitation light: 337 nm, emission light 1: 620 nm, emission light 2: 665 nm).

[0324] 1.3 Data Calculation

[0325] Calculate and analyze IC using a 4-parameter logic model 50 value.

[0326] 1.4 SOS1 inhibitory activity results

[0327] The representative compounds in the examples were tested according to the above method, and the SOS1 inhibitory activity data are shown in the table below.

[0328] Among them, A represents IC 50 <10nM, B represents 10nM≤IC 50 <50nM, C represents 50nM≤IC 50 <100nM, D represents 100nM≤IC 50 <300nM.

[0329] 2.3D cell proliferation inhibition assay

[0330] The cell proliferation inhibition test is used to detect whether the compound inhibits the proliferation and growth of tumor cell lines mediated by SOS1 at the 3D cell level in vitro. 3D detection method.

[0331] 2.1 Reagents and Materials

[0332] NCI-H358: KRAS G12C-mutated non-small cell lung cancer (NSCLC);

[0333] 3D Cell Viability Assay, Promega, G9683;

[0334] RPMI 1640medium,Gibco,A10491-01;

[0335] FBS, Gibco, 10099141C;

[0336] 2.2 Test steps:

[0337] 2.2.1 Cell culture

[0338] Day 1, passage NCI-H358 cells into T75 cell culture flasks;

[0339] On Day 3, the culture medium was removed and the cells were washed once with DPBS. The cells were then incubated at room temperature or at 37°C with 2 mL of TrypLE TM The cells were digested with Express Enzyme until they fell off; 5 mL of fresh culture medium was added and the cells were centrifuged at 1000 rpm for 5 min; the supernatant was discarded and 5 mL of fresh culture medium was added to resuspend the cells. After counting the cells, 40 μL / well were inoculated into a 3D cell plate (Echo Qualified 384-Well Polypropylene Microplate 2.0, Clear, Flat Bottom).

[0340] 2.2.2 3D cell proliferation inhibition

[0341] Day 1: Dissolve the test compound in DMSO to prepare a 10 mM stock solution. After diluting 1000-fold with DMSO, perform a 3-fold serial dilution with 10 steps, starting at 10 μM. Add 200 nL of compound to the culture plate.

[0342] On Day 8, 40 μL / well of 3D CTG reagent was added and the signal value was detected using Envision.

[0343] 2.3 Data Analysis

[0344] Fitting compound IC values ​​using Graphpad Prism 8 nonlinear regression equation 50 value;

[0345] Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope));

[0346] X:Log of cpd concentration;

[0347] Y: Percent inhibition (%inh).

[0348] 2.4 Results of NCI-H358 Cell Proliferation Inhibitory Activity

[0349] The compounds in the examples were tested according to the above method, and the data on their NCI-H358 cell proliferation inhibition activity are shown in the table below.

[0350] Among them, A represents IC50 <50nM, B represents 50nM≤IC 50 <100nM, C represents 100nM≤IC 50 <500nM.

[0351] Biological activity assay experiment 2:

[0352] 1. 3D NCI-H358, NCI-H520, NCI-H1373, UM-UC-3, GP2d, and A549 cell proliferation inhibition assay

[0353] The in vitro proliferation inhibitory effects of the compounds of the present invention on human non-small cell lung cancer cells (NCI-H358, NCI-H1373, A549 and NCI-H520), human colorectal cancer cells (GP2d) and human bladder transitional cell carcinoma cells (UM-UC-3) were investigated, and their inhibitory effects on the above cell proliferation were compared with those of MRTX0902 and BI3406.

[0354] 1.1 Test materials and equipment

[0355] Cell lines:

[0356] NCI-H358: KRAS G12C-mutated non-small cell lung cancer (NSCLC);

[0357] NCI-H520: KRAS wild-type non-small cell lung cancer (NSCLC);

[0358] NCI-H1373: KRAS G12C-mutant non-small cell lung cancer (NSCLC);

[0359] UM-UC-3: KRAS G12C-mutated bladder transitional cell carcinoma (BTCC);

[0360] GP2d: KRAS G12D-mutated colorectal cancer (CRC);

[0361] A549: Non-small cell lung cancer (NSCLC) with KRAS G12S mutation.

[0362] Reagents and consumables:

[0363] F12K Medium, Hyclone, SH30526.01;

[0364] DMEM Medium, Gibco, 11965-092;

[0365] RPMI 1640 Medium, Gibco, A10491-01;

[0366] EMEM Medium, ATCC, 30-2003;

[0367] Penicillin-Streptomycin, Gibco, 15140-122;

[0368] Fetal Bovine Serum (FBS), Gibco, 10099141C;

[0369] Phosphate Buffered Saline (PBS), Gibco, 10010-031;

[0370] TrypLE, Gibco, 12604-021;

[0371] DMSO, Sigma, D8418-1L;

[0372] BI-3406, MCE, HY-125817;

[0373] MRTX0902, Zepi Biotechnology (Shijiazhuang) Co., Ltd., Zepi20221025;

[0374] 3D Cell Viability Assay, Promega, G9683;

[0375] 384 spheroid microplates, Corning, 3830;

[0376] Ultra-Low attachment 96well plate, Corning, 7007;

[0377] White Opaque 96-well Microplate, PerkinElmer, 6005680.

[0378] Instruments and equipment:

[0379] Plate shaker, QILINBEIER, QB-9002;

[0380] Centrifuge, Eppendorf, 5810R;

[0381] CO2 incubator, Thermo Scientific, 371;

[0382] Microscope, OLYMPUS, CKX41;

[0383] Echo Qualified 384-Well Polypropylene, LABCYTE, PP-0200;

[0384] Echo, LABCYTE, 655;

[0385] CountessII,Gibco,AMQAX1000;

[0386] Envision,PerkinElmer,2105.

[0387] 1.2 Test steps

[0388] 1.2.1 Cell culture

[0389] a) NCI-H358, NCI-H520, and NCI-H1373 cells were cultured in 1640 medium supplemented with 1% double antibody and 10% FBS at 37°C and 5% CO2.

[0390] b) A549 cells were cultured in F12K medium supplemented with 1% double antibody and 10% FBS at 37°C and 5% CO2.

[0391] c) GP2d cells were cultured in DMEM medium supplemented with 1% double antibody and 10% FBS at 37° C. and 5% CO 2 .

[0392] d) UM-UC-3 cells were cultured in EMEM medium supplemented with 1% double antibody and 10% FBS at 37°C and 5% CO2.

[0393] 1.2.2 Cell plating

[0394] The cells were routinely cultured until the cell saturation reached 80%-90%. When the cell number reached the required level, the cells were harvested.

[0395] Resuspend in the appropriate culture medium, count, and prepare a cell suspension of appropriate density. For NCI-H358, plate 2000 cells / well in a 384-well plate; for NCI-H520, plate 2000 cells / well in a 384-well plate; for A549, plate 1000 cells / well in a 384-well plate; for NCI-H1373, plate 1000 cells / well in a 96-well plate; for GP2d, plate 1250 cells / well in a 96-well plate; and for UM-UC-3, plate 1000 cells / well in a 384-well plate.

[0396] 1.2.3 Preparation of compounds

[0397] a) Serial dilution of positive compounds (MRTX0902 and BI-3406):

[0398] 384-well plate dilution system: Compound MRTX0902 was dissolved in DMSO to a 30 mM stock solution. MRTX0902 and BI-3406 were diluted to 10 mM in DMSO and then serially diluted 3-fold to a total of 10 concentration gradients (10,000, 3,333, 1,111, 370, 123, 41.2, 13.7, 4.57, 1.52, and 0.51 μM). Using a nanoliter pipette system (Echo 650 Liquid Handler), 40 nL of the above-described serially diluted compounds were added to each well of a 384-well cell culture plate. The mixture was centrifuged at 1,000 rpm for 1 min. The final compound concentration gradient in the reaction system (40 μL) was 10,000, 3,333, 1,111, 370, 123, 41.2, 13.7, 4.57, 1.52, and 0.51 nM.

[0399] 96-well plate dilution system: MRTX0902 and BI-3406 were diluted to 2000 μM in DMSO and then serially diluted 3-fold to a total of 10 concentration gradients (2000, 667, 222, 74.1, 24.7, 8.23, 2.74, 0.91, 0.30, and 0 μM). Using a nanoliter pipette system (Echo 650 Liquid Handler), 500 nL of the above-described diluted compounds were added to each well of a 96-well cell culture plate. The mixture was centrifuged at 1000 rpm for 1 min. The final compound concentration in the reaction system (100 μL) was 10,000, 3333, 1111, 370, 123, 41.2, 13.7, 4.57, 1.52, and 0 nM.

[0400] b) Gradual dilution of the compound of the present invention:

[0401] 384-well plate dilution system: Compounds were dissolved in DMSO to a 27.4 mM stock solution, diluted to 9.13 mM with DMSO, and then serially diluted 3-fold to a total of 10 concentration gradients (9135, 3044, 1014, 338, 112, 37.6, 12.5, 4.18, 1.39, and 0.46 μM). Using a nanoliter pipette system (Echo 650 Liquid Handler), 40 nL of the compound was added to each well of a 384-well cell culture plate. The mixture was centrifuged at 1000 rpm for 1 min. The final concentration gradient of the compound in the reaction system (40 μL) was 9135, 3045, 1015, 338, 113, 37.6, 12.5, 4.18, 1.39, and 0.46 nM.

[0402] 96-well plate dilution system: Compounds were diluted to 1827 μM in DMSO and then serially diluted 3-fold to a total of 10 concentration gradients (1827, 609, 203, 67.7, 22.6, 7.52, 2.51, 0.84, 0.28, and 0 μM). Using a nanoliter pipette system (Echo 650 Liquid Handler), 500 nL of the above-described gradient compound was added to each well of a 96-well cell culture plate. Centrifuge at 1000 rpm for 1 min. The final compound concentration in the reaction system (100 μL) was 9135, 3045, 1015, 338, 113, 37.6, 12.5, 4.18, 1.39, and 0 nM, respectively.

[0403] 1.2.4 CTG method detection

[0404] After culturing the cells in a 37°C, 5% CO2 incubator for 7 days:

[0405] a) Add 20 μL of CTG reagent (CelltiterGlo 3D kit) to each well of a 384-well plate, centrifuge at 1000 rpm for 1 min, shake on a high-speed shaker for 20 minutes, and store at room temperature in the dark for 120 minutes.

[0406] b) Add 50 μL of CTG reagent (CelltiterGlo 3D kit) to each well of a 96-well plate, centrifuge at 1000 rpm for 1 min, shake on a fast shaker for 20 minutes, and store in the dark at room temperature for 120 minutes. Transfer 100 μL to a White Opaque 96-well Microplate.

[0407] c) Read the chemiluminescent signal using an Envision instrument.

[0408] 1.2.5 Data Analysis

[0409] IC was calculated using GraphPad Prism 8 software. 50 , the IC of the compound is obtained using the following nonlinear fitting formula 50 (50% inhibitory concentration):

[0410] Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope));

[0411] Y: Percent inhibition / %inh; X: Log value of compound concentration (Log of cpd concentration).

[0412] Inhibition rate (%) = 100-(compound well reading value-low reading control well reading value) / (high reading control well reading value-low reading control well reading value)*100%;

[0413] High read value control wells: cells plus 40nL DMSO (NCI-H358, NCI-H520, A549, UM-UC-3)

[0414] Add 500 nL DMSO (NCI-H1373, GP2d) to the cells;

[0415] Low-reading control wells: no cell culture medium.

[0416] 1.3 Test results

[0417] The exemplary compounds were tested according to the above method, and the cell proliferation inhibition activity data are shown in the table below:

[0418] 2. 3D MIA PaCa-2, NCI-H441, and DLD-1 Cell Proliferation Inhibition Assay

[0419] The in vitro proliferation inhibitory effect of the compound of the present invention on human pancreatic cancer cells (MIA PaCa-2), human non-small cell lung cancer cells (NCI-H441) and human colorectal cancer cells (DLD-1) was investigated, and the inhibitory effect of the compound of the present invention on the proliferation of the above three cell lines was compared with that of MRTX0902.

[0420] 2.1 Test materials and equipment

[0421] Cell lines:

[0422] MIA PaCa-2: human pancreatic cancer cells (PAC) with KRAS G12C mutation;

[0423] H441: KRAS G12V-mutated non-small cell lung cancer (NSCLC);

[0424] DLD-1: human colorectal cancer (CRC) with KRAS G13D mutation.

[0425] Reagents and consumables:

[0426] DMEM basic (1×): 500 mL, Gibco, batch number: 8122483;

[0427] Horse serum: 500 mL, Inner Mongolia Jinyuankang Company, batch number: 20200701;

[0428] Penicillin-Streptomycin, Gibco, 15140-122;

[0429] RPMI Medium 1640 basic (1×): 500 mL, Gibco, batch number: 8122656;

[0430] FETAL BOVINE SERUM (FBS): 500 mL, Gibco, lot number: 2528128CP;

[0431] 0.25% Trypsin-EDTA (1×): 500 mL, Gibco, batch number: 2360145;

[0432] PBS pH 7.4 (1×): 500 mL, Gibco, batch number: 8121763;

[0433] DMSO (cell culture grade): 500 mL, AMRESCO, batch number: 21A2756279;

[0434] 3D Cell Viability Assay: 100 mL, Promega, Lot No. 0000537948;

[0435] MRTX0902, Zepi Biotechnology (Shijiazhuang) Co., Ltd., Zepi20221025;

[0436] Low-adsorption plate: 96-well, Corning, lot number: 02722003.

[0437] Instruments and equipment:

[0438] Model 371 CO2 incubator: Thermo, equipment number: ZS01-0746;

[0439] IX70-142 inverted microscope: Olympus, equipment number: 0243;

[0440] HFsafe-1500LC biological safety cabinet: Shanghai Lishen Scientific Instrument Co., Ltd., equipment number: ZS01-0747;

[0441] TD6 centrifuge: Changsha Xiangrui Centrifuge Co., Ltd., equipment number: ZS01-0750;

[0442] MS105 electronic balance: METTLER TOLEDO, equipment number: ZY01-0136;

[0443] Varioskan Flash fluorescence microplate reader: Thermo, equipment number: 0845.

[0444] 2.2 Test steps:

[0445] 2.2.1 Preparation of compounds

[0446] a) In the MIA PaCa-2 cell proliferation inhibition assay, the final concentration of the compound of the present invention was 9134.57 nM as the starting concentration, and 9 concentrations were set in 5× descending dilutions, namely 9134.57, 1826.91, 365.38, 73.08, 14.62, 2.92, 0.58, 0.12, and 0.02 nM; the final concentration of MRTX0902 as a single drug was 10 μM as the starting concentration, and 9 concentrations were set in 3× descending dilutions, namely 10000, 3333.33, 1111.11, 370.37, 123.46, 41.15, 13.72, 4.57, and 1.52 nM.

[0447] b) In the DLD-1 cell proliferation inhibition assay, the final concentration of the compound of the present invention was 9134.57 nM as the starting concentration, and 9 concentrations were set in 3× decreasing dilutions, namely 9134.57, 3044.86, 1014.95, 338.32, 112.77, 37.59, 12.53, 4.18, and 1.39 nM; the final concentration of MRTX0902 was 10 μM as the starting concentration, and 9 concentrations were set in 3× decreasing dilutions, namely 10000, 3333.33, 1111.11, 370.37, 123.46, 41.15, 13.72, 4.57, and 1.52 nM.

[0448] c) In the NCI-H441 proliferation inhibition assay, the final concentration of the compound of the present invention started at 9134.57 nM, and 9 concentrations were set in 5× descending dilutions, namely 9134.57, 1826.91, 365.38, 73.08, 14.62, 2.92, 0.58, 0.12, and 0.02 nM; the final concentration of MRTX0902 started at 10 μM, and 9 concentrations were set in 5× descending dilutions, namely 10000, 2000, 400, 80, 16, 3.2, 0.64, 0.13, and 0.03 nM.

[0449] 2.2.2 Cell culture and detection

[0450] MIA PaCa-2 cells were cultured in high-glucose DMEM supplemented with 10% FBS and 2.5% horse serum; NCI-H441 and DLD-1 cells were cultured in RPMI Medium 1640 Basic supplemented with 10% FBS at 37°C and 5% CO2.

[0451] A certain number of cell lines in the logarithmic growth phase were plated in a low-adsorption 96-well plate (100 μL / well). 100 μL of culture medium containing different concentration gradients of the compound of the present invention or MRTX0902 was added to each well. Three replicates were set for each drug concentration, and corresponding blank wells (only culture medium) and normal wells (drug concentration was 0) were set. After 7 days of drug treatment, the plate was equilibrated at room temperature for 30 minutes, 120 μL of supernatant was aspirated from each well, 50 μL of CellTiter-Glo detection reagent was added, and the mixture was shaken and mixed at room temperature in the dark for 20 minutes. The luminescence value was detected by chemiluminescence using an enzyme reader.

[0452] 2.2.3 Data Analysis

[0453] The cell growth inhibition rate was calculated using the following formula:

[0454] Inhibition rate (%) = (luminescence value 正常孔 - Luminous value 给药孔 ) / (luminous value 正常孔 - Luminous value 空白孔 )×100%.

[0455] According to the inhibition rate of each concentration, the drug half-maximal inhibition concentration IC was fitted using the nonlinear regression equation of GraphPad Prism 5. 50 .

[0456] 2.3 Test results

[0457] The cell proliferation inhibition activity data of the exemplary compounds tested according to the above method are shown in the following table:

Claims

1. Use of a compound as represented by formula (B) or its stereoisomer, optical isomer, pharmaceutically acceptable salt, prodrug, solvate or isotope derivative or a pharmaceutical composition in the preparation of a drug for preventing and / or treating tumors or cancers, in, R 1 Select from -OR A 、-N(R D )R B or R C ; When R 1 For-OR A , R A Selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl are each optionally substituted by 1-3 identical or different R a1 replace; If present, each R a1 are independently selected from halogen, hydroxy, cyano, amino, nitro, oxo, formyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -COC 1-6 Alkyl, -CH 2 COC 1-6 Alkyl, -CH 2 CON(C 1-6 alkyl) 2 、-CH 2 CONHC 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C 1-6 alkyl) 2 , C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl; When R 1 -N(R D )R B , R B Selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl are each optionally substituted by 1-3 identical or different R b1 replace; If present, each R b1 are independently selected from halogen, hydroxy, cyano, amino, nitro, oxo, formyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -COC 1-6 Alkyl, -CH 2 COC 1-6 Alkyl, -CH 2 CON(C 1-6 alkyl) 2 、-CH 2 CONHC 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C 1-6 alkyl) 2 , C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl; R D is selected from hydrogen, halogen, hydroxy, cyano, amino, nitro, oxo, formyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -COC 1-6 Alkyl, -CH 2 COC 1-6 Alkyl, -CH 2 CON(C 1-6 alkyl) 2 、-CH 2 CONHC 1-6 Alkyl, -NHC 1-6 Alkyl or -N(C 1-6 alkyl) 2 ; When R 1 For R C , R C Selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl are each optionally substituted by 1-4 identical or different R c1 replace; If present, each R c1 are independently selected from halogen, hydroxy, cyano, amino, nitro, oxo, formyl, methylsulfonyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -COC 1-6 Alkyl, -COC 3-6 Cycloalkyl, -CH 2 COC 1-6 Alkyl, -CH 2 CON(C 1-6 alkyl) 2 、-CH 2 CONHC 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C 1-6 alkyl) 2 , C 3-10 Cycloalkyl, C 6-10 aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -COC 1-6 Alkyl, -COC 3-6 Cycloalkyl, -CH 2 COC 1-6 Alkyl, -CH 2 CON(C 1-6 alkyl) 2 、-CH 2 CONHC 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C 1-6 alkyl) 2 , C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl are optionally substituted with one or more selected from deuterium, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Alkoxy or halogen substituents; R 2 is 1 or 2, each of which, when present, is independently selected from hydrogen, halogen, hydroxy, cyano, amino, nitro, formyl, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy; R 3 Selected from hydrogen, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl and 3-6 membered heterocyclyl are both optionally substituted with one or more hydroxyl or halogen; Ring B is selected from C 4-12 Cycloalkyl, C 4-12 Cycloalkenyl, C 4-12 Heterocyclic group, C 6-12 Aryl, C 5-12 Heteroaryl, C 6-12 Aryl C 4-12 Cycloalkyl, C 6-12 Aryl C 4-12 Heterocyclic or C 6-12 Aryl C 4-12 Cycloalkenyl; If present, each R 4 are each independently selected from hydrogen, cyano, halogen, amino, hydroxyl, oxo, nitro, C 1-6 alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, -C 0-6 Alkyl-NH-C 1-6 Alkyl, -C 0-6 Alkyl-N(C 1-6 Alkyl)(C 1-6 Alkyl), C 3-6 Cycloalkyl, C 3-6 A halogenated cycloalkyl or a 3-6 membered heterocyclic group, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, -C 0-6 Alkyl-NH-C 1-6 Alkyl, -C 0-6 Alkyl-N(C 1-6 Alkyl)(C 1-6 Alkyl), C 3-6 Cycloalkyl, C 3-6 The halogenated cycloalkyl and 3-6 membered heterocyclic groups are optionally substituted by one or more of the following substituents: halogen, hydroxyl, amino, -SO 2 -C 1-4 Alkyl or oxo; w is 0, 1, 2, 3 or 4; Unless otherwise specified, the heteroatoms in the above heteroaryl and heterocyclic groups are each independently selected from O, N or S, and the number of heteroatoms is 1, 2, 3 or 4; The pharmaceutical composition comprises the compound or its stereoisomer, optical isomer, pharmaceutically acceptable salt, prodrug, solvate or isotopic derivative.

2. The use according to claim 1, It is characterized in that R 1 For-OR A , R A Selected from C 1-6 Alkyl, C 3-10 Cycloalkyl, C 6-10 aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl are each optionally substituted by 1-3 identical or different R a1 replace; If present, each R a1 are independently selected from halogen, hydroxy, cyano, amino, nitro, oxo, formyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -COC 1-6 Alkyl, -CH 2 COC 1-6 Alkyl, -CH 2 CON(C 1-6 alkyl) 2 、-CH 2 CONHC 1-6 Alkyl, -NHC 1-6 Alkyl or -N(C 1-6 alkyl) 2 ; More preferably, R A Selected from C 3-6 Cycloalkyl, C 6-10 aryl, 3-6 membered heterocyclyl or 5-6 membered heteroaryl, wherein the C 3-6 Cycloalkyl, C 6-10 Aryl, 3-6 membered heterocyclyl and 5-6 membered heteroaryl are each optionally substituted by 1-3 identical or different R a1 replace; If present, each R a1 Each is independently selected from halogen, hydroxy, cyano, amino, oxo, formyl, C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl or -COC 1-6 alkyl; More preferably, R A is selected from 5-6 membered heterocyclyl or 5-6 membered heteroaryl, wherein the 5-6 membered heterocyclyl and the 5-6 membered heteroaryl are optionally substituted by 1-3 identical or different R a1 replace; If present, each R a1 Each is independently selected from halogen, hydroxy, cyano, amino, oxo, formyl, C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl or -COC 1-4 alkyl; More preferably, R A is selected from 5-6 membered heterocyclic groups, wherein the 5-6 membered heterocyclic groups are optionally substituted by 1-2 identical or different R a1 replace; If present, each R a1 Each is independently selected from halogen, oxo, formyl, acetyl, methyl, ethyl, n-propyl, isopropyl or methoxy; More preferably, R A is selected from 5-6 membered monocyclic heterocyclic groups, wherein the 5-6 membered monocyclic heterocyclic groups are optionally substituted by 1-2 identical or different R a1 Substitution; the heteroatoms in the 5-6 membered monocyclic heterocyclic group are each independently selected from O, N or S, and the number of heteroatoms is 1; If present, each R a1 Each is independently selected from halogen, oxo, formyl, acetyl, methyl, ethyl, n-propyl, isopropyl or methoxy; More preferably, R A is selected from tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl or tetrahydrothiopyranyl, wherein the tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl and tetrahydrothiopyranyl are each optionally substituted by 1-2 identical or different R a1 replace; If present, each R a1 Each is independently selected from halogen, oxo, formyl, acetyl, methyl, ethyl, n-propyl, isopropyl or methoxy; More preferably, R A Selected from the following groups:

3. The use according to claim 1, It is characterized in that R 1 -N(R D )R B , R B Selected from C 1-6 Alkyl, C 3-10 Cycloalkyl, C 6-10 aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl are each optionally substituted by 1-3 identical or different R b1 replace; If present, each R b1 are independently selected from halogen, hydroxy, cyano, amino, nitro, oxo, formyl, C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl or -COC 1-6 alkyl; More preferably, R B Selected from C 1-6 alkyl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl, wherein the C 1-6 The alkyl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl groups are each optionally substituted by 1-3 identical or different R b1 replace; If present, each R b1 are independently selected from halogen, hydroxy, cyano, amino, nitro, oxo, formyl, C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl or -COC 1-6 alkyl; More preferably, R B Selected from C 1-6 alkyl or a 5-6 membered monocyclic heterocyclic group, wherein the C 1-6 The alkyl group and the 5-6 membered monocyclic heterocyclic group are each optionally substituted by 1-2 identical or different R b1 Substitution; the heteroatoms in the 5-6 membered monocyclic heterocyclic group are each independently selected from O, N or S, and the number of heteroatoms is 1; If present, each R b1 are independently selected from halogen, oxo, formyl, C 1-4 Alkyl, -OC 1-4 Alkyl or -COC 1-4 alkyl; More preferably, R B is selected from methyl, ethyl, n-propyl, isopropyl, oxadiinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl or tetrahydrothiopyranyl, wherein the methyl, ethyl, n-propyl, isopropyl, oxadiinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl and tetrahydrothiopyranyl are optionally substituted by 1-2 identical or different R b1 replace; If present, each R b1 Each is independently selected from oxo, formyl, acetyl, methyl, ethyl, methoxy or ethoxy; More preferably, R B Selected from the following groups: R D Selected from hydrogen, C 1-6 Alkyl or -OC 1-6 Alkyl; further preferably, R D Selected from hydrogen or C 1-3 Alkyl; More preferably, R D is selected from hydrogen or methyl; most preferably, R D For hydrogen.

4. The use according to claim 1, It is characterized in that R 1 For R C , R C Selected from C 3-10 Cycloalkyl, C 6-10 aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl, wherein the C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl are each optionally substituted by 1-4 identical or different R c1 replace; If present, each R c1 are independently selected from halogen, hydroxy, cyano, amino, nitro, oxo, formyl, methylsulfonyl, C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -COC 1-6 Alkyl, -COC 3-6 Cycloalkyl, -CH 2 COC 1-6 Alkyl, -CH 2 CON(C 1-6 alkyl) 2 、-CH 2 CONHC 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C 1-6 alkyl) 2 , C 3-10 Cycloalkyl or 3-10 membered heterocyclic group, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -COC 1-6 Alkyl, -COC 3-6 Cycloalkyl, -CH 2 COC 1-6 Alkyl, -CH 2 CON(C 1-6 alkyl) 2 、-CH 2 CONHC 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C 1-6 alkyl) 2 , C 3-10 The cycloalkyl and 3-10 membered heterocyclic groups are optionally substituted with one or more selected from deuterium, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Alkoxy or halogen substituents; More preferably, R C Selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl, wherein the C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl are each optionally substituted by 1-4 identical or different R c1 replace; If present, each R c1 are independently selected from halogen, hydroxy, cyano, amino, nitro, oxo, formyl, methylsulfonyl, C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -COC 1-4 Alkyl, -COC 3-6 Cycloalkyl, -CH 2 COC 1-4 Alkyl, -CH 2 CON(C 1-4 alkyl) 2 、-CH 2 CONHC 1-4 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, wherein the C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -COC 1-4 Alkyl, -COC 3-6 Cycloalkyl, -CH 2 COC 1-4 Alkyl, -CH 2 CON(C 1-4 alkyl) 2 、-CH 2 CONHC 1-4 Alkyl, C 3-6 The cycloalkyl and 3-6 membered heterocyclic groups are optionally substituted with one or more selected from deuterium, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Alkoxy or halogen substituents; More preferably, R C is selected from 3-10 membered heterocyclyl or 5-10 membered heteroaryl, wherein the 3-10 membered heterocyclyl and the 5-10 membered heteroaryl are optionally substituted by 1-4 identical or different R c1 replace; If present, each R c1 are independently selected from halogen, hydroxy, cyano, amino, oxo, formyl, methylsulfonyl, C 1-4 Alkyl, -OC 1-4 Alkyl, -COC 1-4 Alkyl, -COC 3-6 Cycloalkyl, -CH 2 CON(C 1-4 alkyl) 2 or a 3-6 membered heterocyclic group, wherein the C 1-4 Alkyl, -OC 1-4 Alkyl, -COC 1-4 Alkyl, -COC 3-6 Cycloalkyl, -CH 2 CON(C 1-4 alkyl) 2 and 3-6 membered heterocyclyl are each optionally substituted with one or more substituents selected from deuterium, hydroxy, cyano, methyl, methoxy or halogen; More preferably, R C is selected from a 5-6 membered monocyclic heterocyclic group, a 6-10 membered spiro heterocyclic group, a 6-8 membered bridged heterocyclic group, an 8-10 membered fused heterocyclic group or a 5-6 membered monocyclic heteroaryl, wherein the 5-6 membered monocyclic heterocyclic group, the 6-10 membered spiro heterocyclic group, the 6-8 membered bridged heterocyclic group, the 8-10 membered fused heterocyclic group and the 5-6 membered monocyclic heteroaryl are optionally substituted by 1-4 identical or different R c1 replace; If present, each R c1 are each independently selected from halogen, hydroxy, cyano, amino, oxo, formyl, acetyl, propionyl, methylsulfonyl, methoxy, ethoxy, methyl, ethyl, n-propyl, isopropyl, -CH 2 CON(CH 3 ) 2 , -CO-cyclopropyl, -CO-cyclobutyl, 4-membered heterocyclic group, 5-membered heterocyclic group or 6-membered heterocyclic group, wherein the acetyl, propionyl, methanesulfonyl, methoxy, ethoxy, methyl, ethyl, n-propyl, isopropyl, -CH 2 CON(CH 3 ) 2 , -CO-cyclopropyl, -CO-cyclobutyl, 4-membered heterocyclyl, 5-membered heterocyclyl and 6-membered heterocyclyl are each optionally substituted with one or more substituents selected from deuterium, hydroxyl, cyano, methyl, methoxy or halogen; More preferably, R C is selected from a 6-membered monocyclic heterocyclic group, a 4-membered / 6-membered spiro heterocyclic group, a 4-membered / 4-membered spiro heterocyclic group, a 6-membered / 5-membered fused heterocyclic group, a 7-membered bridged heterocyclic group or a 6-membered monocyclic heteroaryl, wherein the 6-membered monocyclic heterocyclic group, the 4-membered / 6-membered spiro heterocyclic group, the 4-membered / 4-membered spiro heterocyclic group, the 6-membered / 4-membered fused heterocyclic group, the 7-membered bridged heterocyclic group and the 6-membered monocyclic heteroaryl are optionally substituted by 1-4 identical or different R c1 replace; If present, each R c1 are each independently selected from halogen, hydroxy, cyano, amino, oxo, formyl, acetyl, propionyl, methylsulfonyl, methoxy, ethoxy, methyl, ethyl, n-propyl, isopropyl, -CH 2 CON(CH 3 ) 2 , -CO-cyclopropyl, 4-membered heterocyclyl, 5-membered heterocyclyl or 6-membered heterocyclyl, wherein the acetyl, propionyl, methanesulfonyl, methoxy, ethoxy, methyl, ethyl, n-propyl, isopropyl, -CH 2 CON(CH 3 ) 2 , -CO-cyclopropyl, 4-membered heterocyclyl, 5-membered heterocyclyl and 6-membered heterocyclyl are optionally substituted with one or more substituents selected from deuterium, hydroxyl, cyano, methyl, methoxy or halogen; More preferably, R C Selected from The R C are optionally replaced by 1-4 identical or different R c1 replace; If present, each R c1 Each is independently selected from F, Cl, Br, hydroxyl, cyano, amino, oxo, mesyl, acetyl, -COCH 2 CH 3 、-COCH 2 OH, -COCH 2 CN, -CH(OH)(CH 3 ) 2 , hydroxymethyl, hydroxyethyl, -CH 2 OCH 3 、-CH 2 CH 2 OCH 3 , methoxy, methyl, CD 3 , ethyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, -CH 2 CON(CH 3 ) 2 or morpholinyl; More preferably, optionally R c1 Replaced by R C Selected from the following groups:

5. The use according to any one of claims 1 to 4, It is characterized in that R 2 is 1 or 2, each of which, when present, is independently selected from hydrogen, halogen, hydroxy, cyano, amino, nitro, formyl, oxo, methoxy, methyl, ethyl, n-propyl or isopropyl; More preferably, R 2 is 1 or 2, each of which, when present, is independently selected from hydrogen, halogen, hydroxy, cyano, amino, nitro, methoxy or methyl; More preferably, R 2 is 1 or 2, each of which is independently selected from hydrogen or methyl; More preferably, R 2 For hydrogen.

6. The use according to any one of claims 1 to 5, It is characterized in that R 3 is selected from hydrogen, halogen, hydroxy, amino, cyano, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or methoxy; More preferably, R 3 is selected from hydrogen, halogen, hydroxy, amino, cyano, methyl, ethyl, n-propyl, isopropyl or cyclopropyl; More preferably, R 3 is selected from hydrogen, F, Cl, Br, amino, methyl, ethyl or cyclopropyl.

7. The use according to any one of claims 1 to 6, It is characterized in that Ring B is selected from C 4-12 Cycloalkenyl, 4-12 membered heterocyclic group, C 6-12 Aryl, C 6-8 Aryl C 4-6 Cycloalkyl, C 6-8 Aryl and 4-6 membered heterocyclic or 5-12 membered heteroaryl; More preferably, ring B is selected from C 6-10 Aryl, 5-10 membered heteroaryl or C 6-8 Aryl 4-6 membered heterocyclic group; More preferably, ring B is selected from phenyl, pyridyl or benzotetrahydrofuranyl.

8. The use according to any one of claims 1 to 7, It is characterized in that If present, each R 4 are each independently selected from hydrogen, cyano, halogen, amino, nitro, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 3-6 Cycloalkyl, C 3-6 A halogenated cycloalkyl or a 3-6 membered heterocyclic group, wherein the C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 3-6 Cycloalkyl, C 3-6 The halogenated cycloalkyl and 3-6 membered heterocyclic groups are optionally substituted by one or more of the following substituents: halogen, hydroxyl, amino, -SO 2 -C 1-4 Alkyl or oxo; w is 0, 1, 2 or 3; Further preferably, each R 4 are each independently selected from hydrogen, cyano, halogen, amino, nitro, C 1-4 Alkyl, C 1-4 Haloalkyl or C 1-4 Hydroxyalkyl, wherein the C 1-4 Alkyl, C 1-4 Haloalkyl and C 1-4 Hydroxyalkyl is optionally substituted by one or more of the following substituents: halogen, hydroxyl or amino; w is 1, 2 or 3; Further preferably, each R 4 Each is independently selected from hydrogen, cyano, halogen, amino, nitro, methyl, ethyl, n-propyl or isopropyl, wherein the methyl, ethyl, n-propyl and isopropyl are optionally substituted with one or more of the following substituents: halogen or hydroxyl; w is 1, 2 or 3; Further preferably, each R 4 Each is independently selected from hydrogen, halogen, amino, cyano, methyl, ethyl or isopropyl, wherein the methyl, ethyl and isopropyl are optionally substituted with one or more of the following substituents: halogen or hydroxyl; w is 1, 2 or 3; Further preferably, each R 4 Each is independently selected from hydrogen, fluorine, amino, cyano, methyl, trifluoromethyl, difluoromethyl, monofluoromethyl, -CF 2 CH 2 OH, -C(CH 3 ) 2 OH, -CF 2 CH 3 or -CH 2 CHF 2 ; w is 1, 2 or 3.

9. The use according to any one of claims 1 to 8, It is characterized in that The compound has a structure as shown in formula (C): The substituents in formula (C) are as defined in formula (B).

10. The use according to claim 1, It is characterized in that The compound has a structure as shown in formula (D): Among them, each R 4 are independently selected from cyano, halogen, amino, C 1-6 Alkyl or C 1-6 haloalkyl, wherein the C 1-6 Alkyl and C 1-6 The haloalkyl groups are optionally substituted with one or more hydroxyl groups; w is 1 or 2; R 1 Select from -OR A 、-N(R D )R B or R C ; When R 1 For-OR A , R A is selected from 3-10 membered heterocyclic groups, wherein the 3-10 membered heterocyclic groups are optionally substituted by 1-3 identical or different R a1 replace; If present, each R a1 Each independently selected from C 1-6 Alkyl or -COC 1-6 alkyl; When R 1 -N(R D )R B , R B Selected from C 1-6 alkyl or 3-10 membered heterocyclic group, wherein the C 1-6 The alkyl group and the 3-10 membered heterocyclic group are each optionally substituted by 1-3 identical or different R b1 replace; If present, each R b1 Each independently selected from -OC 1-6 alkyl; R D Selected from hydrogen; When R 1 For R C , R C is selected from 3-10 membered heterocyclyl or 5-10 membered heteroaryl, wherein the 3-10 membered heterocyclyl and the 5-10 membered heteroaryl are optionally substituted by 1-4 identical or different R c1 replace; If present, each R c1 Each is independently selected from halogen, hydroxy, cyano, amino, mesyl, C 1-6 Alkyl, -OC 1-6 Alkyl, -COC 1-6 Alkyl, -COC 3-6 Cycloalkyl, -CH 2 CON(C 1-6 alkyl) 2 or a 3-10 membered heterocyclic group, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl, -COC 1-6 Alkyl, -COC 3-6 Cycloalkyl, -CH 2 CON(C 1-6 alkyl) 2 and 3-10 membered heterocyclic groups are optionally substituted with one or more selected from deuterium, hydroxyl, cyano, C 1-3 Alkoxy or halogen substituents; Unless otherwise specified, the heteroatoms in the above heteroaryl and heterocyclic groups are each independently selected from O, N or S, and the number of heteroatoms is 1, 2, 3 or 4.

11. The use according to claim 10, It is characterized in that R 1 For-OR A , R A is selected from 3-6 membered heterocyclic groups, wherein the 3-6 membered heterocyclic groups are optionally substituted by 1-3 identical or different R a1 replace; If present, each R a1 Each independently selected from C 1-6 Alkyl or -COC 1-6 alkyl; More preferably, R A is selected from 5-6 membered heterocyclic groups, wherein the 5-6 membered heterocyclic groups are optionally substituted by 1-2 identical or different R a1 replace; If present, each R a1 Each is independently selected from acetyl, methyl, ethyl, n-propyl or isopropyl; More preferably, R A is selected from 5-6 membered monocyclic heterocyclic groups, wherein the 5-6 membered monocyclic heterocyclic groups are optionally substituted by 1-2 identical or different R a1 Substitution; the heteroatoms in the 5-6 membered monocyclic heterocyclic group are each independently selected from O, N or S, and the number of heteroatoms is 1; If present, each R a1 Each independently selected from acetyl, methyl or ethyl; More preferably, R A is selected from tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl or tetrahydrothiopyranyl, wherein the tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl and tetrahydrothiopyranyl are each optionally substituted by 1-2 identical or different R a1 replace; If present, each R a1 Each independently selected from acetyl, methyl or ethyl; More preferably, R A Selected from the following groups:

12. The use according to claim 10, It is characterized in that R 1 -N(R D )R B , R B Selected from C 1-6 alkyl or a 3-6 membered monocyclic heterocyclic group, wherein the C 1-6 The alkyl group and the 3-6 membered monocyclic heterocyclic group are each optionally substituted by 1-2 identical or different R b1 Substitution; the heteroatoms in the 3-6 membered monocyclic heterocyclic group are each independently selected from O, N or S, and the number of heteroatoms is 1; If present, each R b1 Each independently selected from -OC 1-4 alkyl; More preferably, R B is selected from methyl, ethyl, n-propyl, isopropyl, oxadiinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl or tetrahydrothiopyranyl, wherein the methyl, ethyl, n-propyl, isopropyl, oxadiinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl and tetrahydrothiopyranyl are optionally substituted by 1-2 identical or different R b1 replace; If present, each R b1 Each independently selected from methoxy or ethoxy; More preferably, R B Selected from the following groups: R D Selected from hydrogen, C 1-6 Alkyl or -OC 1-6 Alkyl; further preferably, R D Selected from hydrogen or C 1-3 Alkyl; More preferably, R D is selected from hydrogen or methyl; most preferably, R D For hydrogen.

13. The use according to claim 10, It is characterized in that R 1 For R C , R C is selected from 3-10 membered heterocyclyl or 5-10 membered heteroaryl, wherein the 3-10 membered heterocyclyl and the 5-10 membered heteroaryl are optionally substituted by 1-4 identical or different R c1 replace; If present, each R c1 Each is independently selected from halogen, hydroxy, cyano, amino, mesyl, C 1-4 Alkyl, -OC 1-4 Alkyl, -COC 1-4 Alkyl, -COC 3-6 Cycloalkyl, -CH 2 CON(C 1-4 alkyl) 2 or a 3-6 membered heterocyclic group, wherein the C 1-4 Alkyl, -OC 1-4 Alkyl, -COC 1-4 Alkyl, -COC 3-6 Cycloalkyl, -CH 2 CON(C 1-4 alkyl) 2 and 3-6 membered heterocyclyl are each optionally substituted with one or more substituents selected from deuterium, hydroxy, cyano, methoxy or halogen; More preferably, R C is selected from a 5-6 membered monocyclic heterocyclic group, a 6-10 membered spiro heterocyclic group, a 6-8 membered bridged heterocyclic group, an 8-10 membered fused heterocyclic group or a 5-6 membered monocyclic heteroaryl, wherein the 5-6 membered monocyclic heterocyclic group, the 6-10 membered spiro heterocyclic group, the 6-8 membered bridged heterocyclic group, the 8-10 membered fused heterocyclic group and the 5-6 membered monocyclic heteroaryl are optionally substituted by 1-4 identical or different R c1 replace; If present, each R c1 are each independently selected from halogen, hydroxy, cyano, amino, methanesulfonyl, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, acetyl, propionyl, -CO-cyclopropyl, -CO-cyclobutyl, -CH 2 CON(CH 3 ) 2 , 4-membered heterocyclic group, 5-membered heterocyclic group or 6-membered heterocyclic group, wherein the methanesulfonyl, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, acetyl, propionyl, -CO-cyclopropyl, -CO-cyclobutyl, -CH 2 CON(CH 3 ) 2 , 4-membered heterocyclyl, 5-membered heterocyclyl and 6-membered heterocyclyl are each optionally substituted with one or more substituents selected from deuterium, hydroxyl, cyano, methoxy or halogen; More preferably, R C is selected from a 6-membered monocyclic heterocyclic group, a 4-membered / 6-membered spiro heterocyclic group, a 4-membered / 4-membered spiro heterocyclic group, a 7-membered bridged heterocyclic group, a 6-membered / 5-membered fused heterocyclic group or a 6-membered monocyclic heteroaryl, wherein the 6-membered monocyclic heterocyclic group, the 4-membered / 6-membered spiro heterocyclic group, the 4-membered / 4-membered spiro heterocyclic group, the 7-membered bridged heterocyclic group, the 6-membered / 4-membered fused heterocyclic group and the 6-membered monocyclic heteroaryl are optionally substituted by 1-4 identical or different R c1 replace; If present, each R c1 are each independently selected from halogen, hydroxy, cyano, amino, methanesulfonyl, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, acetyl, propionyl, -CO-cyclopropyl, -CH 2 CON(CH 3 ) 2 , 4-membered heterocyclyl, 5-membered heterocyclyl or 6-membered heterocyclyl, wherein the methanesulfonyl, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, acetyl, propionyl, -CO-cyclopropyl, 4-membered heterocyclyl, 5-membered heterocyclyl and 6-membered heterocyclyl are optionally substituted with one or more substituents selected from deuterium, hydroxyl, cyano, methoxy or halogen; More preferably, R C Selected from The R C are optionally replaced by 1-4 identical or different R c1 replace; If present, each R c1 Each is independently selected from F, Cl, Br, hydroxy, cyano, amino, methylsulfonyl, methyl, ethyl, isopropyl, CD 3 , hydroxymethyl, hydroxyethyl (e.g., 2-hydroxyethyl), -CH(OH)(CH 3 ) 2 、-CH 2 OCH 3 、-CH 2 CH 2 OCH 3 , monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl (e.g., 2-fluoroethyl), difluoroethyl (e.g., 2,2-difluoroethyl), trifluoroethyl (e.g., 2,2,2-trifluoroethyl), methoxy, acetyl, -COCH 2 CH 3 、-COCH 2 OH, -COCH 2 CN, -CH 2 CON(CH 3 ) 2 , oxadiazine (e.g., ) or morpholinyl (e.g., morpholin-4-yl); More preferably, optionally R c1 Replaced by R C Selected from the following groups:

14. The use according to any one of claims 10 to 13, It is characterized in that Every R 4 are independently selected from cyano, halogen, amino, C 1-4 Alkyl or C 1-4 haloalkyl, wherein the C 1-4 Alkyl and C 1-4 The haloalkyl groups are optionally substituted with one or more hydroxyl groups; w is 1 or 2; Further preferably, each R 4 Each is independently selected from cyano, fluorine, amino, methyl, trifluoromethyl, difluoromethyl, monofluoromethyl, -CF 2 CH 2 OH, -CF 2 C(CH 3 ) 2 OH, -CF 2 CH 3 or -CH 2 CHF 2 ; w is 1 or 2.

15. The use according to any one of claims 10 to 14, It is characterized in that The compound has a structure as shown in formula (E): The substituents in formula (E) are as defined in formula (D).

16. Use of a compound or its stereoisomer, optical isomer, pharmaceutically acceptable salt, prodrug, solvate or isotope derivative or a pharmaceutical composition in the preparation of a drug for preventing and / or treating tumors or cancer, wherein the compound is selected from compounds having the following structure: The pharmaceutical composition comprises the compound or its stereoisomer, optical isomer, pharmaceutically acceptable salt, prodrug, solvate or isotopic derivative; Preferably, the compound is selected from compounds having the following structures:

17. The use according to any one of claims 1 to 16, It is characterized in that The pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

18. The use according to any one of claims 1 to 17, It is characterized in that The tumor or cancer is pancreatic cancer, colorectal cancer or bladder cancer (such as bladder transitional cell carcinoma).

19. The use according to any one of claims 1 to 17, It is characterized in that The tumor or cancer is pancreatic cancer, colorectal cancer or bladder cancer (such as bladder transitional cell carcinoma) caused by RAS mutation; Preferably, the tumor or cancer is lung cancer (such as non-small cell lung cancer), pancreatic cancer, colorectal cancer or bladder cancer (such as bladder transitional cell carcinoma) caused by KRAS mutation, and the lung cancer (such as non-small cell lung cancer) is lung cancer (non-small cell lung cancer) caused by non-KRAS G12C mutation; More preferably, the tumor or cancer is a tumor or cancer caused by KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12S or KRAS G13D mutation; Further preferably, the tumor or cancer is lung cancer (such as non-small cell lung cancer), pancreatic cancer, colorectal cancer or bladder cancer (such as bladder transitional cell carcinoma) caused by KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12S or KRAS G13D mutations, and the lung cancer (such as non-small cell lung cancer) is lung cancer (non-small cell lung cancer) caused by non-KRAS G12C mutations; More preferably, the tumor or cancer is pancreatic cancer caused by KRAS G12C mutation, bladder cancer (such as bladder transitional cell carcinoma) caused by KRAS G12C mutation, colorectal cancer caused by KRAS G12D mutation, lung cancer (such as non-small cell lung cancer) caused by KRAS G12V mutation, lung cancer (such as non-small cell lung cancer) caused by KRAS G12S mutation or colorectal cancer caused by KRAS G13D mutation.

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