Application of heterocyclic antitumor compound

Abstract

The invention relates to the technical field of medicines, and provides a compound, and application of a stereoisomer, an optical isomer, a medicinal salt, a prodrug, a solvate (e.g., a hydrate) or an isotope derivative of the compound in preparation of medicines for treating tumors or cancers. The compound provided by the invention has a tri-heterocyclic structure (such as a structure as shown in formula (A)), is novel in structure, and provides a new direction for the development of SOS1 inhibitor drugs. # imgabs0 #

Description

Technical Field

[0001] 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

[0002] 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). RAS family proteins are a class of small molecule GTPases and are also the first oncogenes identified in human tumors. RAS family proteins have weak intrinsic GTPase activity and slow nucleotide exchange rate. The binding of GTPase activating proteins (GAPs) such as NF1 increases the GTPase activity of RAS family proteins.

[0003] Mutations in RAS enzymes are closely related to tumorigenesis, and the types of RAS mutations are different in different types of tumors. In human tumors, KRAS mutations (e.g., amino acids G12, G13, Q61, A146) are the most common, accounting for about 85%, while NRAS (e.g., amino acids G12, G13, Q61, A146) and HRAS (e.g., amino acids G12, G13, Q61) account for 12% and 3%, respectively. Changes in RAS family proteins (e.g., mutations, overexpression, gene amplification) have also been described as resistance mechanisms to cancer drugs such as the EGFR antibodies cetuximab and panitumumab and the EGFR tyrosine kinase inhibitor osimertinib. For oncogenic RAS mutants, GAP activity is weakened or greatly reduced, resulting in permanent activation, which is the basis of oncogenic RAS signaling. Direct inhibition of RAS has proven to be extremely challenging and elusive to drug due to the picomolar affinity of GTP for its binding site, the lack of other well-defined pockets, and the fact that RAS interacts with GEFs, GAPs, and effectors through extended and flat protein-protein interactions. Therefore, there may be new hope for inhibiting RAS activation by targeting the upstream guanine nucleotide exchange factor protein SOS.

[0004] There are two human isoforms of SOS, SOS1 and SOS2, but most studies have focused on SOS1. Human SOS1 consists of 1333 amino acids (15 kDa), which include 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 and a Cdc25 domain, as well as a C-terminal region. Among them, PH, Rem and Cdc25 are SOS cat Components of the core catalytic domain.

[0005] In the past few decades, RAS family protein-SOS1 protein interactions have gained increasing recognition. In addition, recently, studies have 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.

[0006] 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, it is still urgently needed to develop new compounds with potential for marketing and better efficacy and pharmacokinetic results. Summary of the invention

[0007] Specifically, in another aspect of the present invention, there is provided a compound as shown in the following formula (A), and its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates or isotope derivatives for use in the preparation of drugs for treating tumors or cancers.

[0008]

[0009] in, represents a single bond or a double bond;

[0010] Y and Z are both selected from C or N, when Y is N, Z is C, when Y is C, Z is N;

[0011] Y and Z and the atoms to which they are attached together form a ring A, wherein the ring A is selected from a 5-12 membered heterocyclyl or a 5-12 membered heteroaryl;

[0012] R 2 is 1, 2 or 3, 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, -C 1-6 Alkyl-NH(C 1-6Alkyl), -C 1-6 Alkyl-N(C 1-6 Alkyl)2, 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 1-6 Alkoxy, -C 1-6 Alkyl-NH(C 1-6 Alkyl), -C 1-6 Alkyl-N(C 1-6 Alkyl)2, 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 all optionally substituted with one or more cyano, hydroxyl or halogen;

[0013] 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;

[0014] Ring B is selected from C 4-12 Cycloalkyl, C 4-12 Cycloalkenyl, 4-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, C 6-12 Aryl C 4-12 Cycloalkyl, C 6-12 Aryl 4-12 membered heterocyclic group or C 6-12 Aryl C 4-12 Cycloalkenyl;

[0015] 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 1-6Alkyl)(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, hydroxy, amino, -SO2-C 1-4 Alkyl or oxo; w is 0, 1, 2, 3 or 4;

[0016] when When it is a double bond, X is selected from C, and R connected to it 1 Select from -OR A 、-N(R D )R B or R C ;

[0017] 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;

[0018] 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 1-6Alkyl, -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;

[0019] 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;

[0020] 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, -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;

[0021] R D is selected from hydrogen, halogen, hydroxy, cyano, amino, nitro, oxo, formyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, -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;

[0022] 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;

[0023] 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, -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, 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, -COC3-6 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 with one or more selected from deuterium, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Alkoxy or halogen substituents;

[0024] when When it is a single bond, X is selected from N, and R connected to it 1 Selected from C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, C 6-10 aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl, wherein the C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl are each optionally substituted by one or more identical or different R a4 and / or R b4 replace;

[0025] If present, each R a4 Each independently 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 one or more identical or different R b4 and / or R c4 replace;

[0026] If present, each R b4 Each independently selected from -OR c4 、-NR c4 R c4 , halogen, -CN, -C(O)R c4 、-C(O)OR c4 、-C(O)NR c4 Rc4 、-OC(O)R c4 、-S(O)2R c4 、-S(O)2NR c4 R c4 、-NHC(O)R c4 、-N(C 1-4 alkyl)C(O)R c4 、-NHC(O)OR c4 or a divalent substituent =O or =NH, whereby =O and =NH may be substituents only in non-aromatic ring systems;

[0027] If present, each R c4 are each independently selected from hydrogen, 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 one or more identical or different R d4 and / or R e4 replace;

[0028] If present, each R d4 Each independently selected from -OR e4 、-NR e4 R e4 , halogen, -CN, -C(O)R e4 、-C(O)OR e4 、-C(O)NR e4 R e4 、-S(O)2R e4 、-S(O)2NR e4 R e4 、-NHC(O)R e4 、-N(C 1-4 alkyl)C(O)R e4 or a divalent substituent =O, where =O may be the only substituent in a non-aromatic ring system;

[0029] If present, each R e4 are each independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10aryl, 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 all optionally substituted with one or more hydrogen, cyano, hydroxyl or halogen;

[0030] Here, Z and Y are included in the atoms or atomic number of ring A.

[0031] 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.

[0032] Preferably, the present invention provides a compound, and use of its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates or isotopic derivatives in the preparation of a drug for treating tumors or cancer, which has a structure as shown in formula (A'):

[0033]

[0034] The substituents in formula (A') are as defined in formula (A).

[0035] The present invention also provides a compound represented by the following formula (I), and use of its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs or solvates in the preparation of drugs for treating tumors or cancers:

[0036]

[0037] in, represents a single bond or a double bond;

[0038] Y and Z are both selected from C or N, when Y is N, Z is C, when Y is C, Z is N;

[0039] Y and Z and the atoms to which they are attached together form a ring A, wherein the ring A is selected from a 5-12 membered heterocyclyl or a 5-12 membered heteroaryl;

[0040] R 2 is 1, 2 or 3, 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, -C 1-6 Alkyl-NH(C 1-6 Alkyl), -C 1-6 Alkyl-N(C 1-6 Alkyl)2, C 2-6 Alkenyl, C 2-6 Alkynyl, C3-10 Cycloalkyl, C 6-10 aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-6 Alkyl-NH(C 1-6 Alkyl), -C 1-6 Alkyl-N(C 1-6 Alkyl)2, 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 all optionally substituted with one or more cyano, hydroxyl or halogen;

[0041] 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;

[0042] 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;

[0043] 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, C3-6 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, hydroxy, amino, -SO2-C 1-4 Alkyl or oxo; w is 0, 1, 2, 3 or 4;

[0044] when When it is a double bond, X is selected from C, and R connected to it 1 Select from -OR A 、-N(R D )R B or R C ;

[0045] 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;

[0046] 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, -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;

[0047] 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;

[0048] 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, -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;

[0049] 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, -COC1-6 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;

[0050] 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 1-3 identical or different R c1 replace;

[0051] If present, each R c1 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, -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, 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, -CH2COC 1-6 Alkyl, -CH2CON(C 1-6 Alkyl)2, -CH2CONHC 1-6 Alkyl, -NHC1-6 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 hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy or halogen substituents;

[0052] when When it is a single bond, X is selected from N, and R connected to it 1 Selected from C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, C 6-10 aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl, wherein the C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl are each optionally substituted by one or more identical or different R a4 and / or R b4 replace;

[0053] If present, each R a4 Each independently 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 one or more identical or different R b4 and / or R c4 replace;

[0054] If present, each R b4 Each independently selected from -OR c4 、-NR c4 R c4 , halogen, -CN, -C(O)R c4 、-C(O)OR c4 、-C(O)NR c4 R c4 、-OC(O)R c4 、-S(O)2R c4 、-S(O)2NR c4 R c4 、-NHC(O)Rc4 、-N(C 1-4 alkyl)C(O)R c4 、-NHC(O)OR c4 or a divalent substituent =O or =NH, whereby =O and =NH may be substituents only in non-aromatic ring systems;

[0055] If present, each R c4 are each independently selected from hydrogen, 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 one or more identical or different R d4 and / or R e4 replace;

[0056] If present, each R d4 Each independently selected from -OR e4 、-NR e4 R e4 , halogen, -CN, -C(O)R e4 、-C(O)OR e4 、-C(O)NR e4 R e4 、-S(O)2R e4 、-S(O)2NR e4 R e4 、-NHC(O)R e4 、-N(C 1-4 alkyl)C(O)R e4 or a divalent substituent =O, where =O may be the only substituent in a non-aromatic ring system;

[0057] If present, each R e4 are each independently selected from hydrogen, 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 6-10Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl are all optionally substituted with one or more hydrogen, cyano, hydroxyl or halogen;

[0058] Here, Z and Y are included in the atoms or atomic number of ring A.

[0059] 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.

[0060] Preferably, the present invention provides a compound, and the use of its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs or solvates in the preparation of a drug for treating tumors or cancer, which has a structure as shown in formula (II):

[0061]

[0062] The substituents in formula (II) are as defined in formula (I).

[0063] Preferably, the present invention provides a compound, and the use of its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs or solvates in the preparation of a drug for treating tumors or cancer, which has a structure as shown in formula (III):

[0064]

[0065] The substituents in formula (III) are as defined in formula (I).

[0066] Preferably, the present invention provides a compound, and the use of its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs or solvates in the preparation of a drug for treating tumors or cancer, which has a structure as shown in formula (IV):

[0067]

[0068] The substituents in formula (IV) are as defined in formula (I).

[0069] In a preferred embodiment of the present invention, is a double bond, X is selected from C, and R connected thereto 1 For-OR A .

[0070] Preferably, 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 6-10Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl are each optionally substituted by 1-3 identical or different R a1 replace;

[0071] 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, -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.

[0072] 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;

[0073] 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.

[0074] 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;

[0075] 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.

[0076] More preferably, R Ais 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;

[0077] If present, each R a1 Each is independently selected from halogen, oxo, formyl, acetyl, methyl, ethyl, n-propyl, isopropyl or methoxy.

[0078] 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;

[0079] If present, each R a1 Each is independently selected from halogen, oxo, formyl, acetyl, methyl, ethyl, n-propyl, isopropyl or methoxy.

[0080] 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;

[0081] If present, each R a1 Each is independently selected from halogen, oxo, formyl, acetyl, methyl, ethyl, n-propyl, isopropyl or methoxy.

[0082] More preferably, R A Selected from the following groups:

[0083] In a preferred embodiment of the present invention, is a double bond, X is selected from C, and R connected thereto 1 -N(R D )R B .

[0084] Preferably, 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 6-10Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl are each optionally substituted by 1-3 identical or different R b1 replace;

[0085] 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.

[0086] 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;

[0087] 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.

[0088] 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;

[0089] 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.

[0090] 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 each optionally substituted by 1-2 identical or different R b1 replace;

[0091] If present, each R b1 Each is independently selected from oxo, formyl, acetyl, methyl, ethyl, methoxy or ethoxy.

[0092] More preferably, R B Selected from the following groups:

[0093] Preferably, 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 Selected from hydrogen.

[0094] In a preferred embodiment of the present invention, is a double bond, X is selected from C, and R connected thereto 1 For R C .

[0095] Preferably, R C 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 c1 replace;

[0096] If present, each R c1 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, -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, C2-6 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 The cycloalkyl and 3-10 membered heterocyclic groups are optionally substituted with one or more selected from hydroxyl, C 1-3 Alkyl, C 1-3 The substituent is substituted with alkoxy or halogen.

[0097] More preferably, R C Selected from C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl are each optionally substituted by 1-3 identical or different R c1 replace;

[0098] If present, each R c1 are independently selected from halogen, hydroxy, cyano, amino, nitro, oxo, formyl, C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -COC 1-4 Alkyl, -CH2CON(C 1-4 Alkyl)2, -CH2CONHC 1-4 alkyl or 3-6 membered heterocyclic group, wherein the C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -COC 1-4 Alkyl, -CH2CON(C 1-4 Alkyl)2, -CH2CONHC 1-4 The alkyl group and the 3-6 membered heterocyclyl group are both optionally substituted with one or more substituents selected from hydroxy, methyl, methoxy or halogen.

[0099] 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 1-3 identical or different R c1 replace;

[0100] If present, each R c1 Each is independently selected from halogen, hydroxy, cyano, amino, oxo, formyl, C 1-4 Alkyl, -OC 1-4 Alkyl, -COC 1-4 Alkyl, -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, -CH2CON(C 1-4 The 2- and 3-6-membered heterocyclyl groups are each optionally substituted by one or more substituents selected from hydroxy, methyl, methoxy or halogen.

[0101] 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 or a 5-6 membered monocyclic heteroaryl group, wherein the 5-6 membered monocyclic heterocyclic group, the 6-10 membered spiro heterocyclic group, the 6-8 membered bridged heterocyclic group and the 5-6 membered monocyclic heteroaryl group are optionally substituted by 1-3 identical or different R c1 replace;

[0102] If present, each R c1 Each is independently selected from halogen, hydroxyl, cyano, amino, oxo, formyl, acetyl, propionyl, methoxy, ethoxy, methyl, ethyl, n-propyl, isopropyl, -CH2CON(CH3)2 or 6-membered heterocyclyl, wherein the acetyl, propionyl, methoxy, ethoxy, methyl, ethyl, n-propyl, isopropyl, -CH2CON(CH3)2 and 6-membered heterocyclyl are optionally substituted with one or more substituents selected from hydroxyl, methyl, methoxy or halogen.

[0103] More preferably, R C is selected from 6-membered monocyclic heterocyclic radical, 4 / 6-spiro heterocyclic radical, 4 / 4-spiro heterocyclic radical, 7-membered bridged heterocyclic radical or 6-membered monocyclic heteroaryl, wherein the 6-membered monocyclic heterocyclic radical, 4 / 6-spiro heterocyclic radical, 4 / 4-spiro heterocyclic radical, 7-membered bridged heterocyclic radical and 6-membered monocyclic heteroaryl are optionally substituted by 1-3 identical or different R c1 replace;

[0104] If present, each R c1 Each is independently selected from halogen, hydroxy, cyano, amino, oxo, formyl, acetyl, -COCH2CH3, -COCH2OH, hydroxymethyl, hydroxyethyl, -CH2OCH3, methoxy, ethoxy, methyl, ethyl, n-propyl, isopropyl, -CH2CON(CH3)2 or a 6-membered heterocyclyl.

[0105] More preferably, RC Selected from

[0106] The R C are optionally replaced by 1-2 identical or different R c1 replace;

[0107] If present, each R c1 Each is independently selected from F, Cl, Br, hydroxy, cyano, amino, oxo, acetyl, -COCH2CH3, -COCH2OH, hydroxymethyl, hydroxyethyl, -CH2OCH3, methoxy, methyl, ethyl, isopropyl, -CH2CON(CH3)2 or morpholinyl.

[0108] More preferably, optionally R c1 Replaced by R C Selected from the following groups:

[0109]

[0110] In a preferred embodiment of the present invention, Ring A is selected from a 5-10 membered heterocyclyl or a 5-10 membered heteroaryl, wherein the heteroatoms in the 5-10 membered heterocyclyl and the 5-10 membered heteroaryl are each independently selected from O or N, and the number of heteroatoms is 1-4.

[0111] Further preferably, Ring A is selected from a 5-membered monocyclic heterocyclic group, a 6-membered monocyclic heterocyclic group, a 5-membered monocyclic heteroaryl, a 6-membered monocyclic heteroaryl, a 5 / 5-membered fused heterocyclic group, a 5 / 4-membered fused heterocyclic group, a 5 / 6-membered fused heterocyclic group, a 6 / 5-membered fused heterocyclic group, a 6 / 4-membered fused heterocyclic group, a 6 / 6-membered fused heterocyclic group, a 5 / 3-membered spiro heterocyclic group, a 5 / 5-membered spiro heterocyclic group, a 5 / 4-membered spiro heterocyclic group, a 5 / 6-membered spiro heterocyclic group, a 6 / 3-membered spiro heterocyclic group, a 6 / 5-membered spiro heterocyclic group, a 6 / 4-membered spiro heterocyclic group or a 6 / 6-membered spiro heterocyclic group, wherein the 5-membered monocyclic heterocyclic group The heteroatoms in the heterocyclyl, 6-membered monocyclic heterocyclyl, 5-membered monocyclic heteroaryl, 6-membered monocyclic heteroaryl, 5 / 5-membered fused heterocyclyl, 5 / 4-membered fused heterocyclyl, 5 / 6-membered fused heterocyclyl, 6 / 5-membered fused heterocyclyl, 6 / 4-membered fused heterocyclyl, 6 / 6-membered fused heterocyclyl, 5 / 3-membered spiro heterocyclyl, 5 / 5-membered spiro heterocyclyl, 5 / 4-membered spiro heterocyclyl, 5 / 6-membered spiro heterocyclyl, 6 / 3-membered spiro heterocyclyl, 6 / 5-membered spiro heterocyclyl, 6 / 4-membered spiro heterocyclyl and 6 / 6-membered spiro heterocyclyl are each independently selected from N, and the number of heteroatoms is 1-4.

[0112] Further preferably, Ring A is selected from a 5-membered monocyclic heterocyclyl, a 6-membered monocyclic heterocyclyl, a 5-membered monocyclic heteroaryl, a 6-membered monocyclic heteroaryl, a 5 / 5-membered fused heterocyclyl, a 5 / 6-membered fused heterocyclyl or a 5 / 3-membered spiro heterocyclyl, wherein the heteroatoms in the 5-membered monocyclic heterocyclyl, the 6-membered monocyclic heterocyclyl, the 5-membered monocyclic heteroaryl, the 6-membered monocyclic heteroaryl, the 5 / 5-membered fused heterocyclyl, the 5 / 6-membered fused heterocyclyl and the 5 / 3-membered spiro heterocyclyl are each independently selected from N, and the number of heteroatoms is 1-3.

[0113] More preferably, ring A is selected from a 5-membered monocyclic heterocyclic group or a 5-membered monocyclic heteroaryl group, and the heteroatoms in the 5-membered monocyclic heterocyclic group and the 5-membered monocyclic heteroaryl group are selected from N, and the number of the heteroatoms is 1-3.

[0114] More preferably, ring A is selected from the following groups:

[0115] More preferably, ring A is selected from the following groups:

[0116] In a preferred embodiment of the present invention, R 2 is 1, 2 or 3, each of which, when present, is independently selected from hydrogen, halogen, hydroxy, cyano, amino, nitro, formyl, oxo, C 1-3 Alkyl, C 1-3 Alkoxy, -C 1-3 Alkyl-NH(C 1-3 Alkyl) or -C 1-3 Alkyl-N(C 1-3 alkyl)2, wherein the C 1-3 Alkyl, C 1-3 Alkoxy, -C 1-3 Alkyl-NH(C 1-3 Alkyl) and -C 1-3 Alkyl-N(C 1-3 alkyl)2 are optionally substituted by one or more hydroxyl groups or halogen;

[0117] More preferably, R 2 is 1, 2 or 3, each of which, when present, is independently selected from hydrogen, halogen, hydroxy, cyano, amino, nitro, formyl, oxo, methoxy, methyl, ethyl, n-propyl or isopropyl;

[0118] 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;

[0119] More preferably, R 2is 1 or 2, each of which, when present, is independently selected from hydrogen or methyl.

[0120] In a preferred embodiment of the present invention, R 3 Selected from hydrogen, halogen, hydroxyl, amino, cyano, C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 Cycloalkyl, wherein the C 1-4 Alkyl, C 1-4 Alkoxy and C 3-6 The cycloalkyl groups are optionally substituted with one or more hydroxyl groups or halogen groups;

[0121] More preferably, R 3 is selected from hydrogen, halogen, hydroxy, amino, cyano, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or methoxy;

[0122] More preferably, R 3 is selected from hydrogen, halogen, hydroxy, amino, cyano, methyl, ethyl, n-propyl, isopropyl or cyclopropyl;

[0123] More preferably, R 3 is selected from hydrogen, F, Cl, Br, amino, methyl, ethyl or cyclopropyl.

[0124] In a preferred embodiment of the present invention, ring B is selected from C 4-12 Cycloalkenyl, C 4-12 Heterocyclic group, C 6-12 Aryl, C 6-8 Aryl C 4-6 Cycloalkyl, C 6-8 Aryl C 4-6 Heterocyclic or C 5-12 Heteroaryl.

[0125] More preferably, ring B is selected from C 6-10 Aryl or C 5-10 Heteroaryl.

[0126] Further preferably, ring B is selected from phenyl or pyridyl.

[0127] In a preferred embodiment of the invention, 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, C1-4 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, hydroxy, amino, -SO2-C 1-4 alkyl or oxo; w is 0, 1, 2 or 3.

[0128] 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 groups are optionally substituted with one or more of the following substituents: halogen, hydroxyl or amino; w is 1, 2 or 3.

[0129] 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 by one or more of the following substituents: halogen or hydroxyl; w is 1, 2 or 3.

[0130] Further preferably, each R 4 Each is independently selected from hydrogen, halogen, amino, 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.

[0131] Further preferably, each R 4 Each is independently selected from hydrogen, halogen, amino, methyl, trifluoromethyl, difluoromethyl, monofluoromethyl, -CF2CH2OH, -C(CH3)2OH or -CF2CH3; w is 1, 2 or 3.

[0132] The present invention also provides a compound, and use of its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates or isotope derivatives in the preparation of drugs for treating tumors or cancers, which has a structure as shown in formula (B):

[0133]

[0134] Among them, R 1 Select from -OR A 、-N(R D )R B or R C ;

[0135] When R1 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;

[0136] 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, -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;

[0137] 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;

[0138] 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, -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;

[0139] 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, -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;

[0140] 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;

[0141] If present, each R c1are 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 1-6 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, 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 with one or more selected from deuterium, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Alkoxy or halogen substituents;

[0142] 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;

[0143] 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, C1-6 Alkoxy, C 3-6 Cycloalkyl and 3-6 membered heterocyclyl are both optionally substituted with one or more hydroxyl or halogen;

[0144] 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;

[0145] 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, hydroxy, amino, -SO2-C 1-4 Alkyl or oxo; w is 0, 1, 2, 3 or 4;

[0146] 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.

[0147] 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, 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;

[0148] 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, -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.

[0149] 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;

[0150] 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.

[0151] 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 Ra1 replace;

[0152] 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.

[0153] 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;

[0154] If present, each R a1 Each is independently selected from halogen, oxo, formyl, acetyl, methyl, ethyl, n-propyl, isopropyl or methoxy.

[0155] 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;

[0156] If present, each R a1 Each is independently selected from halogen, oxo, formyl, acetyl, methyl, ethyl, n-propyl, isopropyl or methoxy.

[0157] 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;

[0158] If present, each R a1 Each is independently selected from halogen, oxo, formyl, acetyl, methyl, ethyl, n-propyl, isopropyl or methoxy.

[0159] More preferably, R A Selected from the following groups:

[0160] In a preferred embodiment of the present invention, R 1 -N(R D )R B , R B Selected from C1-6 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;

[0161] 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.

[0162] 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;

[0163] 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.

[0164] 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;

[0165] 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.

[0166] More preferably, R Bis 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 each optionally substituted by 1-2 identical or different R b1 replace;

[0167] If present, each R b1 Each is independently selected from oxo, formyl, acetyl, methyl, ethyl, methoxy or ethoxy.

[0168] More preferably, R B Selected from the following groups:

[0169] 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 Selected from hydrogen.

[0170] In a preferred embodiment of the present invention, 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;

[0171] 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, -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 3-10Cycloalkyl 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, -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 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 The substituent is substituted with alkoxy or halogen.

[0172] 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;

[0173] 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, -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 selected from deuterium, hydroxyl, cyano, C 1-3 Alkyl, C1-3 The substituent is substituted with alkoxy or halogen.

[0174] 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;

[0175] 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, -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.

[0176] 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;

[0177] If present, each R c1 Each is independently selected from halogen, hydroxyl, 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, hydroxyl, cyano, methyl, methoxy or halogen.

[0178] More preferably, R Cis 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;

[0179] If present, each R c1 Each is independently selected from halogen, hydroxyl, 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, hydroxyl, cyano, methyl, methoxy or halogen.

[0180] More preferably, R C Selected from

[0181] The R C are optionally replaced by 1-4 identical or different R c1 replace;

[0182] If present, each R c1 Each is independently selected from F, Cl, Br, hydroxyl, cyano, amino, oxo, mesyl, 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.

[0183] More preferably, optionally R c1 Replaced by R C Selected from the following groups:

[0184]

[0185] In a preferred embodiment of the present invention, R 2is 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.

[0186] 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.

[0187] More preferably, R 2 is 1 or 2, each of which, when present, is independently selected from hydrogen or methyl.

[0188] More preferably, R 2 For hydrogen.

[0189] 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.

[0190] More preferably, R 3 is selected from hydrogen, halogen, hydroxy, amino, cyano, methyl, ethyl, n-propyl, isopropyl or cyclopropyl.

[0191] More preferably, R 3 is selected from hydrogen, F, Cl, Br, amino, methyl, ethyl or cyclopropyl.

[0192] 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 is a 4-6 membered heterocyclic group or a 5-12 membered heteroaryl group.

[0193] 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.

[0194] More preferably, ring B is selected from phenyl, pyridyl or benzotetrahydrofuranyl.

[0195] In a preferred embodiment of the invention, 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 3-6A 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, hydroxy, amino, -SO2-C 1-4 alkyl or oxo; w is 0, 1, 2 or 3.

[0196] 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 groups are optionally substituted with one or more of the following substituents: halogen, hydroxyl or amino; w is 1, 2 or 3.

[0197] 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 by one or more of the following substituents: halogen or hydroxyl; w is 1, 2 or 3.

[0198] 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 by one or more of the following substituents: halogen or hydroxy; w is 1, 2 or 3.

[0199] Further 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.

[0200] The present invention provides a compound, and use of its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates or isotope derivatives in the preparation of drugs for treating tumors or cancers, which has a structure as shown in formula (C):

[0201]

[0202] The substituents in formula (C) are as defined in formula (B).

[0203] The present invention also provides a compound, and use of its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates or isotope derivatives in the preparation of drugs for treating tumors or cancers, which has a structure as shown in formula (D):

[0204]

[0205] Among them, R 1 , R 4 , w are defined as described in formula (A), (A'), (I), (II), (III), (IV), (B) or (C).

[0206] Preferably, if present, 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;

[0207] R 1 Select from -OR A 、-N(R D )R B or R C ;

[0208] 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;

[0209] If present, each R a1 Each independently selected from C 1-6 Alkyl or -COC 1-6 alkyl;

[0210] 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;

[0211] If present, each R b1 Each independently selected from -OC 1-6 alkyl;

[0212] R D Selected from hydrogen;

[0213] 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;

[0214] 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, -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 with one or more selected from deuterium, hydroxyl, cyano, C 1-3 The substituent is substituted with alkoxy or halogen.

[0215] 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.

[0216] 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;

[0217] If present, each R a1 Each independently selected from C 1-6 Alkyl or -COC 1-6 alkyl.

[0218] 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;

[0219] If present, each R a1 Each is independently selected from acetyl, methyl, ethyl, n-propyl or isopropyl.

[0220] 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;

[0221] If present, each R a1 Each is independently selected from acetyl, methyl or ethyl.

[0222] 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;

[0223] If present, each R a1 Each is independently selected from acetyl, methyl or ethyl.

[0224] More preferably, R A Selected from the following groups:

[0225] In a preferred embodiment of the present invention, 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;

[0226] If present, each R b1 Each independently selected from -OC 1-4 alkyl.

[0227] 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 each optionally substituted by 1-2 identical or different R b1 replace;

[0228] If present, each Rb1 Each is independently selected from methoxy or ethoxy.

[0229] More preferably, R B Selected from the following groups:

[0230] In a preferred embodiment of the present invention, 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;

[0231] 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, -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 by one or more substituents selected from deuterium, hydroxy, cyano, methoxy or halogen.

[0232] 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;

[0233] If present, each R c1Each is independently selected from halogen, hydroxyl, 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, hydroxyl, cyano, methoxy, or halogen.

[0234] 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;

[0235] If present, each R c1 Each is independently selected from halogen, hydroxyl, 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, hydroxyl, cyano, methoxy or halogen.

[0236] More preferably, R C Selected from The R C are optionally replaced by 1-4 identical or different R c1 replace;

[0237] If present, each R c1Each is independently selected from F, Cl, Br, hydroxyl, cyano, amino, methanesulfonyl, methyl, ethyl, isopropyl, CD3, hydroxymethyl, hydroxyethyl (e.g., 2-hydroxyethyl), -CH(OH)(CH3)2, -CH2OCH3, -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).

[0238] More preferably, optionally R c1 Replaced by R C Selected from the following groups:

[0239]

[0240]

[0241] In a preferred embodiment of the invention, if present, each 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 each optionally substituted with one or more hydroxy groups; w is 1 or 2.

[0242] Further preferably, each R 4 Each is independently selected from cyano, fluorine, amino, methyl, trifluoromethyl, difluoromethyl, monofluoromethyl, -CF2CH2OH, -CF2C(CH3)2OH, -CF2CH3 or -CH2CHF2; w is 1 or 2.

[0243] The present invention provides a compound, and use of its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates or isotope derivatives in the preparation of drugs for treating tumors or cancers, which has a structure as shown in formula (E):

[0244]

[0245] The substituents in formula (E) are as defined in formula (D).

[0246] The present invention also provides a compound, and use of its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates or isotope derivatives in the preparation of drugs for treating tumors or cancers, which has a structure as shown in formula (F) or formula (F'):

[0247]

[0248] Among them, R c1 , R 4 , w is defined as in formula (D) or (E); v is 0 or 1, when v is 1, preferably R c1 Connected to the N atom.

[0249] 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 oxadiinyl (e.g., ).

[0250] More preferably, Selected from the following groups:

[0251] The present invention provides a compound, and use of its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates or isotope derivatives in the preparation of drugs for treating tumors or cancers, which has a structure as shown in formula (G) or formula (G'):

[0252]

[0253] Among them, R c1 , R 4 , w is defined as in formula (D) or (E); v is 0 or 1, when v is 1, preferably R c1 Connected to the N atom.

[0254] Preferably, R c1 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.

[0255] More preferably, Selected from the following groups:

[0256] Preferably, the present invention provides a compound, and use of its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates or isotopic derivatives in the preparation of a drug for treating tumors or cancer, which has the following structure:

[0257]

[0258]

[0259]

[0260]

[0261]

[0262]

[0263] Preferably, the present invention provides a compound, and use of its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates or isotopic derivatives in the preparation of a drug for treating tumors or cancer, which has the following structure:

[0264]

[0265]

[0266]

[0267]

[0268]

[0269]

[0270] The present invention also provides a use of a pharmaceutical composition in preparing a drug for treating tumors or cancers, wherein the pharmaceutical composition comprises the compound of the present invention, and its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates or isotope derivatives.

[0271] The present invention also provides a use of a pharmaceutical composition in the preparation of a drug for treating tumors or cancers, wherein the pharmaceutical composition comprises the compound of the present invention, and its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates or isotope derivatives, and pharmaceutically acceptable excipients.

[0272] In a preferred embodiment of the present invention, the aforementioned tumor or cancer is pancreatic cancer, colorectal cancer, bladder cancer (such as bladder transitional cell carcinoma).

[0273] In a preferred embodiment of the present invention, the tumor or cancer is a tumor or cancer with a RAS mutation; preferably, the tumor or cancer with a RAS mutation is pancreatic cancer, colorectal cancer, bladder cancer (such as bladder transitional cell carcinoma).

[0274] In a preferred embodiment of the present invention, the tumor or cancer is a KRAS mutated tumor or cancer; preferably, the KRAS mutated tumor or cancer is lung cancer (such as non-small cell lung cancer), pancreatic cancer, colorectal cancer, bladder cancer (such as bladder transitional cell carcinoma), and the lung cancer (such as non-small cell lung cancer) is non-KRAS G12C mutated lung cancer (non-small cell lung cancer).

[0275] In a preferred embodiment of the present invention, the tumor or cancer is a tumor or cancer with KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12V, KRAS G12S, or KRAS G13D mutations; preferably, the tumor or cancer with KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12V, KRAS G12S, or KRAS G13D mutations 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 non-KRAS G12C mutations; more preferably, the tumor or cancer is pancreatic cancer with KRAS G12C mutations, bladder cancer (such as bladder transitional cell carcinoma) with KRAS G12C mutations, Colorectal cancer with KRAS G12D mutation, lung cancer with KRAS G12V mutation (such as non-small cell lung cancer), lung cancer with KRAS G12S mutation (such as non-small cell lung cancer), and colorectal cancer with KRAS G13D mutation.

[0276] In another aspect of the present invention, a method for treating pancreatic cancer, colorectal cancer, and bladder cancer (such as bladder transitional cell carcinoma) is provided, comprising administering to the individual a therapeutically effective amount of the compound as described above, and its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates or isotope derivatives.

[0277] In another aspect of the present invention, a method for treating a tumor or cancer with a RAS mutation is provided; preferably, the tumor or cancer with a RAS mutation is pancreatic cancer, colorectal cancer, or bladder cancer (such as bladder transitional cell carcinoma).

[0278] In another aspect of the present invention, a method for treating a KRAS mutated tumor or cancer is provided, comprising administering to the individual a therapeutically effective amount of the compound as described above, and its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates or isotope derivatives, wherein the KRAS mutated tumor or cancer is lung cancer (such as non-small cell lung cancer), pancreatic cancer, colorectal cancer, 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.

[0279] In another aspect of the present invention, there is provided a method for treating a tumor or cancer with KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12S, or KRAS G13D mutations, comprising administering to the individual a therapeutically effective amount of the compound represented by formula (A), and its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates, or isotopic derivatives; preferably, the tumor disease with KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12S, or KRAS G13D mutations 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; more preferably, the tumor or cancer is pancreatic cancer with a KRAS G12C mutation, bladder cancer (such as bladder transitional cell carcinoma) with a KRAS G12C mutation, or KRAS Colorectal cancer with KRAS G12D mutation, lung cancer with KRAS G12V mutation (such as non-small cell lung cancer), lung cancer with KRAS G12S mutation (such as non-small cell lung cancer), colorectal cancer with KRAS G13D mutation.

[0280] The beneficial effects of the present invention are as follows:

[0281] For the novel compounds designed by the present invention, in vitro enzyme inhibition tests have shown that these compounds 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 tests have shown that these compounds have significant inhibitory activity on 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, and have no proliferation activity on wild-type KRAS cells, with good selectivity. DETAILED DESCRIPTION

[0282] [Definition of terms]

[0283] The terms "optional", "optionally", "optionally" or "arbitrarily" 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.

[0284] Unless otherwise specified, the term "alkyl" refers to a linear or branched monovalent saturated aliphatic hydrocarbon group, usually containing 1 to 20 carbon atoms, preferably containing 1 to 10 carbon atoms (i.e., C 1-10 Alkyl), further preferably containing 1-8 carbon atoms (i.e. C 1-8 Alkyl), more preferably containing 1 to 6 carbon atoms (i.e. C 1-6 Alkyl), such as "C 1-6 The 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, etc.

[0285] Unless otherwise specified, the term "alkenyl" refers to a straight 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 (i.e. C 2-8 Alkenyl), more preferably containing 2 to 6 carbon atoms (i.e., C 2-6 alkenyl), such as "C 2-6 "Alkenyl" means that the group is 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, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl and 1,3-butadienyl, etc.

[0286] 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 to 8 carbon atoms (i.e. C 2-8 Alkynyl), more preferably containing 2 to 6 carbon atoms (i.e. 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, etc.

[0287] Unless otherwise specified, the term "cycloalkyl" refers to a monovalent aliphatic hydrocarbon group which is monocyclic or polycyclic (eg, fused, bridged or spiro) and which contains no unsaturated bonds and generally contains 3 to 12 carbon atoms (ie, C 3-12 cycloalkyl), more preferably containing 3 to 10 carbon atoms (i.e., C 3-10 Cycloalkyl), preferably 3-6 carbon atoms (i.e. C 3-6 Cycloalkyl), 4-6 carbon atoms (i.e. C 4-6 Cycloalkyl), 5-6 carbon atoms (i.e. C 5-6 Non-limiting examples of monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, 2-ethylcyclopentyl, and dimethylcyclobutyl. Non-limiting examples of fused-ring cycloalkyls include, but are not limited to, decahydronaphthyl, octahydroindenyl, octahydropentalenyl, and the like. Non-limiting examples of bridged-ring cycloalkyls include, but are not limited to, Non-limiting examples of spirocyclic cycloalkyls include, but are not limited to wait.

[0288] 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 (i.e., C 4-12 Cycloalkenyl), or 3-10 carbon atoms (i.e. C 3-10 Cycloalkenyl), preferably 3-6 carbon atoms (i.e. C 3-6 Cycloalkenyl), 4-6 carbon atoms (i.e. C 4-6 Cycloalkenyl), 5-6 carbon atoms (i.e. 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.

[0289] Unless otherwise specified, the term "alkoxy" refers to an "-O-alkyl" group, wherein the alkyl group is as defined above, i.e., contains 1-20 carbon atoms, preferably, contains 1-10 carbon atoms, more preferably 1-8 carbon atoms, more preferably 1-6 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.

[0290] 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 include CCl3, CF3, CHCl2, CH2Cl, CH2Br, CH2I, CH2CF3, CF2CF3, etc. Different expressions can be used for haloalkyl, for example, "C 1-6 "Haloalkyl" can also be expressed as "haloC 1-6 Alkyl". 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 "haloC 1-6 Alkoxy". The term "halocycloalkyl" means a cycloalkyl group as defined above in which one, two or more hydrogen atoms or all hydrogen atoms are replaced by halogen.

[0291] 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, usually 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 heteroatoms are 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, pyridone, etc. Polycyclic heterocyclic groups include spirocyclic, fused and bridged heterocyclic groups. Non-limiting examples of fused heterocyclic groups include, but are not limited to, decahydroquinolinyl, octahydroindolyl, etc. Non-limiting examples of bridged heterocyclic groups include, but are not limited to Non-limiting examples of spirocyclic heterocyclic groups include, but are not limited to wait.

[0292] Unless otherwise specified, the term "aryl" refers to a monovalent aromatic ring system of a monocyclic or polycyclic (e.g., fused ring) ring, 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, etc.

[0293] Unless otherwise specified, the term "heteroaryl" refers to a monocyclic or polycyclic (e.g., fused) monovalent aromatic ring system, usually containing 5-12 membered structures, or preferably 5-10 membered structures, 5-8 membered structures, more preferably 5-6 membered structures, wherein 1, 2, 3 or more ring atoms are heteroatoms and the remaining atoms are carbon, the heteroatoms are each 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, and the like.

[0294] Unless otherwise specified, the term "hydroxy" refers to a "-OH" group.

[0295] Unless otherwise specified, the term "cyano" refers to a "-CN" group.

[0296] 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 of the 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.

[0297] Unless otherwise specified, the term "nitro" refers to a "-NO2" group.

[0298] Unless otherwise specified, the term "formyl" or "aldehyde" refers to a "-C(=O)H" group.

[0299] Unless otherwise specified, the term "oxo" refers to a "=O" group attached to a carbon atom, and the term "oxidation" refers to a "=O" group attached to a heteroatom (eg, a sulfur atom).

[0300] Unless otherwise specified, the term "pharmaceutically acceptable salt", "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt" refers to salts that are suitable for use in contact with mammalian tissues, especially human tissues, without excessive toxicity, irritation, allergic response, etc., and 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.

[0301] 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. The physical association includes hydrogen bonding. In certain cases, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate will be capable of being separated. The solvent molecules in the solvate may exist in a regular arrangement and / or a disordered arrangement. The solvate may contain stoichiometric or non-stoichiometric amounts of solvent molecules. "Solvate" encompasses solution phase and separable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.

[0302] Unless otherwise specified, the compounds of the present invention also include their "isotopic derivatives" (such as deuterated compounds). The term "isotopic derivative" means that the compounds of the present invention may exist in an isotopically traced 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 amount of atoms found in nature. Isotopes may be radioactive or non-radioactive isotopes. Isotopes commonly used as isotope 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 isotope: 15 O. 17 O and 18 O; and sulfur isotopes: 35 S. These isotope-labeled compounds can be used to study the distribution of drug 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), the substitution can enhance metabolic stability, prolong half-life, thereby achieving the purpose of reducing dosage and providing therapeutic advantages. Isotope-labeled compounds generally start from labeled starting materials and use known synthesis techniques to complete their synthesis like non-isotope-labeled compounds.

[0303] 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 increased solubility in pharmaceutical compositions compared to the parent drug.

[0304] Unless otherwise specified, the term "optical isomers" refers to substances with exactly the same molecular structure, similar physical and chemical properties, but different optical rotations.

[0305] Unless otherwise specified, the term "stereoisomer" refers to compounds with the same chemical constitution but different arrangements of atoms or groups 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, diastereomers, for example, by chromatography and / or fractional crystallization based on the differences in the physical and chemical properties of the components.

[0306] Unless otherwise indicated, the structural formulas described in the present invention include all isomeric forms (such as enantiomers, diastereomers, and geometric isomers (or conformers)): for example, R, S configurations containing asymmetric centers, (Z), (E) isomers of double bonds, and (Z), (E) conformers. Therefore, single stereochemical isomers of the compounds of the present invention or mixtures of their enantiomers, diastereomers, or geometric isomers (or conformers) are all within the scope of the present invention.

[0307] 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, wherein the substituents are preferably selected from the following groups: halogen, hydroxyl, 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 The aryl group and the 5-10 membered heteroaromatic ring group can be optionally selected from halogen, hydroxyl, amino, cyano, C 1-6 Alkyl or C 1-6 The alkoxy group is substituted with one or more substituents.

[0308] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples that do not specify specific conditions are usually performed under conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise defined, all professional and scientific terms used in the text have the same meanings as those familiar to professionals in the field. In addition, any method and material similar or equivalent to the described content can be applied to the method of the present invention. The preferred implementation methods and materials shown in the text are for demonstration purposes only.

[0309] The structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) or / and liquid chromatography-mass spectrometry (LC-MS) or / and liquid chromatography (HPLC). The instrument used for NMR determination is Bruker AVANCE III 600MHz, the instrument used for LC-MS is WATERS ACQUITY UPLC H-Class PLUS or / and SQD2; the instrument used for HPLC is WATERSe2695_2998 or / and Agilent 1100.

[0310] 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.

[0311] Preparation Example 1: Synthesis of Intermediate A

[0312]

[0313] Synthesis of intermediate A-2

[0314] Dissolve 1-(3-nitro-5-trifluoromethyl-phenyl)-ethanone (10.00 g, 43.0 mmol) in ethanol (200 mL), then add iron powder (7.22 g, 129.0 mmol) and concentrated hydrochloric acid (50 mL), and react the system at 80°C for 2 h. LC-MS monitoring shows that there is no residue of the raw material, cool and filter, evaporate the filtrate under reduced pressure to remove the solvent, and separate and purify the residue by column chromatography (dichloromethane: methanol = 50: 1-20: 1) to obtain A-2 (8.12 g, 40.0 mmol, 92%). ESI-MS: m / z 204.12 [M+H]+ .

[0315] Synthesis of intermediate A-3

[0316] 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), and the system was reacted at 80 ° C for 2 h. LC-MS monitoring showed that there was no residual raw material. 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 the product A-3 (34.65 g, 113.1 mmol, 85%). ESI-MS: m / z 307.12 [M+H] + .

[0317] Synthesis of intermediate A-4

[0318] 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 temperature of the reaction system was slowly raised to room temperature, and LC-MS monitoring showed that there was no residual raw material. The reaction solution was quenched with ice water, 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] + .

[0319] Synthesis of Intermediate A

[0320] A-4 (28.43 g, 92.2 mmol) was dissolved in a hydrochloric acid dioxane solution (50 mL), and the system was reacted at room temperature for 2 h. LC-MS monitoring showed that there was no residual raw material. The solvent was evaporated under reduced pressure to obtain intermediate A, which was directly used for the next step of reaction in the form of hydrochloride. ESI-MS: m / z 205.22 [M+H] + .

[0321] The following intermediates can be obtained by referring to the synthesis method of intermediate A or the related synthesis method in CN110167928A.

[0322] If necessary, the crude product was purified by chromatography.

[0323]

[0324]

[0325] Example 1: Synthesis of Compound 1

[0326]

[0327] Synthesis of intermediate 1-1

[0328] 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 there was no residual raw material. 100 mL of water was added to the reaction solution, and ethyl acetate was extracted (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] + .

[0329] Synthesis of intermediate 1-2

[0330] 1-1 (5.03 g, 26.9 mmol) was dissolved in acetonitrile (80 mL), and then N-bromosuccinimide (7.17 g, 40.3 mmol) was added. The reaction was carried out at room temperature for 1.5 h, and LC-MS monitoring showed that there was no residual raw material. The reaction solution was quenched with ice water, 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: 3) to obtain 1-2 (6.85 g, yield 96%). ESI-MS: m / z 265.10 / 267.13 [M+H] + .

[0331] Synthesis of intermediate 1-3

[0332] 1-2 (6.85 g, 25.8 mmol) was dissolved in 80 mL of acetonitrile, and then 15 mL of methanesulfonic acid was added. The system was reacted at 130 ° C for 8 h. LC-MS monitoring showed that there was no residual raw material. The reaction solution was quenched with ice water, 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: 3) to obtain 1-3 (1.51 g, yield 21%). ESI-MS: m / z 274.02 / 275.98 [M+H] + .

[0333] Synthesis of intermediates 1-4

[0334] 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), and the system was reacted at 80°C for 2 h. LC-MS monitored that no raw material remained. 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] + .

[0335] Synthesis of intermediates 1-5

[0336] Dissolve 1-4 in 30 mL of chloroform, then add 10 mL of triethyl orthoformate, and react at 80 ° C for 2 h. LC-MS monitoring shows that there is no residual raw material. The reaction solution is quenched with ice water, extracted with ethyl acetate (100 mL × 3), the organic phases are combined, washed with saturated sodium chloride (100 mL × 2), and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, and the residue is separated and purified by column chromatography (petroleum ether: ethyl acetate = 5: 1-1: 3) to obtain 1-5 (1.00 g, two-step yield 65%). ESI-MS: m / z 280.00 / 282.02 [M+H] + .

[0337] Synthesis of intermediates 1-6

[0338] 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), and 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, 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] + .

[0339] Synthesis of intermediates 1-7

[0340] 1-6 (800 mg, 2.68 mmol) was dissolved in 30 mL N, N-dimethylformamide, followed by diisopropylethylamine (697 mg, 5.40 mmol) and intermediate B (612 mg, 3.24 mmol), and the system was reacted at 120 ° C for 2 h. LC-MS monitoring showed that there was no residual raw material. The reaction solution was quenched with ice water, 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] + .

[0341] Synthesis of intermediates 1-8

[0342] 1-7 (100 mg, 0.22 mmol) was dissolved in dioxane (40 mL) and water (10 mL), followed by the addition of potassium hydroxide (25 mg, 0.44 mmol), tris(dibenzylideneacetone)dipalladium (18 mg, 0.02 mmol), and 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (10 mg, 0.02 mmol). The whole system was stirred at 100°C for 3 h. TLC monitoring showed that there was no residual raw material. 50 mL of water was added to the reaction solution, and ethyl acetate was extracted (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. 1-8 (40 mg, yield 47%) was obtained by separation and purification by column chromatography (dichloromethane:methanol=60:1-20:1). ESI-MS: m / z 389.15[M+H] + .

[0343] Synthesis of compound 1

[0344] 1-8 (40 mg, 0.10 mmol) was dissolved in N,N-dimethylformamide (15 mL), and then (R)-3-hydroxytetrahydrofuran p-toluenesulfonate (30 mg, 0.12 mmol) and cesium carbonate (65 mg, 0.20 mmol) were added. The whole system was stirred at 80°C for 3 h. TLC monitoring showed that there was no residual raw material. 30 mL of water was added to the reaction solution, and ethyl acetate was extracted (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 compound 1 (30 mg, yield 65%) was obtained by column chromatography separation and purification (dichloromethane: methanol = 60:1-20:1). ESI-MS: m / z 459.25 [M+H] + . 1HNMR (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),5.71-5.6 4(m,1H),5.47-5.45(m,1H),4.05-4.03(m,1H),3.98-3.94(m,2H),3.8 8-3.84(m,1H),2.46(s,3H),2.42-2.37(m,2H),1.66(d,J=7.2Hz,3H).

[0345] Example 2: Synthesis of Compound 2

[0346]

[0347] Synthesis of intermediate 2-1

[0348] 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 whole system was stirred at 100 ° C for 3 h. TLC monitoring showed that there was no residual raw material. 50 mL of water was added to the reaction solution, and ethyl acetate was extracted (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 obtain 2-1 (100 mg, yield 82%). ESI-MS: m / z 554.19 [M+H] + .

[0349] Synthesis of intermediate 2-2

[0350] 2-1 (100 mg, 0.18 mmol) was dissolved in 4M hydrochloric acid ethyl acetate solution (10 mL), stirred at room temperature for 2 h, and TLC monitoring showed that no raw 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] + .

[0351] Synthesis of compound 2

[0352] Dissolve 2-2 in dichloromethane (10 mL), then add triethylamine (36 mg, 0.36 mmol) and acetic anhydride (22 mg, 0.22 mmol), stir at room temperature for 2 h, TLC monitoring shows that there is no residual raw material, add water to the reaction solution to quench, extract with ethyl acetate (30 mL×3), combine the organic phases, wash with saturated sodium chloride (50 mL×2), dry with anhydrous sodium sulfate, remove the solvent under reduced pressure, separate and purify by column chromatography (dichloromethane: methanol = 60:1-15:1), and 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).

[0353] Example 3: Synthesis of Compound 3

[0354]

[0355] 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), sodium tert-butoxide (42 mg, 0.44 mmol), and the whole system was stirred at 120°C for 3 h. TLC monitoring showed that there was no residual raw material. 50 mL of water was added to the reaction solution, and ethyl acetate was extracted (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 compound was separated and purified by column chromatography (dichloromethane:methanol=60:1-20:1) to obtain compound 3 (41 mg, yield 40%). 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).

[0356] Example 4: Synthesis of Compound 4

[0357]

[0358] 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), sodium tert-butoxide (42 mg, 0.44 mmol), and the whole system was stirred at 120°C for 3 h. TLC monitoring showed that there was no residual raw material. 50 mL of water was added to the reaction solution, and ethyl acetate was extracted (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 compound 4 (50 mg, yield 50%) was obtained by separation and purification by column chromatography (dichloromethane:methanol=60:1-20:1). ESI-MS: m / z458.16[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).

[0359] Example 5: Synthesis of Compound 5

[0360]

[0361] Synthesis of intermediate 5-1

[0362] 4,6-dichloro-2-methylpyrimidine-5-carboxaldehyde (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 system was reacted at 80 ° C for 6 h, and LC-MS monitored that there was no residual raw material. The reaction system was directly separated and purified by column chromatography (n-hexane: ethyl acetate = 20: 1-10: 1) to obtain 5-1 (1.71 g, 6.54 mmol, yield 63%). ESI-MS: m / z 260.85 [M+H] + .

[0363] Synthesis of intermediate 5-2

[0364] 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 system was reacted at room temperature for 12 h. LC-MS monitoring showed that there was no residual raw material. Water (30 mL) was added to the reaction solution, and ethyl acetate was extracted (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: 1-3: 1) to obtain 5-2 (2.30 g, 5.99 mmol, yield 92%). ESI-MS: m / z 385.15 [M+H] + .

[0365] Synthesis of intermediate 5-3

[0366] 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. Solids precipitated from the reaction solution. LC-MS monitoring showed that there was no residual raw material. Water (10 mL) was added to the reaction solution, and the solution was filtered to obtain a white solid 5-3 (1.60 g, 4.79 mmol, yield 80%), ESI-MS: m / z 335.07 [M+H] +.

[0367] Synthesis of intermediate 5-4

[0368] 5-3 (1.60 g, 4.79 mmol) was dissolved in dichloromethane (30 mL), and then bromine (1.15 g, 7.19 mmol) was added. The system was reacted at room temperature for 12 h. LC-MS monitored that there was no residual raw material. The reaction system was directly separated and purified by column chromatography (n-hexane: ethyl acetate = 5:1-3:1) to obtain 5-4 (1.80 g, 4.36 mmol, yield 91%). ESI-MS: m / z 412.98 / 415.00 [M+H] + .

[0369] Synthesis of intermediate 5-5

[0370] 5-4 (1.80 g, 4.36 mmol) was dissolved in dichloromethane (20 mL), and then 5 mL of trifluoroacetic acid was added. The system was reacted at room temperature for 4 h. LC-MS monitored that there was no residual raw material. The solvent was evaporated under reduced pressure, and 15 mL of water was added to the residue. The pH was adjusted to 8-9 with saturated sodium carbonate aqueous solution, and 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] + .

[0371] Synthesis of intermediate 5-6

[0372] 5-5 (0.90 g, 2.88 mmol) was dissolved in toluene (20 mL), and then trimethylaluminum (1.9 mL, 3.75 mmol, 2.0 M in toluene) was slowly added. The system was reacted at 120 ° C for 5 h. LC-MS monitored that there was no residual raw material. The reaction solution was quenched with saturated aqueous ammonium chloride solution, and toluene was evaporated under reduced pressure. 15 mL of water was added to the residue, and ethyl acetate was extracted (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, yield 70%). ESI-MS: m / z 294.87 / 296.83 [M+H] + .

[0373] Synthesis of intermediate 5-7

[0374] 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 bath. After the addition, the ice bath was removed. The system was reacted at room temperature for 72 h. LC-MS monitored that there was no residual raw material. Sodium carbonate solution was slowly added under ice bath to quench the reaction, and solid was precipitated. 5-7 (0.46 g, 1.64 mmol, yield 82%) was obtained by filtration. ESI-MS: m / z 280.82 / 282.84 [M+H]+.

[0375] Synthesis of intermediate 5-8

[0376] 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)ethylamine 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 system was reacted at room temperature for 8 h. LC-MS monitoring showed that there was no residual raw material. Water (30 mL) was added to the reaction solution, and ethyl acetate was extracted (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 obtain 5-8 (40 mg, 0.089 mmol, yield 49%). ESI-MS:m / z451.94 / 453.94[M+H] + .

[0377] Synthesis of compound 5

[0378] 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]dichloropalladium (13 mg, 0.018 mmol), and cesium carbonate (58 mg, 0.178 mmol). The system was reacted at 100°C for 4 h, and no raw material remained after LC-MS monitoring. 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 obtain 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).

[0379] Example 6: Synthesis of Compound 6

[0380]

[0381] Synthesis of intermediate 6-1

[0382] 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 system was reacted at room temperature for 8 h. LC-MS monitoring showed that there was no residual raw material. Water (30 mL) was added to the reaction solution, and ethyl acetate was used for extraction (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 obtain 6-1 (60 mg, yield 36%). ESI-MS: m / z 466.91 / 469.12 [M+H] + .

[0383] Synthesis of compound 6

[0384] 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]dichloropalladium (19 mg, 0.026 mmol), and cesium carbonate (84 mg, 0.258 mmol). The system was reacted at 100 °C for 4 h, and no raw material remained after LC-MS monitoring. 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 obtain 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).

[0385] Example 7: Synthesis of Compound 7

[0386]

[0387] Synthesis of intermediate 7-1

[0388] 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)ethylamine 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 system was reacted at room temperature for 8 h. LC-MS monitoring showed that there was no residual raw material. Water (30 mL) was added to the reaction solution, and ethyl acetate was extracted (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 obtain 7-1 (110 mg, yield 68%). ESI-MS: m / z 451.93 / 453.93 [M+H] + .

[0389] Synthesis of compound 7

[0390] 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, and LC-MS monitored that no raw material remained. 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 obtain 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).

[0391] Example 8: Synthesis of Compound 8

[0392]

[0393] Synthesis of intermediate 8-1

[0394] 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), and the system was reacted at room temperature for 8 h. LC-MS monitoring showed that there was no residual raw material. Water (30 mL) was added to the reaction solution, and ethyl acetate was extracted (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 obtain 8-1 (127 mg, yield 75%). ESI-MS: m / z 470.98 / 472.98 [M+H] + .

[0395] Synthesis of compound 8

[0396] 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]dichloropalladium (36 mg, 0.049 mmol), and cesium carbonate (159 mg, 0.488 mmol). The system was reacted at 100 °C for 4 h, and LC-MS monitored that no raw material remained. 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).

[0397] Example 9: Synthesis of Compound 9

[0398]

[0399] Synthesis of intermediate 9-1

[0400] 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 then concentrated sulfuric acid (16 mL) was added. The system was reacted at 80 ° C for 5 h. LC-MS monitoring showed that there was no residual raw material. Water (100 mL) was added to the reaction solution, and ethyl acetate was extracted (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 9-1 (5.00 g, yield 92%). ESI-MS: m / z 187.02 [M+H] + .

[0401] Synthesis of intermediate 9-2

[0402] 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, and no residual raw material was detected by LC-MS. The reaction solution was quenched with ice water, 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: 3) to obtain 9-2 (6.85 g, yield 96%). ESI-MS: m / z 265.10 / 267.12 [M+H] + .

[0403] Synthesis of intermediate 9-3

[0404] 9-2 (6.85 g, 25.8 mmol) was dissolved in acetonitrile (80 mL), and then methanesulfonic acid (15 mL) was added. The system was reacted at 130 ° C for 8 h. LC-MS monitoring showed that there was no residual raw material. The reaction solution was quenched with ice water, 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: 3) to obtain 9-3 (1.51 g, yield 21%). ESI-MS: m / z 274.02 / 276.11 [M+H] + .

[0405] Synthesis of intermediate 9-4

[0406] 9-3 (1.51 g, 5.50 mmol) was dissolved in ethanol (50 mL), and then hydrazine hydrate (1.76 g, 55.0 mmol) was added. The system was reacted at 80 ° C for 2 h. LC-MS monitored that there was no residual raw 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] + .

[0407] Synthesis of intermediate 9-5

[0408] 9-4 was dissolved in chloroform (30 mL), and then triethyl orthoformate (10 mL) was added. The system was reacted at 80 ° C for 2 h. LC-MS monitoring showed that there was no residual raw material. The reaction solution was quenched with ice water, 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: 3) to obtain 9-5 (1.00 g, yield 65%). ESI-MS: m / z 280.02 / 282.14 [M+H] + .

[0409] Synthesis of intermediate 9-6

[0410] 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), and 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, 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] + .

[0411] Synthesis of intermediate 9-7

[0412] 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), and the system was reacted at 120 ° C for 2 h. LC-MS monitoring showed that there was no residual raw material. The reaction solution was quenched with ice water, 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] + .

[0413] Synthesis of compound 9

[0414] 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 there was no residual raw 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 obtain 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).

[0415] Example 10: Synthesis of Compound 10

[0416]

[0417] Synthesis of Intermediate 10-1

[0418] 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), and the system was reacted at 120 ° C for 2 h. LC-MS monitoring showed that there was no residual raw material. The reaction solution was quenched with ice water, 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] + .

[0419] Synthesis of compound 10

[0420] 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 raw material. Water (50 mL) was added to the reaction solution, and ethyl acetate was extracted (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).

[0421] Example 11: Synthesis of Compound 11

[0422]

[0423] Synthesis of Intermediate 11-1

[0424] The 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 monitored that there was no residual raw material. The reaction system was cooled, saturated brine was added, 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] + .

[0425] Synthesis of Intermediate 11-2

[0426] The 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 showed that there was no residual raw material. The reaction solution was slowly dripped into a saturated sodium bicarbonate solution to quench the reaction. Ethyl acetate was added for extraction, washed with saturated brine, dried over anhydrous sodium sulfate, and 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] + .

[0427] Synthesis of Intermediate 11-3

[0428] The intermediate 11-2 (0.26 g, 0.94 mmol) was dissolved in N,N-dimethylformamide (5 mL), and the intermediate B (0.27 g, 1.22 mmol) and benzotriazole-1-yl-oxytripyrrolidinophosphine hexafluorophosphate (0.74 g, 1.41 mmol) were added, and the reaction was carried out at room temperature for 2 h. LC-MS monitoring showed that there was no residual raw material. Saturated brine was added to the reaction system, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and 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] + .

[0429] Synthesis of Intermediate 11-4

[0430] 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-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (10 mg, 0.02 mmol). The whole system was stirred at 100 °C for 3 h. TLC monitoring showed that there was no residual raw 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 was removed under reduced pressure. The mixture 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] + .

[0431] Synthesis of compound 11

[0432] 11-4 (71 mg, 0.16 mmol) was dissolved in N,N-dimethylformamide (15 mL), and then (R)-3-hydroxytetrahydrofuran p-toluenesulfonate (47 mg, 0.19 mmol) and cesium carbonate (104 mg, 0.32 mmol) were added. The whole system was stirred at 80°C for 3 h. TLC monitoring showed that there was no residual raw material. 30 mL of water was added to the reaction solution, and ethyl acetate was extracted (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 compound was separated 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 HNMR (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).

[0433] Embodiment 12-30:

[0434] The compounds of the following Examples 12-30 can be obtained by referring to the synthesis method of Examples 1-11.

[0435]

[0436]

[0437]

[0438] Example 31: Synthesis of Compound 31

[0439]

[0440] Synthesis of compound 31

[0441] The intermediate 7-1 (99 mg, 0.22 mmol) of 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 whole system was stirred at 100°C for 3 h. TLC monitoring showed that there was no residual raw material. 50 mL of water was added to the reaction solution, and ethyl acetate was extracted (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 compound 31 (69 mg, 0.14 mmol, yield 64%) was obtained by separation and purification by column chromatography (dichloromethane:methanol=60:1-15:1). 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).

[0442] Embodiment 32-92:

[0443] The compounds of the following Examples 32-92 can be obtained by referring to the synthesis method of Examples 1-11.

[0444]

[0445]

[0446]

[0447]

[0448]

[0449]

[0450]

[0451]

[0452]

[0453] Example 93: Synthesis of Compound 93

[0454]

[0455] Synthesis of compound 93

[0456] The intermediate 5-8 (40 mg, 0.089 mmol) of Example 5 was dissolved in dioxane (10 mL) and water (2 mL), followed by the addition of 1-acetyl-5,6-dihydro-2H-pyridine-4-boronic acid pinacol ester (34 mg, 0.133 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (13 mg, 0.018 mmol), and cesium carbonate (58 mg, 0.178 mmol). The system was reacted at 100°C for 4 h, and LC-MS monitored that there was no residual raw 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 obtain compound 93 (29 mg, 0.058 mmol, yield 65%). 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).

[0457] Examples 94-108:

[0458] The compounds of the following Examples 94-108 can be obtained by referring to the synthesis method of Example 93.

[0459]

[0460]

[0461]

[0462]

[0463] Example 109: Synthesis of Compound 109

[0464]

[0465] The intermediate 5-8 (40 mg, 0.089 mmol) in Example 5 was dissolved in dioxane (10 mL) and water (2 mL), followed by the addition of 1-(methyl-d3)-pyridin-2-one-4-boronic acid pinacol ester (32 mg, 0.133 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (13 mg, 0.018 mmol), and cesium carbonate (58 mg, 0.178 mmol). The system was reacted at 100°C for 4 h, and LC-MS monitored that there was no residual raw 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 obtain compound 109 (25 mg, 0.051 mmol, yield 57%). 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).

[0466] Examples 110-121:

[0467] The compounds of the following Examples 110-121 can be obtained by referring to the synthesis method of Example 93.

[0468]

[0469]

[0470]

[0471] Example 122: Synthesis of Compound 122

[0472]

[0473] Synthesis of Intermediate 122-1

[0474] 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 whole system was stirred at 100 ° C for 3 h. TLC monitoring showed that there was no residual raw material. 50 mL of water was added to the reaction solution, and ethyl acetate was extracted (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 obtain 122-1 (100 mg, yield 82%). ESI-MS: m / z 555.19 [M+H] + .

[0475] Synthesis of Intermediate 122-2

[0476] 122-1 (100 mg, 0.18 mmol) was dissolved in 4M hydrochloric acid ethyl acetate solution (10 mL), stirred at room temperature for 2 h, and no raw material remained after TLC monitoring. 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] + .

[0477] Synthesis of compound 122

[0478] 122-2 was dissolved in dichloromethane (10 mL), and then triethylamine (36 mg, 0.36 mmol) and methanesulfonyl chloride (25 mg, 0.22 mmol) were added. The mixture was stirred at room temperature for 2 h. TLC monitoring showed that no raw material remained. Water was added to the reaction solution to quench the mixture. 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: 1-15: 1) to obtain compound 122 (50 mg, yield 52%). 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).

[0479] Embodiment 123-124:

[0480] The compounds of the following Examples 123-124 can be obtained by referring to the synthesis method of Example 93.

[0481]

[0482]

[0483] Example 125: Synthesis of Compound 125

[0484]

[0485] 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-heptenoic acid)manganese (7.6 mg, 0.01 mmol) were added in sequence at room temperature. The reaction solution was replaced three times under an oxygen atmosphere and stirred at room temperature for 16 h under an oxygen balloon atmosphere. 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, which 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] + . 1HNMR (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).

[0486] Biological activity assay experiment 1:

[0487] 1. K-Ras G12D Binding analysis with hSOS1

[0488] This assay can be used to examine the potency of compounds in inhibiting 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 G12D Inhibitory effect on hSOS1.

[0489] 1.1 Reagents

[0490] 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);

[0491] GST-tagged hK-RasG12D (produced in-house);

[0492] His-tagged hSOS1 (produced in-house);

[0493] Preparation of Ras mixed solution

[0494] 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.

[0495] Preparation of SOS mixed solution

[0496] 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.

[0497] Dissolve the compound to be tested in DMSO at a concentration of 100 times the experimental concentration. Use a Hummingbird liquid handler or Echo acoustic system to transfer 50 nL into a black microplate.

[0498] 1.2 Experimental procedures

[0499] All experimental steps were completed at 20°C. In the experiment, 2.5μL of Ras mixture was added to all wells of the test plate through a multidrop dispenser. After 2 minutes of pre-incubation, 2.5μL of SOS mixture was added to all wells except the edge wells, and 2.5μL of compound control solution was added to the edge wells. After incubation for 60 minutes, the HTRF module of Pheraster (excitation light: 337nm, emission light 1: 620nm, emission light 2: 665nm) was used.

[0500] 1.3 Data Calculation

[0501] Calculate and analyze IC using a 4-parameter logic model 50 value.

[0502] 1.4 SOS1 inhibitory activity results

[0503] 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.

[0504] Example Compound No. <![CDATA[Active IC 50 (nM)]]> Example Compound No. <![CDATA[Active IC 50 (nM)]]> 1 B 2 B 3 B 4 B 5 B 6 A 7 A 8 A 9 B 10 B 11 D 12 A 31 B 65 B 71 A 97 A 98 A 99 B 109 B 118 A 122 A 123 A 124 A

[0505] 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.

[0506] 2.3D cell proliferation inhibition assay

[0507] The cell proliferation inhibition assay is used to detect whether the compound inhibits the proliferation and growth of SOS1-mediated tumor cell lines at the 3D cell level in vitro. CellTiter-Glo 3D detection method.

[0508] 2.1 Reagents and Materials

[0509] NCI-H358: Non-small cell lung cancer (NSCLC) with KRAS G12C mutation;

[0510] CellTiter-Glo 3D Cell Viability Assay, Promega, G9683;

[0511] RPMI 1640medium,Gibco,A10491-01;

[0512] FBS, Gibco, 10099141C;

[0513] 2.2 Test steps:

[0514] 2.2.1 Cell culture

[0515] Day 1, passage NCI-H358 into T75 cell culture flasks;

[0516] On Day 3, remove the culture medium, rinse once with DPBS, and use 2 mL of TrypLE TM The cells were digested with ExpressEnzyme until the cells fell off; 5 mL of fresh culture medium was added and centrifuged at 1000 rpm for 5 min; the supernatant was discarded, 5 mL of fresh culture medium was added to resuspend the cells, and after counting the cells, 40 μL / well was inoculated into a 3D cell plate (Echo Qualified 384-Well Polypropylene Microplate 2.0, Clear, Flat Bottom).

[0517] 2.2.2 3D cell proliferation inhibition

[0518] Day 1, dissolve the test compound in DMSO to prepare a 10mM stock solution; dilute 1000 times with DMSO solution, then perform 3-fold gradient dilution, 10 concentration gradients, and the starting concentration is 10μM; add 200nL of the compound to the culture plate;

[0519] Day 8, add 40 μL / well 3D CTG reagent and use Envision to detect the signal value.

[0520] 2.3 Data Analysis

[0521] Fitting compound IC using Graphpad Prism 8 nonlinear regression equation 50 value;

[0522] Y=Bottom+(Top-Bottom) / (1+10^((LogIC50-X)*HillSlope));

[0523] X: Log of cpd concentration;

[0524] Y:Percent inhibition (%inh)

[0525] 2.4 NCI-H358 Cell Proliferation Inhibitory Activity Results

[0526] The compounds in the examples were tested according to the above method, and the NCI-H358 cell proliferation inhibitory activity data are shown in the table below.

[0527] Example Compound No. <![CDATA[Active IC 50 (nM)]]> Example Compound No. <![CDATA[Active IC 50 (nM)]]> 2 C 3 C 4 C 5 A 6 A 7 A 12 C 31 A 65 C 71 C 94 C 95 C 97 C 98 C 99 C 100 C 101 C 102 C 103 C 104 C 105 C 106 C 107 C 108 B 109 B 110 C 111 C 112 C 113 C 117 C 118 C 119 B 120 C 121 C 122 B 123 B 124 B 125 B

[0528] Among them, A represents IC 50 <50nM, B represents 50nM≤IC 50 <100nM, C represents 100nM≤IC 50 <500nM.

[0529] Biological activity assay experiment 2:

[0530] 1.3D NCI-H358, NCI-H520, NCI-H1373, UM-UC-3, GP2d, A549 cell proliferation inhibition test

[0531] The in vitro proliferation inhibitory effect of the compound 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 cancer cells (UM-UC-3) was investigated, and the inhibitory effect of the compound of the present invention on the above cell proliferation was compared with that of MRTX0902 and BI3406

[0532] 1.1 Test materials and equipment

[0533] Cell lines:

[0534] NCI-H358: Non-small cell lung cancer (NSCLC) with KRAS G12C mutation;

[0535] NCI-H520: KRAS wild-type non-small cell lung cancer (NSCLC);

[0536] NCI-H1373: Non-small cell lung cancer (NSCLC) with KRAS G12C mutation;

[0537] UM-UC-3: KRAS G12C-mutated bladder transitional cell carcinoma (BTCC);

[0538] GP2d: KRAS G12D-mutated colorectal cancer (CRC);

[0539] A549: Non-small cell lung cancer (NSCLC) with KRAS G12S mutation.

[0540] Reagents and consumables:

[0541] F12K Medium, Hyclone, SH30526.01;

[0542] DMEM Medium, Gibco, 11965-092;

[0543] 1640 Medium, Gibco, A10491-01;

[0544] EMEM Medium, ATCC, 30-2003;

[0545] Penicillin-Streptomycin, Gibco, 15140-122;

[0546] Fetal Bovine Serum, Gibco, 10099-141C;

[0547] Phosphate Buffered Saline (PBS), Gibco, 10010-031;

[0548] TrypLE, Gibco, 12604-021;

[0549] DMSO, Sigma, D8418-1L;

[0550] BI-3406, MCE, HY-125817;

[0551] MRTX0902, Zepi Biotechnology (Shijiazhuang) Co., Ltd., Zepi20221025

[0552] 3D Cell Viability assay kit, Promega, G9683;

[0553] 384 Corning spheroid microplates, Corning, 3830;

[0554] Ultra-Low attachment 96 well plate, Corning, 7007;

[0555] White Opaque 96-well Microplate, PerkinElmer, 6005680.

[0556] Instruments and equipment:

[0557] Plate shaker, QILINBEIER, QB-9002;

[0558] Centrifuge, Eppendorf, 5810R;

[0559] CO2 incubator, Thermo Scientific, 371;

[0560] Microscope, OLYMPUS, CKX41;

[0561] Echo Qualified 384-Well Polypropylene, LABCYTE, PP-0200;

[0562] Echo, LABCYTE, 655;

[0563] CountessII,Gibco,AMQAX1000;

[0564] Envision,PerkinElmer,2105.

[0565] 1.2 Test steps:

[0566] 1.2.1 Cell culture

[0567] 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.

[0568] b) A549 cells were cultured in F12K medium, supplemented with 1% double antibody and 10% FBS, and cultured at 37°C and 5% CO2.

[0569] c) GP2d cells were cultured in DMEM medium, supplemented with 1% double antibody and 10% FBS, and cultured at 37°C and 5% CO2.

[0570] d) UM-UC-3 cells were cultured in EMEM medium, supplemented with 1% double antibody and 10% FBS, and cultured at 37°C and 5% CO2.

[0571] 1.2.2 Cell plating

[0572] a) The cells are routinely cultured until the cell saturation reaches 80%-90%. When the cell quantity reaches the required level, the cells are harvested.

[0573] Resuspend with corresponding culture medium, count, and prepare cell suspension of appropriate density. Among them, NCI-H358, 2000 cells / well are plated in 384 Well Plate; NCI-H520, 2000 cells / well are plated in 384 Well Plate; A549, 1000 cells / well are plated in 384 Well Plate; NCI-H1373, 1000 cells / well are plated in 96 Well Plate; GP2d, 1250 cells / well are plated in 96 Well Plate; UM-UC-3, 1000 cells / well are plated in 384 Well Plate.

[0574] 1.2.3 Preparation of compounds

[0575] a) Serial dilution of positive compounds (MRTX0902 and BI-3406):

[0576] 384-well plate dilution system: Dissolve the compound MRTX0902 in DMSO solvent to a 30 mM stock solution, dilute MRTX0902 and BI-3406 to 10 mM with DMSO, and then perform 3-fold serial dilutions, with a total of 10 concentration gradients (the concentration gradients are 10000, 3333, 1111, 370, 123, 41.2, 13.7, 4.57, 1.52, 0.51 μM). Use a nanoliter pipetting system (Echo650 Liquid Handler) to add 40 nL of the above gradient dilution compounds to each well of a 384-well cell culture plate, centrifuge at 1000 rpm for 1 min, and the concentration gradient of the compound in the final reaction system (40 μL) is 10000, 3333, 1111, 370, 123, 41.2, 13.7, 4.57, 1.52, 0.51 nM.

[0577] 96-well plate dilution system: MRTX0902 and BI-3406 were diluted to 2000 μM with DMSO solvent and then serially diluted 3 times, with a total of 10 concentration gradients (the concentration gradients were 2000, 667, 222, 74.1, 24.7, 8.23, 2.74, 0.91, 0.30, 0 μM). 500 nL of the above gradient dilution compounds were added to each well of the 96-well cell culture plate using a nanoliter pipetting system (Echo 650 Liquid Handler), and centrifuged at 1000 rpm for 1 min. The concentration gradient of the compound in the final reaction system (100 μL) was 10000, 3333, 1111, 370, 123, 41.2, 13.7, 4.57, 1.52, 0 nM.

[0578] b) Dilution of the compound of the present invention:

[0579] 384-well plate dilution system: Dissolve the compound into a 27.4mM stock solution with DMSO solvent, dilute it to 9.13mM with DMSO, and then perform 3-fold serial dilutions, with a total of 10 concentration gradients (the concentration gradients are 9135, 3044, 1014, 338, 112, 37.6, 12.5, 4.18, 1.39, 0.46μM). Use a nanoliter pipetting system (Echo 650 Liquid Handler) to add 40nL of the above gradient diluted compound to each well of a 384-well cell culture plate, centrifuge at 1000rpm for 1min, and the concentration gradient of the compound in the final reaction system (40μL) is 9135, 3045, 1015, 338, 113, 37.6, 12.5, 4.18, 1.39, 0.46nM.

[0580] 96-well plate dilution system: dilute the compound to 1827 μM with DMSO solvent and then perform 3-fold serial dilutions, with a total of 10 concentration gradients (the concentration gradients are 1827, 609, 203, 67.7, 22.6, 7.52, 2.51, 0.84, 0.28, 0 μM). Add 500 nL of the above gradient dilution compound to each well of the 96-well cell culture plate using a nanoliter pipetting system (Echo 650 Liquid Handler), centrifuge at 1000 rpm for 1 min, and the concentration gradient of the compound in the final reaction system (100 μL) is 9135, 3045, 1015, 338, 113, 37.6, 12.5, 4.18, 1.39, 0 nM.

[0581] 1.2.4CTG method detection

[0582] After the cells were cultured in a 37°C, 5% CO2 incubator for 7 days:

[0583] a) Add 20 μL CTG reagent (CelltiterGlo 3D kit) to each well of a 384-well plate, centrifuge at 1000 rpm for 1 min, place on a fast shaker for 20 min, and place at room temperature away from light for 120 min.

[0584] b) Add 50 μL CTG reagent (CelltiterGlo 3D kit) to each well of the 96-well plate, centrifuge at 1000 rpm for 1 min, place on a fast shaker for 20 minutes, place at room temperature in the dark for 120 minutes, and then transfer 100 μL to a White Opaque 96-well Microplate.

[0585] c) Read the chemiluminescent signal using Envision instrument.

[0586] 1.2.5 Data Analysis

[0587] IC was calculated using GraphPad Prism 8 software 50 , the IC of the compound is obtained using the following nonlinear fitting formula 50 (half inhibitory concentration):

[0588] Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope))

[0589] Y: Inhibition rate X: Log value of compound concentration

[0590] 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%

[0591] High read value control well: cells plus 40nL DMSO (NCI-H358, NCI-H520, A549, UM-UC-3)

[0592] Add 500nL DMSO (NCI-H1373, GP2d) to cells

[0593] Low reading control wells: no cell culture medium

[0594] 1.3 Test results

[0595] The exemplary compounds were tested according to the above method, and the cell proliferation inhibition activity data are shown in the following table:

[0596]

[0597]

[0598] 2.3D MIA PaCa-2, NCI-H441 and DLD-1 cell proliferation inhibition assay

[0599] 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.

[0600] 2.1 Test materials and equipment

[0601] Cell lines:

[0602] MIA PaCa-2: human pancreatic cancer cells (PAC) with KRAS G12C mutation;

[0603] H441: Non-small cell lung cancer (NSCLC) with KRAS G12V mutation;

[0604] DLD-1: human colorectal cancer (CRC) with KRAS G13D mutation.

[0605] Reagents and consumables:

[0606] DMEM basic (1×): 500 mL, Gibco, batch number: 8122483;

[0607] Horse serum: 500 mL, Inner Mongolia Jinyuankang Company, batch number: 20200701;

[0608] Penicillin-Streptomycin, Gibco, 15140-122;

[0609] RPMI Medium 1640 basic (1×): 500 mL, Gibco, batch number: 8122656;

[0610] FETAL BOVINE SERUM (FBS): 500 mL, Gibco, batch number: 2528128CP;

[0611] 0.25% Trypsin-EDTA (1×): 500 mL, Gibco, batch number: 2360145;

[0612] PBS pH 7.4 (1×): 500 mL, Gibco, batch number: 8121763;

[0613] DMSO (cell culture grade): 500 mL, AMRESCO, batch number: 21A2756279;

[0614] CellTiter-Glo 3D Cell Viability Assay: 100 mL, Promega, Lot No.: 0000537948;

[0615] MRTX0902, Zepi Biotechnology (Shijiazhuang) Co., Ltd., Zepi20221025;

[0616] Low-adsorption plate: 96-well, Corning, lot number: 02722003.

[0617] Instruments and equipment:

[0618] Model 371 CO2 incubator: Thermo, equipment number: ZS01-0746;

[0619] IX70-142 inverted microscope: Olympus, equipment number: 0243;

[0620] HFsafe-1500LC biological safety cabinet: Shanghai Lishen Scientific Instrument Co., Ltd., equipment number: ZS01-0747;

[0621] TD6 centrifuge: Changsha Xiangrui Centrifuge Co., Ltd., equipment number: ZS01-0750;

[0622] MS105 Mettler electronic balance: METTLERTOLEDO, equipment number: ZY01-0136;

[0623] Varioskan Flash fluorescence microplate reader: Thermo, equipment number: 0845.

[0624] 2.2 Test steps:

[0625] 2.2.1 Preparation of compounds

[0626] In the MIA PaCa-2 cell proliferation inhibition test, the final concentration of the compound of the present invention was 9134.57 nM as the initial concentration, and 9 concentrations were set by 5× decreasing dilution, 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 started at 10 μM, and 9 concentrations were set in 3× descending dilutions, namely 10000, 3333.33, 111.11, 370.37, 123.46, 41.15, 13.72, 4.57, and 1.52 nM; in the DLD-1 cell proliferation inhibition assay, the final concentration of the compound of the present invention started at 9134.57 nM, and 9 concentrations were set in 3× descending 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 started at 10 μM, and 9 concentrations were set in 3× decreasing dilution, namely 10000, 3333.33, 1111.11, 370.37, 123.46, 41.15, 13.72, 4.57, and 1.52 nM; 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× decreasing dilution, 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 by 5× decreasing dilution, namely 10000, 2000, 400, 80, 16, 3.2, 0.64, 0.13, and 0.03 nM.

[0627] 2.2.2 Cell culture and detection

[0628] MIA PaCa-2 cells were cultured in high-glucose DMEM containing 10% FBS and 2.5% horse serum; NCI-H441 and DLD-1 cells were cultured in RPMI Medium 1640basic containing 10% FBS at 37°C and 5% CO2.

[0629] A certain number of cell lines in the logarithmic growth phase were inoculated in a low-adsorption 96-well plate (100 μL / well), and 100 μL of culture solution containing different concentration gradients of the compound of the present invention or MRTX0902 was added to each well. Three replicate wells 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 action, the well plate was balanced 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, and the luminescence value was detected by chemiluminescence method using an enzyme marker.

[0630] The cell growth inhibition rate was calculated using the following formula:

[0631] Inhibition rate (%) = (luminescence value 正常孔 - Luminous value 给药孔 ) / (luminous value 正常孔 - Luminous value 空白孔 )×100%

[0632] According to the inhibition rate of each concentration, the drug half-inhibitory concentration IC was fitted using the GraphPad Prism 5 nonlinear regression equation. 50 .

[0633] 2.3 Test results

[0634] The cell proliferation inhibition activity data of the exemplary compounds tested according to the above method are shown in the following table:

[0635]

Claims

1. A compound as shown in formula (A), and its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates or isotope derivatives in the preparation of drugs for treating tumors or cancers, in, represents a single bond or a double bond; Y and Z are both selected from C or N, when Y is N, Z is C, when Y is C, Z is N; Y and Z and the atoms to which they are attached together form a ring A, wherein the ring A is selected from a 5-12 membered heterocyclyl or a 5-12 membered heteroaryl; R 2 is 1, 2 or 3, 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, -C 1-6 Alkyl-NH(C 1-6 Alkyl), -C 1-6 Alkyl-N(C 1-6 Alkyl)2, 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 1-6 Alkoxy, -C 1-6 Alkyl-NH(C 1-6 Alkyl), -C 1-6 Alkyl-N(C 1-6 Alkyl)2, 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 all optionally substituted with one or more cyano, hydroxyl or halogen; 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, 4-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, C 6-12 Aryl C 4-12 Cycloalkyl, C 6-12 Aryl 4-12 membered heterocyclic group 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, hydroxy, amino, -SO2-C 1-4 Alkyl or oxo; w is 0, 1, 2, 3 or 4; when When it is a double bond, X is selected from C, and R connected to it 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, -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; 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, -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; 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, -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; 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, -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, 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 with one or more selected from deuterium, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Alkoxy or halogen substituents; when When it is a single bond, X is selected from N, and R connected to it 1 Selected from C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, C 6-10 aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl, wherein the C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl are each optionally substituted by one or more identical or different R a4 and / or R b4 replace; If present, each R a4 Each independently 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 one or more identical or different R b4 and / or R c4 replace; If present, each R b4 Each independently selected from -OR c4 、-NR c4 R c4 , halogen, -CN, -C(O)R c4 、-C(O)OR c4 、-C(O)NR c4 R c4 、-OC(O)R c4 、-S(O)2R c4 、-S(O)2NR c4 R c4 、-NHC(O)R c4 、-N(C 1-4 alkyl)C(O)R c4 、-NHC(O)OR c4 or a divalent substituent =O or =NH, whereby =O and =NH may be substituents only in non-aromatic ring systems; If present, each R c4 are each independently selected from hydrogen, 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 one or more identical or different R d4 and / or R e4 replace; If present, each R d4 Each independently selected from -OR e4 、-NR e4 R e4 , halogen, -CN, -C(O)R e4 、-C(O)OR e4 、-C(O)NR e4 R e4 、-S(O)2R e4 、-S(O)2NR e4 R e4 、-NHC(O)R e4 、-N(C 1-4 alkyl)C(O)R e4 or a divalent substituent =O, where =O may be the only substituent in a non-aromatic ring system; If present, each R e4 are each independently selected from hydrogen, 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 all optionally substituted with one or more hydrogen, cyano, hydroxyl or halogen; wherein Z and Y are included in the atoms or atomic numbers of ring A; 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.

2. The compound according to claim 1, and the use of its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs or solvates, characterized in that: The compound has a structure as shown in formula (A'): The substituents in formula (A') are as defined in formula (A).

3. A compound as shown in formula (I), and its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs or solvates in the preparation of drugs for treating tumors or cancers, in, represents a single bond or a double bond; Y and Z are both selected from C or N, when Y is N, Z is C, when Y is C, Z is N; Y and Z and the atoms to which they are attached together form a ring A, wherein the ring A is selected from a 5-12 membered heterocyclyl or a 5-12 membered heteroaryl; R 2 is 1, 2 or 3, 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, -C 1-6 Alkyl-NH(C 1-6 Alkyl), -C 1-6 Alkyl-N(C 1-6 Alkyl)2, 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 1-6 Alkoxy, -C 1-6 Alkyl-NH(C 1-6 Alkyl), -C 1-6 Alkyl-N(C 1-6 Alkyl)2, 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 all optionally substituted with one or more cyano, hydroxyl or halogen; 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, hydroxy, amino, -SO2-C 1-4 Alkyl or oxo; w is 0, 1, 2, 3 or 4; when When it is a double bond, X is selected from C, and R connected to it 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, -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; 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, -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; 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, -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; 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 1-3 identical or different R c1 replace; If present, each R c1 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, -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, 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, -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 hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy or halogen substituents; when When it is a single bond, X is selected from N, and R connected to it 1 Selected from C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, C 6-10 aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl, wherein the C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl are each optionally substituted by one or more identical or different R a4 and / or R b4 replace; If present, each R a4 Each independently 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 one or more identical or different R b4 and / or R c4 replace; If present, each R b4 Each independently selected from -OR c4 、-NR c4 R c4 , halogen, -CN, -C(O)R c4 、-C(O)OR c4 、-C(O)NR c4 R c4 、-OC(O)R c4 、-S(O)2R c4 、-S(O)2NR c4 R c4 、-NHC(O)R c4 、-N(C 1-4 alkyl)C(O)R c4 、-NHC(O)OR c4 or a divalent substituent =O or =NH, whereby =O and =NH may be substituents only in non-aromatic ring systems; If present, each R c4 are each independently selected from hydrogen, 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 one or more identical or different R d4 and / or R e4 replace; If present, each R d4 Each independently selected from -OR e4 、-NR e4 R e4 , halogen, -CN, -C(O)R e4 、-C(O)OR e4 、-C(O)NR e4 R e4 、-S(O)2R e4 、-S(O)2NR e4 R e4 、-NHC(O)R e4 、-N(C 1-4 alkyl)C(O)R e4 or a divalent substituent =O, where =O may be the only substituent in a non-aromatic ring system; If present, each R e4 are each independently selected from hydrogen, 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 all optionally substituted with one or more hydrogen, cyano, hydroxyl or halogen; wherein Z and Y are included in the atoms or atomic numbers of ring A; 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.

4. The compound according to claim 3, and the use of its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs or solvates, characterized in that: The compound has a structure as shown in formula (II): The substituents in formula (II) are as defined in formula (I).

5. The compound according to claim 3, and the use of its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs or solvates, characterized in that: The compound has a structure as shown in formula (III): The substituents in formula (III) are as defined in formula (I).

6. The compound according to claim 3, and the use of its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs or solvates, characterized in that: The compound has a structure as shown in formula (IV): The substituents in formula (IV) are as defined in formula (I).

7. The compound according to any one of claims 1 to 6, and the use of its stereoisomer, optical isomer, pharmaceutically acceptable salt, prodrug or solvate, characterized in that: is a double bond, X is selected from C, and R connected thereto 1 For-OR A ; Preferably, 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, -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; 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:

8. The compound according to any one of claims 1 to 6, and the use of its stereoisomer, optical isomer, pharmaceutically acceptable salt, prodrug or solvate, characterized in that: is a double bond, X is selected from C, and R connected thereto 1 -N(R D )R B ; Preferably, 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, ethoxy; More preferably, R B Selected from the following groups: Preferably, 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 Selected from hydrogen.

9. The compound according to any one of claims 1 to 6, and the use of its stereoisomer, optical isomer, pharmaceutically acceptable salt, prodrug or solvate, characterized in that: is a double bond, X is selected from C, and R connected thereto 1 For R C ; Preferably, R C 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 c1 replace; If present, each R c1 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, -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, 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 The cycloalkyl and 3-10 membered heterocyclic groups are optionally substituted with one or more selected from hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy or halogen substituents; More preferably, R C Selected from C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl are each optionally substituted by 1-3 identical or different R c1 replace; If present, each R c1 are independently selected from halogen, hydroxy, cyano, amino, nitro, oxo, formyl, C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -COC 1-4 Alkyl, -CH2CON(C 1-4 Alkyl)2, -CH2CONHC 1-4 alkyl or 3-6 membered heterocyclic group, wherein the C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -COC 1-4 Alkyl, -CH2CON(C 1-4 Alkyl)2, -CH2CONHC 1-4 The alkyl group and the 3-6 membered heterocyclyl group are each optionally substituted with one or more substituents selected from hydroxy, methyl, methoxy or halogen; 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 1-3 identical or different R c1 replace; If present, each R c1 Each is independently selected from halogen, hydroxy, cyano, amino, oxo, formyl, C 1-4 Alkyl, -OC 1-4 Alkyl, -COC 1-4 Alkyl, -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, -CH2CON(C 1-4 alkyl)2 and 3-6 membered heterocyclyl are each optionally substituted by one or more substituents selected from hydroxy, 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 or a 5-6 membered monocyclic heteroaryl group, wherein the 5-6 membered monocyclic heterocyclic group, the 6-10 membered spiro heterocyclic group, the 6-8 membered bridged heterocyclic group and the 5-6 membered monocyclic heteroaryl group are optionally substituted by 1-3 identical or different R c1 replace; If present, each R c1 Each is independently selected from halogen, hydroxy, cyano, amino, oxo, formyl, acetyl, propionyl, methoxy, ethoxy, methyl, ethyl, n-propyl, isopropyl, -CH2CON(CH3)2 or 6-membered heterocyclyl, wherein the acetyl, propionyl, methoxy, ethoxy, methyl, ethyl, n-propyl, isopropyl, -CH2CON(CH3)2 and 6-membered heterocyclyl are optionally substituted with one or more substituents selected from hydroxy, methyl, methoxy or halogen; More preferably, R C is selected from 6-membered monocyclic heterocyclic radical, 4 / 6-spiro heterocyclic radical, 4 / 4-spiro heterocyclic radical, 7-membered bridged heterocyclic radical or 6-membered monocyclic heteroaryl, wherein the 6-membered monocyclic heterocyclic radical, 4 / 6-spiro heterocyclic radical, 4 / 4-spiro heterocyclic radical, 7-membered bridged heterocyclic radical and 6-membered monocyclic heteroaryl are optionally substituted by 1-3 identical or different R c1 replace; If present, each R c1 Each is independently selected from halogen, hydroxy, cyano, amino, oxo, formyl, acetyl, -COCH2CH3, -COCH2OH, hydroxymethyl, hydroxyethyl, -CH2OCH3, methoxy, ethoxy, methyl, ethyl, n-propyl, isopropyl, -CH2CON(CH3)2 and 6-membered heterocyclyl; More preferably, R C Selected from The R C are optionally replaced by 1-2 identical or different R c1 replace; If present, each R c1 Each is independently selected from F, Cl, Br, hydroxy, cyano, amino, oxo, acetyl, -COCH2CH3, -COCH2OH, hydroxymethyl, hydroxyethyl, -CH2OCH3, methoxy, methyl, ethyl, isopropyl, -CH2CON(CH3)2 and morpholinyl; More preferably, optionally R c1 Replaced by R C Selected from the following groups:

10. The compound according to any one of claims 1 to 9, and the use of its stereoisomer, optical isomer, pharmaceutically acceptable salt, prodrug or solvate, characterized in that: Ring A is selected from a 5-10 membered heterocyclyl or a 5-10 membered heteroaryl, wherein the heteroatoms in the 5-10 membered heterocyclyl and the 5-10 membered heteroaryl are each independently selected from O or N, and the number of heteroatoms is 1-4; Further preferably, Ring A is selected from a 5-membered monocyclic heterocyclic group, a 6-membered monocyclic heterocyclic group, a 5-membered monocyclic heteroaryl, a 6-membered monocyclic heteroaryl, a 5 / 5-membered fused heterocyclic group, a 5 / 4-membered fused heterocyclic group, a 5 / 6-membered fused heterocyclic group, a 6 / 5-membered fused heterocyclic group, a 6 / 4-membered fused heterocyclic group, a 6 / 6-membered fused heterocyclic group, a 5 / 3-membered spiro heterocyclic group, a 5 / 5-membered spiro heterocyclic group, a 5 / 4-membered spiro heterocyclic group, a 5 / 6-membered spiro heterocyclic group, a 6 / 3-membered spiro heterocyclic group, a 6 / 5-membered spiro heterocyclic group, a 6 / 4-membered spiro heterocyclic group or a 6 / 6-membered spiro heterocyclic group, wherein the 5-membered monocyclic heterocyclic group The heteroatoms in the heterocyclyl, 6-membered monocyclic heterocyclyl, 5-membered monocyclic heteroaryl, 6-membered monocyclic heteroaryl, 5 / 5-membered fused heterocyclyl, 5 / 4-membered fused heterocyclyl, 5 / 6-membered fused heterocyclyl, 6 / 5-membered fused heterocyclyl, 6 / 4-membered fused heterocyclyl, 6 / 6-membered fused heterocyclyl, 5 / 3-membered spiro heterocyclyl, 5 / 5-membered spiro heterocyclyl, 5 / 4-membered spiro heterocyclyl, 5 / 6-membered spiro heterocyclyl, 6 / 3-membered spiro heterocyclyl, 6 / 5-membered spiro heterocyclyl, 6 / 4-membered spiro heterocyclyl and 6 / 6-membered spiro heterocyclyl are each independently selected from N, and the number of heteroatoms is 1-4; Further preferably, Ring A is selected from a 5-membered monocyclic heterocyclyl, a 6-membered monocyclic heterocyclyl, a 5-membered monocyclic heteroaryl, a 6-membered monocyclic heteroaryl, a 5 / 5-membered fused heterocyclyl, a 5 / 6-membered fused heterocyclyl or a 5 / 3-membered spiro heterocyclyl, wherein the heteroatoms in the 5-membered monocyclic heterocyclyl, the 6-membered monocyclic heterocyclyl, the 5-membered monocyclic heteroaryl, the 6-membered monocyclic heteroaryl, the 5 / 5-membered fused heterocyclyl, the 5 / 6-membered fused heterocyclyl and the 5 / 3-membered spiro heterocyclyl are each independently selected from N, and the number of heteroatoms is 1-3; Further preferably, ring A is selected from a 5-membered monocyclic heterocyclic group or a 5-membered monocyclic heteroaryl group, and the heteroatoms in the 5-membered monocyclic heterocyclic group and the 5-membered monocyclic heteroaryl group are selected from N, and the number of heteroatoms is 1-3; More preferably, ring A is selected from the following groups: More preferably, ring A is selected from the following groups:

11. The compound according to any one of claims 1 to 10, and the use of its stereoisomer, optical isomer, pharmaceutically acceptable salt, prodrug or solvate, characterized in that: R 2 is 1, 2 or 3, each of which, when present, is independently selected from hydrogen, halogen, hydroxy, cyano, amino, nitro, formyl, oxo, C 1-3 Alkyl, C 1-3 Alkoxy, -C 1-3 Alkyl-NH(C 1-3 Alkyl) or -C 1-3 Alkyl-N(C 1-3 alkyl)2, wherein the C 1-3 Alkyl, C 1-3 Alkoxy, -C 1-3 Alkyl-NH(C 1-3 Alkyl) and -C 1-3 Alkyl-N(C 1-3 alkyl)2 are optionally substituted by one or more hydroxyl groups or halogen; More preferably, R 2 is 1, 2 or 3, 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, when present, is independently selected from hydrogen or methyl.

12. The compound according to any one of claims 1 to 11, and the use of its stereoisomer, optical isomer, pharmaceutically acceptable salt, prodrug or solvate, characterized in that: R 3 Selected from hydrogen, halogen, hydroxyl, amino, cyano, C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 Cycloalkyl, wherein the C 1-4 Alkyl, C 1-4 Alkoxy and C 3-6 The cycloalkyl groups are optionally substituted with one or more hydroxyl groups or halogen groups; More preferably, 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.

13. The compound according to any one of claims 1 to 12, and the use of its stereoisomer, optical isomer, pharmaceutically acceptable salt, prodrug or solvate, characterized in that: Ring B is selected from C 4-12 Cycloalkenyl, C 4-12 Heterocyclic group, C 6-12 Aryl, C 6-8 Aryl C 4-6 Cycloalkyl, C 6-8 Aryl C 4-6 Heterocyclic or C 5-12 heteroaryl; More preferably, ring B is selected from C 6-10 Aryl or C 5-10 heteroaryl; Further preferably, ring B is selected from phenyl or pyridyl.

14. The compound according to any one of claims 1 to 13, and the use of its stereoisomer, optical isomer, pharmaceutically acceptable salt, prodrug or solvate, 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, hydroxy, amino, -SO2-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, 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, halogen, amino, methyl, trifluoromethyl, difluoromethyl, monofluoromethyl, -CF2CH2OH, -C(CH3)2OH or -CF2CH3; w is 1, 2 or 3.

15. A compound as represented by formula (B), and use of its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates or isotopic derivatives, 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, -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; 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, -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; 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, -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; 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, -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, 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 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, hydroxy, amino, -SO2-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.

16. The compound according to claim 15, and the use of its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates or isotopic derivatives, 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, -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; 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:

17. The compound according to claim 15, and the use of its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates or isotopic derivatives, 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, 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 Selected from hydrogen.

18. The compound according to claim 15, and the use of its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates or isotopic derivatives, 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, -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, -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 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, -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 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, -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 by 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 each 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; 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 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; 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, -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; More preferably, optionally R c1 Replaced by R C Selected from the following groups:

19. The compound according to any one of claims 15 to 18, and the use of its stereoisomer, optical isomer, pharmaceutically acceptable salt, prodrug, solvate or isotope derivative, 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.

20. The compound according to any one of claims 15 to 19, and the use of its stereoisomer, optical isomer, pharmaceutically acceptable salt, prodrug, solvate or isotope derivative, 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.

21. The compound according to any one of claims 15 to 20, and the use of its stereoisomer, optical isomer, pharmaceutically acceptable salt, prodrug, solvate or isotope derivative, 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.

22. The compound according to any one of claims 15 to 21, and the use of its stereoisomer, optical isomer, pharmaceutically acceptable salt, prodrug, solvate or isotope derivative, 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, hydroxy, amino, -SO2-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, -CF2CH2OH, -C(CH3)2OH, -CF2CH3 or -CH2CHF2; w is 1, 2 or 3.

23. The compound according to any one of claims 15 to 22, and the use of its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates or isotopic derivatives, characterized in that: The compound has a structure as shown in formula (C): The substituents in formula (C) are as defined in formula (B).

24. A compound as represented by formula (D), and the use of its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates or isotopic derivatives, in, If present, 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; 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, -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 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.

25. The compound according to claim 24, and the use of its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates or isotopic derivatives, 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:

26. The compound according to claim 24, and the use of its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates or isotopic derivatives, 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 Selected from hydrogen.

27. The compound according to claim 24, and the use of its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates or isotopic derivatives, 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, -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 by 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 Each is independently selected from halogen, hydroxyl, cyano, amino, methanesulfonyl, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, acetyl, propionyl, -CO-cyclopropyl, -CO-cyclobutyl, -CH2CON(CH3)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, -CO-cyclobutyl, -CH2CON(CH3)2, 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 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 Each is independently selected from halogen, hydroxy, cyano, amino, methanesulfonyl, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, acetyl, propionyl, -CO-cyclopropyl, -CH2CON(CH3)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, hydroxy, 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, hydroxyl, cyano, amino, methanesulfonyl, methyl, ethyl, isopropyl, CD3, hydroxymethyl, hydroxyethyl (e.g., 2-hydroxyethyl), -CH(OH)(CH3)2, -CH2OCH3, -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); More preferably, optionally R c1 Replaced by R C Selected from the following groups:

28. The compound according to any one of claims 24 to 27, and the use of its stereoisomer, optical isomer, pharmaceutically acceptable salt, prodrug, solvate or isotope derivative, characterized in that: If present, each R 4 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 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, -CF2CH2OH, -CF2C(CH3)2OH, -CF2CH3 or -CH2CHF2; w is 1 or 2.

29. The compound according to any one of claims 24 to 28, and the use of its stereoisomer, optical isomer, pharmaceutically acceptable salt, prodrug, solvate or isotope derivative, characterized in that: The compound has a structure as shown in formula (E): The substituents in formula (E) are as defined in formula (D).

30. The use according to claim 1, wherein Formula (A) is selected from the following compounds, and their stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates or isotopic derivatives:

31. The use as claimed in claim 1, wherein formula (A) is selected from the following compounds, and stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates or isotopic derivatives thereof:

32. Use of a pharmaceutical composition in the preparation of a drug for treating tumors or cancer, wherein the pharmaceutical composition comprises a compound according to any one of claims 1 to 31, and a stereoisomer, optical isomer, pharmaceutically acceptable salt, prodrug, solvate or isotope derivative thereof; Optionally, it further comprises a pharmaceutically acceptable excipient.

33. A use according to any one of claims 1 to 32, characterized in that The tumor or cancer is pancreatic cancer, colorectal cancer, bladder cancer (such as bladder transitional cell carcinoma).

34. A use according to any one of claims 1 to 32, characterized in that The tumor or cancer is a tumor or cancer with a RAS mutation; preferably, the tumor or cancer with a RAS mutation is pancreatic cancer, colorectal cancer, or bladder cancer (such as bladder transitional cell carcinoma).

35. A use according to any one of claims 1 to 32, characterized in that The tumor or cancer is a KRAS mutated tumor or cancer; preferably, the KRAS mutated tumor or cancer is lung cancer (such as non-small cell lung cancer), pancreatic cancer, colorectal cancer, bladder cancer (such as bladder transitional cell carcinoma), and the lung cancer (such as non-small cell lung cancer) is a non-KRAS G12C mutated lung cancer (non-small cell lung cancer).

36. A use according to any one of claims 1 to 32, characterized in that The tumor or cancer is a tumor or cancer with KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12S, or KRAS G13D mutations; preferably, the tumor or cancer with KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12S, or KRAS G13D mutations 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 non-KRAS G12C mutation; more preferably, the tumor or cancer is pancreatic cancer with KRAS G12C mutation, bladder cancer (such as bladder transitional cell carcinoma) with KRAS G12C mutation, colorectal cancer with 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 KRAS G13D mutation. G13D mutation in colorectal cancer.

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