2-aminopyrimidine compounds having divinylphosphoryl and use thereof

Abstract

Provided are a class of 2-aminopyrimidine compounds having divinylphosphoryl and a use thereof. Specifically, provided are a compound represented by formula (I), a stereoisomer, a tautomer, a crystal form, a pharmaceutically acceptable salt, a hydrate, a solvate or a prodrug thereof. The compound is an EGFR inhibitor, and can be used for preparing a drug for treating and / or preventing EGFR-related diseases.

Description

A class of 2-aminopyrimidine compounds with divinylphosphonic groups and their applications Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to a class of 2-aminopyrimidine compounds with a divinylphosphonate group and their applications. Background Technology

[0002] Epidermal growth factor receptor (EGFR), also known as ErbB1 (HER1), is a transmembrane glycoprotein belonging to the ErbB family of receptor tyrosine kinases. This family also includes ErbB2 (HER2, NEU), ErbB3 (HER3), and ErbB4 (HER4). EGFR consists of 1186 amino acids and its structure is mainly composed of an extracellular domain (N-terminus), a transmembrane domain (hydrophobic α-helix structure), and an intracellular domain (C-terminus). When ligands such as epidermal growth factor (EGF) or tumor necrosis factor (TNF-α) bind to the extracellular domain, the kinase region of EGFR forms a homodimer or undergoes heterodimerization with other family members. In this dimerization conformation, the kinase region of EGFR can be phosphorylated by ATP, triggering the autophosphorylation of key tyrosine residues in the cytoplasmic regulatory region, thereby activating downstream signaling pathways involved in cell proliferation and survival, such as the Ras / Raf / MEK / ERK1 / 2, PI3K / AKT, and JAK / STAT pathways. EFGR mutations lead to persistent activation of the EGFR signaling pathway and cause abnormal cell proliferation. In tumor cells, various oncogenic factors affect the tyrosine activation of EGFR, including EGFR gene mutations, EGFR protein overexpression, and increased gene copy number. Abnormal activation of EGFR tyrosine kinase inhibits normal tumor cell apoptosis and promotes their survival, proliferation, invasion, and metastasis. Many types of tumors exhibit high EGFR expression, such as head and neck tumors, colorectal cancer, and lung cancer. Currently, EGFR has become one of the important therapeutic targets in the field of anti-tumor therapy, and an increasing number of small molecule EGFR inhibitors are widely used clinically, such as gefitinib, erlotinib, icotinib, and osimertinib.

[0003] Lung cancer is one of the most common malignant tumors, with the highest incidence rate globally. Approximately 1.6 million new cases of lung cancer are diagnosed each year, which can be divided into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), with NSCLC accounting for about 85%. EGFR is the most common driver gene in NSCLC, with a positive rate of 17% in all NSCLC cases. In China, about 30% of lung cancer patients have EGFR mutations, mainly L858R point mutations and exon 19 deletion mutations, accounting for over 90% of cases. These patients are sensitive to EGFR inhibitors. First-generation EGFR inhibitors such as erlotinib and gefitinib have shown good efficacy, shrinking tumors and prolonging progression-free survival in over 60% of patients. However, the vast majority of patients develop resistance within 6-12 months, with the "gatekeeper" mutation T790M significantly reducing sensitivity to first-generation inhibitors. Second-generation irreversible pan-EGFR inhibitors (such as afatinib) are significantly more effective than first-generation inhibitors in EGFR-mutant lung cancer patients. However, these drugs also possess strong wild-type EGFR inhibitory activity, and their inhibitory activity against wild-type EGFR is significantly higher than that against the resistant T790M mutation, causing toxic side effects such as skin rashes, and resulting in poor efficacy in resistant patients. Third-generation inhibitors, represented by osimertinib, have successfully solved the T790M resistance problem and exhibit high selectivity against wild-type EGFR. However, current third-generation EGFR inhibitors also show resistance issues, primarily due to EGFR-dependent resistance mutations, such as the C797S mutation. This mutation leads to the loss of covalent binding sites, resulting in a significant reduction in drug efficacy.

[0004] Therefore, there is an urgent clinical need for a novel EGFR inhibitor with high selectivity and efficacy. Summary of the Invention

[0005] To address the above problems, the present invention provides 2-aminopyrimidine compounds with a divinylphosphonate group, wherein the covalently charged divinylphosphonate group is mounted on a small molecule compound with a 2-aminopyrimidine skeleton.

[0006] In a first aspect, the present invention provides a compound of formula (I), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs.

[0007] in,

[0008] W is selected from the following group: not found, O, S, NR a CR b R b '; where R a R b and R bEach element is independently selected from the following groups: H, halogens, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups;

[0009] Cycle A is selected from the following group: 4-12 membered heterocyclic groups, C 6-10 Aryl, 5-12 heteroaryl;

[0010] R1 and R1' are each independently selected from the following groups: H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-10 A cyclic alkyl group, a 4-10 membered heterocyclic group, or R1, R1' together with the nitrogen atom attached thereto form a 4-9 membered nitrogen-containing heterocyclic group, wherein the nitrogen-containing heterocyclic group is optionally further substituted by a 4-9 membered nitrogen-containing heterocyclic group; one or more hydrogen atoms on each of the above groups (including each nitrogen-containing heterocyclic group) are optionally replaced by R c replace;

[0011] Among them, R c Selected from the following groups: halogen, cyano, hydroxyl, amino, carboxyl, C 1-6 amide group, C 2-6 Ester group, oxy group (=O), C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 sulfonyl, C 3-8 Cycloalkyl groups;

[0012] R2 is selected from the following group: H, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 4-10 membered heterocyclic groups, C 6-10 aryl, 5-9 membered heteroaryl; one or more hydrogens on the above groups are optionally R c replace;

[0013] R3, R4, R5, and R5' are each independently selected from the following groups: H, halogens, C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy groups; or R5, R5' and the atoms attached to them together form 5-7 heteroaryl groups;

[0014] In each of the above groups, one, two, three, or four hydrogens are optionally substituted by groups selected from the group consisting of: halogen, cyano, hydroxyl, amino, carboxyl, C. 1-6 amide group, C 2-6 Ester group, oxy group (=O), C 1-6 Alkyl, C 1-6 Alkoxy;

[0015] Unless otherwise specified, the heteroaryl group is an aromatic cyclic group containing 1, 2, 3 or 4 heteroatoms selected from N, O or S on a cyclic skeleton; the heterocyclic group is a saturated or partially unsaturated cyclic group containing 1, 2, 3 or 4 heteroatoms selected from N, O or S that is not aromatic, and it can be a monocyclic, fused, bridged or spirocyclic group.

[0016] In another preferred embodiment, W is NH.

[0017] In another preferred embodiment, W is absent.

[0018] In a preferred embodiment, ring A is selected from the group consisting of: 4-7 member monoheterocyclic groups, 9-12 member fused heterocyclic groups, phenyl, naphthyl, 5-7 member monoheteroaryl, and 9-12 member fused heteroaryl.

[0019] Preferably, ring A is selected from the group consisting of 9-12 member nitrogen-containing fused heterocyclic groups, phenyl groups, and 9-12 member nitrogen-containing fused heteroaryl groups;

[0020] More preferably, the ring A is selected from the group consisting of: phenyl 5-7-membered nitrogen-containing heterocyclic group, 5-7-membered nitrogen-containing heteroaryl 5-7-membered nitrogen-containing heterocyclic group, phenyl, 5-7-membered nitrogen-containing heteroaryl 5-7-membered nitrogen-containing heteroaryl, and phenyl 5-7-membered nitrogen-containing heteroaryl.

[0021] In another preferred embodiment, W is NH and ring A is phenyl.

[0022] In another preferred embodiment, W is absent, and ring A is selected from the group consisting of phenyl 5-7-membered nitrogen-containing heterocyclic groups and phenyl 5-7-membered nitrogen-containing heteroaryl groups; and ring A is connected to a pyridine ring via a nitrogen atom.

[0023] In a preferred embodiment, R1 and R1' are each independently selected from the group consisting of: H, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-8 A 5-8 membered nitrogen-containing monoheterocyclic group is formed by a cycloalkyl group, a 4-8 membered heterocyclic group, or R1, R1' together with the nitrogen atom attached thereto, wherein the nitrogen-containing heterocyclic group is optionally further replaced by a 5-8 membered nitrogen-containing heterocyclic group;

[0024] Preferably, R1 and R1' are each independently selected from the group consisting of: H, C1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-7 A 5-7 membered nitrogen-containing monoheterocyclic group is formed by a cycloalkyl group, a 4-7 membered heterocyclic group, or R1, R1' together with the nitrogen atom attached thereto, wherein the nitrogen-containing heterocyclic group is optionally further replaced by a 5-7 membered nitrogen-containing heterocyclic group;

[0025] More preferably, R1 and R1' are each independently selected from the following group: C 1-4 Alkyl groups, or R1, R1', together with the nitrogen atom attached to them, form a group selected from the following group:

[0026] In another preferred embodiment, the R c Selected from the following groups: halogen, cyano, hydroxyl, amino, carboxyl, C 1-4 amide group, C 2-4 Ester group, oxy group (=O), C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 1-4 sulfonyl, C 3-6 Cycloalkyl group.

[0027] In a preferred embodiment, R2 is selected from the group consisting of: H, halogens, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 3-8 Cycloalkyl, 4-8-membered heterocyclic, phenyl, 5-7-membered heteroaryl;

[0028] Preferably, R2 is selected from the group consisting of: H, fluorine, chlorine, bromine, and C. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Fluoroalkyl, C 3-7 Cycloalkyl, 4-7 heterocyclic, phenyl, 5-7 nitrogen-containing heteroaryl.

[0029] In another preferred embodiment, R3, R4, R5, and R5' are each independently selected from the group consisting of: H, halogens, C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy groups; or R5, R5' and the atoms attached to them together form 5-6 heteroaryl groups.

[0030] In a preferred embodiment, R3 is selected from the group consisting of: H, C 1-4Alkyl, C 1-4 Alkyl group.

[0031] In another preferred embodiment, R4 is selected from the group consisting of: H, halogens, C. 1-4 alkyl.

[0032] In a preferred embodiment, R5 and R5' are selected from the group consisting of: H, fluorine, chlorine, bromine, and C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy groups, or R5, R5', together with the atoms attached to them, form 5-6 membered heteroaryl groups.

[0033] In another preferred embodiment, R5' is H.

[0034] In another preferred embodiment, R5, R5' and the atoms attached to them together form a 5-6 member sulfur-containing heteroaryl group.

[0035] In a preferred embodiment, the compound has the structure shown in formula (II):

[0036] The definitions of rings A, W, Y, R2, R3, R5, and R5' are as described above;

[0037] Y is selected from the following group: O, NR e or CR f R f ';

[0038] R e R f and R f Each element is independently selected from the following groups: H, halogens, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Sulfonyl group, 4-9 membered heterocyclic group; one or more hydrogen atoms in each of the above groups are optionally substituted by groups selected from the group consisting of: halogen, cyano, hydroxyl, amino, carboxyl, C 1-4 amide group, C 2-4 Ester group, oxy group (=O), C 1-4 Alkyl, C 1-4 Alkyl group.

[0039] In another preferred embodiment, the R e C 1-4 alkyl.

[0040] In another preferred embodiment, the R f and R f Each is independently selected from the following groups: H, C 1-4 Alkylamino, 5-7 membered nitrogen-containing heterocyclic groups.

[0041] In another preferred embodiment, the compound has the structure shown in formula (III) or formula (IV):

[0042] The definitions of Y, R2, R3, R5, and R5' are as described above.

[0043] In a preferred embodiment, the compound is selected from the group consisting of:

[0044] A second aspect of the present invention provides a pharmaceutical composition comprising:

[0045] (i) the compounds, stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs as described in the first aspect of the invention; and

[0046] (ii) Pharmaceutically acceptable carriers, excipients or excipients.

[0047] A second aspect of the invention provides the use of compounds, stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs as described in the first aspect of the invention, or pharmaceutical compositions as described in the second aspect of the invention, for the preparation of medicaments for the treatment and / or prevention of diseases mediated by kinase activity or expression levels selected from the group consisting of: ACK, ALK, AXL, BRK, CSF1R, EGFR, FAK, FER, FES, FGFR1, FGFR2, FGFR3, FGR, FLT3, FLT4, FRK, FYN[isoform a], FYN[isoform b], HCK, HER4, IGF1R, INSR, IRR, ITK, JAK1, JAK2, JAK3, KDR, KIT, LCK, LYNa, LYNb, MER, PDGFRα, PDGFRβ, PYK2, RET, ROS, SRC, SRM, TRKA, TRKB, TRKC, TXK, YES;

[0048] Preferably, the diseases associated with kinase activity or expression level are selected from the group consisting of: tumors, cancers, and malignant cell proliferation.

[0049] More preferably, the diseases associated with kinase activity or expression are selected from the group consisting of: lung cancer, colorectal cancer, brain tumor, kidney cancer, liver cancer, bile duct cancer, thyroid cancer, gastric cancer, esophageal cancer, oral cancer, nasopharyngeal cancer, pancreatic cancer, sarcoma, bladder cancer, breast cancer, cervical cancer, endometrial cancer, ovarian cancer, and prostate cancer. In another preferred embodiment, the kinase is EGFR, more preferably EGFR. L858R,T790M,C797S .

[0050] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Attached Figure Description

[0051] Figure 1 shows the relationship between compound B11 and EGFR. L858R,T790M,C797S High-resolution mass spectrum of the intact protein after incubation. Detailed Implementation

[0052] Through long-term and in-depth research and extensive screening, the inventors discovered for the first time that the divinylphosphonate group is a novel irreversible covalent warhead targeting lysine. When this group is mounted on a suitable kinase inhibitor backbone, it can undergo an irreversible reaction with the kinase protein's catalytic lysine, forming a covalent bond and permanently inhibiting the protein's enzymatic function. Based on this, this invention utilizes this divinylphosphonate group as a covalent warhead, mounting it on a class of small molecules with a 2-aminopyrimidine backbone, obtaining a series of compounds with strong inhibitory activity against various EGFR mutants and good selectivity for wild-type EGFR, which is of significant value for the development of related antitumor drugs.

[0053] the term

[0054] As used herein, the terms “containing” or “including (comprise)” can be open-ended, semi-closed, or closed-ended. In other words, the terms also include “consistently made of” or “made of”.

[0055] As used herein, the term "alkyl" refers to a monovalent, straight-chain or branched saturated hydrocarbon group consisting of carbon and hydrogen atoms, for example, "C 1-6 "Alkyl" means an alkyl group having 1 to 6 carbon atoms (e.g., 1, 2, 3, 4, 5, or 6). Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl. In this application, alkyl is also intended to include deuterated alkyl groups, examples of which include, but are not limited to, CD3, CD2CD3, and CD2CD2CD3.

[0056] As used herein, the term "alkenyl" refers to a straight-chain or branched unsaturated hydrocarbon group consisting of carbon and hydrogen atoms and having at least one double bond, such as "C 2-6 "Alkenyl" refers to an alkenyl group having 2 to 6 (e.g., 2, 3, 4, 5, or 6) carbon atoms. Examples of alkenyl groups include, but are not limited to: vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, and 1,3-butadienyl.

[0057] As used herein, the term "alkynyl" refers to a straight-chain or branched unsaturated hydrocarbon group consisting of carbon and hydrogen atoms and having at least one triple bond. For example, "C 2-6 "Alynyl" refers to an alkynyl group having 2 to 6 (e.g., 2, 3, 4, 5, or 6) carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, and 1-butynyl.

[0058] As used herein, the term "cycloalkyl" refers to a monovalent saturated carbocyclic group consisting of carbon and hydrogen atoms, such as "C". 3-8 "Cycloalkyl" refers to a cycloalkyl group containing 3 to 8 (e.g., 3, 4, 5, 6, 7, or 8) carbon atoms, preferably C4. 3-6 Cycloalkyl groups. Cycloalkyl groups can be monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or similar groups, or bicyclic, such as fused rings, bridged rings or spirocyclic rings.

[0059] As used herein, the term "alkoxy" refers to the formula -OR z Group, wherein R z Alkyl groups are defined herein. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, tert-butoxy, etc.

[0060] As used herein, "halogen" refers to F, Cl, Br, I and their isotopes, including but not limited to F, 18 F, Cl, 32 Cl, Br, I.

[0061] As used in this article, the term "nitro" refers to -NO2.

[0062] As used in this article, the term "cyano" refers to -CN.

[0063] As used in this article, the term "amino" refers to -NH2.

[0064] As used in this article, the term "carboxyl group" refers to -COOH.

[0065] As used in this article, the term "oxo" refers to the =O portion.

[0066] As used herein, the term "ester group" refers to -COOR y , where Ry It can be independently selected from the group consisting of: hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclic groups. Examples of ester groups include, but are not limited to: -COOCH3, -COOCH2CH3, -COOCH2CH2CH3, -COOCH2CH(CH3)2, etc.

[0067] As used herein, the term "amide group" refers to -CONR x R x ', where R x and R x It can be independently selected from the group consisting of: hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclic. R x and R x They can be the same or different. Examples of amide groups include, but are not limited to: -CONH2, -CONHCH3, -CON(CH3)2, etc.

[0068] As used herein, the term "haloalkyl" refers to a group obtained by substituting one or more hydrogen atoms in an alkyl group as described above with the same or different halogens. Wherein, "C..." 1-6 "Halogenated alkyl" is preferably C 1-4 Haloalkyl groups, examples of which include, but are not limited to: -CH2Cl, -CH2CF3, -CH2CCl3, perfluoroalkyl groups (e.g., -CF3-, -CF2CF3), etc.

[0069] As used herein, the term "haloalkoxy" refers to a group obtained by substituting one or more hydrogen atoms in an alkoxy group as described above with the same or different halogens. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, 2,2,2-trifluoroethoxy, etc.

[0070] As used herein, the term "alkylamino" refers to the formula -NR u R u 'group, wherein R u and R u Each is independently H or an alkyl group as defined herein, and R u and R u 'Not both H. Alkylamino can be monoalkylamino or dialkylamino, and examples of alkylamino include, but are not limited to: N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino, etc.

[0071] As used herein, the term "acyl" refers to a group of the formula -C(O)-. The acyl group is preferably -C(O)C.1-6 Alkyl group, -C(O)NHC 1-6 Alkyl, -C(O)N(C) 1-6 Alkyl group 2, more preferably -C(O)C1-C3 alkyl group, -C(O)NH2, -C(O)NHC 1-3 Alkyl, -C(O)N(C1-C3 alkyl)2. Examples of acyl groups include, but are not limited to: acetyl, n-propionyl, isopropionyl, n-butyryl, isobutyryl, tert-butyryl, -C(O)NHCH3, -C(O)N(CH3)2, etc.

[0072] As used herein, the term "sulfonyl" refers to the -S(O)2- group. The sulfonyl group is preferably -S(O)2-(C 1-6 Alkyl groups, such as -S(O)2-CH3, -S(O)2-CH2CH3, etc.

[0073] As used herein, the term "heterocyclic group" refers to a fully or partially saturated monocyclic, bicyclic, or polycyclic cyclic group with one or more heteroatoms selected from N, S, or O. For example, "4-7 membered heterocyclic group" refers to a group having 4-7 (e.g., 4, 5, 6, or 7) ring members. The nitrogen or sulfur atom may be oxidized, or the nitrogen atom may be quaternized. The heterocyclic group can be attached to any heteroatom or carbon residue in a ring or ring system molecule. Monocyclic heterocyclic groups include, but are not limited to: azacyclic butyl, pyrrolyl, oxacyclic butyl, pyrazolinyl, imidazolinyl, imidazoalkyl, oxazolinyl, isoxazolinyl, thiazoalkyl, isothiazolinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperidinyl, 2-oxopiperidinyl, 2-oxopiperylyl, hexahydroachenginyl, 4-piperidinoneyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxane, and tetrahydro-1,1-dioxothiophene, etc. Polycyclic heterocyclic groups include, but are not limited to, spirocyclic, fused-ring, and bridged-ring heterocyclic groups; wherein the spirocyclic, fused-ring, and bridged-ring heterocyclic groups involved are optionally connected to other groups by single bonds, or further cyclically linked to other cycloalkyl, heterocyclic, aryl, and heteroaryl groups by any two or more atoms on the ring.

[0074] As used herein, the term "fused heterocyclic group" refers to a bicyclic structure formed by the fusion of two rings, which is not aromatic as a whole, and wherein at least one ring is a heteroaromatic ring; preferably, one ring is a benzene ring or a 5-6 membered heteroaromatic ring, and the other ring is a 5-6 membered heterocycle. Fused heterocyclic groups can be attached to other groups at any possible position, and examples of fused heterocyclic groups include, but are not limited to:

[0075] As used herein, the term "bi-heterocyclic group" refers to two or more heterocycles linked by carbon-carbon single bonds, for example...

[0076] As used herein, the term "aryl" refers to an aromatic cyclic hydrocarbon group (including monocyclic, bicyclic, or polycyclic groups), such as "C 6-12 "Aryl" refers to an aromatic cyclic hydrocarbon group having 6-12 (6, 7, 8, 9, 10, 11, or 12) ring carbon atoms. It contains two or more aromatic rings (such as bicyclic rings), and the aromatic rings of the aryl group can be linked by single bonds (such as biphenyl) or fused (such as naphthalene, anthracene, etc.). Examples of aryl groups (especially monocyclic and bicyclic groups) include, but are not limited to, phenyl, biphenyl, or naphthyl. Aryl groups can be fused with heterocyclic groups through single bonds or any two adjacent ring carbon atoms, for example: benzotetrahydrofuranyl, benzotetrahydropyranyl, benzodioxane, etc. wait.

[0077] As used herein, the term "heteroaryl" refers to an aromatic cyclic group (including monocyclic, bicyclic, or polycyclic groups) whose cyclic skeleton contains 1, 2, 3, or 4 heteroatoms selected from N, S, or O. For example, "5-12-membered heteroaryl" refers to a monocyclic, bicyclic, or tricyclic group having 5 to 12 (5, 6, 7, 8, 9, 10, 11, or 12) ring atoms. Examples of heteroaryl groups include, but are not limited to: imidazole, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, thiophene, furanyl, pyranyl, pyridinyl, pyrroleyl, pyrazolyl, pyrimidinyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothiophene, benzothiaranyl, benzoimidazolyl, benzooxazolyl, benzooxadiazolyl, benzothiazolyl, benzothiazolyl, benzopyranyl, indoleyl, isoindoleyl, triazolyl, triazinyl, quinoxolinyl, purine, quinazolinyl, quinazinyl, naphridinyl, pteridinyl, carbazoleyl, and azazolyl. basalt, diazoxide acridine group, etc.

[0078] As used herein, the term "fused heteroaryl" refers to a bicyclic structure formed by the fusion of two rings, wherein at least one ring is a heteroaryl ring; preferably, one ring is a benzene ring or a 5-6 membered heteroaryl ring, and the other ring is a 5-6 membered heteroaryl ring. Fused heteroaryl groups can be attached to other groups at any possible position, and examples of fused heteroaryl groups include, but are not limited to:

[0079] In this invention, the alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups, unless otherwise specified, include substituted alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups. The substituents include, but are not limited to, halogen, hydroxyl, cyano, acyl, sulfonyl, ester, sulfinyl, alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, acyl, and ester groups.

[0080] As used herein, the term "substitution" refers to the replacement of one or more hydrogen atoms on a particular group by a particular substituent. The particular substituent is either the substituent described accordingly above or the substituent appearing in the various embodiments. Unless otherwise specified, a substituted group may have a substituent selected from a particular group at any substituted site of that group, and the substituents may be the same or different at each position. Those skilled in the art will understand that the combinations of substituents contemplated in this invention are those that are stable or chemically feasible.

[0081] Unless otherwise specified, the groups described in this invention may be substituted with substituents selected from the group consisting of: D, halogen, cyano, nitro, hydroxyl, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, 3-12 membered heterocyclic groups, C3-C6 alkyl, ... 12 cycloalkyl, 5-10 heteroaryl and C6-C 10 Aryl.

[0082] In this document, “optionally” means that the event or condition described below may, but is not required to, occur, and the description includes both the possibility that the event or condition occurs and the possibility that the event or condition does not occur.

[0083] In this article, the term "multiple" refers to 2, 3, 4, 5, or a positive integer greater than 5.

[0084] Active ingredients

[0085] As used herein, “compound of the present invention” means a compound of formula (I), and also includes its stereoisomers, its optical isomers, its pharmaceutically acceptable salts, its crystal forms, its isotopic derivatives, its prodrugs, its metabolites, its solvates or hydrates thereof.

[0086] Unless otherwise specified, the structural formulas described in this invention are intended to include all stereoisomers (such as cis-trans isomers, enantiomers, diastereomers, and conformational isomers): R and S configurations containing an asymmetric center, (Z) and (E) isomers of double bonds, cis-trans isomers of cycloalkanes, etc. Therefore, any single stereochemical isomer of the compounds of this invention, or a mixture of its enantiomers, diastereomers, or conformational isomers, is within the scope of this invention.

[0087] The compounds of this invention may contain cis-trans isomers, one or more chiral carbon atoms, and thus can produce cis-trans isomers, chiral isomers, enantiomers, diastereomers, and other combinations of stereoisomers. Cis-trans isomerism refers to the diastereomeric phenomenon in which different functional groups in a compound molecule are arranged differently in space due to a restrictive factor that limits free rotation. This restrictive factor is generally caused by non-rotating functional groups in the structure of organic compounds, such as C=C double bonds, C=N double bonds, C=S double bonds, N=N double bonds, heterocycles, or cycloalkanes. Organic molecules containing such isomers, such as alkenes, azo compounds, and cycloalkanes, are considered cis-trans isomers. Cis refers to the same ligands being in adjacent positions, generally denoted by "cis" or "cis-"; trans refers to the same ligands being in diagonal positions, generally denoted by "trans" or "trans-". Each chiral carbon atom can be defined as (R)- or (S)- based on stereochemistry. This invention aims to include all possible isomers, their racemic and optically pure forms. The compounds of this invention can be prepared using racemic, cis-trans, chiral, diastereomer, or enantiomers as starting materials or intermediates. Optically active isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as crystallization and chiral chromatography.

[0088] Conventional techniques for preparing / separating individual optical isomers (i.e., cis-trans isomers and chiral isomers) include chiral synthesis from suitable cis-trans precursors or optically pure precursors, or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high-performance liquid chromatography.

[0089] To design the synthesis of a specific stereoisomer of the compound of this invention, it can be prepared asymmetrically or derivatized with a chiral auxiliary. The resulting stereo mixture is then separated, and the chiral auxiliary is removed to obtain pure cis-trans monomers, chiral monomers, or mixed stereoisomers. If the molecule contains a cis-trans isomer center, it can be purified by column chromatography (normal-phase silica gel column or reverse-phase high-performance liquid chromatography) to obtain pure cis or trans products. Alternatively, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, it can be formed with a suitable optically active acid or base to form a diastereomeric salt, which is then separated by conventional methods such as separation crystallization or chromatography to obtain pure enantiomers.

[0090] This invention also includes isotopically labeled compounds (i.e., isotopic derivatives), equivalent to the original compounds disclosed herein. However, it is common practice to see one or more atoms replaced by atoms with different atomic weights or mass numbers. Examples of isotopes in the isotopic derivatives of this invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine isotopes, respectively as follows: 2 H, 3 H,13 C 11 C 14 C 15 N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F and 36 Cl. Isotope derivatives of the compounds of this invention are all within the scope of protection of this invention. In this document, 3 H-labeled compounds and 14 C-labeled compounds are useful in tissue distribution experiments of drugs and substrates. Tritium (i.e., 3 H) and carbon-14 (i.e. 14 C) Labeled compounds are relatively easy to prepare and detect, making them the preferred choice among isotopes. Furthermore, heavier isotope substitutions, such as deuterium, are also possible. 2 H, due to its excellent metabolic stability, offers advantages in certain therapies, such as increasing half-life or reducing dosage in vivo, and therefore may be preferred in some cases. Isotopically labeled compounds can be prepared using general methods, by replacing the non-isotopic reagent with an readily available isotopically labeled reagent, according to the scheme disclosed in the examples.

[0091] As used herein, the term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0092] "Pharmaceutically acceptable acid addition salts" refer to salts formed with inorganic or organic acids that retain the bioavailability of the free base without other side effects. Inorganic acid salts include, but are not limited to, hydrochlorides, hydrobroms, sulfates, nitrates, and phosphates; organic acid salts include, but are not limited to, formates, acetates, 2,2-dichloroacetate, trifluoroacetate, propionates, hexanoates, octanoates, decanoates, undecenoates, glycolates, gluconates, lactates, sebates, adipates, glutarate, malonates, oxalates, maleates, succinates, fumarates, tartrates, citrates, palmitates, stearates, oleates, cinnamates, laurates, malates, glutamates, pyroglutamates, aspartate, benzoates, methanesulfonates, benzenesulfonates, p-toluenesulfonates, alginates, ascorbic acid salts, salicylates, 4-aminosalicylic acid salts, and naphthalene disulfonates. These salts can be prepared using methods known in this field.

[0093] "Pharmaceutically acceptable base addition salts" refer to salts formed with inorganic or organic bases that retain the bioavailability of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Preferred inorganic salts are ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, the following: primary amines, secondary amines, and tertiary amines; substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. These salts can be prepared by methods known in the art.

[0094] Metabolites of the compound represented by formula (I) and its pharmaceutically acceptable salts, as well as prodrugs that can be converted in vivo into the compound represented by formula (I) and its pharmaceutically acceptable salts, are also included within the scope of protection of this invention.

[0095] As used herein, the term "solvent" refers to a complex of a compound of formula (I) coordinated with a solvent molecule in a specific ratio.

[0096] As used herein, the term "hydrate" refers to a complex of the compound represented by formula (I) coordinated with water molecules in a specific ratio.

[0097] As described herein, the compounds of the present invention can be substituted with any number of substituents or functional groups to broaden their scope. Generally, the term "substitution" refers to replacing a hydrogen radical with a substituent of a specified structure. When multiple positions in a particular structure are substituted by multiple specific substituents, each position of the substituent can be the same or different. The term "substitution" as used herein includes all permissible organic group substitutions. In a broad sense, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic groups. As described herein, heteroatomic nitrogen may be supplemented with a hydrogen substituent or any permissible organic group described above to complete its valence state. Furthermore, the present invention is not intended to limit permissible substituted organic groups in any way. The present invention considers the combination of substituents and variable groups to be beneficial in the treatment of diseases in the form of stable compounds. The term "stable" here means having a stable compound that, when tested over a sufficiently long period, maintains sufficient integrity of the compound structure, preferably remaining effective for a sufficiently long period, and is used herein for the purposes described above.

[0098] Pharmaceutical Compositions and Administration

[0099] Because the compounds of this invention can inhibit EGFR and are used to treat diseases such as lung cancer, colorectal cancer, brain tumors, kidney cancer, liver cancer, bile duct cancer, thyroid cancer, stomach cancer, esophageal cancer, oral cancer, nasopharyngeal cancer, pancreatic cancer, sarcoma, bladder cancer, breast cancer, cervical cancer, endometrial cancer, ovarian cancer, and prostate cancer, the compounds of this invention, their stereoisomers, their optical isomers, their pharmaceutically acceptable salts, their crystal forms, their isotope derivatives, their prodrugs, their metabolites, their solvates or hydrates thereof, and pharmaceutical compositions containing the compounds of this invention as the main active ingredient, can be used to prevent and / or treat (stabilize, alleviate or cure) EGFR-related diseases (lung cancer, colorectal cancer, brain tumors, kidney cancer, liver cancer, bile duct cancer, thyroid cancer, stomach cancer, esophageal cancer, oral cancer, nasopharyngeal cancer, pancreatic cancer, sarcoma, bladder cancer, breast cancer, cervical cancer, endometrial cancer, ovarian cancer, prostate cancer, etc.).

[0100] The pharmaceutical compositions of the present invention comprise the compound of the present invention within a safe and effective range and a pharmaceutically acceptable excipient or carrier. "Safe and effective range" refers to an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably, 10-200 mg of the compound of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0101] "Pharmaceutically acceptable carriers" refer to one or more compatible solid or liquid fillers or gelling substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with and with the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), and emulsifiers (such as Tween). Wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0102] There are no particular limitations on the administration of the compounds or pharmaceutical compositions of the present invention. Representative administration methods include, but are not limited to, oral administration and parenteral administration (intravenous, intramuscular, or subcutaneous).

[0103] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following components: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain complex silicates, and sodium carbonate; (e) slowing agents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. Buffers may also be included in capsules, tablets, and pills.

[0104] Solid dosage forms such as tablets, sugar pills, capsules, pellets, and granules can be prepared using coatings and shells, such as casings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compound from such compositions can be delayed in a portion of the digestive tract. Examples of encapsulating components that can be used are polymeric substances and waxes. If necessary, the active compound may also be formed into microcapsules with one or more of the excipients described above.

[0105] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0106] In addition to these inert diluents, the composition may also contain auxiliaries such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.

[0107] In addition to the active ingredient, the suspension may contain suspending agents, such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0108] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0109] Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays, and inhalers. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as needed.

[0110] The compounds of this invention can be administered alone or in combination with other pharmaceutically acceptable compounds.

[0111] When administered in combination, the pharmaceutical composition further comprises one or more (two, three, four, or more) other pharmaceutically acceptable compounds. One or more (two, three, four, or more) of these other pharmaceutically acceptable compounds may be used simultaneously, separately, or sequentially with the compounds of the present invention for the prevention and / or treatment of EGFR-related diseases.

[0112] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is administered to the mammal (such as a human) requiring treatment. The dosage at the time of administration is the pharmaceutically considered effective dose. For a person weighing 60 kg, the daily dose is typically 1-2000 mg, preferably 20-500 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the scope of the skill of a skilled physician.

[0113] The main advantages of this invention are:

[0114] The compounds of this invention exhibit strong inhibitory activity against various mutants of EGFR and good selectivity against wild-type EGFR. Therefore, the compounds of this invention are of great value for the development of related anti-tumor drugs.

[0115] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, were generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are weight percentages and parts by weight.

[0116] Preparation of intermediates

[0117] Synthesis of intermediate M1

[0118] Step 1: Synthesis of compound M1-2

[0119] Take a 100ml round-bottom flask and add 1-methyl-4-(piperidin-4-yl)piperazine (3.2g) and K2CO3 (2g) to 40ml of DMF solution (2g) of M1-1. Stir at 70℃ for 5h. After the reaction is complete, add it to water and extract with ethyl acetate. Repeat the process several times. Combine the organic phases and wash with saturated brine. Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (PE:EA = 1:1) to obtain yellow solid M1-2 (2.3g). LCMS (ESI): m / z = 398 [M+H] + .

[0120] Step 2: Synthesis of compound M1

[0121] Take a 100ml round-bottom flask, add 2.32g of NH4Cl solid dissolved in water to 26ml of EtOH solution containing 1.3g of M1-2, then add 1g of iron powder, displace the nitrogen gas, and reflux at 75℃ with stirring for 2h. After the reaction is complete, filter with diatomaceous earth, evaporate the filtrate to dryness, then add it to water and extract with ethyl acetate. Repeat the process several times, combine the organic phases, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain brown solid M1. LCMS (ESI): m / z = 368 [M+H] + .

[0122] Synthesis of intermediate M2

[0123] Step 1: Synthesis of compound M2-2

[0124] Take a 100ml round-bottom flask and add 1-methyl-4-(piperidin-4-yl)piperazine (0.9g) and K2CO3 (0.6g) to a 20ml DMF solution of M2-1 (1g). Stir at 70℃ for 5h. After the reaction is complete, add it to water and extract with ethyl acetate. Repeat the process several times, combine the organic phases, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (PE:EA = 1:1) to obtain a yellow solid M2-2 (1.2g). LCMS (ESI): m / z = 376 [M+H] + .

[0125] Step 2: Synthesis of compound M2

[0126] Take a 100ml round-bottom flask, add Pd / C to 24ml of MeOH solution containing 1.2g of M2-2 to displace hydrogen gas, and stir at room temperature for 5 hours. After the reaction is complete, filter the diatomaceous earth and add the filtrate to silica gel for mixing. The crude product is purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain a white solid M2 (0.8g). LCMS (ESI): m / z = 346 [M+H] + .

[0127] Synthesis of intermediate M3

[0128] Step 1: Synthesis of compound M1-3

[0129] Take 100 ml of sealed tube (bracket end), add 0.8 g of 1-methyl-4-pyrazoleboronic acid pinacol ester, 0.2 g of G2-sphos, 0.15 g of sphos, and 1.1 g of K2CO3 to the EtOH (24 ml) solution of M1-2 (1.2 g), replace with nitrogen gas, and stir at 80 °C for 5 h. After the reaction is complete, add it to water, extract with ethyl acetate, repeat the process several times, combine the organic phases, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (PE:EA = 1:2) to obtain brown liquid M3-1 (0.8 g). LCMS (ESI): m / z = 443 [M+H] + .

[0130] Step 2: Synthesis of Compound 3

[0131] Take a 100ml round-bottom flask, add Pd / C to 16ml of MeOH solution (0.8g) of M3-1 to displace hydrogen gas, and stir at room temperature for 5 hours. After the reaction is complete, filter with diatomaceous earth, and add the filtrate to silica gel for mixing. The crude product is purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain brown liquid M3 (0.6g). LCMS (ESI): m / z = 413 [M+H] + .

[0132] Synthesis of intermediate M4

[0133] Step 1: Synthesis of compound M4-2

[0134] Take a 100ml round-bottom flask and add N-methylpiperazine (0.5g) and K2CO3 (1g) to a DMF (20ml) solution of M4-1 (1g). Stir at 70℃ for 5h. After the reaction is complete, add it to water and extract with ethyl acetate. Repeat the process several times. Combine the organic phases and wash with saturated brine. Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (PE:EA = 1:1) to obtain a yellow solid M4-2 (1g). LCMS (ESI): m / z = 286 [M+H] + .

[0135] Step 2: Synthesis of compound M4-3

[0136] Take 100 ml of sealed tube (bracket end), add 0.87 g of 1-methyl-4-pyrazoleboronic acid pinacol ester, 0.23 g of G2-sphos, 0.15 g of sphos, and 0.96 g of K2CO3 to a 20 ml EtOH solution of M4-2 (1 g), replace with nitrogen gas, and stir at 80 °C for 5 h. After the reaction is complete, add it to water, extract with ethyl acetate, repeat the process several times, combine the organic phases, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (PE:EA = 1:2) to obtain a brown liquid M4-3 (0.7 g). LCMS (ESI): m / z = 332 [M+H] + .

[0137] Step 3: Synthesis of compound M4

[0138] Take a 100ml round-bottom flask, add Pd / C to a MeOH (14ml) solution of M4-3 (0.7g) to displace hydrogen gas, and stir at room temperature for 5 hours. After the reaction is complete, filter the diatomaceous earth and add the filtrate to silica gel for mixing. The crude product is purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain a white solid M4 (0.5g). LCMS (ESI): m / z = 302 [M+H] + .

[0139] Synthesis of intermediate M5

[0140] Step 1: Synthesis of compound M5-2

[0141] Take a 100ml round-bottom flask, add pyran (0.55g) and K2CO3 (1.1g) to 20ml of DMF solution containing 1g of M5-1, and stir at 70℃ for 5h. After the reaction is complete, add it to water and extract with ethyl acetate. Repeat the process several times, combine the organic phases, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (PE:EA = 1:1) to obtain a yellow solid M5-2. LCMS (ESI): m / z = 257 [M+H] + .

[0142] Step 2: Synthesis of compound M5-3

[0143] Take 38 ml of the sealing tube (bracket). Add 0.5 g of 1-methyl-4-pyrazoleboronic acid pinacol ester, 0.16 g of G2-sphos, 0.1 g of sphos, and 0.6 g of K2CO3 to the EtOH (10 ml) solution of M5-2 (0.56 g), purging with nitrogen, and stir at 80 °C for 5 h. After the reaction is complete, add it to water and extract with ethyl acetate. Repeat the process several times, combine the organic phases, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (PE:EA = 1:2) to obtain brown liquid M5-3 (0.3 g). LCMS (ESI): m / z = 303 [M+H] + .

[0144] Step 3: Synthesis of compound M5

[0145] Take a 50ml round-bottom flask, add Pd / C to 6ml of MeOH solution containing 0.3g of M4-3 to displace hydrogen gas, and stir at room temperature for 5 hours. After the reaction is complete, filter the diatomaceous earth and add the filtrate to silica gel for mixing. The crude product is purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain a white solid M5. LCMS (ESI): m / z = 273 [M+H] + .

[0146] Synthesis of intermediate M6

[0147] Step 1: Synthesis of compound M6-2

[0148] Take a 100ml round-bottom flask and add 1-methyl-4-(piperidin-4-yl)piperazine (6g) and K2CO3 (6.7g) to a 60ml DMF solution of M6-1 (3g). Stir at 70℃ for 5h. After the reaction is complete, add it to water and extract with ethyl acetate. Repeat the process several times, combine the organic phases, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (PE:EA = 1:1) to obtain brown liquid M6-2 (2g). LCMS (ESI): m / z = 349 [M+H] + .

[0149] Step 2: Synthesis of compound M6

[0150] Take a 100ml round-bottom flask, add Pd / C to 40ml of MeOH solution containing 2g of M6-2 to replace the hydrogen gas, and stir at room temperature for 5 hours. After the reaction is complete, filter with diatomaceous earth, and add the filtrate to silica gel for mixing. The crude product is purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain brown liquid M6 (1.5g). LCMS (ESI): m / z = 319 [M+H] + .

[0151] Synthesis of intermediate M7

[0152] Step 1: Synthesis of compound M7-2

[0153] Take a 100ml round-bottom flask and add 0.5g of 1-methyl-4-(piperidin-4-yl)piperazine and 0.5g of K2CO3 to 10ml of DMF solution (2g) of M7-1. Stir at 70℃ for 5h. After the reaction is complete, add it to water and extract with ethyl acetate. Repeat the process several times, combine the organic phases, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (PE:EA = 1:1) to obtain a yellow solid M7-2 (1.69g). LCMS (ESI): m / z = 369 [M+H] + .

[0154] Step 2: Synthesis of compound M7

[0155] Take a 100ml round-bottom flask, add 2g of NH4Cl solid dissolved in water (4ml) to 14ml of EtOH solution (0.69g) of M7-2, then add 1.5g of iron powder, displace nitrogen gas, and stir at 90℃ for 2h. After the reaction is complete, filter with diatomaceous earth, evaporate the filtrate to dryness, then add it to water and extract with ethyl acetate. Repeat the operation several times, combine the organic phases, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain brown liquid M7. LCMS (ESI): m / z = 339 [M+H] + .

[0156] Synthesis of intermediate M8

[0157] Step 1: Synthesis of compound M8-1

[0158] Take 38 ml of sealed tube (bracket end), add 0.67 g of 1-methyl-4-pyrazoleboronic acid pinacol ester, 0.2 g of G2-sphos, 0.11 g of sphos, and 0.75 g of K2CO3 to 15 ml of EtOH solution of M7-2 (1 g), replace with nitrogen gas, and stir at 80 °C for 5 h. After the reaction is complete, add it to water, extract with ethyl acetate, repeat the process several times, combine the organic phases, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (PE:EA = 1:2) to obtain brown liquid M8-1 (0.6 g). LCMS (ESI): m / z = 415 [M+H] + .

[0159] Step 2: Synthesis of compound M8

[0160] Take a 100ml round-bottom flask, add Pd / C to 12ml of MeOH solution containing M8-1 (0.6g) to displace hydrogen gas, and stir at room temperature for 5 hours. After the reaction is complete, filter the diatomaceous earth and add the filtrate to silica gel for mixing. The crude product is purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain gray solid M8 (0.4g). LCMS (ESI): m / z = 385 [M+H] + .

[0161] Synthesis of intermediate M9

[0162] Step 1: Synthesis of compound M9-2

[0163] Take a 100ml round-bottom flask and add 1-methyl-4-(piperidin-4-yl)piperazine (1.5g) and K2CO3 (1.5g) to a 20ml DMF solution of M9-1 (1g). Stir at 70℃ for 5h. After the reaction is complete, add it to water and extract with ethyl acetate. Repeat the process several times, combine the organic phases, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (PE:EA = 1:1) to obtain a yellow solid M9-2 (1.2g). LCMS (ESI): m / z = 373 [M+H] + .

[0164] Step 2: Synthesis of compound M9

[0165] Take a 100ml round-bottom flask, add Pd / C to 24ml of MeOH solution containing 1.2g of M9-2 to displace hydrogen gas, and stir at room temperature for 5 hours. After the reaction is complete, filter the diatomaceous earth and add the filtrate to silica gel for mixing. The crude product is purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain a white solid M9 (0.8g). LCMS (ESI): m / z = 353 [M+H] + .

[0166] Synthesis of intermediate M10

[0167] Step 1: Synthesis of compound M10-2

[0168] Take a 100ml round-bottom flask and add 1.2g of 4-methanesulfonyl-piperidine and 1.2g of K2CO3 to 20ml of DMF solution containing 1g of M10-1. Stir at 70℃ for 5 hours. After the reaction is complete, add it to water and extract with ethyl acetate. Repeat the process several times. Combine the organic phases and wash with saturated brine. Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (PE:EA = 1:1) to obtain a yellow solid M10-2 (1g). LCMS (ESI): m / z = 320 [M+H] + .

[0169] Step 2: Synthesis of compound M10

[0170] Take a 100ml round-bottom flask, add 1.2g of NH4Cl solid dissolved in water to a 1g EtOH solution of M10-2, then add 2.4g of iron powder, displace the nitrogen gas, and stir at 90℃ for 2h. After the reaction is complete, filter with diatomaceous earth, evaporate the filtrate to dryness, then add it to water and extract with ethyl acetate. Repeat the operation several times, combine the organic phases, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain a brown liquid M10. LCMS (ESI): m / z = 290 [M+H] + .

[0171] Synthesis of intermediate M11

[0172] Step 1: Synthesis of compound M11-2

[0173] Take a 100ml round-bottom flask, add pyran (0.5g) and K2CO3 (1g) to 20ml of DMF solution containing 1g of M11-1, and stir at 70℃ for 5h. After the reaction is complete, add it to water and extract with ethyl acetate. Repeat the process several times, combine the organic phases, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (PE:EA = 1:1) to obtain a yellow solid M10-2 (1.2g). LCMS (ESI): m / z = 273 [M+H] + .

[0174] Step 2: Synthesis of compound M11

[0175] Take a 100ml round-bottom flask, add 0.8g of NH4Cl solid dissolved in water to 12ml of EtOH solution (M11-2, 0.6g), then add iron powder (1.6g), replace with nitrogen gas, and stir at 90℃ for 2h. After the reaction is complete, filter with diatomaceous earth, evaporate the filtrate to dryness, then add it to water and extract with ethyl acetate. Repeat the operation several times, combine the organic phases, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain brown liquid M11 (0.4g). LCMS (ESI): m / z = 253 [M+H] + .

[0176] Synthesis of intermediate M12

[0177] Step 1: Synthesis of compound M12-1

[0178] Take 15 ml of sealed tube (bracket end), add 0.28 g of 1-methyl-4-pyrazoleboronic acid pinacol ester, 0.15 g of G2-sphos, 0.08 g of sphos, and 0.7 g of K2CO3 to 6 ml of EtOH solution (0.3 g of M11-2), replace with nitrogen gas, and stir at 80 °C for 5 h. After the reaction is complete, add it to water, extract with ethyl acetate, repeat the process several times, combine the organic phases, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (PE:EA = 1:2) to obtain brown liquid M12-1 (0.2 g). LCMS (ESI): m / z = 319 [M+H] + .

[0179] Step 2: Synthesis of compound M12

[0180] Take a 50ml round-bottom flask, add Pd / C to 4ml of MeOH solution containing 0.2g of M12-1 to displace hydrogen gas, and stir at room temperature for 5 hours. After the reaction is complete, filter the diatomaceous earth and add the filtrate to silica gel for mixing. The crude product is purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain a brown liquid M12. LCMS (ESI): m / z = 289 [M+H] + .

[0181] Synthesis of intermediate M13

[0182] Step 1: Synthesis of compound M13-2

[0183] Take a 100ml round-bottom flask and add pyran (0.6g) and K2CO3 (1.2g) to a 20ml DMF solution of M13-1 (1g). Stir at 70℃ for 5h. After the reaction is complete, add it to water and extract with ethyl acetate. Repeat the process several times. Combine the organic phases and wash with saturated brine. Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (PE:EA = 1:1) to obtain a yellow solid M13-2 (0.86g). LCMS (ESI): m / z = 243 [M+H] + .

[0184] Step 2: Synthesis of compound M13-3

[0185] Take 38 ml of sealed tube (bracket end), add 0.88 g of 1-methyl-4-pyrazoleboronic acid pinacol ester, 0.25 g of G2-sphos, 0.15 g of sphos, and 1 g of K2CO3 to 15 ml of EtOH solution containing 0.86 g of M13-2, replace with nitrogen gas, and stir at 80 °C for 5 h. After the reaction is complete, add it to water, extract with ethyl acetate, repeat the process several times, combine the organic phases, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (PE:EA = 1:2) to obtain a yellow solid M13-3 (0.6 g). LCMS (ESI): m / z = 289 [M+H] + .

[0186] Step 3: Synthesis of compound M13

[0187] Take a 50ml round-bottom flask, add Pd / C to 12ml of MeOH solution containing 0.6g of M13-3 to displace hydrogen gas, and stir at room temperature for 5 hours. After the reaction is complete, filter the diatomaceous earth and add the filtrate to silica gel for mixing. The crude product is purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain a white solid M13. LCMS (ESI): m / z = 259 [M+H] + .

[0188] Synthesis of intermediate M14

[0189] Step 1: Synthesis of compound M14-1

[0190] Take 15 ml of sealed tube (bracket end), add 1-ethyl-4-pyrazoleboronic acid pinacol ester (0.1 g), G2-sphos (26 mg), sphos (15 mg), and K2CO3 (0.1 g) to 2 ml of EtOH solution of M11-2 (0.1 g), replace with nitrogen gas, and stir at 80 °C for 5 h. After the reaction is complete, add it to water, extract with ethyl acetate, repeat the process several times, combine the organic phases, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (PE:EA = 1:1) to obtain brown liquid M14-1 (0.1 g). LCMS (ESI): m / z = 333 [M+H] + .

[0191] Step 2: Synthesis of compound M14

[0192] Take a 25ml round-bottom flask, add Pd / C to 2ml of MeOH solution containing 0.1g of M14-1 to displace hydrogen gas, and stir at room temperature for 5 hours. After the reaction is complete, filter the diatomaceous earth and add the filtrate to silica gel for mixing. The crude product is purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain a white solid M14 (60mg). LCMS (ESI): m / z = 303 [M+H] + .

[0193] Synthesis of intermediate M15

[0194] Step 1: Synthesis of compound M15-1

[0195] Take 15 ml of sealed tube (bracket end), add 0.1 g of 1-cyclopropyl-4-pyrazoleboronic acid pinacol ester, 27 mg of G2-sphos, 16 mg of sphos, and 0.1 g of K2CO3 to 2 ml of EtOH solution (0.1 g) of M11-2, replace with nitrogen gas, and stir at 80 °C for 5 h. After the reaction is complete, add it to water, extract with ethyl acetate, repeat the process several times, combine the organic phases, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (PE:EA = 1:1) to obtain brown liquid M15-1 (0.1 g). LCMS (ESI): m / z = 345 [M+H] + .

[0196] Step 2: Synthesis of compound M15

[0197] Take a 25ml round-bottom flask, add Pd / C to 2ml of MeOH solution containing 0.1g of M15-1 to displace hydrogen gas, and stir at room temperature for 5 hours. After the reaction is complete, filter the diatomaceous earth and add the filtrate to silica gel for mixing. The crude product is purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain a white solid M15 (70mg). LCMS (ESI): m / z = 315 [M+H] + .

[0198] Synthesis of intermediate M16

[0199] Step 1: Synthesis of compound M16-2

[0200] Take a 100ml round-bottom flask and add N,N,N'-trimethylethylenediamine (0.94g) and K2CO3 (0.89g) to a 20ml solution of M16-1 (1g) in DMF. Stir at 70℃ for 5h. After the reaction is complete, add it to water and extract with ethyl acetate. Repeat the process several times, combine the organic phases, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (PE:EA = 1:1) to obtain a yellow solid M16-2 (0.8g). LCMS (ESI): m / z = 317 [M+H] + .

[0201] Step 2: Synthesis of compound M16

[0202] Take a 100ml round-bottom flask, add 0.44g of NH4Cl solid dissolved in water to 10ml of EtOH solution (0.5g) of M16-2, then add 0.85g of iron powder, displace nitrogen gas, and stir at 90℃ for 2h. After the reaction is complete, filter with diatomaceous earth, evaporate the filtrate to dryness, then add it to water and extract with ethyl acetate. Repeat the operation several times, combine the organic phases, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain brown solid M16 (0.5g). LCMS (ESI): m / z = 287 [M+H] + .

[0203] Synthesis of intermediate M17

[0204] Step 1: Synthesis of compound M17

[0205] Take 38 ml of the sealed tube (with a branch end), add Pd / C to 6 ml of MeOH solution containing 0.5 g of M17-1 to displace hydrogen gas, and stir at room temperature for 5 h. After the reaction is complete, filter the diatomaceous earth and add the filtrate to silica gel for mixing. The crude product is purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain a white solid M17. LCMS (ESI): m / z = 412 [M+H] + .

[0206] Synthesis of intermediate M18

[0207] Step 1: Synthesis of compound M18-2

[0208] Take a 100ml round-bottom flask and add 1-methyl-4-(piperidin-4-yl)piperazine (5.8g) and K2CO3 (5.8g) to 20ml of DMF solution (4g) of M18-1. Stir at 70℃ for 5h. After the reaction is complete, add it to water and extract with ethyl acetate. Repeat the process several times. Combine the organic phases and wash with saturated brine. Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (PE:EA = 1:1) to obtain yellow solid M18-2 (5.6g). LCMS (ESI): m / z = 336 [M+H] + .

[0209] Step 2: Synthesis of compound M18-3

[0210] In a 100ml round-bottom flask, dibromohydantoin (2.56g) was slowly added to a 40ml DMF solution of M18-2 (2g) under ice-water bath conditions. The reaction was allowed to proceed to room temperature for 15min, then quenched with sodium thiosulfate. The mixture was then added to water and extracted with ethyl acetate. This process was repeated several times. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (PE:EA = 1:2) to obtain a brown liquid, M18-3 (0.25g). LCMS (ESI): m / z = 414 / 416 [M+H] + .

[0211] Step 3: Synthesis of compound M18-4

[0212] Take 38 ml of sealed tube (with branch end), and add MeB(OH)₂ (54 mg), Pd(dppf)Cl₂ (88 mg), and Cs₂O₃ (393 mg) to 5 ml of MeOH solution containing 0.25 g of M18-3. After the reaction is complete, filter with diatomaceous earth and add the filtrate to silica gel for mixing. Purify the crude product by silica gel column chromatography (DCM:MeOH = 10:1) to obtain a white solid M18-4 (50 mg). LCMS (ESI): m / z = 350 [M+H] + .

[0213] Step 4: Synthesis of compound M18

[0214] Take a 50ml round-bottom flask, add Pd / C to 2ml of a MeOH solution containing 50mg of M18-4 to displace hydrogen gas, and stir at room temperature for 5 hours. After the reaction is complete, filter the diatomaceous earth and add the filtrate to silica gel for mixing. The crude product is purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain a white solid M18 (40mg). LCMS (ESI): m / z = 273 [M+H] + .

[0215] Synthesis of intermediate M19

[0216] Step 1: Synthesis of compound M19-2

[0217] Take a 100ml round-bottom flask and add morpholine (2.3g) and DIEA (4.4ml) to a 50ml DMF solution of M19-1 (5g). Stir at room temperature for 10 hours. After the reaction is complete, add it to water and extract with ethyl acetate. Repeat the process several times. Combine the organic phases and wash with saturated brine. Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (PE:EA = 1:1) to obtain a yellow solid M19-2 (6.4g). LCMS (ESI): m / z = 240 [M+H] + .

[0218] Step 2: Synthesis of compound M19-3

[0219] Take a 100ml round-bottom flask and slowly add NBS (1.1g) to a CH3CN (26ml) solution of M19-2 (1.3g) under ice-water bath conditions. Raise the temperature to room temperature and react for 2 hours. Quench the reaction with sodium thiosulfate, then add the solution to water and extract with ethyl acetate. Repeat this process several times. Combine the organic phases and wash with saturated brine. Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. Purify the crude product by silica gel column chromatography (PE:EA = 1:2) to obtain a brown liquid M19-3 (1.5g). LCMS (ESI): m / z = 318 / 320 [M+H] + .

[0220] Step 3: Synthesis of compound M19-4

[0221] Take 15 ml of sealed tube (bracket end), add 1-methyl-4-pyrazoleboronic acid pinacol ester (1.2 g), G2-sphos (0.34 g), sphos (0.2 g), and K2CO3 (1.3 g) to a commercially available solution of M19-3 (1.5 g) in EtOH (30 ml), replace with nitrogen, and stir at 80 °C for 5 h. After the reaction is complete, add it to water, extract with ethyl acetate, repeat the process several times, combine the organic phases, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, add silica gel powder and concentrate under reduced pressure to obtain crude product. The crude product is purified by silica gel column chromatography (PE:EA = 1:2) to obtain brown liquid M19-4 (1.2 g). LCMS (ESI): m / z = 320 [M+H]+.

[0222] Step 2: Synthesis of compound M19

[0223] Take a 100ml round-bottom flask, add 1.2g of solid NH4Cl dissolved in water to 24ml of EtOH solution containing 1.2g of M19-4, then add 1.1g of iron powder, displace the nitrogen gas, and stir at 90℃ for 2h. After the reaction is complete, filter with diatomaceous earth, evaporate the filtrate to dryness, then add it to water and extract with ethyl acetate. Repeat the process several times, combine the organic phases, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain brown solid M19 (0.5g). LCMS (ESI): m / z = 290 [M+H] + .

[0224] Example 1: Synthesis of Compound A1

[0225] Step 1: Synthesis of Compounds 1-2

[0226] Take a 500ml round-bottom flask and add diethyl phosphite (12.6g), Pd(OAc)₂ (1.24g), DPPF (3.04g), and DIEA (17.7g) to 1-1 (10g) of DMF / DME solution (150ml / 15ml). Replace with nitrogen and reflux at 100℃ with stirring for 10h. After the reaction is complete, add it to water and extract with ethyl acetate. Repeat this process several times, combine the organic phases, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (PE:EA = 3:1) to obtain a brown liquid 1-2 (12g). LCMS (ESI): m / z = 230 [M+H] + .

[0227] Step 2: Synthesis of compounds 1-3

[0228] Take a 100ml three-necked flask and, at 0℃, add 0.98g of 60% NaH to 1-2 (1g) of DMF solution (10ml), stir for 30min, then add it to 10ml of 2,4-dichlorothiophenepyrimidine DMF solution. After the addition is complete, gradually restore to room temperature and stir overnight. Once the reaction is complete, add it to water and extract with ethyl acetate. Repeat this process several times, combine the organic phases, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (PE:EA = 2:1) to obtain a brown liquid 1-3 (0.8g). LCMS (ESI): m / z = 398 [M+H] + .

[0229] Step 3: Synthesis of compounds 1-4

[0230] Take 15 ml of the sealed tube, add 1-3 (0.8 g), SOCl2 solution (3 ml), and a few drops of DMF, and stir at 90 °C for 10 h. After the reaction is complete, concentrate directly under reduced pressure to obtain crude product 1-4. LCMS (ESI): m / z = 370 [M+H] + .

[0231] Step 4: Synthesis of compounds 1-5

[0232] Take a 100ml three-necked flask and dissolve crude product 1-4 (0.9g) in 18ml ultradry THF solution, purging under nitrogen. Add vinyl magnesium bromide slowly dropwise at -78℃, reacting for 2 hours after the addition is complete. After the reaction is complete, return to room temperature and quench with NH4Cl. Add water and extract with ethyl acetate. Repeat this process several times, combining the organic phases and washing with saturated brine. Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. Purify the crude product by silica gel column chromatography (PE:EA = 1:1) to obtain a light brown solid 1-5 (0.5g). LCMS (ESI): m / z = 362 [M+H] + .

[0233] Step 5: Synthesis of compound A1

[0234] Take 15 ml of sealed tube, add 1-6 (67 mg) and TFA (83 μL) to 1 ml of t-BuOH solution (40 mg) of 1-5, and stir at 110 °C for 10 h. After the reaction is complete, add water, adjust the pH to weakly alkaline with NaHCO3, extract with ethyl acetate, repeat the process several times, combine the organic phases, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain crude product. The crude product is purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain a pale yellow oil liquid A1 (40 mg). Further purification by pre-HPLC (HCl) yields a pale yellow solid (20 mg). LCMS (ESI): m / z = 630 [M+H] + . 1H NMR (400MHz, Methanol-d4) δ8.28 (s, 1H), 8.09 (s, 1H), 7.77 (dt, J = 15.5, 8.0 Hz,2H),7.70–7.49(m,2H),7.30(d,J=5.3Hz,2H),7.02(s,1H),6.67(m,J=27. 1,18.5,12.7Hz,2H),6.47–6.12(m,4H),3.94(s,3H),3.94–3.40(m,12H),3. 35(s,1H),3.05(s,3H),2.50(d,J=14.6Hz,2H),2.37(td,J=11.9,3.7Hz,2H).

[0235] Example 2 Synthesis of compound A2

[0236] Step 1: Synthesis of compound A2

[0237] Take 15 ml of the sealed tube, add M1 (61 mg) and TFA (83 μL) to 1 ml of a 40 mg t-BuOH solution, and stir at 110 °C for 10 h. After the reaction is complete, add water, adjust the pH to weakly alkaline with NaHCO3, extract with ethyl acetate, repeat the process several times, combine the organic phases, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain a pale yellow oil solid A2 (45 mg). Further purification by pre-HPLC (HCl) yields a pale yellow solid (22 mg). LCMS (ESI): m / z = 693 [M+H] + . 1 H NMR(400MHz, Methanol-d4)δ8.35–8.05(m,2H),7.69(td,J=22.2,10.8Hz,3H),7.52–7.46( m,1H),7.32(d,J=5.4Hz,1H),6.86(s,1H),6.67(m,J=26.8,18.3,12.9Hz,2H),6.42–6.21(m ,4H),4.72(hept,J=6.0Hz,1H),3.53(d,J=11.8Hz,10H),3.40(s,1H),2.99(s,3H),2.88–2. 78(m,2H),2.28(d,J=11.6Hz,2H),2.01(qd,J=10.2,8.6,5.5Hz,2H),1.29(d,J=6.0Hz,6H).

[0238] Example 3 Synthesis of compound A3

[0239] Step 1: Synthesis of compound A3

[0240] Take 15 ml of the sealed tube, add M2 (58 mg) and TFA (83 μL) to 1 ml of a 40 mg t-BuOH solution, and stir at 110 °C for 10 h. After the reaction is complete, add water, adjust the pH to weakly alkaline with NaHCO3, extract with ethyl acetate, repeat the process several times, combine the organic phases, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain a pale yellow oil solid A3 (38 mg). Further purification by pre-HPLC (HCl) yields a pale yellow solid (20 mg). LCMS (ESI): m / z = 673 [M+H]+. 1H NMR(400MHz, Methanol-d4)δ8.29–8.24(m,2H),7.78–7.65(m,2H),7.49(s,1H),7.39–7.28(m ,2H),6.94(s,1H),6.77-6.57(m,J=26.7,18.4,12.9Hz,2H),6.42–6.19(m,4H),4.70(hept,J =6.0Hz,1H),3.71(m,J=77.7Hz,10H),3.42(d,J=12.2Hz,2H),3.05(s,3H),3.01(d,J=12.8Hz ,1H),2.38(d,J=9.8Hz,2H),2.24(s,3H),2.15(dd,J=12.0,3.8Hz,2H),1.27(d,J=6.0Hz,6H).

[0241] Example 4 Synthesis of compound A4

[0242] Step 1: Synthesis of compound A4

[0243] Take 15 ml of the sealed tube, add M3 (68 mg) and TFA (83 μL) to 1 ml of a 40 mg t-BuOH solution, and stir at 110 °C for 10 h. After the reaction is complete, add water, adjust the pH to weakly alkaline with NaHCO3, extract with ethyl acetate, repeat the process several times, combine the organic phases, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain a pale yellow oil solid A4 (44 mg). Further purification by pre-HPLC (HCl) yields a pale yellow solid (25 mg). LCMS (ESI): m / z = 738 [M+H] + . 1 H NMR(400MHz, Methanol-d4)δ8.25(d,J=5.4Hz,1H),8.10(s,1H),7.77(s,1H),7.64(s,1H),7.5 2(s,2H),7.31(d,J=5.5Hz,2H),6.88(s,1H),6.78-6.57(m,J=26.6,18.4,12.8Hz,2H),6.45–6 .22(m,4H),4.72(hept,J=6.0Hz,1H),3.99(s,3H),3.97–3.38(m,10H),3.35(s,1H),3.03(s,3 H),2.80–2.69(m,2H),2.30–2.23(m,2H),2.05(qd,J=11.9,4.1Hz,2H).1.28(d,J=6.0Hz,6H).

[0244] Example 5 Synthesis of Compound A5

[0245] Step 1: Synthesis of compound A5

[0246] Take 15 ml of the sealed tube, add M4 (63 mg) and TFA (100 μL) to 1 ml of a t-BuOH solution (50 mg), and stir at 110 °C for 10 h. After the reaction is complete, add water, adjust the pH to weakly alkaline with NaHCO3, extract with ethyl acetate, repeat the process several times, combine the organic phases, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain a pale yellow oil solid A5 (56 mg). Further purification by pre-HPLC (HCl) yields a pale yellow solid (29 mg). LCMS (ESI): m / z = 628 [M+H] + . 1H NMR(400MHz,Methanol-d4)δ8.45–8.19(d,2H),8.13(s,1H),7.91(s,1H),7.59 -7.73(d,J=31.2Hz,2H),7.32(m,J=5.4Hz,3H),6.95(s,1H),6.80–6.56(m,2H),6.49–6.12(m,4H),4.00(s,J=2.0H z, 3H), 3.93 (s, J = 2.0Hz, 3H), 3.56 (d, J = 11.7Hz, 2H), 3.37 (t, J = 11.7Hz, 4H), 3.15 (t, J = 12.5Hz, 2H), 3.01 (s, 3H).

[0247] Example 6 Synthesis of Compound A6

[0248] Step 1: Synthesis of compound A6

[0249] Take 15 ml of the sealed tube, add M5 (72 mg) and TFA (100 μL) to 1 ml of a t-BuOH solution (50 mg), and stir at 110 °C for 10 h. After the reaction is complete, add water, adjust the pH to weakly alkaline with NaHCO3, extract with ethyl acetate, repeat the process several times, combine the organic phases, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain a pale yellow oil solid A6 (40 mg). Further purification by pre-HPLC (HCl) yields a pale yellow solid (20 mg). LCMS (ESI): m / z = 598 [M+H] + . 1 H NMR (400MHz, Methanol-d4) δ8.34–8.10(m,3H),7.62(s,1H),7.46(s,1H),7.33(d,J=5.5Hz,2H),7.19(s,1H),6.77-6.57 (m,J=26.8,18.4,12.7Hz,2H),6.49–6.17(m,4H),4.00(s,3H),3.83(t,J=4.5Hz,4H),2.97(t,J=4.6Hz,4H),2.31(s,3H).

[0250] Example 7 Synthesis of Compound A7

[0251] The synthesis steps 1, 2, and 3 are the same as those for compound A1 to obtain 7-3.

[0252] Step 4: Synthesis of compound A7

[0253] Take 15 ml of sealed tube, add 1-6 (80 mg) and TFA (100 μL) to 1 ml of t-BuOH solution (50 mg) of 7-3, and stir at 110 °C for 10 h. After the reaction is complete, add it to water, adjust the pH to weakly alkaline with NaHCO3, extract with ethyl acetate, repeat the process several times, combine the organic phases, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain colorless oil solid A7 (40 mg). Further purification by pre-HPLC (HCl) yields a white solid (20 mg). LCMS (ESI): m / z = 604 [M+H] + .

[0254] Example 8 Synthesis of Compound A8

[0255] The synthesis steps 1, 2, and 3 are the same as those for compound A1 to obtain 8-3.

[0256] Step 4: Synthesis of compound A8

[0257] Take 15 ml of the sealed tube, add 1-6 (71 mg) and TFA (80 μL) to 1 ml of t-BuOH solution (40 mg) of 8-3, and stir at 110 °C for 10 h. After the reaction is complete, add water, adjust the pH to weakly alkaline with NaHCO3, extract with ethyl acetate, repeat the process several times, combine the organic phases, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain colorless oil solid A8 (35 mg). Further purification by pre-HPLC (HCl) yields a white solid (15 mg). LCMS (ESI): m / z = 609 [M+H] + . 1 H NMR (400MHz, Methanol-d4) δ8.23(s,1H),8.06(s,1H),7.72(m,J=14.1,7.4H z,2H),7.54(d,J=8.1Hz,2H),7.33(s,1H),7.06–6.97(d,1H),6.77-6.57(m, J=27.0,18.5,12.7Hz,2H),6.48–6.21(m,4H),3.98(s,1H),3.95(s,3H),3.8 6–3.52(m,12H),3.05(s,3H),2.51(d,J=10.7Hz,2H),2.37(q,J=11.8Hz,2H).

[0258] Example 9 Synthesis of Compound A9

[0259] The synthesis steps 1, 2, and 3 are the same as those for compound A1 to obtain 9-3.

[0260] Step 4: Synthesis of compound A9

[0261] Take 15 ml of the sealed tube, add 1-6 (108 mg) and TFA (120 μL) to 1.5 ml of t-BuOH solution (60 mg of 9-3), and stir at 110 °C for 10 h. After the reaction is complete, add water, adjust the pH to weakly alkaline with NaHCO3, extract with ethyl acetate, repeat the process several times, combine the organic phases, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain a pale yellow oil solid A9 (55 mg). Further purification by pre-HPLC (HCl) yields a pale yellow solid (30 mg). LCMS (ESI): m / z = 602 [M+H] + . 1 H NMR (400MHz, Methanol-d4) δ8.06(m,J=8.5,4.4Hz,1H),7.85(s,1H),7.73(m,J=13.9,7.2,4.9Hz,3H),7.57(m,J=7.3,4.2Hz,2 H),7.21(m,J=11.5,7.0,2.5Hz,1H),6.75-6.65(m,J=26.4,18.5,12.7Hz,2H),6.43–6.15(m,4H),4.01(d,J=2.9Hz,6H),3.93(m J=11.6,9.8,5.6Hz,6H),3.42(s,1H),3.08(s,3H),2.78–2.69(m,2H),2.68(s,3H),2.66–2.49(m,4H),1.36(q,J=7.1Hz,3H).

[0262] Example 10 Synthesis of compound A10

[0263] The synthesis steps 1, 2, and 3 are the same as those for compound A1 to obtain 10⁻³.

[0264] Step 4: Synthesis of compound A10

[0265] Take 15 ml of sealed tube, add 1-6 (63 mg) and TFA (80 μL) to 1 ml of 10-3 (40 mg) t-BuOH solution, and stir at 110 °C for 10 h. After the reaction is complete, add water, adjust the pH to weakly alkaline with NaHCO3, extract with ethyl acetate, repeat the process several times, combine the organic phases, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain a pale yellow oil solid A10 (35 mg). Further purification by pre-HPLC (HCl) yields a pale yellow solid (20 mg). LCMS (ESI): m / z = 609 [M+H] + . 1 H NMR(400MHz, Methanol-d4)δ8.06(m,J=8.5,4.4Hz,1H),7.85(s,1H),7.73(m,J=13.9,7 .2,4.9Hz,3H),7.57(m,J=7.3,4.2Hz,2H),7.21(m,J=11.5,7.0,2.5Hz,1H),6.73-6.57 (m,J=26.4,18.5,12.7Hz,2H),6.43–6.15(m,4H),4.01(d,J=2.9Hz,6H),3.93(m,J=11. 6,9.8,5.6Hz,6H),3.42(s,1H),3.08(s,3H),,2.75–2.55(m,8H),1.36(m,J=7.1Hz,4H).

[0266] Example 11 / 14 Synthesis of compounds A11 and A14

[0267] Step 1: Synthesis of compound A14

[0268] Take 15 ml of sealed tube, add M6 (136 mg) and TFA (160 μL) to 1 ml of 10⁻³ (80 mg) t-BuOH solution, and stir at 110 °C for 10 h. After the reaction is complete, add water, adjust the pH to weakly alkaline with NaHCO₃, extract with ethyl acetate, repeat the process several times, combine the organic phases, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain a pale yellow oil solid A14 (80 mg). (40 mg) is then purified by pre-HPLC (HCl) to obtain a pale yellow solid (21 mg). LCMS (ESI): m / z = 667 [M+H] + . 1H NMR(400MHz, Methanol-d4)δ8.15(d,J=67.0Hz,2H),7.77–7.58(m,2H),7.47(m,J=7.6, 2.4Hz,1H),7.28(s,1H),6.90(s,1H),6.77-6.60(m,J=26.8,18.4,12.8Hz,2H),6.48–6 .21(m,4H),4.00–3.89(m,2H),3.87(s,3H),3.84–3.47(m,8H),3.39(d,J=12.3Hz,2H), 3.05(s,3H),2.99(d,J=12.2Hz,1H),2.41–2.33(m,2H),2.18(s,3H),2.15–2.04(m,2H).

[0269] Step 2: Synthesis of compound A11

[0270] Take 15 ml of the sealed tube, and add vinyl borate (15 mg), Pd(dppf)Cl2 (5 mg), and Cs2CO3 (63 mg) dissolved in water to 1 ml of A14 (40 mg) 1,4-dioxane solution. , The mixture was stirred at 100℃ for 10 h. After the reaction was complete, it was added to water and extracted with ethyl acetate. This process was repeated several times. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain a pale yellow oil solid A11 (35 mg). Further purification by pre-HPLC (HCl) yielded a pale yellow solid (15 mg). LCMS (ESI): m / z = 719 [M+H] + . 1H NMR(400MHz, Methanol-d4)δ8.18(s,1H),7.98(s,1H),7.66(m,J=20.6,15.7,7.0Hz,2H),7.49–7.40(m,1H) ,7.34(s,1H),6.95(s,1H),6.82(m,J=17.0,10.9Hz,1H),6.75-6.57(m,J=26.5,18.5,12.7Hz,2H),6.46–6. 20(m,4H),5.84(d,J=17.0Hz,1H),5.61(d,J=11.1Hz,1H),3.90(s,3H),3.87–3.56(m,8H),3.44(d,J=11.9H z,2H),3.09(m,1H),3.06(s,3H),2.42–2.34(m,2H),2.20(s,3H),2.20–2.08(m,2H),1.30(d,J=4.0Hz,2H).

[0271] Example 12 Synthesis of compound A12

[0272] Step 1: Synthesis of compound A12

[0273] Take 15 ml of the sealed tube, add M7 (52 mg) and TFA (80 μL) to 1 ml of a 10⁻³ (40 mg) t-BuOH solution, and stir at 110 °C for 10 h. After the reaction is complete, add water, adjust the pH to weakly alkaline with NaHCO₃, extract with ethyl acetate, repeat the process several times, combine the organic phases, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain a pale yellow oil solid A12 (45 mg). Further purification by pre-HPLC (HCl) yields a pale yellow solid (21 mg). LCMS (ESI): m / z = 688 [M+H] + . 1 H NMR(400MHz, Methanol-d4)δ8.29(s,1H),7.99(s,1H),7.75–7.40(m,4H),6.83(s,1H),6.77-6.57(m,J=26.9,17.7,12.7,3.5Hz,2H),6.47– 6.24(m,4H),3.92(s,1H),3.90(s,3H),3.86–3.47(m,10H),3.05(s,3H),2.85(t,J=11.8Hz,2H),2.35(d,J=11.5Hz,2H),2.13–1.99(m,2H).

[0274] Example 13 Synthesis of compound A13

[0275] Step 1: Synthesis of compound A13

[0276] Take 15 ml of the sealed tube, add M18 (68 mg) and TFA (80 μL) to 1 ml of a 10⁻³ (40 mg) t-BuOH solution, and stir at 110 °C for 10 h. After the reaction is complete, add water, adjust the pH to weakly alkaline with NaHCO₃, extract with ethyl acetate, repeat the process several times, combine the organic phases, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain a pale yellow oil solid A13 (48 mg). Further purification by pre-HPLC (HCl) yields a pale yellow solid (23 mg). LCMS (ESI): m / z = 672 [M+H] + . 1 H NMR(400MHz, Methanol-d4)δ8.26(s,1H),7.97(s,1H),7.67–7.32(m,4H),7.17( d,J=6.1Hz,1H),6.77-6.57(m,J=26.7,18.5,12.7Hz,2H),6.51–6.19(m,4H),4. 08–3.66(m,8H),3.59(d,J=12.0Hz,2H),3.06(s,3H),3.06(s,H),2.94(t,J=11. 8Hz,2H),2.44–2.37(m,2H),2.23(d,J=6.1Hz,2H),2.11(m,J=12.0,4.5Hz,2H).

[0277] Example 15 Synthesis of Compound A15

[0278] Step 1: Synthesis of compound A13

[0279] Take 15 ml of the sealed tube, add M4 (56 mg) and TFA (80 μL) to 1 ml of a 10⁻³ (40 mg) t-BuOH solution, and stir at 110 °C for 10 h. After the reaction is complete, add water, adjust the pH to weakly alkaline with NaHCO₃, extract with ethyl acetate, repeat the process several times, combine the organic phases, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain a pale yellow oil solid A15 (38 mg). Further purification by pre-HPLC (HCl) yields a pale yellow solid (16 mg). LCMS (ESI): m / z = 650 [M+H] + . 1 H NMR (400MHz, Methanol-d4) δ8.09(s,2H),7.87(s,2H),7.50–7.39(m,1H),7.35(s,1H),7.13(s,2H),6.78(s,1H),6.52(m,J=26.7,18.5,12.7Hz ,2H),6.33–6.05(m,4H),3.92(s,3H),3.77(s,3H),3.38(d,J=11.9Hz,2 H),3.28–3.16(m,4H),2.97(t,J=11.5Hz,2H),2.83(s,3H),1.12(s,1H).

[0280] Example 16 Synthesis of Compound A16

[0281] Step 1: Synthesis of compound A16

[0282] Take 15 ml of the sealed tube, add M8 (60 mg) and TFA (80 μL) to 1 ml of a 10⁻³ (40 mg) t-BuOH solution, and stir at 110 °C for 10 h. After the reaction is complete, add water, adjust the pH to weakly alkaline with NaHCO₃, extract with ethyl acetate, repeat the process several times, combine the organic phases, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain a pale yellow oil solid A16 (35 mg). Further purification by pre-HPLC (HCl) yields a pale yellow solid (26 mg). LCMS (ESI): m / z = 732 [M+H] + . 1H NMR (400MHz, Methanol-d4) δ8.53–7.95(m,3H),7.75(s,1H),7.64–7.41(m,2H),7.33(m,J= 23.0,13.8Hz,2H),6.92(q,J=5.1,4.6Hz,1H),6.82–6.59(m,2H),6.58–5.91(m,4H),4.00( s,J=6.6Hz,3H),3.94(s,J=6.8Hz,3H),3.76–3.66(m,4H),3.37(d,J=11.5Hz,4H),3.28–3. 14(m,4H),2.93(s,3H),2.63–2.51(m,2H),2.33–2.08(m,2H),1.31(dd,J=13.4,6.1Hz,1H).

[0283] Example 17 Synthesis of Compound A17

[0284] Step 1: Synthesis of compound A17

[0285] Take 15 ml of the sealed tube, add M8 (54 mg) and TFA (80 μL) to 1 ml of a 10⁻³ (40 mg) t-BuOH solution, and stir at 110 °C for 10 h. After the reaction is complete, add water, adjust the pH to weakly alkaline with NaHCO₃, extract with ethyl acetate, repeat the process several times, combine the organic phases, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain a pale yellow oil solid A17 (50 mg). Further purification by pre-HPLC (HCl) yields a pale yellow solid (24 mg). LCMS (ESI): m / z = 695 [M+H] + . 1H NMR (400MHz, Methanol-d4) δ8.24(s,1H),8.07(s,1H),7.70(m,J=14.0,7.7,1.5Hz,1H),7.62( s,1H),7.52–7.41(m,1H),7.29(s,1H),6.87(s,1H),6.76-6.57(m,J=26.8,18.4,12.9Hz,2H), 6.51–6.16(m,4H),4.66(p,J=6.0Hz,1H),4.10–3.40(m,10H),3.04(s,3H),2.93(s,2H),2.33( d,J=12.0Hz,2H),2.15(s,3H),2.11–1.95(m,2H),1.28(d,J=6.0Hz,6H),0.89(t,J=6.7Hz,1H).

[0286] Example 18 Synthesis of Compound A18

[0287] Steps 1, 2, 3, and 4 of the synthesis were the same as those for compound A1 to obtain 18-5.

[0288] Step 4: Synthesis of compound A18

[0289] Take 15 ml of the sealed tube and add 1-6 (63 mg) and TFA (80 μL) to 1 ml of a 10-3 (40 mg) t-BuOH solution. Stir at 110 °C for 10 h. After the reaction is complete, add water and adjust the pH to weakly alkaline with NaHCO3. Extract with ethyl acetate, repeating the process multiple times. Combine the organic phases and wash with saturated brine. Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. Purify the crude product by silica gel column chromatography (DCM:MeOH = 10:1) to obtain a pale yellow oil solid A18 (35 mg). Further purification by pre-HPLC (HCl) yields a pale yellow solid (20 mg). LCMS (ESI): m / z = 609 [M+H] + . 1H NMR(400MHz, Methanol-d4)δ9.08–8.76(m,3H),8.28(s,1H),8.08(s,1H),7.32(s,1H),7.24-7.03(m,J=28.8,18.8,12.6Hz,2H),6.90(s,1H),6. 56–6.08(m,4H),3.87(s,3H),3.83–3.33(m,10H),3.03(s,3H),2.97(s,2 H),2.34(d,J=11.7Hz,2H),2.19(s,3H),2.15–2.02(m,2H),1.28(s,1H).

[0290] Example 19 Synthesis of Compound A19

[0291] Step 1: Synthesis of compound A19

[0292] Take 15 ml of sealed tube, add M18 (40 mg) and TFA (60 μL) to 1 ml of 10⁻³ (30 mg) t-BuOH solution, and stir at 110 °C for 10 h. After the reaction is complete, add water, adjust the pH to weakly alkaline with NaHCO₃, extract with ethyl acetate, repeat the process several times, combine the organic phases, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain a pale yellow oil solid A19 (40 mg). It is then purified by pre-HPLC (HCl) to obtain a pale yellow solid.

[0293] Example 20 Synthesis of Compound A20

[0294] Step 1: Synthesis of compound A20

[0295] Take 15 ml of the sealed tube, add M18 (40 mg) and TFA (60 μL) to 1 ml of t-BuOH solution (30 mg) of 18-5, and stir at 110 °C for 10 h. After the reaction is complete, add water, adjust the pH to weakly alkaline with NaHCO3, extract with ethyl acetate, repeat the process several times, combine the organic phases, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain a pale yellow oil solid A20 (35 mg). It is then purified by pre-HPLC (HCl) to obtain a pale yellow solid (20 mg).

[0296] Example 21 Synthesis of Compound B1

[0297] Step 1: Synthesis of compound B1-2

[0298] Boc₂O and DMAP were added to a THF solution of B1-1, and the mixture was stirred at room temperature for 6 hours. After the reaction was complete, the solution was extracted with Na₂S₂O₃ in water using ethyl acetate. This process was repeated multiple times. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (PE:EA = 2:1) to give a brown liquid, B1-2. LCMS (ESI): m / z = [M + H] + .

[0299] Step 2: Synthesis of compound B1-3

[0300] Diethyl phosphite (5.6 g), Pd(OAc)₂ (0.46 g), DPPF (1.34 g), and DIEA (3.65 g) were added to a DMF / DME solution (90 ml / 9 ml) of B1-2 (6 g). Nitrogen gas was purged, and the mixture was stirred at 100 °C for 10 h. After the reaction was complete, the mixture was added to water and extracted with ethyl acetate. This process was repeated several times. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (PE:EA = 2:1) to obtain a brown liquid, B1-3 (6.5 g). LCMS (ESI): m / z = 445 [M+H] + .

[0301] Step 3: Synthesis of compound B1-4

[0302] At 0°C, 0.38 g of NaH was added to 10 ml of a DMF solution containing 1 g of B1-3 and stirred for 30 min. Then, 10 ml of a DMF solution containing 1.2 g of 2,4,5-trichloropyrimidine was added dropwise. After the addition was complete, the mixture was gradually brought to room temperature and stirred overnight. Once the reaction was complete, the mixture was added to water and extracted with ethyl acetate. This process was repeated several times. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (PE:EA = 1:1) to obtain a brown solid, B1-4 (1.2 g). LCMS (ESI): m / z = 400 [M+H] + .

[0303] Step 3: Synthesis of compound B1-5

[0304] Take 15 ml of sealed tube, add B1-4 (1.2 g), SOCl2 solution (2.4 ml), and a few drops of DMF, and stir at 90 °C for 10 h. After the reaction is complete, concentrate directly under reduced pressure to obtain the crude product. Take 100 ml of three-necked flask, dissolve the crude product in ultra-dry THF solution, and purge under nitrogen. At -78 °C, slowly add vinyl magnesium bromide (8 ml), and react for 1 h after the addition is complete. After the reaction is complete, restore to room temperature, quench with NH4Cl, add to water, extract with ethyl acetate, repeat the operation several times, combine the organic phases, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (PE:EA = 1:1) to obtain a light brown solid B1-5 (0.6 g). LCMS (ESI): m / z = 364 [M+H] + .

[0305] Step 5: Synthesis of compound B1

[0306] Take 15 ml of sealed tube, add 1-6 (83 mg) and TFA (100 μL) to 1 ml of t-BuOH solution of B1-5 (50 mg), and stir at 110 °C for 10 h. After the reaction is complete, add water, adjust the pH to weakly alkaline with NaHCO3, extract with ethyl acetate, repeat the process several times, combine the organic phases, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain crude product. The crude product is purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain a pale yellow oil liquid B1 (60 mg). Further purification by pre-HPLC (HCl) yields a pale yellow solid (30 mg). LCMS (ESI): m / z = 632 [M+H] + . 1 H NMR(400MHz, Methanol-d4)δ8.74(s,1H),8.44(d,J=8.9Hz,1H),8.17(d,J=4.8Hz,1H),7.86–7.78(m,2H),7.49(s,1H),7.42–7.29(m,2 H),7.23(d,J=8.9Hz,1H),6.84–6.65(m,2H),6.47–6.30(m,4H),4.05(s,3H),3.99–3.55(m,13H),3.04(s,3H),2.52(d,J=31.9Hz,4H).

[0307] Example 22 Synthesis of Compound B2

[0308] Step 1: Synthesis of compound B2

[0309] Take 15 ml of sealed tube, add B2-1 (64 mg) and TFA (100 μL) to 1 ml of a solution of B1-5 (50 mg) in t-BuOH, and stir at 110 °C for 10 h. After the reaction is complete, add water, adjust the pH to weakly alkaline with NaHCO3, extract with ethyl acetate, repeat the process several times, combine the organic phases, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain a pale yellow oil liquid B2 (54 mg). Further purification by pre-HPLC (HCl) yields a pale yellow solid (25 mg). LCMS (ESI): m / z = 602 [M+H] + . 1 H NMR (400MHz, Methanol-d4) δ8.75(s,1H),8.18(d,J=4.8Hz,1H),7.96(d,J=9.2Hz,2H),7.83(dd,J=11.4,7.5Hz,2H),7.64(d ,J=9.2Hz,2H),7.42–7.30(m,2H),6.84–6.65(m,2H),6.47–6.29(m,4H),3.41–3.72(m,13H),3.03(s,3H),2.58–2.36(m,4H).

[0310] Example 23 Synthesis of Compound B3

[0311] Step 1: Synthesis of compound B3

[0312] Take 15 ml of sealed tube, add B3-1 (57 mg) and TFA (80 μL) to 1 ml of B1-5 (40 mg) in t-BuOH solution, and stir at 110 °C for 10 h. After the reaction is complete, add water, adjust the pH to weakly alkaline with NaHCO3, extract with ethyl acetate, repeat the process several times, combine the organic phases, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain a pale yellow oil liquid B3 (35 mg). Further purification by pre-HPLC (HCl) yields a pale yellow solid (18 mg). LCMS (ESI): m / z = 589 [M+H] + . 1H NMR (400MHz, Methanol-d4) δ8.73(s,1H),8.18(d,J=4.8Hz,1H),7.92(d,J=8.5Hz,2H),7.83(dd,J=12.2,8.0Hz,2H),7.59(d,J=7.5H z,2H),7.41–7.31(m,2H),6.82–6.66(m,2H),6.47–6.30(m,4H),4.27–3.41(m,13H),2.55(d,J=13.1Hz,2H),2.40(d,J=13.0Hz,2H).

[0313] Example 24 Synthesis of Compound B4

[0314] Step 1: Synthesis of compound B4

[0315] Take 15 ml of the sealed tube, add M9 (62 mg) and TFA (80 μL) to 1 ml of a t-BuOH solution of B1-5 (40 mg), and stir at 110 °C for 10 h. After the reaction is complete, add water, adjust the pH to weakly alkaline with NaHCO3, extract with ethyl acetate, repeat the process several times, combine the organic phases, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain a pale yellow oil liquid B4 (45 mg). Further purification by pre-HPLC (HCl) yields a pale yellow solid (22 mg). LCMS (ESI): m / z = 670 [M+H] + . 1 H NMR (400MHz, Methanol-d4) δ8.68(s,1H),8.16(d,J=4.8Hz,1H),8.09(d,J=2.6Hz,1 H),7.86(dd,J=8.8,2.6Hz,1H),7.81(d,J=8.9Hz,2H),7.43–7.29(m,3H),6.81–6.6 6(m,2H),6.47–6.29(m,4H),3.69(t,J=67.3Hz,9H),3.12(d,J=12.1Hz,2H),3.05(s ,3H),2.87(t,J=11.5Hz,2H),2.27(d,J=10.3Hz,2H),1.94(qd,J=11.8,4.0Hz,2H).

[0316] Example 25 Synthesis of Compound B5

[0317] Step 1: Synthesis of compound B5

[0318] Take 15 ml of sealed tube, add B5-1 (68 mg) and TFA (100 μL) to 1 ml of a t-BuOH solution of B1-5 (40 mg), and stir at 110 °C for 10 h. After the reaction is complete, add water, adjust the pH to weakly alkaline with NaHCO3, extract with ethyl acetate, repeat the process several times, combine the organic phases, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain a pale yellow oil liquid B5 (36 mg). Further purification by pre-HPLC (HCl) yields a pale yellow solid (17 mg). LCMS (ESI): m / z = 577 [M+H] + . 1 H NMR(400MHz, Methanol-d4)δ8.61(s,1H),8.30(d,J=8.9Hz,1H),8.13(d,J=4.8Hz,1H),7.82–7.73(m,2H),7.45(s,1H),7.35– 7.29(m,2H),7.15(d,J=8.9Hz,1H),6.80–6.64(m,2H),6.46–6.30(m,4H),3.97(s,3H),3.79(s,5H),2.97(s,6H),2.46(s,4H).

[0319] Example 26 Synthesis of Compound B6

[0320] Step 1: Synthesis of compound B6

[0321] Take 15 ml of the sealed tube, add M7 (56 mg) and TFA (60 μL) to 1 ml of a t-BuOH solution of B1-5 (30 mg), and stir at 110 °C for 10 h. After the reaction is complete, add water, adjust the pH to weakly alkaline with NaHCO3, extract with ethyl acetate, repeat the process several times, combine the organic phases, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain a pale yellow oil liquid B6 (35 mg). Further purification by pre-HPLC (HCl) yields a pale yellow solid (14 mg). LCMS (ESI): m / z = 666 [M+H] + . 1H NMR(400MHz,Methanol-d4)δ8.62(s,1H),8.22(s,1H),8.17(d,J=4.8Hz,1H),7 .81(dd,J=7.8,2.6Hz,2H),7.34(dt,J=16.1,7.6Hz,2H),6.83(s,1H),6.81–6. 66(m,2H),6.47–6.31(m,4H),3.90(s,10H),3.51(t,J=13.3Hz,4H),3.06(s,3H ), 2.88 (t, J = 11.7Hz, 2H), 2.30 (d, J = 11.0Hz, 2H), 2.03 (qd, J = 12.1, 4.0Hz, 2H).

[0322] Example 27 Synthesis of Compound B7

[0323] Step 1: Synthesis of compound B7

[0324] Take 15 ml of the sealed tube, add M18 (27 mg) and TFA (60 μL) to 1 ml of a t-BuOH solution of B1-5 (30 mg), and stir at 110 °C for 10 h. After the reaction is complete, add water, adjust the pH to weakly alkaline with NaHCO3, extract with ethyl acetate, repeat the process several times, combine the organic phases, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain a pale yellow oil liquid B7 (24 mg). Further purification by pre-HPLC (HCl) yields a pale yellow solid (11 mg). LCMS (ESI): m / z = 650 [M+H] + . 1 H NMR (400MHz, Methanol-d4) δ8.59(s,1H),8.18(d,J=4.8Hz,1H),7.77(d,J=7.7Hz,2H),7.70(s,1H),7.30(p,J=7.3Hz,2H),7.13(s,1H),6.81–6.6 2(m,2H),6.45–6.28(m,4H),3.94–3.54(m,11H),3.05(s,3H),2.92(t,J= 11.9Hz,2H),2.35(d,J=11.0Hz,2H),2.27(s,3H),2.09(q,J=11.9Hz,2H).

[0325] Example 28 Synthesis of Compound B8

[0326] Step 1: Synthesis of compound B8

[0327] Take 15 ml of the sealed tube, add M10 (25 mg) and TFA (60 μL) to 1 ml of B1-5 (30 mg) in a solution of t-BuOH, and stir at 110 °C for 10 h. After the reaction is complete, add water, adjust the pH to weakly alkaline with NaHCO3, extract with ethyl acetate, repeat the process several times, combine the organic phases, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain a pale yellow oil liquid B8 (18 mg). Further purification by pre-HPLC (HCl) yields a pale yellow solid (10 mg). LCMS (ESI): m / z = 615 [M+H] + . 1 H NMR(400MHz, Methanol-d4)δ8.72(s,1H),8.18(d,J=4.8Hz,1H),7.83(dd,J=13.2,7.9Hz,2H),7.70(s,1H),7.46–7.28(m,3H),6.88(s,1H),6.81–6.65 (m,2H),6.47–6.30(m,4H),3.72(d,J=12.5Hz,2H),3.26–3.17(m,1H),2.99 (d,J=11.6Hz,2H),2.96(s,3H),2.16(d,J=12.8Hz,2H),1.96–1.83(m,2H).

[0328] Example 29 Synthesis of Compound B9

[0329] Step 1: Synthesis of compound B9

[0330] Take 15 ml of the sealed tube, add M8 (64 mg) and TFA (60 μL) to 1 ml of B1-5 (30 mg) in a solution of t-BuOH, and stir at 110 °C for 10 h. After the reaction is complete, add water, adjust the pH to weakly alkaline with NaHCO3, extract with ethyl acetate, repeat the process several times, combine the organic phases, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain a pale yellow oil liquid B9 (37 mg). Further purification by pre-HPLC (HCl) yields a pale yellow solid (16 mg). LCMS (ESI): m / z = 712 [M+H] + . 1H NMR(400MHz, Methanol-d4)δ8.67(s,1H),8.23(s,1H),8.19(d,J=4.7Hz,1H),7 .84(d,J=7.6Hz,3H),7.63(s,1H),7.31(t,J=7.6Hz,1H),7.18(t,J=7.9Hz,1H) ,6.89(s,1H),6.83–6.64(m,2H),6.47–6.29(m,4H),4.11–3.49(m,15H),3.17( t,J=12.9Hz,4H),2.92(s,3H),2.55(d,J=13.5Hz,2H),2.16(q,J=12.8Hz,2H).

[0331] Example: Synthesis of compound B10

[0332] Step 1: Synthesis of compound B10

[0333] Take 15 ml of sealed tube, add M4 (50 mg) and TFA (60 μL) to 1 ml of B1-5 (30 mg) in t-BuOH solution, and stir at 110 °C for 10 h. After the reaction is complete, add water, adjust the pH to weakly alkaline with NaHCO3, extract with ethyl acetate, repeat the process several times, combine the organic phases, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain a pale yellow oil liquid B10 (34 mg). Further purification by pre-HPLC (HCl) yields a pale yellow solid (15 mg). LCMS (ESI): m / z = 629 [M+H] + . 1 H NMR (400MHz, Methanol-d4) δ8.63(d,J=2.2Hz,1H),8.21(d,J=2.2Hz,1H),8.17(dd,J=4.8,2.2 Hz,1H),7.82(d,J=8.1Hz,2H),7.78(s,1H),7.61(s,1H),7.30(td,J=7.6,2.1Hz,1H),7.15(t,J =8.0Hz,1H),6.86(d,J=2.2Hz,1H),6.82–6.63(m,2H),6.47–6.30(m,4H),3.97(d,J=2.2Hz,3H ),3.83(s,3H),3.51(d,J=12.0Hz,2H),3.30–3.19(m,4H),3.05(t,J=12.6Hz,2H),2.98(s,3H).

[0334] Example 30 Synthesis of Compound B11

[0335] Step 1: Synthesis of compound B11

[0336] Take 15 ml of the sealed tube, add M12 (48 mg) and TFA (60 μL) to 1 ml of a t-BuOH solution of B1-5 (30 mg), and stir at 110 °C for 10 h. After the reaction is complete, add water, adjust the pH to weakly alkaline with NaHCO3, extract with ethyl acetate, repeat the process several times, combine the organic phases, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain a pale yellow oil liquid B9 (24 mg). Further purification by pre-HPLC (HCl) yields a pale yellow solid (12 mg). LCMS (ESI): m / z = 616 [M+H] + . 1 H NMR (400MHz, Methanol-d4) δ8.63(s,1H),8.24–8.13(m,2H),7.82(d,J=8.2Hz,3H),7.63(s,1H),7.29(t,J=7.6Hz,1H),7. 15(t,J=7.9Hz,1H),6.93(s,1H),6.80–6.64(m,2H),6.46–6.28(m,4H),3.97(s,3H),3.81(d,J=11.8Hz,7H),2.99(s,4H).

[0337] Example 32 Synthesis of compound B12

[0338] Step 1: Synthesis of Compound 12

[0339] Take 15 ml of the sealed tube, add M5 (50 mg) and TFA (60 μL) to 1 ml of B1-5 (30 mg) in a t-BuOH solution, and stir at 110 °C for 10 h. After the reaction is complete, add water, adjust the pH to weakly alkaline with NaHCO3, extract with ethyl acetate, repeat the process several times, combine the organic phases, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain a pale yellow oil liquid B12 (25 mg). Further purification by pre-HPLC (HCl) yields a pale yellow solid (14 mg). LCMS (ESI): m / z = 600 [M+H] + . 1H NMR (400MHz, Methanol-d4) δ8.60(d,J=2.5Hz,1H),8.19(dd,J=4.9,2.5Hz,1H),8.10(d,J=18.3Hz,2H),7.80–7.72(m,3H),7.33(s,1H),7.27(t,J =6.4Hz,1H),7.16(d,J=8.2Hz,1H),6.80–6.61(m,2H),6.45–6.27(m,4H) ,4.01(d,J=2.6Hz,3H),3.86(s,4H),3.15(s,4H),2.36(d,J=2.6Hz,3H).

[0340] Example 33 Synthesis of compound B13

[0341] Step 1: Synthesis of compound B13

[0342] Take 15 ml of sealed tube, add M13 (42 mg) and TFA (60 μL) to 1 ml of B1-5 (30 mg) in t-BuOH solution, and stir at 110 °C for 10 h. After the reaction is complete, add water, adjust the pH to weakly alkaline with NaHCO3, extract with ethyl acetate, repeat the process several times, combine the organic phases, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain a pale yellow oil liquid B13 (26 mg). Further purification by pre-HPLC (HCl) yields a pale yellow solid (14 mg). LCMS (ESI): m / z = 586 [M+H] + . 1 H NMR (400MHz, Methanol-d4) δ8.68(s,1H),8.18(d,J=4.8Hz,1H),8.09–7.93(m,3H),7.83(t,J=7.2Hz,2H),7.66(d,J=9.0Hz,1H),7.48(d,J=9. 0Hz,1H),7.32(t,J=7.5Hz,1H),7.24(t,J=7.8Hz,1H),6.83–6.64(m,2H),6.47–6.29(m,4H),3.99(s,3H),3.90(t,J=4.5Hz,4H),3.30(s,4H).

[0343] Example 34 Synthesis of compound B14

[0344] Step 1: Synthesis of compound B14

[0345] Take 15 ml of the sealed tube, add M11 (50 mg) and TFA (60 μL) to 1 ml of a t-BuOH solution of B1-5 (30 mg), and stir at 110 °C for 10 h. After the reaction is complete, add water, adjust the pH to weakly alkaline with NaHCO3, extract with ethyl acetate, repeat the process several times, combine the organic phases, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain a pale yellow oil liquid B14 (23 mg). Further purification by pre-HPLC (HCl) yields a pale yellow solid (11 mg). LCMS (ESI): m / z = 570 [M+H] + . 1 H NMR (400MHz, Methanol-d4) δ8.60(s,1H),8.19(s,1H),8.14(d,J=4.8Hz,1H),7.80(dd,J=7.6,5.2Hz,2H),7.33(dt, J=19.9,7.2Hz,2H),6.79–6.63(m,3H),6.44–6.29(m,4H),3.90(s,3H),3.82(t,J=4.5Hz,4H),3.00(t,J=4.5Hz,4H).

[0346] Example 35 Synthesis of Compound B15

[0347] Steps 1 and 2 of the synthesis were the same as those for compound B1 to obtain 15-2.

[0348] Step 3: Synthesis of compound B15

[0349] Take 15 ml of sealed tube, add M12 (48 mg) and TFA (60 μL) to 1 ml of B15-2 (30 mg) in t-BuOH solution, and stir at 110 °C for 10 h. After the reaction is complete, add water, adjust the pH to weakly alkaline with NaHCO3, extract with ethyl acetate, repeat the process several times, combine the organic phases, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain a pale yellow oil liquid B15 (25 mg). Further purification by pre-HPLC (HCl) yields a pale yellow solid (13 mg). LCMS (ESI): m / z = 612 [M+H] + . 1H NMR(400MHz, Methanol-d4)δ8.61(s,1H),8.17–8.08(m,2H),7.83–7.67(m,3H),7.46(s,1H),7.26(t,J=7.6Hz,1H),7.0 6(t,J=7.8Hz,1H),6.82(s,1H),6.77–6.59(m,2H),6.43–6.27(m,4H),3.90(s,3H),3.75(d,J=4.9Hz,7H),2.89(s,4H).

[0350] Example 36 Synthesis of Compound B16

[0351] Steps 1 and 2 of the synthesis were the same as those for compound B1 to obtain 15-2.

[0352] Step 3: Synthesis of compound B15

[0353] Take 15 ml of sealed tube, add M12 (48 mg) and TFA (60 μL) to 1 ml of B15-2 (30 mg) in t-BuOH solution, and stir at 110 °C for 10 h. After the reaction is complete, add water, add NaHCO3 to adjust the pH to weakly alkaline, extract with ethyl acetate, repeat the process several times, combine the organic phases, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain crude product. The crude product is purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain pale yellow oil liquid B15 (25 mg). It is then purified by pre-HPLC (HCl) to obtain pale yellow solid (13 mg). 1 H NMR (400MHz, Methanol-d4) δ8.42(d,J=5.1Hz,1H),8.31(s,1H),8.20(d,J=8.5Hz,1H),7.96(s,1H),7.82(s,1H),7.76(d,J=7.9Hz,2H), 7.29(t,J=7.6Hz,1H),7.13(t,J=7.9Hz,1H),6.88(s,1H),6.79–6.64(m,2H),6.46–6.28(m,4H),3.96(s,6H),3.80(s,7H),2.94(s,4H).

[0354] Example 37 Synthesis of Compound B17

[0355] Step 1: Synthesis of compound B17

[0356] Take 15 ml of sealed tube, add M14 (44 mg) and TFA (60 μL) to 1 ml of B16-2 (30 mg) in t-BuOH solution, and stir at 110 °C for 10 h. After the reaction is complete, add water, adjust the pH to weakly alkaline with NaHCO3, extract with ethyl acetate, repeat the process several times, combine the organic phases, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain a pale yellow oil liquid B17 (27 mg). Further purification by pre-HPLC (HCl) yields a pale yellow solid (13 mg). LCMS (ESI): m / z = 674 [M+H] + . 1 H NMR (400MHz, Methanol-d4) δ8.72(d,J=4.0Hz,1H),8.19–8.10(m,2H),7.84–7.74(m,3H),7.54(s,1H),7.29(t,J=6.0Hz,1H),7.20(s ,1H),6.83(s,1H),6.79–6.64(m,2H),6.45–6.29(m,4H),4.03(s,2H),3.94(s,3H),3.76(s,4H),2.87(s,4H),1.36(t,J=6.0Hz,3H).

[0357] Example 38 Synthesis of Compound B18

[0358] Step 1: Synthesis of compound B18

[0359] Take 15 ml of sealed tube, add M15 (54 mg) and TFA (60 μL) to 1 ml of B16-2 (30 mg) in t-BuOH solution, and stir at 110 °C for 10 h. After the reaction is complete, add water, adjust the pH to weakly alkaline with NaHCO3, extract with ethyl acetate, repeat the process several times, combine the organic phases, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain a pale yellow oil liquid B18 (26 mg). Further purification by pre-HPLC (HCl) yields a pale yellow solid (12 mg). LCMS (ESI): m / z = 686 [M+H] + . 1H NMR (400MHz, Methanol-d4) δ8.70(s,1H),8.15(s,2H),7.79(dd,J=20.1,8.4Hz,3H),7.67(s,1H),7.28(t,J=7.6Hz,1H),7.14(t,J=7 .7Hz,1H),6.89(s,1H),6.79–6.64(m,2H),6.45–6.29(m,4H),3.95(s,3H),3.77(s,4H),3.55(s,1H),2.94(s,4H),1.08–0.92(m,4H).

[0360] Example 39 Synthesis of Compound B19

[0361] Step 1: Synthesis of compound B19

[0362] Take 15 ml of the sealed tube, add M5 (40 mg) and TFA (60 μL) to 1 ml of a t-BuOH solution of B16-2 (30 mg), and stir at 110 °C for 10 h. After the reaction is complete, add water, adjust the pH to weakly alkaline with NaHCO3, extract with ethyl acetate, repeat the process several times, combine the organic phases, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain a pale yellow oil liquid B19 (26 mg). Further purification by pre-HPLC (HCl) yields a pale yellow solid (15 mg). LCMS (ESI): m / z = 644 [M+H] + . 1 H NMR (400MHz, Methanol-d4) δ8.68(s,1H),8.17(d,J=3.1Hz,1H),8.05(d,J=11.3Hz,2H),7.76(d,J=8.0Hz,1H),7.69(d,J=11.5Hz,2H),7.25 (d,J=5.9Hz,2H),7.15(d,J=8.2Hz,1H),6.79–6.64(m,2H),6.45–6.27(m,4H),3.99(s,3H),3.84(t,J=3.4Hz,4H),3.08(s,4H),2.34(s,3H).

[0363] Example 40 Synthesis of Compound B20

[0364] Step 1: Synthesis of compound B20

[0365] Take 15 ml of the sealed tube, add M8 (56 mg) and TFA (60 μL) to 1 ml of a solution of B16-2 (30 mg) in t-BuOH, and stir at 110 °C for 10 h. After the reaction is complete, add water, adjust the pH to weakly alkaline with NaHCO3, extract with ethyl acetate, repeat the process several times, combine the organic phases, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain a pale yellow oil liquid B20 (27 mg). Further purification by pre-HPLC (HCl) yields a pale yellow solid (13 mg). LCMS (ESI): m / z = 756 [M+H] + . 1 H NMR (400MHz, Methanol-d4) δ8.64 (s, 1H), 8.18–8.07 (m, 2H), 7.81 (d, J = 8.0Hz, 1H), 7. 74–7.50(m,3H),7.28(t,J=7.6Hz,1H),7.10(t,J=7.9Hz,1H),6.79–6.61(m,3H),6.46 –6.28(m,4H),4.01–3.63(m,14H),3.46(d,J=12.1Hz,1H),3.17(d,J=11.5Hz,2H),3.0 4(s,3H),2.67(d,J=7.8Hz,2H),2.20(d,J=11.7Hz,2H),1.97(q,J=13.6,11.8Hz,2H).

[0366] Example 41 Synthesis of compound B21

[0367] Step 1: Synthesis of compound B21

[0368] Take 15 ml of sealed tube, add M17 (44 mg) and TFA (60 μL) to 1 ml of B16-2 (30 mg) in t-BuOH solution, and stir at 110 °C for 10 h. After the reaction is complete, add water, adjust the pH to weakly alkaline with NaHCO3, extract with ethyl acetate, repeat the process several times, combine the organic phases, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain a pale yellow oil liquid B21 (26 mg). Further purification by pre-HPLC (HCl) yields a pale yellow solid (14 mg). LCMS (ESI): m / z = 756 [M+H] + . 1H NMR(400MHz, Methanol-d4)δ8.78(s,1H),8.33(s,1H),8.20(d,J=4.8Hz,1H),8.0 7(s,1H),7.94(s,1H),7.80(dd,J=19.6,7.8Hz,2H),7.31(t,J=6.2Hz,1H),7.25( s,1H),7.18(t,J=7.5Hz,1H),6.81–6.66(m,2H),6.47–6.30(m,4H),4.04(d,J=11 .9Hz, 6H), 3.63 (s, 2H), 3.25 (t, J = 7.2Hz, 2H), 2.92 (s, 3H), 2.85 (d, J = 3.9Hz, 6H).

[0369] Example 42 Synthesis of compound B22

[0370] Step 1: Synthesis of compound B22

[0371] Take 15 ml of sealed tube, add M16 (50 mg) and TFA (60 μL) to 1 ml of B16-2 (30 mg) in t-BuOH solution, and stir at 110 °C for 10 h. After the reaction is complete, add water, adjust the pH to weakly alkaline with NaHCO3, extract with ethyl acetate, repeat the process several times, combine the organic phases, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain a pale yellow oil liquid B22 (24 mg). Further purification by pre-HPLC (HCl) yields a pale yellow solid (14 mg). LCMS (ESI): m / z = 711 [M+H] + . 1 H NMR (400MHz, Methanol-d4) δ8.77(d,J=9.2Hz,1H),8.27(d,J=8.2Hz,1H),8.15(d,J=4.5Hz,1H),7.83–7.72(m,2H),7.40–7.28(m,2H),7.00(d,J =8.2Hz,1H),6.82–6.62(m,2H),6.47–6.28(m,4H),3.95(d,J=8.1Hz,3H) ,3.41(s,2H),3.33(s,2H),2.94(d,J=9.0Hz,6H),2.79(d,J=9.0Hz,3H).

[0372] Example 43 Synthesis of compound B23

[0373] Step 1: Synthesis of compound B23

[0374] Take 15 ml of sealed tube, add M7 (50 mg) and TFA (60 μL) to 1 ml of B16-2 (30 mg) in t-BuOH solution, and stir at 110 °C for 10 h. After the reaction is complete, add water, adjust the pH to weakly alkaline with NaHCO3, extract with ethyl acetate, repeat the process several times, combine the organic phases, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain crude product. The crude product is purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain pale yellow oil liquid B23 (34 mg). Further purification by pre-HPLC (HCl) yields a pale yellow solid (15 mg). LCMS (ESI): m / z = 711 [M+H] + . 1 H NMR(400MHz, Methanol-d4)δ8.68(s,1H),8.22–8.13(m,2H),7.77(dd,J=24.1,7.5Hz,2H),7.33(dt,J=14.2,7.2Hz,2H),6.81–6.65(m,3H) ,6.46–6.30(m,4H),3.86(s,12H),3.43(d,J=12.0Hz,2H),3.05(s,3H),2.77(t,J=11.7Hz,2H),2.26(d,J=12.1Hz,2H),2.03–1.91(m,2H).

[0375] Example 44 Synthesis of compound B24

[0376] Step 1: Synthesis of compound B24

[0377] Take 15 ml of the sealed tube, add M1 (54 mg) and TFA (60 μL) to 1 ml of a t-BuOH solution of B16-2 (30 mg), and stir at 110 °C for 10 h. After the reaction is complete, add water, adjust the pH to weakly alkaline with NaHCO3, extract with ethyl acetate, repeat the process several times, combine the organic phases, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain a pale yellow oil liquid B24 (26 mg). Further purification by pre-HPLC (HCl) yields a pale yellow solid (14 mg). LCMS (ESI): m / z = 739 [M+H] + . 1H NMR (400MHz, Methanol-d4) δ8.76 (s, 1H), 8.26 (s, 1H), 8.17 (d, J = 4.7Hz, 1H), 7.79 (dd,J=15.7,8.0Hz,2H),7.35(dt,J=21.8,7.4Hz,2H),6.84–6.66(m,3H),6.46–6.2 9(m,4H),4.68(p,J=6.1Hz,1H),3.90–3.45(m,11H),3.04(s,3H),2.81(t,J=11.8H z, 2H), 2.29 (d, J = 11.7Hz, 2H), 2.01 (td, J = 13.4, 9.5Hz, 2H), 1.35 (d, J = 6.0Hz, 6H).

[0378] Example 45 Synthesis of Compound B25

[0379] Step 1: Synthesis of compound B25

[0380] Take 15 ml of the sealed tube, add M20 (54 mg) and TFA (60 μL) to 1 ml of a solution of B16-2 (30 mg) in t-BuOH, and stir at 110 °C for 10 h. After the reaction is complete, add water, adjust the pH to weakly alkaline with NaHCO3, extract with ethyl acetate, repeat the process several times, combine the organic phases, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain a pale yellow oil liquid B25 (25 mg). Further purification by pre-HPLC (HCl) yields a pale yellow solid (12 mg). LCMS (ESI): m / z = 660 / 662 [M+H] + .

[0381] Example 46 Test of the compound's inhibition of kinase protein activity

[0382] Compounds A1-A18 and B1-B24 inhibit EGFR d746-750 / T790M / C797S EGFR L858R / T790M / C797S and EGFR WT Assay for kinase protein activity

[0383] EGFR (d746-750 T790M C797S) (with EGFR d746-750 / T790M / C797S Del / TM / CS are synonyms for EGFR d746-750, T790M, and C797S triple mutants, and EGFR (L858R T790M C797S) (as well as EGFR). L858R / T790M / C797SLR / TM / CS are synonyms for EGFR L858R, T790M, and C797S triple mutants and EGFR (WT) (as opposed to EGFR). WT WT is synonymous with EGFR wild-type. The information regarding the experimental buffer (Assay Buffer) used in the EGFR wild-type test is as follows:

[0384] The kinase and substrate information used in the EGFR(d746-750 T790M C797S) and EGFR(L858R T790M C797S) assays is as follows:

[0385] The kinases and substrates used in the EGFR(WT) assay are as follows:

[0386] Add the solution or perform the corresponding operations in the 384-well plate in the following steps:

[0387] 1. Prepare 2×ATP & substrate solution and 2×kinase & metal solution using Assay Buffer.

[0388] 2. Transfer 50 nL of the compound to a 384-well plate, add 2.5 μL of 2×kinase & metal solution, and incubate in the 384-well plate at 25 °C for 60 minutes.

[0389] 3. Add 2.5 μL of 2× substrate & ATP solution to the wells and incubate at 25°C for 40 minutes.

[0390] 4. Prepare the detection buffer solution using 2×XL665&Antibody solution.

[0391] 5. Add 5 μL of kinase detection reagent to the well and incubate at 25°C for 60 minutes.

[0392] 6. The microplate reader reads the fluorescence signals at 620nm (Cryptate) and 665nm (XL665).

[0393] The analyte was diluted 3-fold sequentially from the highest concentration of 1 μM downwards, resulting in 10 concentration points. Two replicates were used. The inhibition rate of each well was calculated based on the fluorescence readings, a dose-dependent curve was plotted, and the half-maximal inhibitory concentration (IC50) of the analyte was calculated. 50 The results are shown in Table 1:

[0394] Table 1

[0395] Experimental results show that the compounds of this invention have good EGFR mutant inhibitory activity, especially with high selectivity relative to wild-type EGFR, and therefore are expected to be used in drug development as a new generation of EGFR inhibitors to improve the safety and efficacy of treatment.

[0396] Example 47: Cellular antiproliferative activity assay of compounds A1-A18 and B1-B24

[0397] Cells were seeded at a density of 2000 cells / well in 96-well plates. A ring of 200 μL PBS was placed around the cells to prevent excessive evaporation of the medium at the edges, which could lead to significant differences in culture conditions within the wells. The leftmost column of the inner 60 wells was a blank well, filled with an equal volume of PBS. The remaining 54 wells were seeded with 100 μL of cells per well using a micropipeline. The plates were incubated at 37°C for 24 hours. The stock solution of the compound was diluted with complete culture medium, with 50 μL of the corresponding concentration added to each well, up to a maximum concentration of 10 μM. Subsequent 3-fold dilutions were performed, resulting in 10 concentration points. Two replicates were set up. Three days after drug treatment, 50 μL of Cell Tier Glo reagent (Promega#G7570) was added to each well. Lumi luminescence values ​​were read using a microplate reader, the inhibition rate of each well was calculated, a dose-dependent curve was plotted, and the half-maximal effective concentration (EC50) of the test compound against proliferation was calculated. 50 The results are shown in Table 2 below:

[0398] Table 2

[0399] Experimental results show that the compounds of this invention have good EGFR mutant inhibitory activity, especially with high selectivity relative to wild-type EGFR.

[0400] Test Example 48: High-resolution mass spectrometry detection of irreversible binding of covalent compounds to recombinant EGFR protein

[0401] Covalent inhibitors can irreversibly bind to target proteins, thereby exerting a prolonged pharmacological effect. The compounds of this invention, containing a divinylphosphonate group as a covalent warhead, can undergo an irreversible chemical reaction with a conserved catalytic lysine residue in the ATP pocket of the EGFR protein, forming a covalent bond, thus acting as covalent inhibitors. Therefore, the compounds provided by this invention can irreversibly bind to various mutated forms of EGFR protein, including the C797S mutation, thereby resulting in a more prolonged pharmacological effect; while most reported EGFR inhibitors, such as gefitinib, are non-covalent inhibitors, or like osimertinib, although a covalent inhibitor, it covalently targets the cysteine ​​residue at position 797, and is ineffective against the C797S mutation.

[0402] To demonstrate the characteristics of covalent bonding, compounds A5, A10, A17, A18, B11, B16, B20, and B23 are used as examples. Ten equivalents of each compound are combined with one equivalent of EGFR. L858R,T790M,C797S The protein was incubated at 37°C for 1 hour, and the shift in protein molecular weight and the proportion of covalently labeled ion peak intensities were detected using liquid chromatography-high resolution mass spectrometry.

[0403] Experimental results showed that after incubation, EGFR L858R,T790M,C797S The increase in the molecular weight of the protein compared to the molecular weight of the compound demonstrates its irreversible binding and covalent labeling with EGFR. L858R,T790M,C797S The protein's ability, with the results for compound B11 (molecular weight: 615) shown in Figure 1.

[0404] The compound in this application is related to EGFR. L858R,T790M,C797S The following are the results of the percentage of covalently labeled ion peak intensities in the high-resolution mass spectra of the intact protein after incubation:

[0405] The above results indicate that the compound provided by this invention can covalently bind to EGFR. L858R,T790M,C797S Proteins have advantages over non-covalent inhibitors.

[0406] Example 49. Bioassay for the Inhibition of Tyrosine Kinase Family Activity by Compounds

[0407] The inhibitory rates of compounds A10, A18, and B16 on 76 tyrosine kinases were measured at single-point concentrations to evaluate the selectivity of the test compounds for the tyrosine kinase family. The specific testing methods are as described in Example 46.

[0408] The test results are as follows:

[0409] The above results indicate that the compounds of the present invention have significant inhibitory activity against many members of the tyrosine kinase family.

[0410] Example 50. Biological assay for the compound's inhibition of histone activity of the whole kinase.

[0411] The inhibitory rates of compounds A18 and B16 on 416 kinases of the whole kinase community were tested at single-point concentrations to evaluate the selectivity of the test compounds for the whole kinase community. The specific testing method can be found in the experimental procedures described in Example 46.

[0412] The test results are as follows:

[0413] The above results indicate that the compounds provided by this invention have significant inhibitory activity against many members of the kinase family and their mutants.

[0414] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A compound of formula (I), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs, in, W is selected from the following group: not found, O, S, NR a CR b R b '; where R a R b and R b Each element is independently selected from the following groups: H, halogens, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups; Cycle A is selected from the following group: 4-12 membered heterocyclic groups, C 6-10 Aryl, 5-12 heteroaryl; R1 and R1' are each independently selected from the following groups: H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-10 A cyclic alkyl group, a 4-10 membered heterocyclic group, or R1, R1' together with the nitrogen atom attached thereto form a 4-9 membered nitrogen-containing heterocyclic group, wherein the nitrogen-containing heterocyclic group is optionally further substituted by a 4-9 membered nitrogen-containing heterocyclic group; one or more hydrogen atoms on each of the above groups (including each nitrogen-containing heterocyclic group) are optionally replaced by R c replace; Among them, R c Selected from the following groups: halogen, cyano, hydroxyl, amino, carboxyl, C 1-6 amide group, C 2-6 Ester group, oxy group (=O), C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 sulfonyl, C 3-8 Cycloalkyl groups; R2 is selected from the following group: H, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 4-10 membered heterocyclic groups, C 6-10 aryl, 5-9 membered heteroaryl; one or more hydrogens on the above groups are optionally R c replace; R3, R4, R5, and R5' are each independently selected from the following groups: H, halogens, C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy groups; or R5, R5' and the atoms attached to them together form 5-7 heteroaryl groups; In each of the above groups, one, two, three, or four hydrogens are optionally substituted by groups selected from the group consisting of: halogen, cyano, hydroxyl, amino, carboxyl, C. 1-6 amide group, C 2-6 Ester group, oxy group (=O), C 1-6 Alkyl, C 1-6 Alkoxy; Unless otherwise specified, the heteroaryl group is an aromatic cyclic group containing 1, 2, 3 or 4 heteroatoms selected from N, O or S on a cyclic skeleton; the heterocyclic group is a saturated or partially unsaturated cyclic group containing 1, 2, 3 or 4 heteroatoms selected from N, O or S that is not aromatic, and it can be a monocyclic, fused, bridged or spirocyclic group.

2. The compound, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs as claimed in claim 1, characterized in that, The ring A is selected from the group consisting of: 4-7 member monoheterocyclic groups, 9-12 member fused heterocyclic groups, phenyl, naphthyl, 5-7 member monoheteroaryl, and 9-12 member fused heteroaryl. Preferably, ring A is selected from the group consisting of 9-12 member nitrogen-containing fused heterocyclic groups, phenyl groups, and 9-12 member nitrogen-containing fused heteroaryl groups; More preferably, the ring A is selected from the group consisting of: phenyl 5-7-membered nitrogen-containing heterocyclic group, 5-7-membered nitrogen-containing heteroaryl 5-7-membered nitrogen-containing heterocyclic group, phenyl, 5-7-membered nitrogen-containing heteroaryl 5-7-membered nitrogen-containing heteroaryl, and phenyl 5-7-membered nitrogen-containing heteroaryl.

3. The compound, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs as described in claim 1, characterized in that, R1 and R1' are each independently selected from the following groups: H, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-8 A 5-8 membered nitrogen-containing monoheterocyclic group is formed by a cycloalkyl group, a 4-8 membered heterocyclic group, or R1, R1' together with the nitrogen atom attached thereto, wherein the nitrogen-containing heterocyclic group is optionally further replaced by a 5-8 membered nitrogen-containing heterocyclic group; Preferably, R1 and R1' are each independently selected from the group consisting of: H, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-7 A 5-7 membered nitrogen-containing monoheterocyclic group is formed by a cycloalkyl group, a 4-7 membered heterocyclic group, or R1, R1' together with the nitrogen atom attached thereto, wherein the nitrogen-containing heterocyclic group is optionally further replaced by a 5-7 membered nitrogen-containing heterocyclic group; More preferably, R1 and R1' are each independently selected from the following group: C 1-4 Alkyl groups, or R1, R1', together with the nitrogen atom attached to them, form a group selected from the following group:

4. The compound, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs as described in claim 1, characterized in that, The R2 is selected from the group consisting of: H, halogens, C. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 3-8 Cycloalkyl, 4-8 membered heterocyclic, phenyl, 5-7 membered heteroaryl; Preferably, R2 is selected from the group consisting of: H, fluorine, chlorine, bromine, and C. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Fluoroalkyl, C 3-7 Cycloalkyl, 4-7 heterocyclic, phenyl, 5-7 nitrogen-containing heteroaryl.

5. The compound of claim 1, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs, characterized in that, R3 is selected from the following group: H, C 1-4 Alkyl, C 1-4 Alkyl group.

6. The compound, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs as claimed in claim 1, characterized in that, R5 and R5' are selected from the group consisting of: H, fluorine, chlorine, bromine, and C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy groups, or R5, R5', together with the atoms attached to them, form 5-6 membered heteroaryl groups.

7. The compound of claim 1, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs, characterized in that, The compound has the structure shown in formula (II): The definitions of rings A, W, Y, R2, R3, R5, and R5' are as described in claim 1; Y is selected from the following group: O, NR e or CR f R f '; R e R f and R f Each element is independently selected from the following groups: H, halogens, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Sulfonyl group, 4-9 membered heterocyclic group; one or more hydrogen atoms in each of the above groups are optionally substituted by groups selected from the group consisting of: halogen, cyano, hydroxyl, amino, carboxyl, C 1-4 amide group, C 2-4 Ester group, oxy group (=O), C 1-4 Alkyl, C 1-4 Alkyl group.

8. The compound, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs as claimed in claim 1, characterized in that, The compounds are selected from the group consisting of:

9. A pharmaceutical composition, characterized in that, The composition comprises: (i) The compound, stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug as described in any one of claims 1-8; and (ii) Pharmaceutically acceptable carriers, excipients or excipients.

10. The use of the compound, stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate, or prodrug as claimed in any one of claims 1-8, or the pharmaceutical composition as claimed in claim 9, characterized in that, For the preparation of drugs for the treatment and / or prevention of diseases mediated by the kinase activity or expression level selected from the following groups: ACK, ALK, AXL, BRK, CSF1R, EGFR, FAK, FER, FES, FGFR1, FGFR2, FGFR3, FGR, FLT3, FLT4, FRK, FYN[isoform a], FYN[isoform b], HCK, HER4, IGF1R, INSR, IRR, ITK, JAK1, JAK2, JAK3, KDR, KIT, LCK, LYNa, LYNb, MER, PDGFRα, PDGFRβ, PYK2, RET, ROS, SRC, SRM, TRKA, TRKB, TRKC, TXK, YES; Preferably, the diseases associated with kinase activity or expression level are selected from the group consisting of: tumors, cancers, and malignant cell proliferation. More preferably, the diseases associated with kinase activity or expression are selected from the group consisting of: lung cancer, colorectal cancer, brain tumor, kidney cancer, liver cancer, bile duct cancer, thyroid cancer, gastric cancer, esophageal cancer, oral cancer, nasopharyngeal cancer, pancreatic cancer, sarcoma, bladder cancer, breast cancer, cervical cancer, endometrial cancer, ovarian cancer, and prostate cancer.

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