A heterocyclic compound with anti-tumor activity and its use

Abstract

The present invention relates to the field of medical technology, and provides a class of compounds, and stereoisomers, optical isomers, pharmaceutical salts, prodrugs, solvates (e.g., hydrates) or isotope derivatives thereof. The compounds of the present invention have a tricyclic heterocyclic structure (e.g., a structure as shown in formula (A)), a novel structure, and provide a new direction for the development of SOS1 inhibitor drugs. In vitro enzyme inhibition activity studies have shown that these compounds have a strong inhibitory effect on SOS1 and can be used as promising compounds for the prevention and / or treatment of diseases mediated by SOS1. Moreover, these compounds also show significant inhibitory activity on NCI-H358 cell proliferation. In addition, the present invention studies a specific synthesis method, which has a simple process, is easy to operate, and is conducive to large-scale industrial production and application.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a compound used as a SOS1 inhibitor and a composition, a preparation method and use of the compound. 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, 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] The object of the present invention is to provide a compound with a completely new structure as a SOS1 inhibitor, a composition thereof, a preparation method thereof and use thereof for treating diseases mediated by SOS1.

[0008] In a first aspect of the present invention, there is provided a compound represented by the following formula (A), and its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates or isotopic derivatives:

[0009]

[0010] in, represents a single bond or a double bond;

[0011] Y and Z are both selected from C or N, when Y is N, Z is C, when Y is C, Z is N;

[0012] 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;

[0013] 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, C1-6 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;

[0014] 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;

[0015] 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;

[0016] 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 0-6Alkyl-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;

[0017] 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 ;

[0018] 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;

[0019] If present, each R a1 are independently selected from halogen, hydroxy, cyano, amino, nitro, oxo, formyl, 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 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl;

[0020] 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;

[0021] 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;

[0022] R Dis 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;

[0023] 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;

[0024] 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 2-6Alkynyl, -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;

[0025] 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;

[0026] 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;

[0027] 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;

[0028] 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;

[0029] 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;

[0030] If present, each R e4 are each independently selected from hydrogen, C 1-6 Alkyl, C2-6 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;

[0031] Here, Z and Y are included in the atoms or atomic number of ring A.

[0032] 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.

[0033] Preferably, the present invention provides compounds, and stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates or isotopic derivatives thereof, having a structure as shown in formula (A'):

[0034]

[0035] The substituents in formula (A') are as defined in formula (A).

[0036] The present invention also provides a compound represented by the following formula (I), and its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs or solvates:

[0037]

[0038] in, represents a single bond or a double bond;

[0039] Y and Z are both selected from C or N, when Y is N, Z is C, when Y is C, Z is N;

[0040] 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;

[0041] 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, C2-6 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;

[0042] 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;

[0043] 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;

[0044] 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 1-6Alkyl), 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;

[0045] 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 ;

[0046] 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;

[0047] 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, -COC1-6 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;

[0048] 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;

[0049] 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;

[0050] 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, -OC1-6 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;

[0051] 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;

[0052] 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 1-6Alkyl)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;

[0053] 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;

[0054] 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;

[0055] 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)2NRc4 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;

[0056] 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;

[0057] 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;

[0058] 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 2-6Alkynyl, 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;

[0059] Here, Z and Y are included in the atoms or atomic number of ring A.

[0060] 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.

[0061] Preferably, the present invention provides compounds, and stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs or solvates thereof, having a structure as shown in formula (II):

[0062]

[0063] The substituents in formula (II) are as defined in formula (I).

[0064] Preferably, the present invention provides compounds, and stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs or solvates thereof, having a structure as shown in formula (III):

[0065]

[0066] The substituents in formula (III) are as defined in formula (I).

[0067] Preferably, the present invention provides compounds, and stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs or solvates thereof, having a structure as shown in formula (IV):

[0068]

[0069] The substituents in formula (IV) are as defined in formula (I).

[0070] 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 .

[0071] 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;

[0072] 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.

[0073] 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;

[0074] 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.

[0075] 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;

[0076] 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.

[0077] 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;

[0078] If present, each R a1 Each is independently selected from halogen, oxo, formyl, acetyl, methyl, ethyl, n-propyl, isopropyl or methoxy.

[0079] 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;

[0080] If present, each R a1 Each is independently selected from halogen, oxo, formyl, acetyl, methyl, ethyl, n-propyl, isopropyl or methoxy.

[0081] 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;

[0082] If present, each R a1 Each is independently selected from halogen, oxo, formyl, acetyl, methyl, ethyl, n-propyl, isopropyl or methoxy.

[0083] More preferably, R A Selected from the following groups:

[0084] 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 .

[0085] 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;

[0086] 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.

[0087] 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;

[0088] 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.

[0089] 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;

[0090] 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.

[0091] 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;

[0092] If present, each R b1 Each is independently selected from oxo, formyl, acetyl, methyl, ethyl, methoxy or ethoxy.

[0093] More preferably, R B Selected from the following groups:

[0094] 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.

[0095] 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 .

[0096] 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;

[0097] 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.

[0098] 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;

[0099] 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.

[0100] 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;

[0101] 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.

[0102] 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;

[0103] 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.

[0104] 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;

[0105] 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.

[0106] More preferably, RC Selected from

[0107] The R C are optionally replaced by 1-2 identical or different R c1 replace;

[0108] 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.

[0109] More preferably, optionally R c1 Replaced by R C Selected from the following groups:

[0110]

[0111] 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.

[0112] 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.

[0113] 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.

[0114] 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.

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

[0116] More preferably, ring A is selected from the following groups:

[0117] 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;

[0118] 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;

[0119] 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;

[0120] More preferably, R 2 is 1 or 2, each of which, when present, is independently selected from hydrogen or methyl.

[0121] 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;

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

[0123] More preferably, R 3 is selected from hydrogen, halogen, hydroxy, amino, cyano, methyl, ethyl, n-propyl, isopropyl or cyclopropyl;

[0124] More preferably, R 3 is selected from hydrogen, F, Cl, Br, amino, methyl, ethyl or cyclopropyl.

[0125] 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.

[0126] More preferably, ring B is selected from C 6-10 Aryl or C 5-10 Heteroaryl.

[0127] Further preferably, ring B is selected from phenyl or pyridyl.

[0128] 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, C 1-4 Hydroxyalkyl, C3-6 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.

[0129] 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.

[0130] 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.

[0131] 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.

[0132] 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.

[0133] The present invention also provides compounds, and stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates or isotopic derivatives thereof, having a structure as shown in formula (B):

[0134]

[0135] Among them, R 1 Select from -OR A 、-N(R D )R B or R C ;

[0136] When R 1 For-OR A , RA 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;

[0137] 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;

[0138] 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;

[0139] If present, each R b1are 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;

[0140] 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;

[0141] 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;

[0142] If present, each R c1 are independently selected from halogen, hydroxy, cyano, amino, nitro, oxo, formyl, methylsulfonyl, C1-6 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;

[0143] 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;

[0144] 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 3-6Cycloalkyl and 3-6 membered heterocyclyl are both optionally substituted with one or more hydroxyl or halogen;

[0145] 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;

[0146] 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;

[0147] 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.

[0148] 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;

[0149] 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.

[0150] 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;

[0151] 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.

[0152] 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;

[0153] 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.

[0154] 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;

[0155] If present, each R a1 Each is independently selected from halogen, oxo, formyl, acetyl, methyl, ethyl, n-propyl, isopropyl or methoxy.

[0156] 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;

[0157] If present, each R a1 Each is independently selected from halogen, oxo, formyl, acetyl, methyl, ethyl, n-propyl, isopropyl or methoxy.

[0158] 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;

[0159] If present, each R a1 Each is independently selected from halogen, oxo, formyl, acetyl, methyl, ethyl, n-propyl, isopropyl or methoxy.

[0160] More preferably, R A Selected from the following groups:

[0161] In a preferred embodiment of the present invention, R 1 -N(R D )R B , R B Selected from C 1-6 Alkyl, C3-10 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;

[0162] 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.

[0163] 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;

[0164] 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.

[0165] 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;

[0166] 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.

[0167] 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 optionally substituted by 1-2 identical or different R b1 replace;

[0168] If present, each R b1 Each is independently selected from oxo, formyl, acetyl, methyl, ethyl, methoxy or ethoxy.

[0169] More preferably, R B Selected from the following groups:

[0170] 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.

[0171] 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;

[0172] 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.

[0173] 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;

[0174] 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.

[0175] 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;

[0176] 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.

[0177] 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;

[0178] 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.

[0179] 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;

[0180] 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.

[0181] More preferably, R C Selected from

[0182] The R C are optionally replaced by 1-4 identical or different R c1 replace;

[0183] 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.

[0184] More preferably, optionally R c1 Replaced by R C Selected from the following groups:

[0185]

[0186] 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.

[0187] 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.

[0188] More preferably, R 2 is 1 or 2, each of which, when present, is independently selected from hydrogen or methyl.

[0189] More preferably, R 2 For hydrogen.

[0190] 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.

[0191] More preferably, R 3 is selected from hydrogen, halogen, hydroxy, amino, cyano, methyl, ethyl, n-propyl, isopropyl or cyclopropyl.

[0192] More preferably, R 3 is selected from hydrogen, F, Cl, Br, amino, methyl, ethyl or cyclopropyl.

[0193] 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.

[0194] 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.

[0195] More preferably, ring B is selected from phenyl, pyridyl or benzotetrahydrofuranyl.

[0196] 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.

[0197] 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.

[0198] 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.

[0199] 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.

[0200] 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.

[0201] The present invention provides compounds, and stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates or isotopic derivatives thereof, having a structure as shown in formula (C):

[0202]

[0203] The substituents in formula (C) are as defined in formula (B).

[0204] The present invention also provides compounds, and stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates or isotopic derivatives thereof, having a structure as shown in formula (D):

[0205]

[0206] Among them, R 1 , R 4 , w are defined as described in formula (A), (A'), (I), (II), (III), (IV), (B) or (C).

[0207] 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;

[0208] R 1 Select from -OR A 、-N(R D )R B or R C ;

[0209] 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;

[0210] If present, each R a1 Each independently selected from C 1-6 Alkyl or -COC 1-6 alkyl;

[0211] 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;

[0212] If present, each R b1 Each independently selected from -OC 1-6 alkyl;

[0213] R D Selected from hydrogen;

[0214] 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;

[0215] 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.

[0216] 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.

[0217] 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;

[0218] If present, each R a1 Each independently selected from C 1-6 Alkyl or -COC 1-6 alkyl.

[0219] 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;

[0220] If present, each R a1 Each is independently selected from acetyl, methyl, ethyl, n-propyl or isopropyl.

[0221] More preferably, R Ais 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;

[0222] If present, each R a1 Each is independently selected from acetyl, methyl or ethyl.

[0223] 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;

[0224] If present, each R a1 Each is independently selected from acetyl, methyl or ethyl.

[0225] More preferably, R A Selected from the following groups:

[0226] 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;

[0227] If present, each R b1 Each independently selected from -OC 1-4 alkyl.

[0228] 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;

[0229] If present, each R b1Each is independently selected from methoxy or ethoxy.

[0230] More preferably, R B Selected from the following groups:

[0231] 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;

[0232] 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.

[0233] 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;

[0234] 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.

[0235] 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;

[0236] 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.

[0237] More preferably, R C Selected from

[0238] The R C are optionally replaced by 1-4 identical or different R c1 replace;

[0239] 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).

[0240] More preferably, optionally R c1 Replaced by R C Selected from the following groups:

[0241]

[0242]

[0243] In a preferred embodiment of the invention, 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 each optionally substituted with one or more hydroxy groups; w is 1 or 2.

[0244] 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.

[0245] The present invention provides compounds, and stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates or isotopic derivatives thereof, having a structure as shown in formula (E):

[0246]

[0247] The substituents in formula (E) are as defined in formula (D).

[0248] The present invention also provides compounds, and stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates or isotopic derivatives thereof, having a structure as shown in formula (F) or formula (F'):

[0249]

[0250] 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.

[0251] 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., ).

[0252] More preferably, Selected from the following groups:

[0253] The present invention provides compounds, and stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates or isotopic derivatives thereof, having a structure as shown in formula (G) or formula (G'):

[0254]

[0255] 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.

[0256] 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.

[0257] More preferably, Selected from the following groups:

[0258] Preferably, the present invention provides compounds, and stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates or isotopic derivatives thereof, having the following structure:

[0259]

[0260]

[0261]

[0262]

[0263]

[0264]

[0265] Preferably, the present invention provides compounds, and stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates or isotopic derivatives thereof, having the following structure:

[0266]

[0267]

[0268]

[0269]

[0270]

[0271]

[0272] The object of the present invention also includes providing an intermediate for preparing the compound of the present invention, and its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates or isotopic derivatives, wherein the intermediate is shown in formula (V):

[0273]

[0274] Among them, R 2 , R 3 , Ring A, X, Y, and Z are defined as in formula (A), (I) or (II);

[0275] R 5 It is selected from halogen, hydroxy, -O-methylsulfonyl, -O-p-toluenesulfonyl or -O-trifluoromethanesulfonyl, preferably chlorine or hydroxy.

[0276] R 6 is selected from halogen, preferably bromine or iodine.

[0277] The object of the present invention also includes providing an intermediate for preparing the compound of the present invention, and its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates or isotopic derivatives, wherein the intermediate is shown in formula (VI):

[0278]

[0279] Among them, R 2 , R 3 , R 4 , w, ring A, X, Y, and Z are as defined in formula (A) or (I);

[0280] R 6 is selected from halogen, preferably bromine or iodine.

[0281] Furthermore, the compounds of the present invention, and their stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates or isotopic derivatives, have a structure as shown in formula (VII):

[0282]

[0283] Among them, R 2 , R 3 , R 4 , w, ring A, X, Y, and Z are as defined in formula (II);

[0284] R 6 is selected from halogen, preferably bromine or iodine.

[0285] Furthermore, the compounds of the present invention, and their stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates or isotopic derivatives, have a structure as shown in formula (VIII):

[0286]

[0287] Among them, R 2 , R 3 , R 4 , w, ring A, Y, and Z are as defined in formula (III);

[0288] R 6 is selected from halogen, preferably bromine or iodine.

[0289] Furthermore, the compounds of the present invention, and their stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates or isotopic derivatives, have a structure as shown in formula (IX):

[0290]

[0291] Among them, R 2 , R 3 , R 4, w, ring A, Y, and Z are as defined in formula (IV);

[0292] R 6 is selected from halogen, preferably bromine or iodine.

[0293] The present invention also provides a pharmaceutical composition comprising the compound of the present invention, and its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates or isotopic derivatives.

[0294] The present invention also provides a pharmaceutical composition comprising the compound of the present invention, and its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates or isotope derivatives, and pharmaceutically acceptable excipients.

[0295] The present invention also aims to provide the compounds of the present invention, and their stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates or isotopic derivatives or pharmaceutical compositions of the present invention, for use as medicines.

[0296] The present invention also aims to provide the compounds of the present invention, and their stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates or isotopic derivatives or pharmaceutical compositions of the present invention for use in preventing and / or treating diseases mediated by SOS1.

[0297] The present invention also aims to provide the compounds of the present invention, and their stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates or isotopic derivatives or pharmaceutical compositions of the present invention, which are used for preventing and / or treating diseases caused by RAS mutations.

[0298] The present invention also aims to provide the use of the compound of the present invention, and its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates or isotopic derivatives or the pharmaceutical composition of the present invention in the preparation of drugs for preventing and / or treating diseases mediated by SOS1.

[0299] In some embodiments, the disease mediated by SOS1 is cancer or tumor, and diseases related thereto.

[0300] In some embodiments, the disease mediated by SOS1 is lung cancer (eg, non-small cell lung cancer / NSCLC), and diseases related thereto.

[0301] The present invention also aims to provide the use of the compounds of the present invention, and their stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates or isotopic derivatives, or the pharmaceutical compositions of the present invention in the preparation of drugs for preventing and / or treating diseases caused by RAS mutations.

[0302] In some embodiments, the disease caused by the RAS mutation is cancer or tumor, and diseases related thereto.

[0303] In some embodiments, the disease caused by the RAS mutation is lung cancer (eg, non-small cell lung cancer / NSCLC), and its related diseases.

[0304] The present invention also aims to provide a method for preventing and / or treating diseases mediated by SOS1, which comprises administering to a patient a preventive and / or therapeutically effective dose of a compound of the present invention, and its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates or isotopic derivatives or a pharmaceutical composition of the present invention.

[0305] The purpose of the present invention also includes providing a method for preventing and / or treating diseases caused by RAS mutations, which comprises administering to a patient a preventive and / or therapeutically effective dose of a compound of the present invention, and its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates or isotopic derivatives or a pharmaceutical composition of the present invention.

[0306] The purpose of the present invention also includes providing a compound of the present invention, and its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates or isotopic derivatives or the pharmaceutical composition of the present invention for in vitro non-diagnostic and non-therapeutic inhibition of guanine nucleotide exchange factors (GEFs) activity, wherein the guanine nucleotide exchange factor is selected from SOS1.

[0307] The purpose of the present invention also includes providing a method for non-diagnostic and non-therapeutic inhibition of guanine nucleotide exchange factor activity in vitro, which comprises administering to a subject an inhibitory effective dose of a compound of the present invention, and its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates or isotopic derivatives or a pharmaceutical composition of the present invention, wherein the guanine nucleotide exchange factor is selected from SOS1.

[0308] The beneficial effects of the present invention are as follows:

[0309] The present invention designs a class of novel compounds, which provides a new direction for the development of SOS1 inhibitor drugs. In vitro enzyme inhibition test studies show that these compounds have strong inhibitory effects on SOS1 and can be used as promising compounds for preventing and / or treating diseases mediated by SOS1. Moreover, these compounds also show obvious inhibitory activity on NCI-H358 cell proliferation. In addition, the present invention studies a specific synthesis method, which has a simple process, convenient operation, and is conducive to large-scale industrial production and application. DETAILED DESCRIPTION

[0310] [Definition of terms]

[0311] 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.

[0312] 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.

[0313] 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.

[0314] 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.

[0315] 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.

[0316] 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.

[0317] 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.

[0318] 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.

[0319] 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.

[0320] 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.

[0321] 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.

[0322] Unless otherwise specified, the term "hydroxy" refers to a "-OH" group.

[0323] Unless otherwise specified, the term "cyano" refers to a "-CN" group.

[0324] 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.

[0325] Unless otherwise specified, the term "nitro" refers to a "-NO2" group.

[0326] Unless otherwise specified, the term "formyl" or "aldehyde" refers to a "-C(=O)H" group.

[0327] 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).

[0328] 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.

[0329] 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.

[0330] 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.

[0331] 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.

[0332] 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.

[0333] 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.

[0334] 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.

[0335] 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.

[0336] 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.

[0337] 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.

[0338] 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.

[0339] Preparation Example 1: Synthesis of Intermediate A

[0340]

[0341] Synthesis of intermediate A-2

[0342] 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]+ .

[0343] Synthesis of intermediate A-3

[0344] 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] + .

[0345] Synthesis of intermediate A-4

[0346] 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] + .

[0347] Synthesis of Intermediate A

[0348] 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] + .

[0349] The following intermediates can be obtained by referring to the synthesis method of intermediate A or the related synthesis method in CN110167928A.

[0350] If necessary, the crude product was purified by chromatography.

[0351]

[0352]

[0353] Example 1: Synthesis of Compound 1

[0354]

[0355] Synthesis of intermediate 1-1

[0356] 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] + .

[0357] Synthesis of intermediate 1-2

[0358] 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] + .

[0359] Synthesis of intermediate 1-3

[0360] 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] + .

[0361] Synthesis of intermediates 1-4

[0362] 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] + .

[0363] Synthesis of intermediates 1-5

[0364] 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] + .

[0365] Synthesis of intermediates 1-6

[0366] 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] + .

[0367] Synthesis of intermediates 1-7

[0368] 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] + .

[0369] Synthesis of intermediates 1-8

[0370] 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] + .

[0371] Synthesis of compound 1

[0372] 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).

[0373] Example 2: Synthesis of Compound 2

[0374]

[0375] Synthesis of intermediate 2-1

[0376] 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] + .

[0377] Synthesis of intermediate 2-2

[0378] 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] + .

[0379] Synthesis of compound 2

[0380] 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).

[0381] Example 3: Synthesis of Compound 3

[0382]

[0383] 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).

[0384] Example 4: Synthesis of Compound 4

[0385]

[0386] 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).

[0387] Example 5: Synthesis of Compound 5

[0388]

[0389] Synthesis of intermediate 5-1

[0390] 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] + .

[0391] Synthesis of intermediate 5-2

[0392] 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] + .

[0393] Synthesis of intermediate 5-3

[0394] 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] +.

[0395] Synthesis of intermediate 5-4

[0396] 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] + .

[0397] Synthesis of intermediate 5-5

[0398] 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] + .

[0399] Synthesis of intermediate 5-6

[0400] 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] + .

[0401] Synthesis of intermediate 5-7

[0402] 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]+.

[0403] Synthesis of intermediate 5-8

[0404] 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] + .

[0405] Synthesis of compound 5

[0406] 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).

[0407] Example 6: Synthesis of Compound 6

[0408]

[0409] Synthesis of intermediate 6-1

[0410] 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 / z466.91 / 469.12[M+H] + .

[0411] Synthesis of compound 6

[0412] 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 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=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).

[0413] Example 7: Synthesis of Compound 7

[0414]

[0415] Synthesis of intermediate 7-1

[0416] 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] + .

[0417] Synthesis of compound 7

[0418] 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).

[0419] Example 8: Synthesis of Compound 8

[0420]

[0421] Synthesis of intermediate 8-1

[0422] 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] + .

[0423] Synthesis of compound 8

[0424] 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).

[0425] Example 9: Synthesis of Compound 9

[0426]

[0427] Synthesis of intermediate 9-1

[0428] 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] + .

[0429] Synthesis of intermediate 9-2

[0430] 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] + .

[0431] Synthesis of intermediate 9-3

[0432] 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] + .

[0433] Synthesis of intermediate 9-4

[0434] 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] + .

[0435] Synthesis of intermediate 9-5

[0436] 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] + .

[0437] Synthesis of intermediate 9-6

[0438] 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] + .

[0439] Synthesis of intermediate 9-7

[0440] 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] + .

[0441] Synthesis of compound 9

[0442] 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).

[0443] Example 10: Synthesis of Compound 10

[0444]

[0445] Synthesis of Intermediate 10-1

[0446] 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] + .

[0447] Synthesis of compound 10

[0448] 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 HNMR (600MHz, DMSO-d6): δ9.34(s,1H),8.64(d,J=6.6Hz,1H),7.98(d,J=6.6Hz, 1H),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).

[0449] Example 11: Synthesis of Compound 11

[0450]

[0451] Synthesis of Intermediate 11-1

[0452] 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] + .

[0453] Synthesis of intermediate 11-2

[0454] 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] + .

[0455] Synthesis of intermediate 11-3

[0456] 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] + .

[0457] Synthesis of Intermediate 11-4

[0458] 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] + .

[0459] Synthesis of compound 11

[0460] 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).

[0461] Embodiment 12-30:

[0462] The compounds of the following Examples 12-30 can be obtained by referring to the synthesis method of Examples 1-11.

[0463]

[0464]

[0465]

[0466] Example 31: Synthesis of Compound 31

[0467]

[0468] Synthesis of compound 31

[0469] 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).

[0470] Embodiment 32-92:

[0471] The compounds of the following Examples 32-92 can be obtained by referring to the synthesis method of Examples 1-11.

[0472]

[0473]

[0474]

[0475]

[0476]

[0477]

[0478]

[0479]

[0480] Example 93: Synthesis of Compound 93

[0481]

[0482] Synthesis of compound 93

[0483] 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).

[0484] Examples 94-108:

[0485] The compounds of the following Examples 94-108 can be obtained by referring to the synthesis method of Example 93.

[0486]

[0487]

[0488]

[0489] Example 109: Synthesis of Compound 109

[0490]

[0491] 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).

[0492] Examples 110-121:

[0493] The compounds of the following Examples 110-121 can be obtained by referring to the synthesis method of Example 93.

[0494]

[0495]

[0496] Example 122: Synthesis of Compound 122

[0497]

[0498] Synthesis of Intermediate 122-1

[0499] 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] + .

[0500] Synthesis of Intermediate 122-2

[0501] 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] + .

[0502] Synthesis of compound 122

[0503] 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).

[0504] Embodiment 123-124:

[0505] The compounds of the following Examples 123-124 can be obtained by referring to the synthesis method of Example 93.

[0506]

[0507] Example 125: Synthesis of Compound 125

[0508]

[0509] 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).

[0510] Biological activity assay:

[0511] 1. K-Ras G12D Binding analysis with hSOS1

[0512] This assay can be used to examine the potency of compounds to inhibit the protein-protein interaction between SOS1 and KRAS G12D. GST-KRas bound by anti-GSK-Europium (FRET donor) was detected by homogeneous time-resolved fluorescence (HTRF). G12D The binding of compounds to K-Ras G12D Inhibitory effect on hSOS1.

[0513] 1.1 Reagents

[0514] 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);

[0515] GST-tagged hK-RasG12D (produced in-house);

[0516] His-tagged hSOS1 (produced in-house);

[0517] Preparation of Ras mixed solution

[0518] 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.

[0519] Preparation of SOS mixed solution

[0520] 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.

[0521] 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.

[0522] 1.2 Experimental procedures

[0523] All experimental steps were completed at 20°C. In the experiment, 2.5μL of Ras mixture was added to all wells of the detection 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.

[0524] 1.3 Data Calculation

[0525] Calculate and analyze IC using a 4-parameter logic model 50 value.

[0526] 1.4 SOS1 inhibitory activity results

[0527] 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.

[0528] 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

[0529] 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.

[0530] 2.3D cell proliferation inhibition assay

[0531] The cell proliferation inhibition assay is used to detect whether the compounds inhibit the proliferation and growth of SOS1-mediated tumor cell lines at the 3D cell level in vitro. 3D detection method.

[0532] 2.1 Reagents and Materials

[0533] NCI-H358: Non-small cell lung cancer (NSCLC) with KRAS G12C mutation;

[0534] 3D Cell Viability Assay, Promega, G9683;

[0535] RPMI 1640medium,Gibco,A10491-01;

[0536] FBS, Gibco, 10099141C;

[0537] 2.2 Test steps:

[0538] 2.2.1 Cell culture

[0539] Day 1, passage NCI-H358 into T75 cell culture flasks;

[0540] On Day 3, remove the culture medium, rinse once with DPBS, and use 2 mL of TrypLE TM Express Enzyme was used to digest the cells 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 (EchoQualified 384-Well Polypropylene Microplate 2.0, Clear, Flat Bottom).

[0541] 2.2.2 3D cell proliferation inhibition

[0542] 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;

[0543] Day 8: Add 40 μL / well 3D CTG reagent and use Envision to detect the signal value.

[0544] 2.3 Data Analysis

[0545] Fitting compound IC using Graphpad Prism 8 nonlinear regression equation 50 value;

[0546] Y=Bottom+(Top-Bottom) / (1+10^((LogIC50-X)*HillSlope));

[0547] X: Log of cpd concentration;

[0548] Y:Percent inhibition (%inh)

[0549] 2.4 NCI-H358 Cell Proliferation Inhibitory Activity Results

[0550] The compounds in the examples were tested according to the above method, and the data of NCI-H358 cell proliferation inhibition activity are shown in the table below.

[0551] 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

[0552] Among them, A represents IC 50 <50nM, B represents 50nM≤IC 50 <100nM, C represents 100nM≤IC 50 <500nM.

Claims

1. A compound as represented by formula (A), and its stereoisomers, optical isomers or pharmaceutically acceptable salts, in, represents 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 ring A, which is selected from 5-membered monocyclic 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 or 6 / 6-membered spiro heterocyclyl, wherein The heteroatoms in the 5-membered monocyclic heterocyclic group, the 6-membered monocyclic heterocyclic group, the 5-membered monocyclic heteroaryl, the 6-membered monocyclic heteroaryl, the 5 / 5-membered fused heterocyclic group, the 5 / 4-membered fused heterocyclic group, the 5 / 6-membered fused heterocyclic group, the 6 / 5-membered fused heterocyclic group, the 6 / 4-membered fused heterocyclic group, the 6 / 6-membered fused heterocyclic group, the 5 / 3-membered spiro heterocyclic group, the 5 / 5-membered spiro heterocyclic group, the 5 / 4-membered spiro heterocyclic group, the 5 / 6-membered spiro heterocyclic group, the 6 / 3-membered spiro heterocyclic group, the 6 / 5-membered spiro heterocyclic group, the 6 / 4-membered spiro heterocyclic group and the 6 / 6-membered spiro heterocyclic group are each independently selected from N, and the number of heteroatoms is 1-4; 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; 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; Ring B is selected from C 6-12 Aryl, 5-12 membered heteroaryl or C 6-8 Aryl 4-6 membered heterocyclic group; Every 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; X is selected from C, and R connected thereto 1 Select from -OR A 、-N(R D )R B or R C ; When R 1 For-OR A , 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; When R 1 -N(R D )R B , 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; R D Selected from hydrogen, C 1-6 Alkyl or -OC 1-6 alkyl; 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 1-3 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; 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 its stereoisomers, optical isomers or pharmaceutically acceptable salts, characterized in that: The compound has a structure as shown in formula (A'): The substituents in formula (A') are as defined in formula (A) of claim 1.

3. A compound as shown in formula (I), and its stereoisomers, optical isomers or pharmaceutically acceptable salts, in, represents 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 ring A, which is selected from 5-membered monocyclic 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 or 6 / 6-membered spiro heterocyclyl, wherein The heteroatoms in the 5-membered monocyclic heterocyclic group, the 6-membered monocyclic heterocyclic group, the 5-membered monocyclic heteroaryl, the 6-membered monocyclic heteroaryl, the 5 / 5-membered fused heterocyclic group, the 5 / 4-membered fused heterocyclic group, the 5 / 6-membered fused heterocyclic group, the 6 / 5-membered fused heterocyclic group, the 6 / 4-membered fused heterocyclic group, the 6 / 6-membered fused heterocyclic group, the 5 / 3-membered spiro heterocyclic group, the 5 / 5-membered spiro heterocyclic group, the 5 / 4-membered spiro heterocyclic group, the 5 / 6-membered spiro heterocyclic group, the 6 / 3-membered spiro heterocyclic group, the 6 / 5-membered spiro heterocyclic group, the 6 / 4-membered spiro heterocyclic group and the 6 / 6-membered spiro heterocyclic group are each independently selected from N, and the number of heteroatoms is 1-4; 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; 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; Ring B is selected from C 6-12 Aryl, C 5-12 Heteroaryl or C 6-8 Aryl C 4-6 Heterocyclic group; Every 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; X is selected from C, and R connected thereto 1 Select from -OR A 、-N(R D )R B or R C ; When R 1 For-OR A , 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; When R 1 -N(R D )R B , 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; R D Selected from hydrogen, C 1-6 Alkyl or -OC 1-6 alkyl; 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 1-3 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; 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 its stereoisomers, optical isomers or pharmaceutically acceptable salts, characterized in that: The compound has a structure as shown in formula (II): The substituents in formula (II) are defined as in formula (I) of claim 3.

5. The compound according to any one of claims 1 to 4, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, characterized in that: R 1 For-OR A , 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.

6. The compound according to any one of claims 1 to 4, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, characterized in that: R 1 For-OR A , 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.

7. The compound according to any one of claims 1 to 4, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, characterized in that: R 1 For-OR A , 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.

8. The compound according to any one of claims 1 to 4, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, characterized in that: R 1 For-OR A , R A Selected from the following groups:

9. The compound according to any one of claims 1 to 4, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, characterized in that: R 1 -N(R D )R B , 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; R D Selected from hydrogen or C 1-3 alkyl.

10. The compound according to any one of claims 1 to 4, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, characterized in that: R 1 -N(R D )R B , 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; R D is selected from hydrogen or methyl.

11. The compound according to any one of claims 1 to 4, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, characterized in that: R 1 -N(R D )R B , 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; R D Selected from hydrogen.

12. The compound according to any one of claims 1 to 4, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, characterized in that: R 1 -N(R D )R B , 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; R D Selected from hydrogen or C 1-3 alkyl.

13. The compound according to any one of claims 1 to 4, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, characterized in that: R 1 -N(R D )R B , 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; R D is selected from hydrogen or methyl.

14. The compound according to any one of claims 1 to 4, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, characterized in that: R 1 -N(R D )R B , 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; R D Selected from hydrogen.

15. The compound according to any one of claims 1 to 4, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, characterized in that: R 1 -N(R D )R B , R B Selected from the following groups: R D Selected from hydrogen or C 1-3 alkyl.

16. The compound according to any one of claims 1 to 4, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, characterized in that: R 1 -N(R D )R B , R B Selected from the following groups: R D is selected from hydrogen or methyl.

17. The compound according to any one of claims 1 to 4, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, characterized in that: R 1 -N(R D )R B , R B Selected from the following groups: R D Selected from hydrogen.

18. The compound according to any one of claims 1 to 4, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, characterized in that: R 1 For R C , 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, 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.

19. The compound according to any one of claims 1 to 4, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, characterized in that: R 1 For R C , 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.

20. The compound according to any one of claims 1 to 6, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, characterized in that: R 1 For R C , 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.

21. The compound according to any one of claims 1 to 4, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, characterized in that: R 1 For R C , optionally replaced by R c1 Replaced by R C Selected from the following groups:

22. The compound according to any one of claims 1 to 4, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, characterized in that: 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.

23. The compound according to any one of claims 1 to 4, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, characterized in that: Ring A is selected from a 5-membered monocyclic heterocyclic group or a 5-membered monocyclic heteroaryl group, and the heteroatom in the 5-membered monocyclic heterocyclic group and the 5-membered monocyclic heteroaryl group is selected from N, and the number of the heteroatoms is 1-3.

24. The compound according to any one of claims 1 to 4, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, characterized in that: Ring A is selected from the following groups:

25. The compound according to any one of claims 1 to 4, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, characterized in that: Ring A is selected from the following groups:

26. The compound according to any one of claims 1 to 4, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, 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, methoxy, methyl, ethyl, n-propyl or isopropyl.

27. The compound according to any one of claims 1 to 4, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, characterized in that: R 2 is 1 or 2, each of which when present is independently selected from hydrogen, halogen, hydroxy, cyano, amino, nitro, methoxy or methyl.

28. The compound according to any one of claims 1 to 4, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, characterized in that: R 2 is 1 or 2, each of which, when present, is independently selected from hydrogen or methyl.

29. The compound according to any one of claims 1 to 4, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, characterized in that: R 3 is selected from hydrogen, halogen, hydroxy, amino, cyano, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or methoxy.

30. The compound according to any one of claims 1 to 4, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, characterized in that: R 3 is selected from hydrogen, halogen, hydroxy, amino, cyano, methyl, ethyl, n-propyl, isopropyl or cyclopropyl.

31. The compound according to any one of claims 1 to 4, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, characterized in that: R 3 is selected from hydrogen, F, Cl, Br, amino, methyl, ethyl or cyclopropyl.

32. The compound according to any one of claims 1 to 2, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, characterized in that: Ring B is selected from C 6-10 Aryl or 5-10 membered heteroaryl.

33. The compound according to any one of claims 3 to 4, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, characterized in that: Ring B is selected from C 6-10 Aryl or C 5-10 Heteroaryl.

34. The compound according to any one of claims 1 to 4, and its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs or solvates, characterized in that: Ring B is selected from phenyl or pyridyl.

35. The compound according to any one of claims 1 to 4, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, characterized in that: Every 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.

36. The compound according to any one of claims 1 to 4, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, characterized in that: Every 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.

37. The compound according to any one of claims 1 to 4, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, characterized in that: Every 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.

38. A compound represented by formula (B), and its stereoisomers, optical isomers or pharmaceutically acceptable salts, in, 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 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; When R 1 -N(R D )R B , 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; R D Selected from hydrogen, C 1-6 Alkyl or -OC 1-6 alkyl; 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 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; R 2 is 1 or 2, each of which, when present, is independently selected from hydrogen, halogen, hydroxy, cyano, amino, nitro, formyl, oxo, C 1-3 Alkyl or C 1-3 Alkoxy; 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; Ring B is selected from C 6-12 Aryl, C 5-12 Heteroaryl or C 6-8 Aryl C 4-6 Heterocyclic group; Every 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; 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.

39. The compound according to claim 38, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, characterized in that: R 1 For-OR A , 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.

40. The compound according to claim 38, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, characterized in that: R 1 For-OR A , 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.

41. The compound according to claim 38, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, characterized in that: R 1 For-OR A , 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.

42. The compound according to claim 38, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, characterized in that: R 1 For-OR A , R A Selected from the following groups:

43. The compound according to claim 38, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, characterized in that: R 1 -N(R D )R B , 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; R D Selected from hydrogen or C 1-3 alkyl.

44. The compound according to claim 38, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, characterized in that: R 1 -N(R D )R B , 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; R D is selected from hydrogen or methyl.

45. The compound according to claim 38, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, characterized in that: R 1 -N(R D )R B , 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; R D Selected from hydrogen.

46. ​​The compound according to claim 38, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, characterized in that: R 1 -N(R D )R B , 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; R D Selected from hydrogen or C 1-3 alkyl.

47. The compound according to claim 38, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, characterized in that: R 1 -N(R D )R B , 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; R D is selected from hydrogen or methyl.

48. The compound according to claim 38, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, characterized in that: R 1 -N(R D )R B , 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; R D Selected from hydrogen.

49. The compound according to claim 38, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, characterized in that: R 1 -N(R D )R B , R B Selected from the following groups: R D Selected from hydrogen or C 1-3 alkyl.

50. The compound according to claim 38, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, characterized in that: R 1 -N(R D )R B , R B Selected from the following groups: R D is selected from hydrogen or methyl.

51. The compound according to claim 38, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, characterized in that: R 1 -N(R D )R B , R B Selected from the following groups: R D Selected from hydrogen.

52. The compound according to claim 38, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, characterized in that: R 1 For R C , 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, 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.

53. The compound according to claim 38, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, characterized in that: R 1 For R C , 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, 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.

54. The compound according to claim 38, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, characterized in that: R 1 For R C , 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.

55. The compound according to claim 38, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, characterized in that: R 1 For R C , optionally replaced by R c1 Replaced by R C Selected from the following groups:

56. The compound according to claim 38, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, 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.

57. The compound according to claim 38, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, characterized in that: R 2 is 1 or 2, each of which when present is independently selected from hydrogen, halogen, hydroxy, cyano, amino, nitro, methoxy or methyl.

58. The compound according to claim 38, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, characterized in that: R 2 is 1 or 2, each of which, when present, is independently selected from hydrogen or methyl.

59. The compound according to claim 38, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, characterized in that: R 2 For hydrogen.

60. The compound according to claim 38, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, characterized in that: R 3 is selected from hydrogen, halogen, hydroxy, amino, cyano, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or methoxy.

61. The compound according to claim 38, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, characterized in that: R 3 is selected from hydrogen, halogen, hydroxy, amino, cyano, methyl, ethyl, n-propyl, isopropyl or cyclopropyl.

62. The compound according to claim 38, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, characterized in that: R 3 is selected from hydrogen, F, Cl, Br, amino, methyl, ethyl or cyclopropyl.

63. The compound according to claim 38, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, characterized in that: Ring B is selected from C 6-10 Aryl, 5-10 membered heteroaryl or C 6-8 Aryl and 4-6 membered heterocyclic group.

64. The compound according to claim 38, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, characterized in that: Ring B is selected from phenyl, pyridyl or benzotetrahydrofuranyl.

65. The compound according to claim 38, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, characterized in that: Every 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.

66. The compound according to claim 38, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, characterized in that: Every 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.

67. The compound according to claim 38, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, characterized in that: Every 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.

68. The compound according to any one of claims 38 to 67, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, characterized in that: The compound has a structure as shown in formula (C): The substituents in formula (C) are as defined in formula (B) of claim 38.

69. A compound represented by formula (D), and its stereoisomers, optical isomers or pharmaceutically acceptable salts, in, Every R 4 are independently selected from cyano, halogen, amino, C 1-4 Alkyl or C 1-4 haloalkyl, wherein the C 1-4 Alkyl and C 1-4 The haloalkyl groups are optionally substituted with one or more hydroxyl groups; w is 1 or 2; 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 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; 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.

70. The compound according to claim 69, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, characterized in that: R 1 For-OR A , 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 acetyl, methyl or ethyl.

71. The compound according to claim 69, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, characterized in that: R 1 For-OR A , 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 acetyl, methyl or ethyl.

72. The compound according to claim 69, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, characterized in that: R 1 For-OR A , R A Selected from the following groups:

73. The compound according to claim 69, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, 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.

74. The compound according to claim 69, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, characterized in that: R 1 -N(R D )R B , 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 methoxy or ethoxy.

75. The compound according to claim 69, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, characterized in that: R 1 -N(R D )R B , R B Selected from the following groups:

76. The compound according to claim 69, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, 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.

77. The compound according to claim 69, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, characterized in that: R 1 For R C , 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, 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.

78. The compound according to claim 69, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, characterized in that: R 1 For R C , 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, 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.

79. The compound according to claim 69, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, characterized in that: R 1 For R C , 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, -CH(OH)(CH3)2, -CH2OCH3, -CH2CH2OCH3, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, methoxy, acetyl, -COCH2CH3, -COCH2OH, -COCH2CN, -CH2CON(CH3)2, oxadiazole or morpholinyl.

80. The compound according to claim 69, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, characterized in that: R 1 For R C , optionally replaced by R c1 Replaced by R C Selected from the following groups:

81. The compound according to claim 69, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, characterized in that: Every 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.

82. The compound according to any one of claims 69 to 81, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, characterized in that: The compound has a structure as shown in formula (E): The substituents in formula (E) are as defined in formula (D) of claim 69.

83. The following compounds, and their stereoisomers, optical isomers or pharmaceutically acceptable salts:

84. The following compounds, and their stereoisomers, optical isomers or pharmaceutically acceptable salts:

85. A pharmaceutical composition comprising the compound according to any one of claims 1 to 84, and a stereoisomer, optical isomer or pharmaceutically acceptable salt thereof.

86. The pharmaceutical composition according to claim 85, characterized in that The pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

87. Use of a compound according to any one of claims 1 to 84, a stereoisomer, an optical isomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 85 to 86 in the preparation of a medicament for preventing and / or treating a disease mediated by SOS1.

88. The use according to claim 87, characterized in that The disease mediated by SOS1 is cancer or tumor.

89. The use according to claim 87, characterized in that The disease mediated by SOS1 is lung cancer.

90. The use according to claim 89, characterized in that The lung cancer is non-small cell lung cancer.

91. An intermediate compound as represented by formula (V), and its stereoisomers, optical isomers or pharmaceutically acceptable salts, in, represents a double bond; R 2 , R 3 , Ring A, X, Y, Z are defined as described in Formula (A) of claim 1; or, R 2 , R 3 , Ring A, X, Y, Z are defined as described in Formula (I) of claim 3; or, R 2 , R 3 , Ring A, X, Y, Z are defined as described in formula (II) of claim 4; R 5 is selected from halogen, hydroxy, -O-methylsulfonyl, -O-p-toluenesulfonyl or -O-trifluoromethanesulfonyl; R 6 Selected from halogen.

92. The compound according to claim 91, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, characterized in that: R 5 Selected from chlorine or hydroxyl.

93. The compound according to claim 91, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, characterized in that: R 6 Selected from bromine or iodine.

94. An intermediate compound as represented by formula (VI), and its stereoisomers, optical isomers or pharmaceutically acceptable salts, in, represents a double bond; R 2 , R 3 , R 4 , w, ring A, ring B, X, Y, and Z are as defined in formula (A) of claim 1; or, R 2 , R 3 , R 4 , w, ring A, ring B, X, Y, and Z are defined as described in formula (I) of claim 3; R 6 Selected from halogen.

95. The compound according to claim 94, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, characterized in that: R 6 Selected from bromine or iodine.

96. An intermediate compound represented by formula (VII), and its stereoisomers, optical isomers or pharmaceutically acceptable salts, in, represents a double bond; R 2 , R 3 , R 4 , w, ring A, ring B, X, Y, and Z are defined as described in formula (II) of claim 4; R 6 Selected from halogen.

97. The compound according to claim 96, and its stereoisomers, optical isomers or pharmaceutically acceptable salts, characterized in that: R 6 Selected from bromine or iodine.

Images