Compounds for EGFR protein degradation and their uses

Abstract

This invention relates to compounds for the degradation of EGFR proteins and their uses. Specifically, the compounds of this invention have the structure shown in Formula I, wherein the definitions of each group and substituent are as described in the specification. This invention also discloses methods for preparing the compounds and their uses in the prevention and / or treatment of EGFR-related diseases.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and more specifically to compounds for the degradation of EGFR proteins and their uses. Background Technology

[0002] HER family receptor tyrosine kinases are mediators of cell growth, differentiation, and survival. This receptor family includes four distinct members: epidermal growth factor receptor (EGFR, ErbB1, or HER1), HER2 (ErbB2), HER3 (ErbB3), and HER4 (ErbB4). Upon ligand binding, the receptor forms a homodimer or heterodimer, and subsequent activation of endogenous tyrosine kinase activity leads to receptor autophosphorylation and activation of downstream signaling molecules. EGFR activation regulation due to overexpression or mutation has been demonstrated to be involved in various types of human cancers, including colorectal cancer, pancreatic cancer, glioma, head and neck cancer, and lung cancer, particularly non-small cell lung cancer (NSCLC). Several EGFR-targeting agents have been developed over the years, and three generations of drugs are already in clinical use.

[0003] In clinical practice, patients typically develop EGFR T790M resistance mutations within 8-12 months after using first- or second-generation EGFR inhibitors, rendering the drugs ineffective. Although later-released third-generation EGFR inhibitors, such as osimertinib and amitinib, can effectively overcome EGFR T790M resistance, resistance mutations like EGFR T797S can still occur after a period of use, leading to disease progression.

[0004] The frequent occurrence of mutational resistance during treatment with EGFR small molecule tyrosine kinase inhibitors has become a pressing clinical challenge. While some EGFR allosteric inhibitors, such as EAI045, have been reported to overcome C797S resistance, their clinical efficacy is limited. In recent years, several patents (WO2019149922, WO2021127561) have reported a series of PROTAC-type compounds that can overcome C797S resistance by degrading EGFR proteins, representing a new research direction. Although some progress has been made in EGFR allosteric inhibitors and EGFR degraders, there is still a need to find more clinically valuable EGFR protein modulators for the treatment of diseases caused by EGFR dysregulation, especially in the field of EGFR-positive non-small cell lung cancer. Summary of the Invention

[0005] The purpose of this invention is to provide a compound of Formula I and its use in the prevention and / or treatment of EGFR-related diseases.

[0006] In a first aspect, the present invention provides a compound, said compound being a compound of Formula I, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotopic compound, or prodrug thereof.

[0007] Formula I

[0008] in:

[0009] L is selected from the following group: ;

[0010] Ring A is selected from the following group: ;

[0011] Ring B is selected from the following group: ;

[0012] Among the various types,

[0013] Each X1 and X2 is independently selected from the following groups: CR, N;

[0014] Each X3 is independently selected from the following groups: NH, O, none;

[0015] Each Ar is independently selected from the following group: substituted or unsubstituted phenyl groups, substituted or unsubstituted 5-10 membered heteroaryl groups containing 1, 2, or 3 heteroatoms selected from N, O, or S. , The substitution refers to substitution by one or more (e.g., 2, 3, or 4) substituents selected from the group consisting of: halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, hydroxylated C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkyl-NH-, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 Halogenated cycloalkyl, cyano, oxo, -C(O)NR9R 10 -CO-C 1-6 Alkyl, -CO-C 3-6 cycloalkyl, -CO-C 1-6 Halogenated alkyl groups, -CO-C 3-6 Halogenated cycloalkyl groups, 5-6 membered heteroaryl groups containing 1, 2 or 3 heteroatoms selected from N, O or S;

[0016] Each R1 is independently selected from the following group: hydrogen, deuterium, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 3-6 Halogenated cycloalkyl groups, cyano groups;

[0017] Each of R2 and R3 is independently selected from the following group: hydrogen, deuterium, halogen, C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkyl-NH-, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Halogenated alkyl, cyano, C 3-6 Halogenated cycloalkyl, -NR9C(O)R 10 -C(O)NR9R 10 Methanesulfonyl, Unreplaced or C 1-6 Alkyl-substituted 5-10-membered heteroaryl groups containing 1, 2, or 3 heteroatoms selected from N, O, or S;

[0018] Each R4 is independently selected from the following group: C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 3-6 Halogenated cycloalkyl groups;

[0019] Each R5 is independently selected from the following group: not present, C 1-6 Alkyl, NR, ;

[0020] Each of R6, R7, and R8 is independently selected from the following group: H, halogen, C. 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkyl-NH-, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Halogenated alkyl, cyano, C 3-6 Halogenated cycloalkyl-NR9C(O)R 10 -C(O)NR9R 10 Methanesulfonyl, The hydroxyl group, or R6, forms a 3-6 membered ring with the attached ring;

[0021] Each R9 is independently selected from the following groups: H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 3-6 Halogenated cycloalkyl groups;

[0022] Each R 10 Independently selected from the following groups: H, C 1-6 Alkyl, C 2-6alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Haloalkyl, C 3-6 Halogenated cycloalkyl, methanesulfonyl, ;

[0023] Each m, n, and q is independently selected from the following group: 0, 1, 2, 3, 4, 5;

[0024] Each R 11 Independently selected from the following groups: H, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 3-6 Halogenated cycloalkyl groups;

[0025] Each R is independently selected from the following groups: H, C 1-6 Alkyl, hydroxyl, halogen, C 1-6 Halogenated alkyl groups.

[0026] In another preferred embodiment, at least one of X1 and X2 is N.

[0027] In another preferred embodiment, the 5-10 membered heteroaryl group containing 1, 2, or 3 heteroatoms selected from N, O, or S is selected from the group consisting of pyridyl ( ), thiazolyl ( ), indole Quinoline

[0028] In another preferred embodiment, the 5-6 membered heteroaryl group containing 1, 2, or 3 heteroatoms selected from N, O, or S is selected from the group consisting of: .

[0029] In another preferred embodiment, each Ar is independently selected from the group consisting of substituted phenyl groups, , The substitution refers to substitution by a substituent selected from the group consisting of -C(O)NR9R. 10 5-6 membered heteroaryl groups containing 1, 2 or 3 N atoms;

[0030] R 11 q is as defined in claim 1;

[0031] R9 is selected from the following groups: H, C 1-6 alkyl;

[0032] R 10 Selected from the following groups: H, C 1-6 alkyl;

[0033] And R9 and R10 They are not both H.

[0034] In another preferred embodiment, each Ar is independently selected from the group consisting of substituted phenyl groups, , The substitution refers to substitution by a substituent selected from the group consisting of -C(O)NR9R. 10 5-6 membered heteroaryl groups containing 1, 2 or 3 N atoms;

[0035] R 11 q is as defined in claim 1;

[0036] R9 is H;

[0037] R 10 C 1-6 alkyl.

[0038] In another preferred embodiment, R9 and R 10 One is H and the other is C. 1-6 Alkyl (preferably C) 1-3 Alkyl group, preferably C1 alkyl group.

[0039] In another preferred embodiment, R9 and R 10 One is H, and the other is C selected from the following groups. 1-6 Alkyl groups: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, neopentyl, pterpentyl, hexyl.

[0040] In another preferred embodiment, Ar is a substituted phenyl group, wherein the substitution refers to the substitution by -C(O)NR9R. 10 replace.

[0041] In another preferred embodiment, both X1 and X2 are N; or one of X1 and X2 is N and the other is CR.

[0042] In another preferred embodiment, in L, X1 is N and X2 is CR.

[0043] In another preferred embodiment, in L, X1 is CR and X2 is N.

[0044] In another preferred embodiment, in L, X1 is N and X2 is N.

[0045] In another preferred embodiment, in ring B, X1 is CR and X2 is CR.

[0046] In another preferred embodiment, in ring B, X1 is CR and X2 is N. In another preferred embodiment, R1 is selected from the group consisting of hydrogen, halogen, trifluoromethyl, and cyano.

[0047] In another preferred embodiment, R1 is a halogen selected from the group consisting of: F, Cl, Br, and I.

[0048] In another preferred embodiment, R2 is H.

[0049] In another preferred embodiment, R3 is selected from the following group: H, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl.

[0050] In another preferred embodiment, R3 is selected from the following group: C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl.

[0051] In another preferred embodiment, R3 is C selected from the following group. 1-6 Alkyl groups: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, neopentyl, pterpentyl, hexyl.

[0052] In another preferred embodiment, the compound is a compound represented by formula II, III, IV, V, VI, or VII.

[0053]

[0054] Where R4 is selected from the following group C 1-6 Alkyl groups: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, neopentyl, pterpentyl, hexyl.

[0055] In another preferred embodiment, R6 forms a 3-6 element ring with the connected ring, thereby forming a helical ring, a parallel ring, or a bridge ring. Preferably, R6 is C. 1-4 alkylene groups, and form with linked rings More preferably, R6 is a methylene group;

[0056] X1 and X2 are defined as above.

[0057] In another preferred embodiment, the compound is selected from the group consisting of:

[0058]

[0059]

[0060]

[0061]

[0062]

[0063]

[0064]

[0065]

[0066]

[0067]

[0068]

[0069]

[0070] In another preferred embodiment, the pharmaceutically acceptable salt is an inorganic acid salt or an organic acid salt;

[0071] The inorganic acid salts are selected from the following group: hydrochloride, hydrobromide, hydroiodide, sulfate, hydrogen sulfate, nitrate, phosphate, and acid phosphate;

[0072] The organic acid salts are selected from the group consisting of: formate, acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, malonate, fumarate, maleate, lactate, malate, citrate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, salicylate, picrate, glutamate, ascorbate, camphorate, and camphorsulfonate.

[0073] In another preferred embodiment, the compound is not selected from the group consisting of:

[0074]

[0075]

[0076]

[0077] .

[0078] In another preferred embodiment, the compound is not selected from the group consisting of:

[0079] ,

[0080]

[0081]

[0082]

[0083]

[0084]

[0085]

[0086]

[0087]

[0088]

[0089]

[0090]

[0091]

[0092]

[0093]

[0094]

[0095]

[0096] .

[0097] A second aspect of the present invention provides a pharmaceutical composition comprising a safe and effective amount of the compound described in the first aspect of the present invention and a pharmaceutically acceptable carrier.

[0098] In another preferred embodiment, the pharmaceutical composition further comprises a second active ingredient selected from the group consisting of: gefitinib, erlotinib, icotinib, lapatinib, XL647, NVP-AEE-788, ARRY-334543, vandetanib, PF00299804, cetuximab, panitumumab, pertuzumab, zarumumab, nimotuzumab, MDX-214, CDX-110, IMC-11F8, CNF2024, tanspiramycin, aspiramycin, IPI-504, and NVP-AUY922.

[0099] A third aspect of the invention provides a use of the compound as described in the first aspect of the invention for use selected from the group consisting of:

[0100] 1) To prepare drugs for regulating EGFR kinase activity or treating EGFR-related diseases;

[0101] 2) Prepare drugs for degrading EGFR protein.

[0102] In another preferred embodiment, the EGFR-related disease is an EGFR drug resistance mutation-related disease.

[0103] In another preferred embodiment, the EGFR resistance mutation is selected from the group consisting of: EGFRT790M, EGFRC797S, T780M, C797S, DEL19, L858R, DEL19 / T790M, DEL10 / T790M / C797S, L858R / T790M / C797S, or combinations thereof.

[0104] In another preferred embodiment, the EGFR-related diseases are selected from the group consisting of: inflammation, cancer, cardiovascular disease, infection, immune disease, and metabolic disease.

[0105] In another preferred embodiment, the cancer is selected from the group consisting of: lung cancer (including lung adenocarcinoma and non-small cell lung cancer), breast cancer, prostate cancer, colorectal cancer, liver cancer, pancreatic cancer, ovarian cancer, leukemia, neuroblastoma, gastric cancer, kidney cancer, esophageal cancer, uterine cancer, glioma, and head and neck cancer.

[0106] In another preferred embodiment, the EGFR-related disease is non-small cell lung cancer with EGFR mutations selected from the group consisting of: T790M / L858R, T790M / L858R / C797S, L858R, and L858R / C797S.

[0107] A fourth aspect of the present invention provides a method for preventing and / or treating diseases associated with EGFR drug resistance mutations, comprising the steps of:

[0108] 1) Determine the patient's EGFR activating mutation status;

[0109] 2) If the patient's EGFR activating mutation status meets the treatment criteria, the compound described in the first aspect of the present invention shall be administered to the patient.

[0110] In another preferred embodiment, the patient’s EGFR activating mutation status meets the treatment criteria if the patient has an EGFR mutation selected from the group consisting of: T790M / L858R, T790M / L858R / C797S, L858R, and L858R / C797S.

[0111] In another preferred embodiment, the EGFR resistance mutation-related diseases are selected from the group consisting of: lung cancer (including lung adenocarcinoma and non-small cell lung cancer), breast cancer, prostate cancer, colorectal cancer, liver cancer, pancreatic cancer, ovarian cancer, leukemia, neuroblastoma, gastric cancer, kidney cancer, esophageal cancer, uterine cancer, glioma, and head and neck cancer.

[0112] In another preferred embodiment, the EGFR resistance mutation-related disease is non-small cell lung cancer.

[0113] In another preferred embodiment, the "determination of the patient's EGFR activating mutation status" is determined by the cobas EGFR mutation assay v2.

[0114] 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

[0115] Figure 1 This is a schematic diagram of the cell preparation steps in Experiment Example 2.

[0116] Figure 2This is a schematic diagram of the detection steps in Experiment Example 2. Detailed Implementation

[0117] Through long-term and in-depth research, the inventors unexpectedly prepared a compound with excellent EGFR degradation properties via structural optimization. This compound exhibits excellent inhibitory and / or therapeutic effects on EGFR-related diseases (especially EGFR drug resistance mutation-related diseases), and also possesses excellent pharmacokinetic properties. Based on this, the inventors completed this invention.

[0118] the term

[0119] In this invention, unless otherwise specified, the terms used have the general meanings known to those skilled in the art.

[0120] When a substituent is described using a conventional chemical formula written from left to right, it also includes chemically equivalent substituents obtained when the structural formula is written from right to left. For example, -CH2O- is equivalent to -OCH2-.

[0121] "Alkyl (alone or as part of other groups)" refers to a monovalent, straight-chain or branched saturated hydrocarbon group consisting of 1 to 12 carbon atoms, composed solely of carbon and hydrogen atoms. Alkyl groups are preferably C1-C6 alkyl groups (i.e., containing 1, 2, 3, 4, 5, or 6 carbon atoms). Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, etc. In this application, alkyl is also intended to include substituted alkyl groups, i.e., one or more positions of an alkyl group are substituted, particularly 1-4 substituents, which may be substituted at any position. "Haloalkyl" refers to an alkyl group as defined herein in which one or more hydrogen atoms are replaced by the same or different halogens. Examples of haloalkyl groups include -CH2Cl, -CH2CF3, -CH2CCl3, perfluoroalkyl (e.g., -CF3), etc.

[0122] "alkylene" refers to the divalent group of an alkyl group, such as -CH2-, -CH2CH2- and -CH2CH2CH2-.

[0123] "Alkoxy group (alone or as part of other groups)" refers to an alkyl group having an oxygen group attached thereto, having an alkyl O- structure, wherein the alkyl group has the definition as described above. Preferably, the alkoxy group is a C1-C6 alkoxy group. Alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, tert-butoxy, etc. "Haloalkoxy group" refers to a group of formula -OR, where R is a haloalkyl group as defined herein. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, 2,2,2-trifluoroethoxy, etc.

[0124] "Alkenyl (alone or as part of other groups)" refers to an aliphatic group containing at least one double bond, typically having 2 to 20 carbon atoms. In this invention, "C2-C6 alkenyl" refers to an alkenyl group containing 2, 3, 4, 5, or 6 carbon atoms. Alkenyl groups include, but are not limited to, for example, vinyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, etc. In this invention, alkenyl groups include substituted alkenyl groups.

[0125] "Alkenyl" refers to an alkenyl group with two connection points. For example, "vinylene" represents the group -CH=CH-. Alkenyl groups can also be in an unsubstituted form or in a substituted form with one or more substituents.

[0126] "Alynyl group (alone or as part of other groups)" refers to a straight-chain or branched hydrocarbon chain containing two or more carbon atoms and characterized by having one or more triple bonds, typically having 2 to 20 carbon atoms. In this invention, "C2-6 alkynyl group" refers to an alkynyl group having 2, 3, 4, 5, or 6 carbon atoms. Alynyl groups include, but are not limited to, ethynyl, propynyl, and 3-hexynyl. One of the carbon atoms in the triple bond may optionally be the linking point for an alkynyl substituent. In this invention, alkynyl groups also include substituted alkynyl groups.

[0127] "Imyynyl" refers to an alkynyl group with two connection points. For example, "ethynyl" indicates the group: -C≡C-. Imyynyl can also be in an unsubstituted form or a substituted form with one or more substituents.

[0128] "Cycloalkyl" refers to a monovalent saturated carbocyclic group consisting of a mono- or bicyclic ring, having 3-12, preferably 3-10, and more preferably 3-8 ring atoms. The cycloalkyl group may optionally be substituted with one or more substituents, wherein each substituent is independently a hydroxyl, alkyl, alkoxy, halogen, haloalkyl, amino, monoalkylamino, or dialkylamino group. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0129] “Cycloalkoxy” refers to a group of the formula -OR, where R is a cycloalkyl group as defined herein. Exemplary cycloalkyloxy groups include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, etc. “Cycloalkylalkyl” refers to a cycloalkyl group where the cycloalkyl and alkyl groups are -(cycloalkyl)-alkyl groups as disclosed herein. “Cycloalkylalkyl” is bonded to the parent molecule structure via the cycloalkyl group.

[0130] "Heteroaryl" refers to a monocyclic (e.g., 5- or 6-membered), bicyclic (e.g., 8- or 10-membered), or tricyclic group with 5 to 12 ring atoms, containing at least one aromatic ring with 1, 2, or 3 ring heteroatoms selected from N, O, or S, and the remaining ring atoms being C. It should be clear that the connection point of the heteroaryl group should be located on the aromatic ring. 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, benzofuranyl, benzothiophene, benzothiaranyl, benzoimidazolyl, benzooxazolyl, benzooxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzopyranyl, indolyl, isindolyl, triazolyl, triazinyl, quinoxolinyl, purine, quinazolinyl, quinazinyl, naphridinyl, pteridinyl, carbazole, azazolyl, diazazolyl, acridineyl, etc. Heteroaryl refers to a heteroaryl group having two linkage sites.

[0131] A "heterocyclic system" refers to a monocyclic, bicyclic, or polycyclic system in which at least one ring is saturated or partially unsaturated (but not aromatic) and contains at least one heteroatom. Heterocyclic systems can be attached to side groups at any heteroatom or carbon atom, resulting in a stable structure, and any ring atom can optionally be substituted.

[0132] "Heterocyclic group" refers to a monovalent group in a heterocyclic system, usually a stable monocyclic (e.g., 3-8 ternary, i.e., 3, 4, 5, 6, 7 or 8 ternary), bicyclic (e.g., 5-12 ternary, i.e., 5, 6, 7, 8, 9, 10, 11 or 12 ternary), or polycyclic (e.g., 7-14 ternary, i.e., 7, 8, 9, 10, 11, 12, 13 or 14 ternary), including fused rings, spirocyclic and / or bridged ring structures, which are saturated or partially unsaturated, and contain a carbon atom and one, two, three or four heteroatoms independently selected from N, O and S. Representative heterocyclic groups include the following ring systems, wherein (1) each ring is non-aromatic and at least one ring contains a heteroatom, for example, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, pyrrolylalkyl, pyrrolidoneyl, piperidinyl, pyrrololinyl, decahydroquinolinyl, oxazolylalkyl, piperazineyl, dioxalyl, dioxopentyl, diachexenyl, oxachexenyl, thiaachexenyl, morpholinyl, and quininecycloyl; (2) at least one ring is non-aromatic and contains a heteroatom and at least one other ring is an aromatic carbocyclic ring, for example, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl; and (3) at least one ring is non-aromatic and contains a heteroatom and at least one other ring is aromatic and contains a heteroatom, for example, 3,4-dihydro-1H-pyrano[4,3-c]pyridine and 1,2 3,4-Tetrahydro-2,6-diazanaphthalene. A heterocyclic group refers to a heterocyclic group having two linking sites. In this invention, the heterocyclic group is preferably bicyclic, with one ring being a heteroaryl group, and linked to other parts of the general formula through the heteroaryl group. In this invention, the heterocyclic group is preferably a 5-6 member monocyclic heterocyclic group or an 8-10 member bicyclic heterocyclic group.

[0133] "Heterocyclic alkyl" refers to an alkyl group that has been substituted with a heterocyclic group, wherein the definitions of heterocyclic group and alkyl group are as described above.

[0134] When the substituent is a non-terminal substituent, it is a subunit of the corresponding group. For example, alkyl corresponds to alkylene, cycloalkyl corresponds to cycloalkylene, heterocyclic corresponds to heterocyclic, alkoxy corresponds to alkoxy, etc.

[0135] In this invention, each of the above-mentioned groups such as alkyl, alkoxy, cycloalkyl, heteroalkyl, aryl, heteroaryl, cyclohexaalkyl, alkenyl, alkyne, heterocycle, and heterocyclic can be substituted or unsubstituted.

[0136] In this invention, the term "substitution" refers to the substitution of one or more hydrogen atoms on a specific group by a specific substituent. The specific substituent is 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 specific 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. Typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (e.g., monohalogen substituents or polyhalogen substituents, the latter such as trifluoromethyl or alkyl containing Cl3), cyano, nitro, oxo (e.g., =O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, alkynyl, heterocyclic, aromatic, OR a SR a S(=O)R e S(=O)2R e P(=O)2R e S(=O)2OR e P(=O)2OR e NR b R c NR b S(=O)2R e NR b P(=O)2R e S(=O)2NR b R c P(=O)2NR b R c C(=O)OR d C(=O)R a C(=O)NR b R c OC(=O)R a OC(=O)NR b R c NR b C(=O)OR e NR d C(=O)NR b R c NR d S(=O)2NR b R c NR d P(=O)2NR b R c NR b C(=O)R a , or NR b P(=O)2R e , where Ra It can independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, ynyl, heterocyclic, or aromatic rings, R b R c and R d It can independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocyclic or aromatic ring, or R b and R c It can form heterocycles together with N atoms; R e It can independently represent hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, heterocyclic, or aromatic ring. The above-mentioned typical substituents, such as alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aromatic ring, can be optionally substituted. Such substituents include (but are not limited to): halogen, hydroxyl, cyano, carboxyl (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-12 membered heterocyclic, aryl, heteroaryl, C1-C8 aldehyde, C2-C10 acyl, C2-C10 ester, amino, C1-C6 alkoxy, C1-C10 sulfonyl, and C1-C6 urea, etc.

[0137] "Cyano" refers to the -CN group.

[0138] "Nitro" refers to -NO2.

[0139] "Hydroxy group" refers to -OH.

[0140] "Amino" refers to -NH2 or RNH-, where R is a ketone carbonyl group, sulfonyl group, sulfonamide group, or R a -C(=O)-、R a R b NC(=O)- etc., where R a and R b It can be alkyl, cycloalkyl, aryl, or heteroaryl, etc.

[0141] "Halogen (halogenated)" refers to any halogen group, such as -F, -Cl, -Br or -I.

[0142] "Deuterated compounds" refer to compounds in which one or more hydrogen atoms (H) are replaced by deuterium atoms (D).

[0143] In this invention, the term "multiple" independently refers to 2, 3, 4, or 5.

[0144] compound

[0145] This invention provides a compound, which is a compound of Formula I, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotopic compound, or prodrug thereof.

[0146] Formula I

[0147] The groups are defined above.

[0148] In another preferred embodiment, in the compound, each of the groups is independently the group corresponding to the specific compound.

[0149] As used herein, the term "pharmaceutically acceptable salt" refers to a salt formed by the compounds of the present invention with an acid or base that is suitable for use as a medicine. Pharmaceutically acceptable salts include both inorganic and organic salts. A preferred class of salts are those formed by the compounds of the present invention with an acid. Suitable acids for forming salts include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, and naphthalenesulfonic acid; and amino acids such as proline, phenylalanine, aspartic acid, and glutamic acid.

[0150] Another preferred class of salts are salts formed by the compounds of the present invention with a base, such as alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., magnesium or calcium salts), ammonium salts (such as lower alkanol ammonium salts and other pharmaceutically acceptable amine salts), such as methylamine salts, ethylamine salts, propylamine salts, dimethylamine salts, trimethylamine salts, diethylamine salts, triethylamine salts, tert-butylamine salts, ethylenediamine salts, hydroxyethylamine salts, dihydroxyethylamine salts, trihydroxyethylamine salts, and amine salts formed from morpholine, piperazine, and lysine, respectively.

[0151] The term "solvate" refers to a complex formed by the coordination of the compound of the present invention with solvent molecules in a specific ratio. "Hydrate" refers to a complex formed by the coordination of the compound of the present invention with water.

[0152] Furthermore, the compounds of this invention also include prodrugs of compounds represented by Formula I. The term "prodrug" includes compounds that are themselves biologically active or inactive, and which, upon administration by an appropriate method, are metabolized or chemically reacted in the human body to form compounds of Formula I, or salts or solutions of compounds of Formula I. The prodrugs include (but are not limited to) carboxylic acid esters, carbonates, phosphate esters, nitrate esters, sulfate esters, sulfone esters, sulfoxide esters, amino compounds, carbamates, azo compounds, phosphoramides, glucosides, ethers, acetals, etc.

[0153] The compounds, salts, or solvates of this invention may exist in tautomer forms (e.g., amides and imine ethers). All such tautomers are part of this invention.

[0154] All stereoisomers of compounds (e.g., those with asymmetric carbon atoms due to various substitutions), including their enantiomers and diastereomeric forms, are within the scope of this invention. The independent stereoisomers of the compounds in this invention may not coexist with other isomers (e.g., possessing special activity as a pure or substantially pure optical isomer), or may be mixtures, such as racemates, or mixtures formed with all other stereoisomers or a portion thereof. The chiral center of this invention has two configurations, S or R, as defined by the International Union of Theoretical and Applied Chemistry (IUPAC) in 1974. Racemic forms can be resolved by physical methods, such as stepwise crystallization, or by derivatization into diastereomers followed by crystallization, or by chiral column chromatography. Individual optical isomers can be obtained from racemates by suitable methods, including but not limited to conventional methods, such as recrystallization after salting with an optically active acid.

[0155] The compounds of this invention, obtained sequentially through preparation, separation, and purification, have a weight content equal to or greater than 90%, for example, equal to or greater than 95%, or equal to or greater than 99% (“very pure” compounds), as described in the text. Such “very pure” compounds of this invention are also included as part of this invention.

[0156] All configurational isomers of the compounds of this invention are included within the scope of this invention, whether in mixture, pure, or very pure form. The definition of compounds of this invention includes cis( Z It includes two olefin isomers, cis and trans-I, as well as cis and trans isomers of carbocyclic and heterocyclic compounds.

[0157] Throughout the specification, groups and substituents can be selected to provide stable fragments and compounds.

[0158] Specific functional groups and chemical terminology definitions are detailed below. For the purposes of this invention, chemical elements are defined in the Periodic Table of the Elements, CAS version. Handbook of Chemistry and Physics 75 th The definitions in Ed. are consistent. The definitions of specific functional groups are also described there. In addition, the basic principles of organic chemistry, as well as specific functional groups and reactivity, are explained in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, the full contents of which are included in the references.

[0159] Some compounds of this invention may exist in specific geometric or stereoisomeric forms. This invention covers all compounds, including their cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, racemic mixtures, and other mixtures. Additionally, the asymmetric carbon atom may represent a substituent, such as an alkyl group. All isomers and mixtures thereof are included in this invention.

[0160] According to the present invention, the ratio of isomers in a mixture of isomers can be varied. For example, a mixture containing only two isomers can have the following combinations: 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0. All ratios of isomers are within the scope of the present invention. Similar ratios readily understood by those skilled in the art, as well as ratios for mixtures of more complex isomers, are also within the scope of the present invention.

[0161] This invention also includes isotopically labeled compounds, equivalent to the original compounds disclosed herein. However, in practice, it is common for one or more atoms to be replaced by atoms with different atomic weights or mass numbers. Examples of isotopes that can be included in the compounds 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. The compounds of this invention, or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates, wherein the isotopes or other isotopic atoms of the aforementioned compounds are all within the scope of this invention. Certain isotopically labeled compounds of this invention, for example... 3 H and 14 Radioactive isotopes of carbon are also included, and are useful in tissue distribution experiments of drugs and substrates. Tritium, i.e. 3 H and carbon-14, i.e. 14 C, their preparation and detection are relatively easy. They are the preferred isotopes. In addition, heavier isotopes such as deuterium are used for substitution. 2H, 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 described in the examples.

[0162] To design the synthesis of a specific enantiomer of the compound of this invention, it can be prepared asymmetrically or derivatized with a chiral auxiliary. The resulting diastereomeric mixture is then separated, and the chiral auxiliary is removed to obtain the pure enantiomer. 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 diastereomer salt, which is then separated by conventional methods such as separation crystallization or chromatography to obtain the pure enantiomer.

[0163] As described herein, the compounds of this invention can be expanded with any number of substituents or functional groups. Generally, whether the term "substitution" appears before or after the term "optional," the general formula for substituents in the formulations of this invention refers to replacing a hydrogen radical with a substituent of a specified structure. When multiple positions in a particular structure are replaced by multiple specific substituents, each position of the substituent can be the same or different. The term "substitution" as used herein includes all permissible substitutions in organic compounds. In a broad sense, permissible substituents include acyclic, cyclic, branched-unbranched, carbocyclic, and heterocyclic, aromatic and non-aromatic organic compounds. In this invention, heteroatomic nitrogen may be supplemented with hydrogen substituents or any permissible organic compound described above to complete its valence state. Furthermore, this invention is not intended to limit permissible substituted organic compounds in any way. This 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 refers to a compound that is stable enough to maintain the integrity of its structure when tested over a sufficiently long period of time, preferably remaining effective over a sufficiently long period of time, and is used here for the purposes described above.

[0164] The compounds involved in this application and their pharmaceutically acceptable salt metabolites, as well as prodrugs that can be converted in vivo into structures of the compounds involved in this application and their pharmaceutically acceptable salts, are also included in the claims of this application.

[0165] It should be understood that the embodiments of the present invention specifically describe the preparation methods of the compounds of Formula I of the present invention, but these specific methods do not constitute any limitation on the present invention. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such combinations can be easily performed by those skilled in the art.

[0166] Typically, the raw materials and reagents used in the preparation process of the compounds of the present invention can be purchased commercially unless otherwise specified.

[0167] Typically, in the preparation process, each reaction is carried out under inert gas protection, in a suitable solvent, at 0 to 150°C, and the reaction time is usually 2 to 24 hours.

[0168] Pharmaceutical Compositions and Administration

[0169] The present invention also provides a pharmaceutical composition comprising the said compound and a pharmaceutically acceptable carrier.

[0170] Because the compounds of the present invention have excellent antitumor activity, the compounds of the present invention and their various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compounds of the present invention as the main active ingredient can be used to treat, prevent and alleviate tumor-related diseases.

[0171] The pharmaceutical compositions of the present invention comprise, within a safe and effective range, the compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically 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, 10-1000 mg of the compound of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0172] "Pharmaceutically acceptable carriers" refers 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.), emulsifiers (such as Tween®), wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0173] The pharmaceutical composition is an injection, capsule, tablet, pill, powder, or granule.

[0174] 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, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and local administration.

[0175] The dosage forms of the pharmaceutical compositions of the present invention include (but are not limited to): injections, tablets, capsules, aerosols, suppositories, films, pellets, topical liniments, controlled-release or sustained-release or nano-formulations.

[0176] 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.

[0177] 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.

[0178] 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.

[0179] 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.

[0180] In addition to the active compound, 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.

[0181] 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.

[0182] 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 that may be necessary.

[0183] The compounds of this invention can be administered alone or in combination with other pharmaceutically acceptable compounds (such as antitumor drugs).

[0184] The treatment method of the present invention can be used alone or in combination with other treatment methods or drugs.

[0185] The compound of Formula I can be used in combination with other known drugs for treating or improving similar symptoms. When administered in combination, the original drug's administration method and dosage can remain unchanged, while the compound of Formula I is taken simultaneously or subsequently. When the compound of Formula I is taken concurrently with one or more other drugs, a pharmaceutical composition containing one or more known drugs and the compound of Formula I is preferred. Drug combination also includes taking the compound of Formula I with one or more other known drugs during overlapping time periods. When the compound of Formula I is used in combination with one or more other drugs, the dosage of the compound of Formula I or the known drug may be lower than the dosage of either drug alone.

[0186] Drugs or active ingredients that can be used in combination with the compounds of Formula I include, but are not limited to: gefitinib, erlotinib, icotinib, lapatinib, XL647, NVP-AEE-788, ARRY-334543, vandetanib, PF00299804, cetuximab, panitumumab, pertuzumab, zarumumab, nimotuzumab, MDX-214, CDX-110, IMC-11F8, CNF2024, spiramycin, aspiramycin, IPI-504, and NVP-AUY922.

[0187] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to the mammal (such as a human or mouse) requiring treatment. The dosage administered is the pharmaceutically considered effective dose. For a person weighing 60 kg, the daily dose is typically 1–2000 mg, preferably 50–1000 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.

[0188] Compared with the prior art, the present invention has the following main advantages:

[0189] (1) The compounds of this invention have excellent EGFR degradation performance;

[0190] (2) The compounds of the present invention have excellent inhibitory and / or therapeutic effects on EGFR-related diseases, especially EGFR drug resistance mutation diseases, including but not limited to diseases selected from the group consisting of: H1975 (T790M / L858R), HCC827 (19DEL), PC-9 (19DEL);

[0191] (3) The compounds of the present invention have excellent pharmacokinetic properties;

[0192] (4) The compounds of the present invention are suitable for the prevention and / or treatment of diseases selected from the group consisting of: EGFR-sensitive mutant cancers and diseases that have developed secondary resistance to current EGFR treatment;

[0193] (5) The compounds of the present invention have excellent safety.

[0194] 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, are generally performed under conventional conditions as described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

[0195] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0196] Example 1

[0197] The compounds synthesized in this invention:

[0198]

[0199] T-001

[0200] The experimental procedure is as follows:

[0201] I. Synthesis of Intermediate M1

[0202] The synthesis route is as follows:

[0203]

[0204] Synthesis of intermediate M1

[0205] M1: Add 10g (1.0 equivalent) of compound SM1 to a 100ml single-necked flask, add 43g (5.0 equivalent) of a mixture of N,N-diisopropylethylamine and 100ml of isopropanol, stir well at room temperature, and slowly add 12.2g (1.0 equivalent) of compound SM2. After the addition is complete, purge with nitrogen three times, heat to reflux under nitrogen protection, and stir overnight. Monitor the reaction completion by TLC, evaporate the solvent under reduced pressure, add the residue to 50ml of ethyl acetate (EA), stir at room temperature for 30 minutes, filter, wash the filter cake twice with 15ml of ethyl acetate, and collect the filter cake, which is intermediate M1: 17.4g.

[0206] II. Synthesis of intermediate M2

[0207] The synthesis route is as follows:

[0208] 1. Synthesis of Compound 2

[0209] In a 100 mL three-necked flask, 200 mg of compound 1 (1.0 equivalent), 138 mg of cyclopropylboronic acid (2.0 equivalent), 167 mg of potassium carbonate (1.5 equivalent), 4 mL of 1,4-dioxane, and 0.8 mL of water were mixed thoroughly under nitrogen protection. Then, 70 mg of [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (0.12 equivalent) was added, and the mixture was heated to 100 °C and reacted overnight. The reaction was monitored by TLC until complete. The mixture was filtered through a diatomaceous earth filter, and the mother liquor was collected. The solvent was removed by rotary evaporation, and the mother liquor was extracted three times with 30 mL of water and 15 mL of ethyl acetate. The combined organic phases were mixed and filtered through a column to obtain 150 mg of compound 2. LC-MS [M+1]: 212.

[0210] 2. Synthesis of Compound 3

[0211] In a 50 mL single-necked flask, add 120 mg of compound 2 (1.0 equivalent), 160 mg of N-boc piperazine (1.5 equivalent), 235 mg of potassium carbonate (3.0 equivalent), and 2.5 mL of N,N-dimethylformamide. Under nitrogen protection, the mixture was heated to 110 °C and reacted overnight. The reaction was monitored by TLC until complete. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated to dryness. Column chromatography yielded compound 3: 100 mg. LC-MS [M+1]: 478.

[0212] 3. Synthesis of Compound 4

[0213] In a 50 ml round-bottom flask, compound 3 (100 mg, 1.0 eq) was dissolved in 3 ml of ethanol, and zinc powder (82 mg, 6.0 eq.), ammonium chloride (112 mg, 10.0 eq.), and water (0.6 ml) were added. The reaction solution was heated to 90 ml. o Refluxed at C overnight. LC-MS confirmed complete reaction. The reaction solution was directly mixed with 500 mg of silica gel (100-200 mesh) and purified by column chromatography (EA in PE from 0% to 75%) to obtain target product 4 (60 mg, yellow oil). LC-MS [M+1]: 348.

[0214] 4. Synthesis of intermediate M2

[0215] Compound 4 (60 mg, 1.0 eq), intermediate M1 (51 mg, 1.0 eq), p-toluenesulfonic acid monohydrate (40 mg, 1.2 eq), and 4 ml of isopropanol were added to a 50 ml single-necked flask. The mixture was thoroughly mixed and refluxed overnight. LC-MS was used to confirm the completeness of the reaction. The pH of the reaction solution was adjusted to >7 with saturated sodium bicarbonate solution. Extraction was performed with ethyl acetate, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The sample was mixed with 500 mg of silica gel (100-200 mesh) and purified by column chromatography (MeOH in DCM 0% to 20%) to obtain the target product M2 (50 mg, brown solid). LC-MS [M+1]: 508.

[0216] III. Synthesis of Intermediate M3

[0217] The synthesis route is as follows:

[0218]

[0219] 1. Synthesis of Compound 2

[0220] In a 250 mL three-necked flask, 5 g of compound 1, 10.8 g of n-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester, 60 mL of tetrahydrofuran, 24 mL of methanol, 12 mL of water, 6.8 g of sodium carbonate, and 0.43 g of PdCl2 dppf were mixed thoroughly. After purging with nitrogen, the mixture was heated to 80 °C and reacted overnight. The reaction was monitored by TLC until complete. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, evaporated to dryness, and separated by column chromatography to give 5.8 g of compound 2. LC-MS [M+1]: 275.

[0221] 2. Synthesis of Compound 3

[0222] In a 100 mL three-necked flask, 5.1 g of compound 2, 7.1 g of 3-bromopiperidine-2,6-dione, and 7.2 g of N,N-diisopropylethylamine were dissolved in 51 mL of 1,4-dioxane. The mixture was heated to 100 °C and reacted overnight. The reaction was monitored by TLC until complete. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, evaporated to dryness, and separated by column chromatography to give 3.6 g of compound 3. LC-MS [M+1]: 386.

[0223] 3. Synthesis of Compound 4

[0224] 3.6 g of compound 2, 0.72 g of palladium on carbon, and 36 ml of anhydrous ethanol were added to a high-pressure reactor. The hydrogen pressure was increased to 0.7 MPa, and the reaction was carried out for two days. The mixture was then filtered, and the solvent was removed by rotary evaporation to obtain 1.2 g of compound 4. LC-MS [M+1]: 388.

[0225] 4. Synthesis of Compound 5

[0226] 1.2 g of compound 4 was added to a 100 mL single-necked flask and dissolved in 30 mL of methanol. The mixture was then cooled and added dropwise in an ice-water bath. After the addition was complete, the reaction was carried out at 40 °C for 2 hours. The solvent was removed by rotary evaporation to obtain 1.4 g of compound 5. LC-MS [M+1]: 288.

[0227] 5. Synthesis of Compound 6

[0228] 0.8 g of compound 5 was added to a 100 ml single-necked flask, along with 8 ml of NN-dimethylformamide, NN-diisopropylethylamine, and tert-butyl bromoacetate. The mixture was stirred overnight at room temperature. The reaction was detected by TLC to be complete. The mixture was extracted with ethyl acetate and water, and the organic phase was dried, filtered, and then subjected to column chromatography to obtain 300 mg of compound 6. LC-MS [M+1]: 402.

[0229] 6. Synthesis of compound M3

[0230] 100 mg of compound 6 was added to a 100 ml single-necked flask, followed by 1 ml of dichloromethane and 1.6 ml of trifluoroacetic acid. The mixture was stirred overnight at room temperature. The reaction was confirmed to be complete by TLC. The solvent was removed by rotary evaporation to obtain 150 mg of compound 6. M3, LC-MS [M-1]: 344.

[0231] IV. Synthesis of Compound T-001

[0232] The synthesis route is as follows:

[0233] In a 50 ml round-bottom flask, compounds M2 (50 mg, 1.0 eq) and M3 (70 mg, 1.0 eq) were dissolved in 2 ml of NN-dimethylformamide. The mixture was cooled to 0 °C in an ice-water bath, and NN-diisopropylethylamine (0.2 ml, 10.0 eq) and HATU (50 mg, 1.3 eq) were added with stirring. The mixture was reacted in an ice-water bath for 1 hour under nitrogen protection, and then naturally heated to room temperature. The reaction was confirmed to be complete by TLC. The mixture was extracted with ethyl acetate and water, and the organic phase was dried, filtered, and then subjected to column chromatography to obtain 15 mg of compound T-001. LC-MS [M+1]: 833. HNMR: 1H NMR (400 MHz, DMSO-d6) δ 11.67 (s, 1H), 10.79 (s, 1H), 8.74 (q, J = 4.6 Hz, 1H), 8.65 – 8.45 (m, 1H), 8.25 (s, 1H), 8.12 (s, 1H), 7.71 (dd, J = 8.0, 1.6 Hz, 1H), 7.27 (d, J = 8.1 Hz, 1H), 7.04 (t, J = 7.6 Hz, 1H), 6.73 (s, 1H), 6.62(d, J = 8.1 Hz, 2H), 5.71 (d, J = 7.7 Hz, 1H), 4.37 (t, J = 5.1 Hz, 0H), 4.32– 4.22 (m, 1H), 3.75 (s, 3H), 3.71 (s, 5H), 3.50 – 3.39 (m, 5H), 3.17 (d, J =5.1 Hz, 0H), 3.05 (t, J = 4.8 Hz, 2H), 2.98 (s, 2H), 2.83 – 2.67 (m, 4H), 2.60 (ddd, J = 17.6, 14.1, 4.4 Hz, 1H), 2.22 (td, J = 8.4, 4.4 Hz, 1H), 2.09(dq, J = 13.4, 4.7 Hz, 1H), 1.85 (ddd, J = 25.7, 12.8, 8.0 Hz, 7H), 1.06 (t,J = 7.0 Hz, 1H), 0.88 (dd, J = 8.2, 5.5 Hz, 2H), 0.53 (q, J = 5.1, 4.6 Hz,2H).

[0234] Example 2

[0235] The compounds synthesized in this invention:

[0236]

[0237] T-009

[0238] The experimental procedure is as follows:

[0239] I. Synthesis of Intermediate M1

[0240] The synthesis route is as follows:

[0241]

[0242] Intermediate M1 was synthesized according to the method of Example 1.

[0243] II. Synthesis of intermediate M2

[0244] The synthesis route is as follows:

[0245]

[0246] 1. Synthesis of Compound 2

[0247] In a 100 mL three-necked flask, 500 mg of Compound 1 (1.0 equivalent), 536 mg of vinyl boron trifluoride (2.0 equivalent), 165 mg of potassium carbonate (1.5 equivalent), 5 mL of 1,4-dioxane, and 1 mL of water were mixed thoroughly under nitrogen protection. Then, 175 mg of [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (0.12 equivalent) was added, and the mixture was heated to 100 °C and reacted overnight. The reaction was monitored by TLC until complete. The mixture was filtered through a diatomaceous earth filter, and the mother liquor was collected. The solvent was removed by rotary evaporation, and the mother liquor was extracted three times with 30 mL of water and 15 mL of ethyl acetate. The combined organic phases were stirred and filtered through a column to obtain 320 mg of Compound 2.

[0248] 2. Synthesis of Compound 3

[0249] In a 100 mL single-necked flask, 320 mg of compound 2, 600 mg of N-boc piperazine, and 666 mg of potassium carbonate were dissolved in 30 mL of DMF. The mixture was heated to 110 °C and reacted for 18 h. The solvent was removed by rotary evaporation, and the residue was extracted with water, ethyl acetate, dried over anhydrous sodium sulfate, and evaporated to dryness. Column chromatography yielded 400 mg of compound 3. LC-MS [M+1]: 366.

[0250] 3. Synthesis of Compound 4

[0251] In a 100 ml single-necked flask, 300 mg of compound 3 and 15 mg of palladium on carbon were added to 5 ml of methanol and reacted at room temperature for 18 h. The mixture was filtered through a diatomaceous earth pad, and the mother liquor was collected, dried over anhydrous sodium sulfate, and evaporated to dryness. Column chromatography yielded 250 mg of a brown solid, compound 4. LC-MS [M+1]: 336.

[0252] 4. Synthesis of intermediate M2

[0253] Compound 4 (223 mg, 1.0 eq), intermediate M1 (250 mg, 1.0 eq), p-toluenesulfonic acid monohydrate (156 mg, 1.2 eq), and 4 ml of isopropanol were added to a 50 ml single-necked flask. The mixture was thoroughly mixed and refluxed overnight. LC-MS was used to confirm the completeness of the reaction. The pH of the reaction solution was adjusted to >7 with saturated sodium bicarbonate solution. The solution was extracted with ethyl acetate, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The solution was mixed with silica gel (100-200 mesh) and purified by column chromatography (MeOH in DCM 0% to 20%) to obtain the target product M2 (130 mg, brown solid). LC-MS [M+1]: 496.

[0254] III. Synthesis of Intermediate M3

[0255] The synthesis route is as follows:

[0256]

[0257] 1. Synthesis of Compound 2

[0258] In a 50 ml three-necked flask, compound 1 (0.2.0 g, 8.5 mmol, 1.0 eq) and TEA (2.58 g, 25.5 mmol, 3.0 eq) were dissolved in 20 ml of DMF and cooled to 0 °C. o C. Add (Tf)₂O (3.6 g, 12.76 mmol, 1.5 eq) to the mixture. The reaction mixture was allowed to warm naturally to room temperature and stirred overnight. The reaction was monitored by TLC (potassium permanganate colorimetric method) until complete. The reaction mixture was evaporated to dryness, and the crude product was subjected to column chromatography (100% PE) to give crude compound 2 as a yellow solid (841 mg, 45.6% yield). LC-MS [M+1]: 368. 1H NMR (400 MHz, DMSO-d₆) δ 6.84 (s, 1H), 4.24 (q, J = 4.4 Hz, 3H), 4.05 (t, J = 11.3 Hz, 3H), 1.43 (s, 12H).

[0259] 2. Synthesis of Compound 3

[0260] Pinaryl 4-aminophenylboronic acid ester (367 mg, 3.16 mmol, 1.2 eq), compound 2 (700 mg, 1.9 mmol, 1.0 eq), and sodium carbonate (607 mg, 5.73 mmol, 3.0 eq) were added to a 50 mL three-necked flask. After purging the mixture three times with N2 gas, dioxane (7 mL) and water (1.75 mL) were added. The mixture was then purged three times with N2 gas, and Pd(dppf)Cl2 (140 mg, 0.19 mmol, 0.1 eq) was added. The reaction mixture was incubated at 55 °C under N2 protection. o Stirring at C for 2 hours. TLC showed the starting material disappearing and new spots forming. The reaction solution was filtered and the filtrate was evaporated to dryness. The crude product was subjected to column chromatography (EA in PE from 0% to 40%) to give a white solid compound 3 (230 mg, 32.4% yield). LC-MS [M+1]: 311.

[0261] 3. Synthesis of Compound 4

[0262] In a 50 mL round-bottom flask, compound 3 (230 mg, 0.74 mmol, 1.0 eq) and 3-bromopiperidin-2,6-dione (171 mg, 0.89 mmol, 1.2 eq) were dissolved in 2.3 mL of N,N-dimethylformamide. Sodium bicarbonate (125 mg, 0.65 mmol, 2.0 eq) was added to the mixture. The reaction mixture was stirred at 70 °C for 16 hours under nitrogen protection. After cooling to room temperature, the reaction was confirmed to be complete by TLC. The reaction mixture was diluted with EA (10 mL), and water (10 mL) was added for separation. The aqueous phase was extracted with EA (10 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the crude product was purified by column chromatography (EA in PE from 0% to 50%) to give compound 4 (60 mg, 19% yield). LC-MS [M+1]: 422.

[0263] 4. Synthesis of Compound 5

[0264] Compound 4 (70 mg, 0.16 mmol, 1.0 eq) was dissolved in 1 mL of methanol in a 500 mL round-bottom flask, and palladium on carbon (7 mg) was added to the mixture. The reaction mixture was stirred at room temperature under a H2 balloon for 16 hours. The reaction was confirmed to be complete by LC-MS. The reaction solution was filtered to give crude compound 5 (70 mg, 100% crude). LC-MS [M+1]: 424.

[0265] 5. Synthesis of Compound 6

[0266] Compound 5 (70 mg, 0.16 mmol, 1.0 eq) was dissolved in 2 mL of dichloromethane in a 50 mL round-bottom flask, and 0.5 mL of trifluoroacetic acid was added to the mixture. The reaction mixture was stirred at room temperature for 2 hours. The reaction was confirmed to be complete by LC-MS. The reaction mixture was evaporated to dryness to give compound 6 (54 mg, 100% crude). LC-MS [M+1]: 324.

[0267] 6. Synthesis of Compound 7

[0268] In a 50 mL round-bottom flask, compound 6 (54 mg, 0.17 mmol, 1.0 eq) and tert-butyl bromoacetate (40 mg, 0.2 mmol, 1.2 eq) were dissolved in 1 mL of N,N-dimethylformamide. DIPEA (65 mg, 0.5 mmol, 3.0 eq) was added to the mixture. The reaction mixture was stirred at room temperature for 12 h. TLC was used to confirm the completeness of the reaction. The reaction mixture was diluted with EA (5 mL), and water (5 mL) was added for separation. The aqueous phase was extracted with EA (5 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the crude product was purified by column chromatography (EA in PE from 0% to 60%) to give compound 7 (45 mg, 61.6% yield). LC-MS [M+1]: 438.

[0269] 7. Synthesis of compound M3

[0270] Compound 7 (45 mg, 0.1 mmol, 1.0 eq) was dissolved in 2 mL of dichloromethane in a 50 mL round-bottom flask, and 0.5 mL of trifluoroacetic acid was added to the mixture. The reaction mixture was stirred at room temperature for 2 hours. The reaction was confirmed to be complete by LC-MS. The reaction mixture was evaporated to dryness to give compound M3 (45 mg, 100% crude). LC-MS [M+1]: 382.

[0271] III. Synthesis of Compound T-009

[0272] The synthesis route is as follows:

[0273]

[0274] In a 50 ml round-bottom flask, compounds M2 and M3 were dissolved in 2 ml of NN-dimethylformamide. The mixture was cooled to 0°C in an ice-water bath, and NN-diisopropylethylamine and HATU were added with stirring. The mixture was reacted in an ice-water bath for 1 hour under nitrogen protection, and then naturally heated to room temperature. The reaction was confirmed to be complete by TLC. The mixture was extracted with ethyl acetate and water, and the organic phase was dried, filtered, and then subjected to column chromatography to obtain 100 mg of compound T-009. LC-MS [M+1]: 860.

[0275] The following compounds were synthesized according to the method of Example 2:

[0276]

[0277]

[0278] Example 3

[0279] The compounds synthesized in this invention:

[0280]

[0281] T-005

[0282] The experimental procedure is as follows:

[0283] I. Synthesis of Intermediate M1

[0284] The synthesis route is as follows:

[0285]

[0286] 1. Synthesis of Compound 2

[0287] Add imidazole (587 mg, 1.2 eq) and tetrahydrofuran (20 ml) to a 100 ml three-necked flask, stir to dissolve, and cool to 0 °C. Add sodium hydride (400 mg, 1.4 eq) in portions to the reaction solution, keep warm and stir for 30 minutes, add compound 1, allow to rise naturally to room temperature, then heat to 60 °C and react overnight. The reaction was confirmed to be complete by TLC. Excess sodium hydride was then quenched with water, and the reaction solution was extracted with ethyl acetate. The solution was then filtered through a silica gel column with an organic phase, and 260 mg of the target component was collected.

[0288] 2. Synthesis of Compound 3

[0289] Compound 2 (260 mg, 1.0 eq), palladium on carbon catalyst (13 mg, 5 wt%), and 5 ml of methanol were added to a 50 ml single-necked flask and mixed thoroughly. The mixture was then purged three times with hydrogen balloons and reacted at room temperature under pressure for 20 hours. TLC showed that the starting material reacted completely. The mixture was filtered through a diatomaceous earth filter, and the mother liquor was collected to obtain 160 mg of compound 3.

[0290] 3. Synthesis of intermediate M1

[0291] 160 mg (1.0 equivalent) of compound 3 was added to a 100 mL single-necked flask, followed by 0.8 mL (5.0 equivalent) of a mixture of N,N-diisopropylethylamine and 2 mL of isopropanol. The mixture was stirred at room temperature until homogeneous, and then 183 mg (1.0 equivalent) of trichloropyrimidine was slowly added dropwise. After the addition was complete, nitrogen gas was purged three times. The mixture was heated to reflux under nitrogen protection and stirred overnight. The reaction was monitored by TLC to ensure completion. The solvent was evaporated to dryness under reduced pressure. The residue was added to 50 mL of ethyl acetate (EA), stirred at room temperature for 30 minutes, and filtered. The filter cake was washed twice with 15 mL of ethyl acetate, and the collected filter cake was intermediate M1: 180 mg.

[0292] II. Synthesis of intermediate M2

[0293] The synthesis route is as follows:

[0294]

[0295] 1. Synthesis of intermediate M2

[0296] In a 50 mL single-necked flask, add intermediate M1 (70 mg, 1.0 eq), SM3 (70 mg, 1.0 eq), p-toluenesulfonic acid monohydrate (52 mg, 1.2 eq), and 4 mL of isopropanol. Mix thoroughly and reflux overnight. LC-MS analysis confirms complete reaction. Adjust the pH of the reaction mixture to >7 with saturated sodium bicarbonate solution. Extract with ethyl acetate, wash the organic phase with saturated brine, and dry with anhydrous sodium sulfate. Purify by column chromatography (MeOH in DCM 0% to 20%) with silica gel (100-200 mesh) to obtain target product M2 (40 mg, brown solid). LC-MS [M+1]: 479.

[0297] III. Synthesis of Compound T-005

[0298] The synthesis route is as follows:

[0299]

[0300] Intermediates M2 and M3 were dissolved in 2 ml of NN-dimethylformamide in a 50 ml round-bottom flask. The mixture was cooled to 0°C in an ice-water bath, and NN-diisopropylethylamine and HATU were added with stirring. The reaction was carried out in an ice-water bath for 1 hour under nitrogen protection, and then naturally warmed to room temperature. The reaction was confirmed to be complete by TLC. The mixture was extracted with ethyl acetate and water, and the organic phase was dried, filtered, and then subjected to column chromatography to obtain 20 mg of compound T-005. LC-MS [M+1]: 805; ¹H NMR: 1H NMR (400 MHz, DMSO-d6) δ 10.84 (s, 1H), 10.26 (s, 1H), 8.54 (d, J = 8.5 Hz, 1H), 8.32 (s, 2H), 8.18 (s, 2H), 7.98 (dd, J = 8.2, 1.6 Hz, 1H), 7.52 (d, J = 8.6 Hz, 1H), 7.41(t, J = 7.8 Hz, 1H), 7.31 (t, J =7.8 Hz, 1H), 7.03 (d, J = 8.0 Hz, 2H), 6.77 (d, J = 2.5 Hz, 1H), 6.68 (d, J =8.1 Hz, 2H), 6.56 (dd, J =8.7, 2.5 Hz, 1H), 5.76 (s, 1H), 4.33 (dd, J =9.7,5.1 Hz, 1H), 3.85 (s, 3H), 3.73 (s, 5H), 3.29 (s, 3H), 3.20 (s, 3H), 2.79 (td,J = 12.1,6.1 Hz, 2H), 2.65 (d, J = 4.4 Hz, 1H), 2.20 –2.10 (m, 2H), 1.99 –1.76 (m, 5H), 1.33 (s,2H).

[0301] The following compounds were synthesized according to the method in Example 3:

[0302]

[0303] Example 4

[0304] The compounds synthesized in this invention:

[0305]

[0306] T-013

[0307] The experimental procedure is as follows:

[0308] I. Synthesis of Intermediate M1

[0309] The synthesis route is as follows:

[0310]

[0311] Intermediate M1 was synthesized according to the method of Example 1.

[0312] II. Synthesis of intermediate M2

[0313] The synthesis route is as follows:

[0314]

[0315] 1. Synthesis of Compound 2

[0316] In a 100 mL single-necked flask, compound 1 (1.0 g, 1.0 eq), pinacol diboronate (1.18 g, 1.2 eq), 15 mL of 1,4-dioxane, potassium acetate (911 mg, 3.0 eq), and PdCl2 dppf (113 mg, 0.12 eq) were mixed thoroughly. After purging with nitrogen, the mixture was heated to 85 °C and reacted overnight. The reaction was monitored by TLC until complete. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, evaporated to dryness, and separated by column chromatography to give 1.2 g of compound 2. LC-MS [M+1]: 372.

[0317] 2. Synthesis of Compound 3

[0318] In a 100 mL three-necked flask, 400 mg of compound 2 (1.2 equivalents), 484 mg of SM1 (1.0 equivalents), 345 mg of potassium carbonate (3.0 equivalents), 10 mL of 1,4-dioxane, and 2.5 mL of water were mixed thoroughly under nitrogen protection. Then, 80 mg of [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (0.12 equivalents) was added, and the mixture was heated to 55 °C and reacted for 2 hours. The reaction was monitored by TLC until complete. The mixture was filtered through a diatomaceous earth filter, and the mother liquor was collected. The solvent was removed by rotary evaporation, and the mother liquor was extracted three times with 30 mL of water and 15 mL of ethyl acetate. The combined organic phases were stirred and passed through a column chromatography column to obtain 500 mg of compound 3. LC-MS [M+1]: 462.

[0319] 3. Synthesis of Compound 4

[0320] Compound 3 (500 mg, 1.0 eq), palladium on carbon catalyst (50 mg, 5 wt%), and 5 ml of methanol were added to a 50 ml single-necked flask and mixed thoroughly. The mixture was then purged three times with hydrogen balloons and reacted at room temperature under pressure for 20 hours. TLC showed that the starting material reacted completely. The mixture was filtered through a diatomaceous earth filter, and the mother liquor was collected to obtain 400 mg of compound 4.

[0321] 4. Synthesis of Compound 5

[0322] 400 mg of compound 4 was added to a 100 mL single-necked flask and dissolved in 10 mL of tetrahydrofuran. The mixture was then cooled and added dropwise in an ice-water bath. After the addition was complete, the reaction was carried out at 40 °C for 2 hours. The solvent was removed by rotary evaporation to obtain 330 mg of compound 5. LC-MS [M+1]: 364.

[0323] 5. Synthesis of Compound 6

[0324] 330 mg of compound 5, 4 ml of NN-dimethylformamide, 1.2 ml of NN-diisopropylethylamine (5.0 eq), and tert-butyl bromoacetate (195 mg, 1.1 eq) were added to a 100 ml single-necked flask and stirred overnight at room temperature. The reaction was detected by TLC to be complete. The mixture was extracted with ethyl acetate and water, dried, filtered, and then subjected to column chromatography to obtain 370 mg of compound 6. LC-MS [M+1]: 479.

[0325] 6. Synthesis of intermediate M2

[0326] 350 mg of compound 6 was added to a 100 ml single-necked flask, 3 ml of dichloromethane was added, and 2 ml of trifluoroacetic acid was added dropwise. The mixture was stirred overnight at room temperature. The reaction was detected by TLC to be complete. The solvent was removed by rotary evaporation to obtain 150 mg M2. LC-MS [M-1]: 420.

[0327] III. Synthesis of Compound T-013

[0328] The synthesis route is as follows:

[0329]

[0330] In a 50 ml round-bottom flask, compounds M2 (150 mg, 1.0 eq) and M1 (176 mg, 1.0 eq) were dissolved in 4 ml of NN-dimethylformamide. The mixture was cooled to 0 °C in an ice-water bath, and NN-diisopropylethylamine and HATU (176 mg, 1.3 eq) were added with stirring. The mixture was reacted in an ice-water bath for 1 hour under nitrogen protection, and then naturally warmed to room temperature. The reaction was confirmed to be complete by TLC. The mixture was extracted with ethyl acetate and water, and the organic phase was dried, filtered, and then subjected to column chromatography to obtain 90 mg of compound T-013. LC-MS [M+1]: 899.6.

[0331] 1H NMR (400 MHz, DMSO-d6) δ11.69 (s, 1H), 10.64 (s, 1H), 8.80 (s,1H),8.70 – 8.54 (m, 1H), 8.29 (s,1H), 8.21 (s, 1H), 7.76 (d, J = 7.8 Hz,1H), 7.71– 7.52 (m, 3H), 7.38 (s,1H), 7.13 (q, J = 8.5, 7.6 Hz, 2H), 6.88 (s, 1H), 4.12– 3.93 (m, 6H), 3.79 (d, J = 18.4 Hz, 5H), 3.68 (s,3H), 3.53 – 3.51 (m, 1H),3.20 (d, J =7.6 Hz, 2H), 3.10 (s, 1H), 2.98 (s,2H), 2.93 – 2.78 (m, 8H), 2.69(d, J =7.4 Hz, 1H), 2.33 (d, J = 12.9 Hz,1H), 2.05 (s, 1H), 1.94 (d, J =13.0Hz, 1H), 1.16 (t, J = 7.6 Hz, 3H).

[0332] The following compounds were synthesized according to the method in Example 4:

[0333]

[0334]

[0335] Example 5

[0336] The compounds synthesized in this invention:

[0337]

[0338] T-003

[0339] The experimental procedure is as follows:

[0340] I. Synthesis of Intermediate M1

[0341] The synthesis route is as follows:

[0342]

[0343] Intermediate M1 was synthesized according to the method of Example 1.

[0344] II. Synthesis of intermediate M2

[0345] The synthesis route is as follows:

[0346]

[0347] 1. Synthesis of Compound 2

[0348] In a 100 mL three-necked flask, 500 mg of Compound 1 (1.0 equivalent), 536 mg of vinyl boron trifluoride (2.0 equivalent), 165 mg of potassium carbonate (1.5 equivalent), 5 mL of 1,4-dioxane, and 1 mL of water were mixed thoroughly under nitrogen protection. Then, 175 mg of [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (0.12 equivalent) was added, and the mixture was heated to 100 °C and reacted overnight. The reaction was monitored by TLC until complete. The mixture was filtered through a diatomaceous earth filter, and the mother liquor was collected. The solvent was removed by rotary evaporation, and the mother liquor was extracted three times with 30 mL of water and 15 mL of ethyl acetate. The combined organic phases were stirred and filtered through a column to obtain 320 mg of Compound 2.

[0349] 2. Synthesis of Compound 3

[0350] In a 100 mL single-necked flask, 320 mg of compound 2, 600 mg of N-boc piperazine, and 666 mg of potassium carbonate were dissolved in 30 mL of DMF. The mixture was heated to 110 °C and reacted for 18 h. The solvent was removed by rotary evaporation, and the residue was extracted with water, ethyl acetate, dried over anhydrous sodium sulfate, and evaporated to dryness. Column chromatography yielded 400 mg of compound 3. LC-MS [M+1]: 366.

[0351] 3. Synthesis of Compound 4

[0352] In a 100 ml single-necked flask, 300 mg of compound 3, 3 ml of hydrogen chloride / dioxane, and 5 ml of dichloromethane were mixed and reacted at room temperature for 6 h. The reaction solution was then evaporated to dryness under reduced pressure to give 217 mg of a yellow solid, compound 4. LC-MS [M+1]: 264.

[0353] 4. Synthesis of Compound 5

[0354] 217 mg of compound 4 was dissolved in 3 ml of dichloromethane in a 100 ml single-necked flask. 202 mg of DMAP was added, and the mixture was reacted at room temperature for 5 min. Then, 346 mg of trifluoroacetic anhydride was added, and the mixture was reacted at room temperature for 18 h. The reaction solution was evaporated to dryness under reduced pressure to give 295 mg of yellow solid compound 5. LC-MS [M+1]: 360.

[0355] 5. Synthesis of Compound 6

[0356] In a 100 ml single-necked flask, 295 mg of compound 5 was dissolved in 5 ml of ethanol and 1 ml of water. 320 mg of Zn powder and 435 mg of ammonium chloride solid were added. The mixture was refluxed at 100 °C for 4 h. The Zn powder was filtered through a diatomaceous earth filter. The mother liquor was removed by rotary evaporation under reduced pressure. Column chromatography yielded 100 mg of compound 6. LC-MS [M+1]: 330.

[0357] 6. Synthesis of Compound 7

[0358] 100 mg of compound 6, 90 mg of M1, 347 mg of trifluoroacetic acid, and 3 ml of isopropanol were added to a 50 ml single-necked flask. The mixture was refluxed at 100 °C for 18 h. The reaction solution was quenched with a saturated sodium bicarbonate solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, evaporated to dryness, and subjected to column chromatography to obtain 111 mg of a yellow solid, compound 7. LC-MS [M+1]: 590.

[0359] 7. Synthesis of intermediate M2

[0360] Compound 7 (111 mg, 1.0 eq), potassium hydroxide (105 mg, 10.0 eq), methanol (5 ml), and water (1 ml) were added to a 50 ml single-necked flask. The mixture was thoroughly mixed and heated to 60 °C for 4 h. The reaction was confirmed to be complete by LC-MS. The reaction solution was quenched with water. Extraction was performed with dichloromethane, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The sample was mixed with silica gel (100-200 mesh) and purified by column chromatography (MeOHin DCM 0% to 10%) to obtain the target product M2 (60 mg, brown solid). LC-MS [M+1]: 493.

[0361] III. Synthesis of Compound T-003

[0362] The synthesis route is as follows:

[0363]

[0364] In a 50 mL round-bottom flask, 60 mg of compound M2 and 87 mg of compound SM1 were dissolved in 3 mL of NN-dimethylformamide. The mixture was cooled to 0 °C in an ice-water bath, and 1 mL of NN-diisopropylethylamine and 48 mg of HATU were added with stirring. The reaction was carried out in an ice-water bath under nitrogen protection for 1 hour, and then naturally warmed to room temperature for 2 hours. The reaction was confirmed to be complete by TLC. The mixture was extracted with ethyl acetate and water, and the organic phase was dried, filtered, and then subjected to column chromatography to obtain 100 mg of compound T-003. LC-MS [M+1]: 821. ¹H NMR (400 MHz, DMSO-d6) δ 11.75 (s, 1H), 10.86 (s, 1H), 8.86 (d, J = 4.8 Hz, 1H), 8.63 (s, 1H), 8.43 (s, 1H), 8.20 (s, 1H), 7.83 – 7.72 (m, 2H), 7.29 (s, 1H), 7.13 – 6.96 (m, 4H), 6.81(s, 1H), 6.65 (d, J = 8.6 Hz, 2H), 5.74 (d, J = 7.5 Hz, 1H), 5.59 (d, J =17.8 Hz, 1H), 5.18 (d, J = 11.3 Hz, 1H), 4.32 (ddd, J = 11.8, 7.4, 4.8 Hz,1H), 3.84 (s, 5H), 3.72 (s, 2H), 3.28 (s, 2H), 2.97 (d, J = 32.9 Hz, 6H),2.85 (d, J = 4.5 Hz, 3H), 2.65 (d, J = 4.4 Hz, 1H), 2.20 – 1.84 (m, 5H), 1.77 (d, J = 11.9 Hz, 2H), 1.66 (d, J = 12.6 Hz, 2H).

[0365] Example 6

[0366] The compounds synthesized in this invention:

[0367]

[0368] T-037

[0369] The experimental procedure is as follows:

[0370] I. Synthesis of Intermediate M1

[0371] The synthesis route is as follows:

[0372]

[0373] 1. Synthesis of Compound 2

[0374] In a 50 ml three-necked flask, 4-piperidinone (1.06 g, 6.9 mmol, 1.1 eq) and DIPEA (2.4 g, 18.6 mmol, 3.0 eq) were dissolved in 10 ml of DMF. 3,4-Difluoronitrobenzene (1 g, 6.29 mmol, 1.0 eq) was added to the mixture. The solution was purged three times with N2. The mixture was then diluted to 1:10 ppm. o Stir overnight at C. Monitor the reaction by TLC until complete. Dilute the reaction mixture with EA (10 ml) and stir for 5 min, then add water (10 ml) and allow to stand before separating. Extract the aqueous phase once with EA (10 ml). Combine the organic phases, wash with saturated NaCl (15 ml * 3), dry to anhydrous sodium sulfate, filter, and evaporate the filtrate to dryness. Analyze the crude product by column chromatography (EA in PE from 0% to 40%) to give crude compound 2 as a yellow solid (629 mg, 42% yield). LC-MS [M+1]: 239.

[0375] 2. Synthesis of Compound 3

[0376] 367 mg tert-butyl acetate (3.16 mmol, 1.2 eq) was added to a 100 mL three-necked flask, and after purging three times with N2 gas, anhydrous tetrahydrofuran (10 mL) was added. The mixture was then cooled to -78 °C. o C, Slowly add LDA to the reaction system, -78 o Stir at C for 45 min. Dissolve tert-butyl acetate (367 mg, 3.16 mmol, 1.2 eq) in anhydrous tetrahydrofuran (10 mL) and slowly add it dropwise to the reaction system. Reaction solution -78°C o Stirring at C for 2 hours. TLC showed the disappearance of the starting material and the formation of new spots. Add 10 ml of sat.aq.NH4Cl to the reaction solution to quench the reaction. Add EA to the mixture and allow it to stand and separate. Wash the organic phase with saturated brine (10 ml * 3), dry with anhydrous sodium sulfate, filter, and evaporate the filtrate to dryness. Column chromatography (EA in PE from 0% to 40%) yielded a yellow solid compound 3 (781 mg, 83.2% yield). LC-MS [M+1]: 355.

[0377] 3. Synthesis of Compound 4

[0378] Compound 3 (781 mg, 2.2 mmol, 1.0 eq), ammonium chloride (1.4 g, 21.87 mmol, 10.0 eq), and iron powder (741 mg, 13.2 mmol, 6.0 eq) were dispersed in 10 mL of ethanol:water (4:1) solvent in a 100 mL three-necked flask. The mixture was substituted with N2 three times, and the mixture was heated to reflux for 18 h. TLC showed the disappearance of the starting material, and the solvent was removed by rotary evaporation. The crude product was subjected to column chromatography (EA in PE from 0% to 50%) to give compound 4 (669 mg, 93.6% yield) as a yellow solid. LC-MS [M+1]: 325.

[0379] 4. Synthesis of Compound 5

[0380] In a 100 mL round-bottom flask, compound 4 (669 mg, 2.06 mmol, 1.0 eq) and 3-bromopiperidin-2,6-dione (595 mg, 3.09 mmol, 1.5 eq) were dissolved in 6.69 mL of N,N-dimethylformamide. Sodium bicarbonate (347 mg, 4.13 mmol, 2.0 eq) was added to the mixture. The reaction mixture was stirred at 70 °C for 16 hours under nitrogen protection. After cooling to room temperature, the reaction was confirmed to be complete by TLC. The reaction mixture was diluted with EA (10 mL), and water (100 mL) was added for separation. The aqueous phase was extracted with EA (10 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the crude product was purified by column chromatography (EA in PE from 0% to 57%) to give compound 5 (570 mg, 63.6% yield). LC-MS [M+1]: 436.

[0381] 5. Synthesis of compound M1

[0382] Compound 5 (290 mg, 0.667 mmol, 1.0 eq) was dissolved in 3 mL of dichloromethane in a 50 mL round-bottom flask, and 0.5 mL of trifluoroacetic acid was added to the mixture. The reaction mixture was stirred at room temperature for 2 hours. The reaction was confirmed to be complete by LC-MS. The reaction mixture was evaporated to dryness to give compound M1 (253 mg, 100% crude). LC-MS [M+1]: 381.

[0383] II. Synthesis of Compound T-037

[0384] The synthesis route is as follows:

[0385]

[0386] 1. The synthesis of compound M2 is described in Example 2.

[0387] 2. Synthesis of T-037

[0388] In a 50 mL round-bottom flask, compounds M1 (253 mg, 0.66 mmol, 1.0 eq) and M2 (330 mg, 0.66 mmol, 1.0 eq) were dissolved in 3.3 mL of N,N-dimethylformamide. N,N-diisopropylethylamine (258 mg, 1.98 mmol, 3.0 eq) was added to the mixture. The reaction solution was cooled to 0 °C under nitrogen protection in an ice-water bath. HATU (304 mg, 0.8 mmol, 1.2 eq) was added to the reaction solution with stirring, and the reaction was continued under nitrogen protection in an ice-water bath for 2 hours. The mixture was then allowed to warm naturally to room temperature, and TLC was used to confirm the completeness of the reaction. The reaction solution was diluted with EA (10 mL), and water (10 mL) was added. After stirring for 5 min, the mixture was allowed to stand and separated. The aqueous phase was extracted with EA (10 mL). The combined organic phases were dried with anhydrous sodium sulfate, filtered, and the crude product was purified by column chromatography (MeOH in DCM from 0% to 3%) to obtain compound T-037 (295 mg, 51.69% yield). LC-MS[M+1]: 857. 1H NMR (400 MHz, DMSO-d6) δ11.63 (s,1H), 10.81 (s, 1H), 8.76 (q, J = 4.6 Hz, 1H), 8.57 (d, J = 8.2 Hz,1H), 8.19 (d, J = 31.9Hz, 2H), 7.84– 7.62 (m, 1H), 7.50 (s, 1H), 7.32 (t, J =7.8 Hz, 1H), 7.08 (t, J = 7.5 Hz, 1H), 6.84 (d, J = 20.3 Hz, 2H), 6.51 (dd, J=15.0, 2.5 Hz, 1H), 6.42 (dd, J = 8.8, 2.5 Hz,1H), 5.81 (s, 1H), 4.91 (s,1H), 4.26 (dt, J =12.6, 6.2 Hz, 1H), 3.74 (d, J = 24.6 Hz, 7H),2.99 – 2.82(m, 7H), 2.80 (d, J = 4.4 Hz,3H), 2.74 (s, 1H), 2.66 – 2.53 (m, 5H), 2.09(dq,J = 13.4, 4.8 Hz, 1H), 1.92 – 1.73 (m,3H), 1.69 (d, J = 12.4 Hz, 2H), 1.24(d, J =8.0 Hz, 1H), 1.09 (t, J = 7.4 Hz, 3H).

[0389] The following compounds were synthesized according to the method of Example 6:

[0390]

[0391]

[0392] Example 7

[0393] The compounds synthesized in this invention:

[0394]

[0395] T-023

[0396] The experimental procedure is as follows:

[0397] I. Synthesis of intermediate M3

[0398]

[0399] 1. The synthesis of intermediate M2 is described in Example 2.

[0400] 2. Synthesis of Compound 2

[0401] 600 mg of M2 was weighed and dissolved in 6 mL of LDMF in a 50 mL three-necked flask. Then, 188 mg of Al and 469 mg of DIPEA were added. After purging with N2 three times, the mixture was reacted overnight at 90 °C. TLC monitoring showed the formation of new spots. The reaction solution was then diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and column chromatography yielded 448 mg of compound 2. LC-MS [M+1]: 540.

[0402] 3. Synthesis of intermediate M3

[0403] In a 50 mL single-necked flask, 448 mg of compound 2 and 252 mg of DIPEA were dissolved in 5 mL of DCM. 206 mg of A2 was dissolved in 2 mL of DCM and slowly added dropwise to the reaction solution. After three purgings with N2, the reaction was carried out at room temperature for 2 hours. TLC monitoring was performed until compound 2 no longer decreased. The reaction solution was then directly evaporated under reduced pressure and stirred. Column chromatography yielded 286 mg of intermediate M3. LC-MS [M+1]: 694.

[0404] II. Synthesis of Compound T-023

[0405] The experimental procedure is as follows:

[0406]

[0407] In a 50 ml round-bottom flask, 186 mg of compound M3 and 119 mg of A3 were dissolved in 3 mL of acetonitrile. Then, 82 mg of KI and 159 mg of DIPEA were added. After three gas exchanges with N2, the mixture was reacted at 75 °C for 3 h. TLC analysis confirmed the reaction was complete. The reaction solution was evaporated under reduced pressure, stirred, and subjected to column chromatography to obtain 190 mg of compound T-023. LC-MS [M+1]: 809. ¹H NMR (400 MHz, DMSO-d6) δ 11.72 (s, 1H), 10.87 (s, 1H), 8.90 (q, J = 4.6 Hz, 1H), 8.63 (d, J = 8.5 Hz, 1H), 8.28 (s, 1H), 8.20 (s, 1H), 7.82 (d, J = 7.9 Hz, 1H), 7.54 (s, 1H). 1H), 7.37 (t, J =8.0 Hz, 1H), 7.14 (t, J = 7.6 Hz, 1H), 7.04 (d, J = 8.2 Hz, 2H), 6.86 (s,1H), 6.70 (d, J = 8.3 Hz, 2H), 5.82 (d, J = 8.9 Hz, 1H), 4.35 (ddd, J = 11.9,7.5, 4.8 Hz, 1H), 3.83 (s, 3H), 3.23 (s, 1H), 2.96 (t, J = 4.7 Hz, 5H), 2.86(d, J = 4.5 Hz, 4H), 2.84 – 2.69 (m, 6H), 2.64 (q, J = 7.5 Hz, 4H), 2.00 –1.82 (m, 4H), 1.57 – 1.23 (m, 6H), 1.14 (t, J = 7.5 Hz, 3H).

[0408] The following compounds were synthesized according to the method of Example 7:

[0409]

[0410] Example 8

[0411] The compounds synthesized in this invention:

[0412]

[0413] T-029

[0414] The experimental procedure is as follows:

[0415] I. Synthesis of Intermediate M1

[0416] The synthesis route is as follows:

[0417]

[0418] 1. Synthesis of Compound 2

[0419] In a 50 ml three-necked flask, 1-tert-butyloxycarbonylpiperazine (0.5 g, 3.14 mmol, 1.0 eq) and potassium carbonate (1300 mg, 9.42 mmol, 3.0 eq) were added to 5 ml of DMF. Then, 3,4-difluoronitrobenzene (877 mg, 4.71 mmol, 1.5 eq) was added to the mixture. The mixture was purged three times with N2. The final concentration of the mixture was 90 mL. o Stir overnight at C. Monitor the reaction by TLC until complete. Dilute the reaction mixture with EA (10 ml) and stir for 5 min, then add water (10 ml) and allow to stand before separating. Extract the aqueous phase once with EA (10 ml). Combine the organic phases, wash with saturated NaCl (15 ml * 3), dry to anhydrous sodium sulfate, filter, and evaporate the filtrate to dryness. Analyze the crude product by column chromatography (EA in PE from 0% to 40%) to give crude compound 2 as a yellow solid (1.13 g, 110% yield). LC-MS [M+1]: 326.

[0420] 2. Synthesis of Compound 3

[0421] Compound 2 (1.13 g, 3.47 mmol, 1.0 eq), ammonium chloride (445 mg, 6.95 mmol, 2.0 eq), and iron powder (584 mg, 10.4 mmol, 3.0 eq) were dispersed in 12.5 mL of ethanol:water (5:1) in a 50 mL three-necked flask. The mixture was heated to reflux and reacted for 4 h. TLC showed that the starting material disappeared. The solvent was removed by rotary evaporation. The crude product was subjected to column chromatography (EA in PE from 0% to 40%) to give compound 3 (946 mg, 92.3% yield) as a colorless oil. LC-MS [M+1]: 151.

[0422] 3. Synthesis of Compound 4

[0423] In a 50 mL round-bottom flask, compound 3 (946 mg, 3.2 mmol, 1.0 eq) and 3-bromopiperidin-2,6-dione (923 mg, 4.8 mmol, 1.5 eq) were dissolved in 10 mL of N,N-dimethylformamide. Sodium bicarbonate (538 mg, 6.4 mmol, 2.0 eq) was added to the mixture. The reaction mixture was stirred at 70 °C for 16 hours under nitrogen protection. After cooling to room temperature, the reaction was confirmed to be complete by TLC. The reaction mixture was diluted with EA (10 mL), and water (10 mL) was added for separation. The aqueous phase was extracted with EA (10 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the crude product was purified by column chromatography (EA in PE from 0% to 55%) to give compound 4 (798 mg, 61.4% yield). LC-MS [M+1]: 407.

[0424] 4. Synthesis of Compound 5

[0425] Compound 4 (798 mg, 1.96 mmol, 1.0 eq) was dissolved in 10 mL of dichloromethane in a 50 mL round-bottom flask, and 2 mL of trifluoroacetic acid was added to the mixture. The reaction mixture was stirred at room temperature for 2 hours. The reaction was confirmed to be complete by LC-MS. The reaction mixture was evaporated to dryness to give compound 5 (600 mg, 100% crude). LC-MS [M+1]: 307.

[0426] 5. Synthesis of Compound 6

[0427] In a 50 mL round-bottom flask, compound 5 (300 mg, 1.96 mmol, 1.0 eq) and tert-butyl bromoacetate (460 mg, 2.36 mmol, 1.2 eq) were dissolved in 6 mL of N,N-dimethylformamide. DIPEA (761 mg, 5.9 mmol, 3.0 eq) was added to the mixture. The reaction mixture was stirred at room temperature for 12 h. TLC was used to confirm the completeness of the reaction. The reaction mixture was diluted with EA (10 mL), and water (10 mL) was added for separation. The aqueous phase was extracted with EA (10 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the crude product was purified by column chromatography (EA in PE from 0% to 70%) to give compound 6 (707 mg, 85.6% yield). LC-MS [M+1]: 421.

[0428] 6. Synthesis of compound 7 (i.e., M1)

[0429] Compound 6 (300 mg, 0.71 mmol, 1.0 eq) was dissolved in 3 mL of dichloromethane in a 50 mL round-bottom flask, and trifluoroacetic acid (1 mL) was added to the mixture. The reaction mixture was stirred at room temperature for 2 hours. The reaction was confirmed to be complete by LC-MS. The reaction mixture was evaporated to dryness to give compound M1 (260 mg, 100% crude). LC-MS [M+1]: 365.

[0430] II. The synthesis of T-029

[0431]

[0432] 1. The synthesis of compound M2 is described in Example 2.

[0433] 2. Synthesis of T-029

[0434] In a 50 mL round-bottom flask, compound 7 (260 mg, 0.71 mmol, 1.0 eq) and M2 (352.6 mg, 0.71 mmol, 1.0 eq) were dissolved in 3 mL of N,N-dimethylformamide. N,N-diisopropylethylamine (276 mg, 2.14 mmol, 3.0 eq) was added to the mixture. The reaction solution was cooled to 0 °C under nitrogen protection in an ice-water bath. HATU (325 mg, 0.85 mmol, 1.2 eq) was added to the reaction solution with stirring, and the reaction was continued under nitrogen protection in an ice-water bath for 2 hours. The mixture was then allowed to warm naturally to room temperature, and the reaction was monitored by TLC to ensure complete reaction. The reaction solution was diluted with EA (10 mL), and water (10 mL) was added. After stirring for 5 min, the mixture was allowed to stand and separated. The aqueous phase was extracted with EA (10 mL). The combined organic phases were dried with anhydrous sodium sulfate, filtered, and the crude product was purified by column chromatography (MeOH in DCM from 0% to 3%) to give compound T-029 (244 mg, 40.73% yield). LC-MS[M+1]: 842.36. 1H NMR (400 MHz, DMSO-d6) δ 11.63(s, 1H), 10.81 (s, 1H), 8.75 (q, J = 4.6 Hz,1H), 8.57 (d, J = 8.4Hz, 1H), 8.22 (s,1H), 8.14 (s, 1H), 7.71 (d, J = 7.9 Hz,1H), 7.51 (s, 1H), 7.31 (t, J = 7.9 Hz, 1H), 7.06 (t, J = 7.6 Hz, 1H), 6.84 (d, J = 9.4Hz, 1H),6.80 (s, 1H), 6.52 (dd, J = 15.0,2.5 Hz, 1H), 6.41 (dd, J = 8.8, 2.5 Hz,1H), 5.84 (d, J = 7.7 Hz, 1H), 3.74 (d, J =14.5 Hz, 5H), 3.64 (s, 1H), 3.29 (d, J= 9.3Hz, 1H), 2.89 (s, 5H), 2.85 – 2.78 (m, 6H), 2.73 (td, J = 12.3, 6.1 Hz,2H), 2.62 (q, J= 7.1 Hz, 6H), 2.08 (dq,J = 13.3, 4.7 Hz,1H), 1.85 (qd, J =12.3, 4.7 Hz, 1H), 1.23(d, J = 10.7 Hz, 1H), 1.09 (t, J = 7.5 Hz, 3H).

[0435] Example 9

[0436] The compounds synthesized in this invention:

[0437]

[0438] T-011

[0439] The synthesis route is as follows:

[0440] I. Synthesis of Intermediate M1

[0441]

[0442] 1. Synthesis of Compound 2

[0443] Compound 1 (500 mg, 1.0 eq) and 2 ml of methanol were added to a 100 ml three-necked flask and stirred to dissolve. Glyoxal (960 mg, 2.0 eq) was added to the reaction solution, and after thorough mixing, the mixture was cooled to 0 °C. Ammonia (4 ml) was added, and the mixture was allowed to rise naturally to room temperature. The reaction was allowed to proceed overnight. After the reaction was confirmed to be complete by TLC, the reaction solution was extracted with ethyl acetate, and the sample was passed through a silica gel column with the organic phase mixed. 330 mg of the target component was collected. LC-MS [M+1]: 190.

[0444] 2. Synthesis of Compound 3

[0445] Compound 2 (330 mg, 1.0 eq), palladium on carbon catalyst (16 mg, 5 wt%), and 5 ml of methanol were added to a 50 ml single-necked flask and mixed thoroughly. The mixture was then purged three times with a hydrogen balloon and reacted at room temperature under pressure for 20 hours. TLC showed that the starting material reacted completely. The mixture was filtered through a diatomaceous earth filter, and the mother liquor was collected and purified by column chromatography to obtain 230 mg of compound 3. LC-MS [M+1]: 160.

[0446] 3. Synthesis of intermediate M1

[0447] 230 mg (1.0 equivalent) of compound 3 was added to a 100 mL single-necked flask, followed by 1.3 mL (5.0 equivalent) of a mixture of N,N-diisopropylethylamine and 2 mL of isopropanol. The mixture was stirred at room temperature until homogeneous, and then 530 mg (2.0 equivalent) of trichloropyrimidine was slowly added dropwise. After the addition was complete, nitrogen was purged three times. The mixture was heated to reflux under nitrogen protection and stirred overnight. The reaction was monitored by TLC to ensure completion. The solvent was evaporated to dryness under reduced pressure, and the residue was added to 50 mL of ethyl acetate (EA). The mixture was stirred at room temperature for 30 minutes, filtered, and the filter cake was washed twice with 15 mL of ethyl acetate. The collected filter cake was intermediate M1: 300 mg. LC-MS [M+1]: 305.

[0448] II. Synthesis of intermediate M2

[0449]

[0450] In a 50 mL single-necked flask, add intermediate M1 (150 mg, 1.0 eq), SM3 (150 mg, 1.0 eq), p-toluenesulfonic acid monohydrate (112 mg, 1.2 eq), and 4 mL of isopropanol. Mix thoroughly and reflux overnight. LC-MS analysis confirms complete reaction. Adjust the pH of the reaction mixture to >7 with saturated sodium bicarbonate solution. Extract with ethyl acetate, wash the organic phase with saturated brine, and dry with anhydrous sodium sulfate. Purify by column chromatography (MeOH in DCM 0% to 20%) with silica gel (100-200 mesh) to obtain target product M2 (100 mg, brown solid). LC-MS [M+1]: 476.

[0451] III. Synthesis of Compound T-011

[0452] The synthesis route is as follows:

[0453]

[0454] In a 50 ml round-bottom flask, intermediates M2 and M3 were dissolved in 2 ml of NN-dimethylformamide. The mixture was cooled to 0°C in an ice-water bath, and NN-diisopropylethylamine and HATU were added with stirring. The mixture was reacted in an ice-water bath for 1 hour under nitrogen protection, and then naturally heated to room temperature. The reaction was confirmed to be complete by TLC. The mixture was extracted with ethyl acetate and water, and the organic phase was dried, filtered, and then subjected to column chromatography to obtain 33 mg of compound T-011. LC-MS [M+1]: 804.

[0455] The following compounds were synthesized according to the method of Example 9:

[0456]

[0457] Example 10

[0458] The compounds synthesized in this invention:

[0459]

[0460] T-076

[0461] I. Synthesis of Intermediate M1

[0462]

[0463] 1. Synthesis of Compound 2

[0464] Compound 1 (1 g, 1.0 eq), formamidin acetate (1.15 g, 2.0 eq), and 15 ml of ethylene glycol monomethyl ether were added to a 100 ml three-necked flask. The mixture was heated to 100 °C and reacted overnight. After the reaction was confirmed to be complete by TLC, the pH was adjusted to >7 with saturated sodium bicarbonate aqueous solution. The reaction solution was extracted with ethyl acetate, and the mixture was filtered through a silica gel column with the organic phase stirred. 720 mg of the target component was collected.

[0465] 2. Synthesis of Compound 3

[0466] Compound 2 (720 mg, 1.0 eq), palladium on carbon catalyst (36 mg, 5 wt%), and 10 ml of methanol were added to a 50 ml single-necked flask and mixed thoroughly. The mixture was then purged three times with a hydrogen balloon and reacted at room temperature under pressure for 20 hours. TLC showed that the starting material reacted completely. The mixture was filtered through a diatomaceous earth filter, and the mother liquor was collected and purified by column chromatography to obtain 450 mg of compound 3. LC-MS [M+1]: 162.

[0467] 3. Synthesis of intermediate M1

[0468] 300 mg (1.0 equivalent) of compound 3 was added to a 100 mL single-necked flask, followed by 1.6 mL (5.0 equivalent) of a mixture of N,N-diisopropylethylamine and 5 mL of isopropanol. The mixture was stirred at room temperature until homogeneous, and then 682 mg (2.0 equivalent) of trichloropyrimidine was slowly added dropwise. After the addition was complete, nitrogen was purged three times. The mixture was heated to reflux under nitrogen protection and stirred overnight. The reaction was monitored by TLC to ensure completion. The solvent was evaporated to dryness under reduced pressure, and the residue was added to 50 mL of ethyl acetate (EA). The mixture was stirred at room temperature for 30 minutes, filtered, and the filter cake was washed twice with 15 mL of ethyl acetate. The collected filter cake was intermediate M1: 250 mg. LC-MS [M+1]: 307.

[0469] II. Synthesis of intermediate M2

[0470]

[0471] In a 50 mL single-necked flask, add intermediate M1 (250 mg, 1.0 eq), SM3 (250 mg, 1.0 eq), p-toluenesulfonic acid monohydrate (184 mg, 1.2 eq), and 4 mL of isopropanol. Mix thoroughly and reflux overnight. LC-MS analysis confirms complete reaction. Adjust the pH of the reaction mixture to >7 with saturated sodium bicarbonate solution. Extract with ethyl acetate, wash the organic phase with saturated brine, and dry with anhydrous sodium sulfate. Pour the mixture into silica gel (100-200 mesh) and purify by column chromatography (MeOH in DCM 0% to 20%) to obtain the target product M2 (60 mg, brown solid). LC-MS [M+1]: 507.

[0472] III. Synthesis of Compound T-076

[0473] The synthesis route is as follows:

[0474]

[0475] In a 50 ml round-bottom flask, intermediates M2 (60 mg, 1.0 eq) and M3 were dissolved in 2 ml of NN-dimethylformamide. The mixture was cooled to 0 °C in an ice-water bath, and NN-diisopropylethylamine and HATU were added with stirring. The reaction was carried out in an ice-water bath for 1 hour under nitrogen protection, and then naturally warmed to room temperature. The reaction was confirmed to be complete by TLC. The mixture was extracted with ethyl acetate and water, and the organic phase was dried, filtered, and then subjected to column chromatography to obtain 11 mg of compound T-076. LC-MS [M+1]: 834.6; 1H NMR (400 MHz, DMSO-d6) δ 12.57 (s, 1H), 12.52 (s, 1H), 10.86 (s, 1H), 8.80 (s, 1H), 8.55 (s, 1H), 8.27 (d, J = 1.7 Hz, 1H), 8.18 (s, 1H). 7.58 (s, 1H), 7.51 (d, J = 8.1 Hz, 1H), 7.32 (d, J =8.1 Hz, 1H), 7.02 (d, J = 8.1 Hz, 2H), 6.89 (s, 1H), 6.66 (d, J = 8.1 Hz, 2H), 5.74 (d, J = 7.5 Hz, 1H), 4.37 – 4.28 (m, 1H), 3.89 – 3.76 (m, 5H), 3.73(s, 2H), 3.57 (s, 1H), 3.09 (s, 2H), 3.00 (s, 2H), 2.92 (s, 2H), 2.73 (q, J =7.5 Hz, 3H), 2.45 (s, 2H), 2.27 (s, 2H), 2.19 – 2.10 (m, 2H), 2.06 (d, J =1.9 Hz, 1H), 1.93 (dd, J = 12.4, 8.1 Hz, 2H), 1.80 (s, 2H), 1.72 (s, 2H),1.21 (t, J = 7.5 Hz, 3H).

[0476] Comparative Example 1: Control Compound 1

[0477]

[0478] The experimental procedure is as follows:

[0479] I. Synthesis of Intermediate M1

[0480] The synthesis route is as follows:

[0481]

[0482] Intermediate M1 was synthesized according to the method of Example 1.

[0483] II. Synthesis of intermediate M2

[0484] The synthesis route is as follows:

[0485]

[0486] Intermediate M2 was synthesized according to the method of Example 1.

[0487] III. Synthesis of Control Compound 1

[0488] The synthesis route is as follows:

[0489]

[0490] Compounds M2 and M3 were dissolved in 2 ml of NN-dimethylformamide in a 50 ml round-bottom flask. The mixture was cooled to 0 °C in an ice-water bath, and NN-diisopropylethylamine and HATU were added with stirring. The reaction was carried out in an ice-water bath for 1 hour under nitrogen protection, and then naturally warmed to room temperature. The reaction was confirmed to be complete by TLC. The mixture was extracted with ethyl acetate and water, and the organic phase was dried, filtered, and then subjected to column chromatography to obtain 50 mg of reference compound 1. LC-MS [M+1]: 783; ¹H NMR: 1H NMR (400 MHz, DMSO-d6) δ 11.83 (s, 1H), 10.79 (s, 1H), 8.77 (s, 1H), 8.36 (s, 1H), 8.16 (s, 1H), 8.04 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 10.4 Hz, 2H). 7.06 (t, J = 7.6 Hz, 1H), 6.95 (d, J = 8.1 Hz, 2H), 6.76 – 6.68 (m, 2H), 6.57 (dd, J = 16.5, 7.3 Hz, 3H), 5.67 (d, J = 7.5 Hz, 1H), 4.25 (s, 0H), 3.77 (s, 5H), 3.64 (s, 2H), 3.23 (s, 4H), 3.14 (s, 2H), 2.94 (s, 2H), 2.78 – 2.70 (m, 0H), 2.67 (s, 3H), 2.58 (d, J = 4.3 Hz, 0H),2.34 (s, 1H), 2.15 – 2.03 (m, 3H), 1.85 (dt, J = 12.2, 6.1 Hz, 1H), 1.72 (d,J = 11.7 Hz, 2H), 1.58 (d, J = 12.3 Hz, 2H).

[0491] Test of the inhibitory activity of compounds on cell growth

[0492] Experimental Example 1: Cell Anti-proliferation Experiment

[0493] I. Experimental Materials and Equipment:

[0494] H1975 has an EGFR:T790M / L858R double mutation, PC-9 has an EGFR exon 19 deletion, and HCC827 has an exon 19 deletion mutation. CellCounting-Lite 2.0, Trypsin EDTA, 37℃ CO2 incubator, cell counter, EnVision Serial No. 1050454.

[0495] II. Experimental Preparation:

[0496] 1. 96-hole plate laying

[0497] A) Digest logarithmic phase cells with Trypsin EDTA, add culture medium to stop the reaction, and mix well with a pipette to prepare a cell suspension.

[0498] B) Use Vi-cell to determine cell concentration, and prepare a suspension of 15,000-25,000 cells per milliliter according to the experimental purpose and cell characteristics.

[0499] C) After preparing the cell suspension, mix it gently and add 100 μL to each well, so that the cell density to be tested is 1500-2500 per well.

[0500] 2. Compound treatment

[0501] compound dilution

[0502] A) Weigh approximately 2 mg of the compound and calculate the required volume of DMSO using the formula: Compound mass (mg) * Compound purity (%) / Compound molecular weight * 1000.

[0503] B) Place the inoculated cell culture plate into an incubator and incubate for about 24 hours. Then add compounds in a concentration gradient.

[0504] C) Dilute the 10mM compound stock solution to 50mM with culture medium, and add the 50mM compound solution sequentially to the second column of the deep well plate, and add 375ml of culture medium containing 0.5% DMSO to the third to eleventh columns.

[0505] D) Gradient dilution: Take 125 μL of solution from the second column and add it to the third column, mix well; then take 125 μL of solution from the third column and add it to the fourth column, repeating this operation until the tenth column.

[0506] E) Using a multichannel pipette, aspirate 25 μL of the compound from the deep-well plate and add it to a 96-well culture plate. Repeat this process three times for each compound on the 96-well plate. This will ultimately create a concentration gradient of up to 10,000 nM at a 1:4 ratio on the 96-well plate.

[0507] 3. Add CTG and take readings.

[0508] A) The effects of the compound were observed under an inverted microscope after the 96-well plate was incubated in an incubator for 72 hours.

[0509] B) Add 25 μL of CTG solution to each well, place on a shaker for 10 minutes, and read the OD value of each well.

[0510] 4. Data Analysis

[0511] Calculate the % Cell Viability using the following formula:

[0512] %Cell Viability=100%×(Lum_Sample- Lum_LC ) / (Lum_HC−Lum_LC )

[0513] Lum_HC: 0.1% DMSO control group cell readings

[0514] Lum_Sample: Cell readings with added compounds

[0515] Lum_LC: Blank culture medium reading

[0516] The IC50 value was obtained by curve fitting using GraphPad Prism 8 software.

[0517] As shown in Table 1, where AA≤10nM; 10nM <A≤100nM;100nM<B<1000nM;C≥1000nM。

[0518] Table 1

[0519]

[0520] As can be seen from Table 1, the compounds of the present invention have very good inhibitory effects on H1975 (human lung adenocarcinoma cells), PC-9 (human lung cancer cells), and HCC827 (human non-small cell lung cancer cells).

[0521] Experimental Example 2: EGFR PROTAC HTRF Experiment

[0522] 1. Instruments and reagents

[0523]

[0524] Among them, Baf3-19del-T780M-C797S is a Stable Ba / F3 clone expressing exogenous EGFR gene bearing T790M, C797S and L858R triple amino acid mutations, purchased from Kangyuan Bochuang; Baf3-L858R-T780M-C797S is a Stable Ba / F3 clone expressing exogenous EGFR gene bearing exon19 E746_A750 deletion, T790M, C797S triple mutations, purchased from Kangyuan Bochuang.

[0525] 2. Experimental Procedures

[0526] 1) Cell Preparation:

[0527]

[0528] 2) Reagent Preparation:

[0529]

[0530] Dilute Eu and d2 antibody 20-fold with detection buffer at a rate of 2 μl antibody per well. Then mix the two antibodies well.

[0531] 3) Detection:

[0532]

[0533] 3. Results and Calculations

[0534] Open EnVision, find the HTRF program, set up the plate, and then read the plate.

[0535] Use GraphPad Prism to generate the fitting curve, DC50, and Dmax of the compound.

[0536] As shown in Table 2, for DC50, AA ≤ 10 nM; 10 nM < A ≤ 100 nM; 100 nM < B < 1000 nM; C ≥ 1000 nM; for Dmax, 70% ≤ A ≤ 100%; 50% ≤ B < 70%; C < 50%; NA means not tested.

[0537] Table 2

[0538]

[0539] Among them, BAF3-DTC: Baf3-19del-T780M-C797S is a Stable Ba / F3 clone expressing exogenous EGFR gene bearing T790M, C797S and L858R triple amino acid mutations, purchased from Kangyuan Botech; BAF3-LTC: Baf3-L858R-T780M-C797S is a Stable Ba / F3 clone expressing exogenous EGFR gene bearing exon19 E746_A750 deletion, T790M, C797S triple mutations, purchased from Kangyuan Botech.

[0540] As shown in Table 2, the compounds of the present invention exhibit excellent degradation performance on EGFR cells containing the L858R-T780M-C797S triple mutation and the 19del-T780M-C797S triple mutation.

[0541] Pharmacokinetic studies of compounds

[0542] Experiment 3: Pharmacokinetic Tests in Male SD Rats

[0543] 1.1 Experimental Animals

[0544] Three healthy adult male SD rats, 6-8 weeks old, weighing 200-300 grams.

[0545] 1.2 Equipment and Reagents

[0546] 1.2.1 Equipment

[0547] Analytical balance, animal weighing scale, magnetic stirrer, gavage syringe, refrigerated centrifuge, single-channel manual pipette, liquid chromatography-mass spectrometry (LC-MS) instrument, etc.

[0548] 1.2.2 Reagents

[0549] Weigh 11.2 g of EDTA-Na2 anticoagulant and place it in a reagent bottle. Add 100 mL of physiological saline and shake to dissolve completely. After preparation, dispense into 1.5 mL centrifuge tubes, each containing approximately 20 μL, for whole blood sample collection.

[0550] 2. Experimental Procedure

[0551] 2.1 Drug Preparation

[0552] Accurately weigh approximately 10 mg of the sample to be tested, add 10% of the converted total volume of DMSO to dissolve it, and then slowly add 90% of the total volume of 0.5% MC solvent while stirring. Sonicate and vortex to mix thoroughly to obtain a solution of the preparation that is considered to be homogeneous, with a concentration of 1 mg / mL. Prepare fresh immediately before use.

[0553] Pipe 0.2 mL of the sample into a 1.5 mL centrifuge tube and store at -80°C for analysis of the concentration of the drug solution.

[0554] 2.2 Animal Preparation

[0555] Animals were housed in rat cages and fasted for at least 10 hours starting the day before the experiment, but water was allowed. On the day of the experiment, each animal was weighed and marked on its tail. Blank blood samples were collected before drug administration. Blood was collected via tail vein.

[0556] 2.3 Administration

[0557] Route of administration: Oral administration (po)

[0558] Dosage concentration: 1 mg / ml

[0559] Dosage: 10 mg / kg

[0560] Dosage volume: 10 mL / kg

[0561] Procedure: Hold the rat upright with your left hand wearing a bite-proof glove, insert the gavage needle into the throat through the mouth, and insert the needle when you feel no obvious resistance. Then inject the drug into the stomach.

[0562] 2.4 Sample Collection

[0563] Whole blood (0.1-0.2 ml) was collected from test animals at 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, and 24 h after drug administration. The blood was collected in EDTA-Na2 anticoagulant tubes, inverted 3-4 times to mix, and centrifuged at 4°C, 2000 g for 5 min to separate the supernatant plasma. The plasma was promptly transferred to -80°C for storage until analysis. Blood was collected via tail vein.

[0564] 3. Sample Analysis and Data Processing

[0565] 3.1 Sample Analysis

[0566] Using Shimadzu liquid chromatography and Triple Quad™ 6500 + An AB mass spectrometry method was established for the quantitative detection of analytes. The concentration of the parent drug in plasma was analyzed. The analytical results were subjected to variation control using quality control samples, with the accuracy of the quality control samples expected to be between 80% and 120%.

[0567] 3.2 Data Processing

[0568] The main pharmacokinetic parameters were calculated using a non-compartmental model in Winnonlin Phoenix software. These parameters included the area under the curve (AUC(0-t) and AUC(0-∞)) and the elimination half-life (T0). 1 / 2 ), maximum plasma concentration (C max ), time to reach maximum plasma concentration (T) max ) ) wait.

[0569] The results are shown in Table 3.

[0570] Table 3

[0571]

[0572] As shown in Table 3, the compounds of the present invention have better pharmacokinetic effects than control compound 1.

[0573] 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, characterized in that, The compound is a compound of Formula I, or a pharmaceutically acceptable salt or stereoisomer thereof. Equation I in: L is selected from the following group: Wherein, m is independently selected from the group consisting of 0, 1, 2, or 3; R1 is independently selected from the group consisting of hydrogen, deuterium, halogen, and carbon. 1-6 Alkyl, C 1-6 Haloalkyl; R2 is independently selected from the group consisting of: hydrogen, deuterium, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl; R is independently selected from the group consisting of: H, C 1-6 Alkyl, hydroxyl, halogen, C 1-6 Halogenated alkyl groups; Ring A is selected from the following group: , Where n is independently selected from the following group: 0, 1, 2 or 3; R1 is independently selected from the following group: halogen, C 1-6 Haloalkyl; R2 is independently selected from the group consisting of: hydrogen, deuterium, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl; R6 is independently selected from the group consisting of: H, C 1-6 Alkyl, hydroxyl, halogen, C 1-6 The alkyl halogroup, or R6 forming a 3-6 membered ring with the attached ring; R3 is independently selected from the group consisting of hydrogen, deuterium, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 3-6 Halogenated cycloalkyl groups; each R4 is independently selected from the following group: C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 3-6 Halogenated cycloalkyl groups; R5 is not present; Ring B is selected from the following group: ; Wherein, m is independently selected from the following group: 0, 1, 2 or 3; each R7 is independently selected from the following group: H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, cyano; R is selected from the following group: H, C 1-6 Alkyl, C 1-6 Haloalkyl; R8 is selected from the following group: H, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups; Each X1 and X2 is independently selected from the following groups: CR, N; Each X3 is independently selected from the following group: NH; Each Ar is independently selected from the group consisting of: substituted phenyl groups and substituted pyridyl groups; the substitution refers to substitution by a substituent selected from the group consisting of: -C(O)NR9R 10 5-6 membered heteroaryl groups containing 1, 2 or 3 heteroatoms selected from N, O or S; R9 is selected from the following groups: H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 3-6 Halogenated cycloalkyl groups; R 10 Selected from the following groups: H, C 1-6 Alkyl, C 3-6 cycloalkyl; And the compound is not one of the following: 。 2. The compound according to claim 1, characterized in that, Each Ar is independently selected from the group consisting of substituted phenyl groups; the substitution refers to substitution by a substituent selected from the group consisting of -C(O)NR9R. 10 ; R9 is selected from the following groups: H, C 1-6 alkyl; R 10 Selected from the following groups: H, C 1-6 alkyl; And R9 and R 10 They are not both H.

3. The compound according to claim 1, characterized in that, Each Ar is independently selected from the group consisting of substituted phenyl groups; the substitution refers to substitution by a substituent selected from the group consisting of -C(O)NR9R. 10 ; R 11 q is as defined in claim 1; R9 is H; R 10 C 1-6 alkyl.

4. The compound according to claim 1 or 2, characterized in that, R3 is selected from the following group: C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl.

5. The compound according to claim 1, characterized in that, The compound is of formula II or formula III or the compound shown. 、 Where R4 is selected from the following group C 1-6 Alkyl groups: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, neopentyl, pterpentyl, hexyl.

6. A compound, or a pharmaceutically acceptable salt or stereoisomer thereof, characterized in that, The compounds are selected from the group consisting of: 。 7. A pharmaceutical composition, characterized in that, The compound comprises a safe and effective amount of the compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier.

8. Use of a compound as claimed in claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition as claimed in claim 7, characterized in that, For use in the group selected below: 1) To prepare drugs for regulating EGFR kinase activity or treating EGFR-related diseases; 2) Prepare drugs for degrading EGFR protein.

9. The use as described in claim 8, characterized in that, The EGFR-related diseases mentioned are diseases related to EGFR drug resistance mutations.

10. The use as described in claim 8, characterized in that, The EGFR-related diseases are selected from the following groups: inflammation, cancer, cardiovascular disease, infection, immune disease, and metabolic disease.

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