Compounds for degrading EGFR protein and uses thereof

Abstract

The present invention relates to a compound and its use for degrading EGFR protein.Specifically, the present invention relates to a compound as shown in formula I, wherein the definition of each group and substituent is as described in the specification.The present invention also relates to the application of said compound in the preparation of a drug for regulating EGFR tyrosine kinase activity or for treating EGFR-related diseases, particularly non-small cell lung cancer. [Case 1] TIFF2024540511000225.tif2042

Description

[Technical Field]

[0001] The present invention relates to the field of medical technology, in particular to compounds for degrading EGFR and their application in modulating EGFR kinase activity or in treating EGFR-related diseases, especially cancer. [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, these receptors form homodimers or heterodimers, which subsequently activate their intrinsic tyrosine kinase activity, leading to receptor autophosphorylation and activation of downstream signaling molecules. The regulatory effects of EGFR activation through overexpression or mutation have been shown to be involved in various types of human cancer, including colorectal cancer, pancreatic cancer, glioma, head and neck cancer, and lung cancer, particularly non-small cell lung cancer (NSCLC). Various EGFR-targeting agents have been developed over the years, with three generations of drugs now in clinical use.

[0003] In actual clinical practice, patients typically develop EGFRT790M resistance mutations within 8 to 12 months after first- or second-generation EGFR inhibitor use, resulting in a loss of therapeutic efficacy. However, later-released third-generation EGFR inhibitors, such as osimertinib and ametinib, can effectively overcome EGFRT790M resistance. However, resistance mutations such as EGFRC797S still emerge after a period of use, leading to disease progression.

[0004] The frequent mutational resistance issues during treatment with EGFR small molecule tyrosine kinase inhibitors and non-classical EGFR mutations are clinical problems that urgently need to be addressed. Currently, several EGFR allosteric inhibitor compounds, such as EAI045, have been reported to overcome C797S resistance, but their clinical efficacy has been limited. In recent years, several patents (WO2019149922, WO2021127561) have reported that a series of PROTAC compounds can overcome the C797S resistance issue by degrading the EGFR protein, spurring new research. While progress has been made in EGFR allosteric inhibitors and EGFR degraders, there remains a need for more clinically valuable EGFR protein-modulating drugs for use in the treatment of diseases caused by EGFR dysregulation, particularly in the field of EGFR-positive non-small cell lung cancer. Summary of the Invention [Problem to be solved by the invention]

[0005] It is an object of the present invention to provide compounds of formula I which have EGFR kinase inhibitory and degrading activity and their use in modulating EGFR activity or in the prevention and / or treatment of EGFR-associated diseases. [Means for solving the problem]

[0006] A first aspect of the present invention provides a compound, the compound being represented by formula I, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotope or prodrug thereof: [ka] where: L is [ka] [ka] is selected from the group consisting of A is, [ka] [ka] [ka] is selected from the group consisting of B is [ka] [ka] is selected from the group consisting of In each formula, Each X1 and X2 is independently selected from the group consisting of CR and N; each X3 is independently selected from the group consisting of NH, O, and none; each Ar is independently a phenyl group or a substituted phenyl group, a heteroaryl group or a substituted heteroaryl group; [ka] X4 is selected from the group consisting of CR 11 R 12 , O, and NR, and the substituted phenyl and substituted heteroaryl groups are selected from the group consisting of halogen, C 1-6 Alkyl group, C 1-6 Halogenated alkyl groups, hydroxy-substituted C 1-6 Alkyl group, C 3-6 Cycloalkyl groups, C 1-6 Alkylamino group, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 3-6 Halogenated cycloalkyl groups, cyano groups, oxo groups, -NR9C(O)R 10 , -OC(O)NR9R 10 , -NR9C(O)OR 10 , -C(O)NR9R 10, methanesulfonyl group, -NR9-methanesulfonyl group, [ka] -CO-C 1-6 Alkyl group, -C(=O)OC 1-6 Alkyl group, -CO-C 3-6 Cycloalkyl groups, -CO-C 1-6 Halogenated alkyl groups, -CO-C 3-6 halogenated cycloalkyl groups; Each R1 is independently hydrogen, halogen, or C 1-6 selected from the group consisting of halogenated alkyl groups and cyano groups; Each R2 and R3 is independently H, halogen, or C 1-6 Alkyl group, C 3-6 Cycloalkyl groups, C 1-6 Alkylamino group, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 1-6 Halogenated alkyl group, cyano group, C 3-6 Halogenated cycloalkyl groups, -NR9C(O)R 10 , -C(O)NR9R 10 , methanesulfonyl group, [ka] Unsubstituted or C 1-6 alkyl-substituted 5-10 membered heteroaryl groups containing 1, 2, or 3 heteroatoms selected from N, O, or S; Each R4 is independently C 1-6 Alkyl group, C 1-6 Halogenated alkyl groups, C 3-6 Cycloalkyl groups, C 3-6 selected from the group consisting of halogenated cycloalkyl groups; Each R5 is independently absent or C 1-6 Alkyl groups, NR, [ka] and Each of R6, R7, and R8 independently represents H, halogen, or C 1-6 Alkyl group, C 3-6 Cycloalkyl groups, C 1-6 Alkylamino group, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 1-6 Halogenated alkyl group, cyano group, C 3-6 Cycloalkyl halide -NR9C(O)R 10 , -C(O)NR9R 10 , methanesulfonyl group, [ka] hydroxy groups, or R6 forms a 3- to 6-membered ring with the ring to which it is attached; Each R9 is independently H, C 1-6 Alkyl group, C 6-10 Aryl group, C 1-6 Halogenated alkyl groups, C 3-6 Cycloalkyl groups, C 3-6 selected from the group consisting of halogenated cycloalkyl groups; Each R 10 are independently H, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-6 Cycloalkyl groups, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 1-6 Halogenated alkyl groups, C 3-6 Halogenated cycloalkyl groups, methanesulfonyl groups, [ka] is selected from the group consisting of each m, n, and q is independently selected from the group consisting of 0, 1, 2, 3, 4, and 5; Each R 11 , R 12 are independently H, C 1-6 Alkyl group, C 1-6Halogenated alkyl groups, C 3-6 Cycloalkyl groups, C 3-6 halogenated cycloalkyl groups or R 11 and R 12 form a 5- to 7-membered ring together with the part to which they are attached, Each R 13 are independently H, halogen, C 1-6 Alkyl group, C 1-6 Halogenated alkyl groups, C 3-6 Cycloalkyl groups, C 3-6 halogenated cycloalkyl groups; and Each R is independently H, C 1-6 Alkyl groups, hydroxyl groups, halogens and C 1-6 The halogenated alkyl group is selected from the group consisting of halogenated alkyl groups.

[0007] In another preferred embodiment, L is [ka] is selected from the group consisting of A is, [ka] [ka] is selected from the group consisting of B is [ka] [ka] is selected from the group consisting of In each formula, Each X1 and X2 is independently selected from the group consisting of CR and N; each X3 is independently selected from the group consisting of NH, O, and none; each Ar is independently a phenyl group or a substituted phenyl group, a heteroaryl group or a substituted heteroaryl group; [ka] X4 is selected from the group consisting of CR 11 R 12 , O, and NR, and the substituted phenyl and substituted heteroaryl groups are selected from the group consisting of halogen, C 1-6 Alkyl group, C 1-6 Halogenated alkyl groups, C 3-6 Cycloalkyl groups, C 1-6 Alkylamino group, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 3-6 Halogenated cycloalkyl groups, cyano groups, -NR9C(O)R 10 , -OC(O)NR9R 10 , -NR9C(O)OR 10 , -C(O)NR9R 10 , methanesulfonyl group, [ka] -CO-C 1-6 Alkyl group, -CO-C 3-6 Cycloalkyl groups, -CO-C 1-6 Halogenated alkyl groups, -CO-C 3-6 halogenated cycloalkyl groups; Each R1 is independently hydrogen, halogen, or C 1-6 selected from the group consisting of halogenated alkyl groups and cyano groups; Each R2 and R3 is independently H, halogen, or C 1-6 Alkyl group, C 3-6 Cycloalkyl groups, C 1-6 Alkylamino group, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 1-6 Halogenated alkyl group, cyano group, C 3-6 Halogenated cycloalkyl groups, -NR9C(O)R 10, -C(O)NR9R 10 , methanesulfonyl group, [ka] is selected from the group consisting of Each R4 is independently C 1-6 Alkyl group, C 1-6 Halogenated alkyl groups, C 3-6 Cycloalkyl groups, C 3-6 selected from the group consisting of halogenated cycloalkyl groups; Each R5 is independently absent or C 1-6 alkyl group, NR or [ka] and Each of R6, R7, and R8 independently represents H, halogen, or C 1-6 Alkyl group, C 3-6 Cycloalkyl groups, C 1-6 Alkylamino group, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 1-6 Halogenated alkyl group, cyano group, C 3-6 Cycloalkyl halide -NR9C(O)R 10 , -C(O)NR9R 10 , methanesulfonyl group, [ka] hydroxy group, or R6 is selected from the group consisting of a 3- to 6-membered ring together with the ring to which it is attached (R6 is [ka] and forming a bridged ring with Each R9 is independently H, C 1-6 Alkyl group, C 1-6 Halogenated alkyl groups, C 3-6 Cycloalkyl groups, C 3-6 selected from the group consisting of halogenated cycloalkyl groups; Each R 10 are independently H, C1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-6 Cycloalkyl groups, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 1-6 Halogenated alkyl groups, C 3-6 Halogenated cycloalkyl groups, methanesulfonyl groups, [ka] is selected from the group consisting of each m, n, and q is independently selected from the group consisting of 0, 1, 2, 3, 4, and 5; Each R 11 , R 12 are independently H, C 1-6 Alkyl group, C 1-6 Halogenated alkyl groups, C 3-6 Cycloalkyl groups, C 3-6 halogenated cycloalkyl groups or R 11 and R 12 form a 5- to 7-membered ring together with the part to which they are attached, Each R 13 are independently H, halogen, C 1-6 Alkyl group, C 1-6 Halogenated alkyl groups, C 3-6 Cycloalkyl groups, C 3-6 halogenated cycloalkyl groups; and Each R is independently H, C 1-6 Alkyl groups and C 1-6 The halogenated alkyl group is selected from the group consisting of halogenated alkyl groups.

[0008] In another preferred example, the heteroaryl group is a 5- to 10-membered heteroaryl group containing 1, 2, or 3 heteroatoms each independently selected from the group consisting of N, O, and S.

[0009] In another preferred embodiment, L is [ka] is selected from the group consisting of:

[0010] In another preferred example, both X1 and X2 are N, or one of X1 is N and the other is CR. In another preferred example, R1 is selected from the group consisting of hydrogen, halogen, a trifluoromethyl group, or a cyano group.

[0011] In another preferred example, R6 forms a 3- to 6-membered ring with the ring to which it is connected, thereby forming a spiro ring, a fused ring, or a bridged ring, and preferably, R6 is a C1-4 alkylene group, and the ring to which it is connected [ka] and more preferably, R6 is a methylene group.

[0012] In another preferred example, each Ar is independently selected from the group consisting of a phenyl group or a substituted phenyl group, a heteroaryl group or a substituted heteroaryl group, wherein the heteroaryl group is [ka] is selected from the group consisting of:

[0013] In another preferred embodiment, Ar is [ka] is selected from the group consisting of where X4 is the CR 11 R 12 , O, and NR; Each R 11 are independently H, C 1-6 Alkyl group, C 1-6 Halogenated alkyl groups, C 3-6 Cycloalkyl groups, C 3-6 selected from the group consisting of halogenated cycloalkyl groups; Each R 12are independently H, C 1-6 Alkyl group, C 1-6 Halogenated alkyl groups, C 3-6 Cycloalkyl groups, C 3-6 halogenated cycloalkyl groups or R 11 and R 12 form a 5- to 7-membered ring together with the part to which they are attached, Each R 13 are independently halogen, and q is selected from the group consisting of 0, 1, 2, 3, 4, and 5.

[0014] In another preferred embodiment, A is [ka] is selected from the group consisting of wherein R1 is selected from the group consisting of chlorine, trifluoromethyl, and bromine; Ar is [ka] is selected from the group consisting of Each R3 is independently H, halogen, C 1-6 Alkyl group, C 1-6 Halogenated alkyl group, cyano group, -NR9C(O)R 10 is selected from the group consisting of Each R 12 are independently H, C 1-6 Alkyl group, C 1-6 Halogenated alkyl groups, C 3-6 Cycloalkyl groups, C 3-6 selected from the group consisting of halogenated cycloalkyl groups; Each R 13 are independently halogen; q is selected from the group consisting of 0, 1, 2, 3, 4, and 5; X4, R2, R4, R7, R8, R9, R 10 , R 11 , R5, X1, X2, and m are as described above.

[0015] In another preferred embodiment, B is [ka] wherein R7, R 11 , m are as described above.

[0016] In another preferred embodiment, L is [ka] is selected from Each X1 and X2 is independently selected from CR or N, and each R is independently selected from H, C 1-6 alkyl groups, A is, [ka] [ka] is selected from where: Ar is selected from phenyl or substituted phenyl, heteroaryl or substituted heteroaryl groups, and the substituents on the substituted phenyl and substituted heteroaryl groups are halogen, C 1-6 Alkyl group, C 3-6 Cycloalkyl groups, C 1-6 Alkylamino group, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 3-6 Halogenated cycloalkyl groups, cyano groups, -NR9C(O)R 10 , methanesulfonyl group, [ka] -CO-C 1-6 is an alkyl group, R1 is selected from hydrogen, halogen, a trifluoromethyl group, or a cyano group; R2 and R3 are each independently H, halogen, or C 1-6 Alkyl group, C3-6 Cycloalkyl groups, C 1-6 Alkylamino group, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 3-6 Halogenated cycloalkyl groups, cyano groups, -NR9C(O)R 10 , methanesulfonyl group, [ka] is selected from R4 is C 1-6 Alkyl group, C 1-6 Halogenated alkyl groups, C 3-6 Cycloalkyl groups, C 3-6 halogenated cycloalkyl groups; R5 is either absent or C 1-6 an alkyl group, or [ka] and Each of R6, R7, and R8 independently represents H, halogen, or C 1-6 Alkyl group, C 3-6 Cycloalkyl groups, C 1-6 Alkylamino group, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 3-6 Halogenated cycloalkyl groups, cyano groups, -NR9C(O)R 10 , methanesulfonyl group, [ka] hydroxy group, or R6 forms a 3- to 6-membered ring with the ring to which it is attached; R9 is H, C 1-6 Alkyl group, C 1-6 Halogenated alkyl groups, C 3-6 Cycloalkyl groups, C 3-6 halogenated cycloalkyl groups; R 10 is C 1-6 Alkyl group, C 3-6 Cycloalkyl groups, C 1-6Alkoxy group, C 1-6 Halogenated alkoxy groups, C 3-6 Halogenated cycloalkyl groups, methanesulfonyl groups, [ka] is selected from each m and n is independently selected from 0, 1, 2, 3, 4, and 5; B is [ka] is selected from where R 11 is H, C 1-6 Alkyl group, C 1-6 Halogenated alkyl groups, C 3-6 Cycloalkyl groups, C 3-6 halogenated cycloalkyl groups.

[0017] In another preferred embodiment, L is [ka] is selected from Each of X1 and X2 is as defined above.

[0018] In another preferred embodiment, A is, [ka] is selected from wherein R1 is selected from chlorine and trifluoromethyl; Ar is selected from a phenyl group or a substituted phenyl group, a heteroaryl group or a substituted heteroaryl group; R3, R4, R7, R8, X1, X2, and m are as defined above. In another preferred embodiment, B is [ka] where R7, R 11 , m is as defined above.

[0019] In another preferred embodiment, the compound is selected from the group consisting of: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0020] In another preferred embodiment, the pharmaceutically acceptable salt is an inorganic acid salt or an organic acid salt, the inorganic acid salt is selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, nitrate, phosphate, and acid phosphate; The organic acid salt is 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.

[0021] A second aspect of the present invention provides a pharmaceutical composition comprising a compound according to the first aspect of the present invention and a pharmaceutically acceptable carrier.

[0022] A third aspect of the present invention is 1) Preparation of a medicament for modulating EGFR kinase activity or for treating EGFR-related diseases; 2) preparing a drug for degrading EGFR protein; and 3) the preparation of a medicament for degrading an EGFR mutant protein selected from the group consisting of DEL19, L858R, L858R / T790M, L858R / C797S, DEL19 / T790M / C797S, L858R / T790M / C797S, exon 20 insertion mutation, L861Q, DEL19-G724S, and L858R-L792H.

[0023] In another preferred embodiment, the EGFR-related disease is selected from the group consisting of inflammation, cancer, cardiovascular disease, infection, immune disease, and metabolic disease.

[0024] 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. One embodiment of the present invention relates to a compound of formula I as described herein or a pharmaceutically acceptable salt thereof for use as a medicament for the therapeutic and / or prophylactic treatment of patients suffering from cancer, particularly non-small cell lung cancer, harboring EGFR mutations T790M / L858R, T790M / L858R / C797S, L858R, and / or L858R / C797S, comprising determining the EGFR activating mutation status of the patient and then administering to the patient a compound of formula I as described herein or a pharmaceutically acceptable salt thereof.

[0025] One embodiment of the present invention relates to a compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, for use as a medicament for the therapeutic and / or prophylactic treatment of a patient suffering from cancer, in particular non-small cell lung cancer, having an EGFR activating mutation as determined using the cobas EGFR Mutation Test v2, comprising determining the EGFR activating mutation status of said patient and then administering to said patient a compound of formula I as described herein, or a pharmaceutically acceptable salt thereof. DETAILED DESCRIPTION OF THE INVENTION

[0026] The present invention provides compounds of formula I and pharmaceutically acceptable salts thereof, the preparation of said compounds, medicaments containing same and their manufacture, and the use of said compounds in the therapeutic and / or prophylactic treatment of cancer, particularly non-small cell lung cancer.

[0027] term Unless otherwise stated, the following terms used in this Application, including the specification and claims, have the definitions set forth below. Where a substituent is depicted by a conventional chemical formula written from left to right, the substituent also includes the chemically equivalent substituent that would result if the structural formula were written from right to left. For example, -CHO- is equivalent to -OCH-.

[0028] The term "alkyl group (alone or as part of another group)" refers to a monovalent, linear or branched, saturated hydrocarbon group consisting solely of carbon and hydrogen atoms, containing 1 to 12 carbon atoms. The alkyl group is preferably a C1-C6 alkyl group (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, s-butyl, t-butyl, pentyl, n-hexyl, octyl, dodecyl, and the like. In this application, alkyl groups are intended to include substituted alkyl groups, i.e., alkyl groups substituted at one or more positions, particularly with 1 to 4 substituents, and may be substituted at any position. The term "halogenated alkyl group" refers to an alkyl group as defined herein in which one or more hydrogen atoms have been replaced with the same or different halogens. Examples of halogenated alkyl groups include -CH2Cl, -CH2CF3, -CH2CCl3, perfluoroalkyl groups (e.g., -CF3), and the like.

[0029] An "alkylene group" refers to a divalent alkyl group such as -CH2-, -CH2CH2-, and -CH2CH2CH2-. An "alkoxy group (alone or as part of another group)" refers to an alkyl group having an alkyl-O- structure with an oxygen group attached, where the alkyl group is as defined above, and preferably the alkoxy group is a C1-C6 alkoxy group. Alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, t-butoxy, and the like. A "halogenated alkoxy group" refers to a group of the formula -OR, where R is a halogenated alkyl group as defined herein. Examples of halogenated alkoxy groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, 2,2,2-trifluoroethoxy, and the like.

[0030] A "thioalkyl group" refers to an alkyl group where a carbon is replaced by S, S(O), or S(O)2.

[0031] The term "alkenyl group (alone or as part of another group)" refers to an aliphatic group containing at least one double bond, typically having 2 to 20 carbon atoms. In the present invention, a "C2-C6 alkenyl group" refers to an alkenyl group containing 2, 3, 4, 5, or 6 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like. In the present invention, alkenyl groups include substituted alkenyl groups.

[0032] An "alkenylene group" refers to an alkenyl group having two points of attachment. For example, a "vinylidene group" refers to -CH=CH-. An alkenylene group can be unsubstituted or substituted with one or more substituents.

[0033] The term "alkynyl group (alone or as part of another group)" refers to a straight or branched hydrocarbon chain containing two or more carbon atoms and characterized by one or more triple bonds, typically having from 2 to 20 carbon atoms. 2-6 "Alkynyl group" refers to an alkynyl group having 2, 3, 4, 5, or 6 carbon atoms. Alkynyl groups include, but are not limited to, ethynyl, propargyl, and 3-hexynyl groups. One of the triple bond carbons may optionally be the point of attachment of an alkynyl group substituent. In the present invention, alkynyl groups further include substituted alkynyl groups.

[0034] An "alkynylene group" refers to an alkynyl group that has two points of attachment. For example, an "ethynylene group" refers to the group: -C≡C-. An alkynylene group can be unsubstituted or substituted with one or more substituents.

[0035] "Aliphatic group" refers to a straight-chain, branched-chain, or cyclic hydrocarbon group, including saturated and unsaturated groups such as alkyl, alkenyl, and alkynyl groups. "Aromatic ring system" refers to a monocyclic, bicyclic or polycyclic hydrocarbon ring system in which at least one ring is aromatic.

[0036] An "aryl group (alone or as part of another group)" refers to a monovalent radical of an aromatic ring system. Representative aryl groups include fully aromatic rings such as phenyl, naphthyl, and anthracenyl, as well as ring systems in which an aromatic carbocyclic ring is fused to one or more non-aromatic carbocyclic rings, such as indanyl, phthalimido, naphthylimido, or tetrahydronaphthyl. In the present invention, an aryl group is preferably a C6-C12 aryl group. In the present invention, an aryl group is further intended to include substituted aryl groups.

[0037] An "arylalkyl group" or "aralkyl group" refers to an alkyl group in which an alkyl hydrogen atom is replaced by an aryl group. An aralkyl group includes a group in which one or more hydrogen atoms are replaced by an aryl group, where the aryl and alkyl groups are as described above. Examples of "arylalkyl groups" or "aralkyl groups" include benzyl, 2-phenylethyl, 3-phenylpropyl, 9-fluorenyl, diphenylmethyl, and triphenylmethyl groups.

[0038] "Aryloxy" refers to an --O-(aryl) group, where the aryl portion is as defined herein.

[0039] A "heteroalkyl group" refers to a substituted alkyl group having one or more main chain atoms selected from atoms other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, or combinations thereof. Numerical ranges can be given, e.g., a C1-C6 heteroalkyl group refers to the number of carbon atoms in the chain, including 1 to 6 carbon atoms. For example, the group -CHOCHCH3 would be referred to as a "C3" heteroalkyl group. Bonding to the remainder of the molecule is through a heteroatom or carbon in the heteroalkyl group chain. A "heteroalkylene group" refers to an optionally substituted divalent alkyl group having one or more main chain atoms selected from atoms other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, or combinations thereof.

[0040] "Carbocyclic ring system" refers to a monocyclic, bicyclic or polycyclic hydrocarbon ring system in which each ring is fully saturated or contains one or more units of unsaturation, but none of the rings is aromatic.

[0041] "Carbocyclic" refers to a monovalent radical of a carbon ring system, including, for example, cycloalkyl groups (e.g., cyclopentyl, cyclobutyl, cyclopropyl, cyclohexyl, etc.) and cycloalkenyl groups (e.g., cyclopentenyl, cyclohexenyl, cyclopentadienyl, etc.).

[0042] "Cycloalkyl group" refers to a monovalent saturated carbocyclic group consisting of a monocycle or a bicycle having 3 to 12, preferably 3 to 10, and more preferably 3 to 8 ring atoms. The cycloalkyl group can be optionally substituted with one or more substituents, each of which is independently a hydroxy group, an alkyl group, an alkoxy group, a halogen, a halogenated alkyl group, an amino group, a monoalkylamino group, or a dialkylamino group. Examples of cycloalkyl groups include, but are not limited to, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and the like.

[0043] A "cycloalkoxy group" 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, and the like. A "cycloalkylalkyl group" refers to a -(cycloalkyl)-alkyl group, wherein the cycloalkyl and alkyl groups are as disclosed herein. A "cycloalkylalkyl group" is attached to the parent molecular structure through a cycloalkyl group.

[0044] "Heteroaromatic ring system" refers to a monocyclic (e.g., 5- or 6-membered), bicyclic (6- to 12-membered), or polycyclic system in which at least one ring is aromatic and contains at least one heteroatom (e.g., N, O, or S), and in which none of the other rings is a heterocyclyl group (e.g., as defined below). Optionally, a heteroatom-containing ring that is aromatic contains 1, 2, 3, or 4 ring heteroatoms within the ring. At least one of the rings is heteroaromatic, and the remaining rings may be saturated, partially saturated, or fully unsaturated.

[0045] A "heteroaryl group" refers to a monocyclic (e.g., 5- or 6-membered), bicyclic (e.g., 8- to 10-membered), or tricyclic group having 5 to 12 ring atoms, which includes at least one aromatic ring containing 1, 2, or 3 ring heteroatoms selected from N, O, or S, and the remaining ring atoms are aromatic rings of C, it being understood that the point of attachment of the heteroaryl group should be on an aromatic ring. Examples of heteroaryl groups include imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, thienyl, furyl, pyranyl, pyridyl, pyrrolyl, pyrazolyl, pyrimidinyl, quinolyl, isoquinolyl, benzofuranyl, benzothienyl, benzothiopyranyl, benzimidazolyl, benzophenone, benzothienyl, benzothiopyranyl, benzophenone, benzothienyl ... Examples of heteroaryl groups include, but are not limited to, azolyl, benzoxazolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzopyranyl, indolyl, isoindolyl, triazolyl, triazinyl, quinoxalinyl, purinyl, quinazolinyl, quinazinyl, naphthyridinyl, pteridinyl, carbazolyl, azazolinyl, diazazoyl, acridinyl, and the like. Heteroarylene refers to a heteroaryl group having two binding sites.

[0046] "Heterocyclic ring system" refers to monocyclic, bicyclic, and polycyclic ring systems in which at least one ring is saturated or partially unsaturated (not aromatic) and contains at least one heteroatom. The heterocyclic ring system can be attached to a pendant group at any heteroatom or carbon atom that results in a stable structure, and any ring atom can be optionally substituted.

[0047] "Heterocyclyl group" refers to a monovalent radical of a heterocyclic ring system, typically a stable monocyclic (e.g., 3-8 members, i.e., 3, 4, 5, 6, 7, or 8 members), bicyclic (e.g., 5-12 members, e.g., 5, 6, 7, 8, 9, 10, 11, or 12 members) or polycyclic (e.g., 7-14 members, i.e., 7, 8, 9, 10, 11, 12, 13, or 14) ring system, including fused, spiro, and / or bridged ring structures that are saturated, partially unsaturated, and contain carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S. Representative heterocyclyl groups include the following ring systems: (1) each ring is non-aromatic and at least one ring contains a heteroatom, such as tetrahydrofuryl, tetrahydropyranyl, tetrahydrothienyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, pyrrolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolane, diazepine, oxazepine, thiazepine, morpholinyl, and quinuclidinyl; (2) at least one ring is non-aromatic and at least one ring contains a heteroatom, such as tetrahydrofuryl, tetrahydropyranyl, tetrahydrothienyl, pyrrolidinyl, pyrrolidinyl, piperidinyl, pyrrolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolane, diazepine, oxazepine, thiazepine, morpholinyl, and quinuclidinyl; (3) at least one ring is non-aromatic and contains a heteroatom, and at least one other ring is an aromatic carbocyclic ring, such as a 1,2,3,4-tetrahydroquinolyl group or a 1,2,3,4-tetrahydroisoquinolyl group; and (4) at least one ring is non-aromatic and contains a heteroatom, and at least one other ring is aromatic and contains a heteroatom, such as 3,4-dihydro-1H-pyrano[4,3-c]pyridine and 1,2,3,4-tetrahydro-2,6-naphthyridine. A heterocyclylene group refers to a heterocyclyl group having two binding sites. In the present invention, the heterocyclylene group is preferably bicyclic, in which one ring is a heteroaryl group and is bonded to other moieties of the general formula via the heteroaryl group. In the present invention, the heterocyclylene group is preferably a 5- to 6-membered monocyclic heterocyclylene group or an 8- to 10-membered bicyclic heterocyclylene group.

[0048] "Heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl group, where the definitions of heterocyclyl and alkyl are as previously described. An "alkylamino group" refers to a group having the structure alkyl-NR-, where R is H or an alkyl, cycloalkyl, aryl, or heteroaryl group, as described above.

[0049] A "cycloalkylamino group" is a group of the formula -NR a R b refers to the group, where R a is H, an alkyl group as defined herein, or a cycloalkyl group as defined herein; R b is a cycloalkyl group as defined herein, or R a And R b together with the N atom to which they are attached, form a 3-10-membered N-containing monocyclic or bicyclic heterocyclyl group, such as a tetrahydropyrrolyl group. As used herein, a C3-C8 cycloalkylamino group refers to an amine group containing 3 to 8 carbon atoms.

[0050] In the present invention, an "ester group" refers to an ester having the structure -C(O)-OR or -RC(O)-O-, where R independently represents a hydrogen atom, an alkyl group, a cycloalkyl group, an aryl group, a heteroaryl group, or a heterocyclyl group, as defined above.

[0051] As used herein, the term "amide group" refers to a group having the structure -CONRR', where R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, aryl or substituted aryl, heterocycle or substituted heterocycle as defined above. R and R' can be the same or different in the dialkylamine moiety.

[0052] As used herein, the term "sulfonamide group" refers to a group having the structure -SONR R', where R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, aryl or substituted aryl, heterocycle or substituted heterocycle as defined above. R and R' can be the same or different in the dialkylamine moiety.

[0053] A "ketone carbonyl group" refers to RC(=O)--, where R is an alkyl group, cycloalkyl group, etc., as described above.

[0054] When a substituent is a non-terminal substituent, it is a subunit of the corresponding group, e.g., an alkyl group corresponds to an alkylene group, a cycloalkyl group corresponds to a cycloalkylene group, a heterocyclyl group corresponds to a heterocyclylene group, and an alkoxy group corresponds to an alkyleneoxy group.

[0055] In the present invention, each of the above alkyl groups, alkoxy groups, cycloalkyl groups, heteroalkyl groups, aryl groups, heteroaryl groups, heterocyclic alkyl groups, alkenyl groups, alkynes, heterocycles, heterocyclyl groups, etc. may be substituted or unsubstituted.

[0056] In the present invention, the term "substituted" refers to the replacement of one or more hydrogen atoms on a specific group with a specific substituent. The specific substituent is the substituent described above as appropriate or the substituent described in each Example. Unless otherwise specified, a substituent can have one substituent selected from the specific group at any substitutable position of the group, and the substituent may be the same or different at each position. It will be understood by those skilled in the art that the combination of substituents contemplated by the present invention is stable or chemically achievable. Typical substitutions include hydrogen, deuterium, halogen (e.g., monohalogen or polyhalogen substituents, the latter being trifluoromethyl or alkyl groups containing Cl), cyano, nitro, oxo (e.g., ═O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, alkynyl, heterocyclic, aromatic, OR, and the like. a , S.R. a , S(=O)R e , S(=O)2R e , P(=O)2R e , S(=O)2OR e ,P(=O)2OR e , N.R. b R c , N.R. b S(=O)2R e , N.R. 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 , N.R. b C(=O)OR e , N.R. d C(=O)NR b R c , N.R. d S(=O)NR b R c , N.R. dP(=O)NR b R c , N.R. b C(=O)R a , or NR b P(=O)2R e and the like, where R a can independently represent hydrogen, deuterium, an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, a heterocyclic ring, or an aromatic ring; R b , R c and R d can independently represent hydrogen, deuterium, an alkyl group, a cycloalkyl group, a heterocycle, or an aromatic ring, or R b and R c can form a heterocycle together with the N atom, and R e can independently represent hydrogen, an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, a heterocycle, or an aromatic ring. The above-mentioned typical substituents, such as an alkyl group, a cycloalkyl group, an alkenyl group, a cycloalkenyl group, an alkynyl group, a heterocycle, or an aromatic ring, can be optionally substituted. Examples of the substituents include, but are not limited to, halogen, a hydroxy group, a cyano group, a carboxyl (—COOH), a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C3-C8 cycloalkyl group, a 3- to 12-membered heterocyclyl group, an aryl group, a heteroaryl group, a C1-C8 aldehyde group, a C2-C10 acyl group, a C2-C10 ester group, an amine group, a C1-C6 alkoxy group, a C1-C10 sulfonyl group, and a C1-C6 urea group.

[0057] "Cyano" refers to the radical -CN. "Nitro group" refers to -NO2. "Hydroxy group" refers to -OH.

[0058] "Amino group" refers to -NH2 or RNH-, where R is a ketone carbonyl group, a sulfonyl group, a sulfonamide group, R a -C(=O)-, R a R bNC(=O)-, etc., where R a and R b is an alkyl group, a cycloalkyl group, an aryl group, a heteroaryl group, or the like. "Halogen (halogenated)" refers to any halogen group, for example, -F, -Cl, -Br, or -I.

[0059] "Deuteride" refers to a compound resulting from the replacement of one hydrogen atom (H) or multiple hydrogen atoms (H) with a deuterium atom (D). In the present invention, the term "plurality" refers independently to 2, 3, 4, or 5.

[0060] Active ingredient As used herein, the terms "compound of the invention" or "active ingredient of the invention" are used interchangeably and refer to a compound of Formula I, or a pharmaceutically acceptable salt, hydrate, solvate, isotopic compound (e.g., deuterated compound), or prodrug thereof. The terms further include racemates and optical isomers.

[0061] The compound of formula I has the structure: [ka] The definitions of ring A, ring B and L are as described above. Salts that can be formed with the compounds of the present invention also fall within the scope of the present invention. Unless otherwise specified, it is understood that the compounds of the present invention include their salts. As used herein, the term "salt" refers to acidic or basic salts formed with inorganic or organic acids and bases. Furthermore, when a compound of the present invention contains a basic moiety, including but not limited to pyridine or imidazole, or an acidic moiety, including but not limited to carboxylic acid, the amphoteric ions ("zwitterions") that can be formed are included within the scope of the term "salt." Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, for example, in separation or purification steps during preparation. The compounds of the present invention can form salts; for example, Compound I can be obtained by reacting a certain amount, e.g., an equivalent amount, of an acid or base, salting out in a medium, or lyophilizing in an aqueous solution.

[0062] The basic moiety contained in the compounds of the present invention, including but not limited to an amine, pyridine, or imidazole ring, can form a salt with an organic or inorganic acid. Typical acids that can form salts include acetate (e.g., acetic acid or a trihaloacetic acid such as trifluoroacetic acid), adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, diglycolate, lauryl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, enanthate, caproate, hydrochloride, hydrobromide, hydroiodide, and hydroxyethanesulfonate. Salts include salts (e.g., 2-hydroxyethanesulfonate), lactate, maleate, methanesulfonate, naphthalenesulfonate (e.g., 2-naphthalenesulfonate), nicotinate, nitrate, oxalate, pectinate, persulfate, phenylpropionate (e.g., 3-phenylpropionate), phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate (e.g., formed with sulfuric acid), sulfonate, tartrate, thiocyanate, toluenesulfonate such as p-toluenesulfonate, dodecanoate, and the like.

[0063] Certain compounds of the present invention may contain an acidic moiety, including, but not limited to, a carboxylic acid, and may form salts with a variety of organic or inorganic bases. Typical salts formed with bases include ammonium salts, alkali metal salts such as sodium salts, lithium salts, and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, salts formed with organic bases (e.g., organic amines) such as benzathine, dicyclohexylamine, hydrabamine (salts formed with N,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucosamine, N-methyl-D-glucamide, t-butylamine, and the like, and salts formed with amino acids such as arginine and lysine. Basic nitrogen-containing groups can be combined with, for example, small molecule alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl sulfate, diethyl sulfate, dibutyl sulfate, and dipentyl sulfate), long chain halides (e.g., decyl, dodecyl, tetradecyl, and tetradecyl chlorides, bromides, and iodides), halide quaternary ammonium salts (e.g., benzyl bromide and phenyl bromide), and the like.

[0064] Prodrugs and solvates (or solvates) of the compounds of the invention are also within the scope of the invention. The term "prodrug" herein refers to a compound that, when used to treat a relevant disease, undergoes chemical conversion through metabolic or chemical processes to produce a compound, salt, or solvate of the present invention. The compounds of the present invention include solvates such as hydrates.

[0065] The compounds, salts or solvates of the present invention may exist in their tautomeric form (for example as amides and imine ethers), and all these tautomeric forms are part of the present invention.

[0066] All stereoisomers of the compounds (e.g., due to asymmetric carbon atoms that may be present due to various substitutions), including their enantiomeric and diastereomeric forms, are within the scope of the present invention. Individual stereoisomers of the compounds of the present invention may not exist simultaneously with other isomers (e.g., possess specific activity as pure or substantially pure optical isomers) and may be mixtures, such as racemates, or mixtures of all other stereoisomers or portions thereof. The chiral centers of the present invention have two configurations, S or R, as defined by the International Union of Theoretical and Applied Chemistry (IUPAC) in 1974. Racemic forms can be separated by physical methods, such as fractional crystallization, fractional crystallization by diastereomeric derivatization, or chiral column chromatography. Optical isomers herein can be obtained from the racemates by any suitable method, including, but not limited to, conventional methods, such as salt formation with an optically active acid followed by recrystallization.

[0067] The compounds of the present invention have a weight content of 90% or more, for example, 95% or more, 99% or more ("highly pure" compounds) obtained through preparation, separation, and purification, as described herein. Such "highly pure" compounds of the present invention are included herein as part of the present invention.

[0068] All configurational isomers of the compounds of this invention, whether in mixtures, semi-solid, or highly pure form, are included within the scope. The definition of the compounds of this invention includes the two olefin isomers, cis (Z) and trans (Z), and cis and trans isomers of carbocyclic and heterocyclic rings.

[0069] Throughout the specification, groups and substituents may be chosen to provide stable moieties and compounds.

[0070] Definitions of certain functional groups and chemical terms are explained in detail below. For purposes of this invention, chemical elements are as defined in the Periodic Table of the Elements, CAS vers., Handbook of Chemistry and Physics, 75th Ed. Definitions of certain functional groups are also explained herein. Furthermore, basic principles of organic chemistry, as well as certain functional groups and reactivities, are explained in "Organic Chemistry," Thomas Sorrell, University of Science Books, Sausalito: 1999, the entire contents of which are incorporated herein by reference.

[0071] Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms. The present invention includes all compounds, including cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, racemic mixtures, and other mixtures. Furthermore, asymmetric carbon atoms may represent substituents such as alkyl groups. All isomers and mixtures thereof are included in the present invention.

[0072] In accordance with the present invention, mixtures of isomers can contain various ratios of isomers. For example, mixtures of only two isomers can have combinations of 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0, with all ratios of isomers being within the scope of the present invention. Similar ratios, as would be readily apparent to one skilled in the art, for more complex mixtures of isomers are also within the scope of the present invention.

[0073] The present invention also includes isotopically labeled compounds equivalent to the original compounds disclosed herein. However, in practice, one or more atoms are often replaced with atoms having different atomic weights or mass numbers. Examples of isotopes of compounds that can be mentioned in the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine isotopes, respectively, e.g. 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 In the compounds of the present invention, or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates thereof, isotopes or other isotopic atoms containing the compounds are all within the scope of the present invention. For example, 3 H and 14 Certain isotopically labeled compounds of the present invention, such as radioactive isotopes of C, are also included and are useful in drug and substrate tissue distribution studies. 3 H and carbon-14, i.e. 14 C is relatively easy to prepare and detect. It is the first choice among isotopes. Furthermore, deuterium, i.e. 2 Heavier isotope substitution, such as H, offers certain advantages, such as increased half-life in the body and reduced dosage due to superior metabolic stability, and may therefore be preferred in some cases. Isotopically labeled compounds can be prepared by general methods by substituting readily available isotopically labeled reagents for non-isotopic reagents using protocols disclosed in the Examples.

[0074] If one wishes to design a synthesis of a particular enantiomer of a compound of the present invention, it can be prepared by ab initio synthesis or by derivatization with a chiral auxiliary, and the resulting diastereomeric mixture separated, followed by removal of the chiral auxiliary to yield the pure enantiomer. Furthermore, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, one can form a diastereomeric salt with an appropriate optically active acid or base, and the pure enantiomers can be obtained by conventional means, such as separate crystallization or chromatography.

[0075] As described herein, the compounds of the present invention can have any number of substituents or functional groups to broaden their scope. Generally, the term "substituted," whether preceded or followed by the term "optionally," refers to the general formula of the substituents contained in the formulations of the present invention, where a substituent of the specified structure is used in place of a hydrogen radical. When multiple positions in a particular structure are substituted with multiple specified substituents, the substituents can be the same or different at each position. As used herein, the term "substituted" includes all permissible substitutions of organic compounds. Broadly speaking, permissible substituents include acyclic, cyclic, branched, unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds. In the present invention, heteroatoms, such as nitrogen gas, can have hydrogen substituents or any of the permissible organic compounds listed above to compensate for their valence. Furthermore, the present invention is in no way limited to permissible substituted organic compounds. It is believed that the present invention provides a stable compound form in which combinations of substituents and variables are present, which is advantageous for treating diseases. The term "stable" herein refers to a stable compound that is stable for a sufficiently long period of time, preferably a sufficiently long period of time, to maintain the structural integrity of the compound, and is used herein for the above purposes.

[0076] Metabolites of the compounds referred to in this application and their pharmaceutically acceptable salts, as well as prodrugs that can be converted in vivo to the structures of the compounds referred to in this application and their pharmaceutically acceptable salts, are also included within the scope of the present claims. In another preferred example, in the compound, any one of the groups is the corresponding group in a specific compound.

[0077] Preparation method The following schemes and examples describe methods for preparing compounds of Formula I. Starting materials and intermediates are purchased from commercial sources, prepared by known procedures, or used as otherwise described. In some cases, the order of steps in carrying out the reaction schemes can be varied to facilitate the reaction or to avoid unwanted side reaction products.

[0078] The preparation method of the compound of formula I of the present invention will be described in more detail below, but these specific methods do not limit the present invention in any way. The compound of the present invention can be conveniently prepared by any combination of various synthetic methods described herein or known in the art, and such combinations can be easily performed by those skilled in the art.

[0079] Generally, during the preparation, each reaction is carried out under inert gas protection in a suitable solvent at 0 to 150°C, and the reaction time is generally 2 to 24 hours.

[0080] A preferred preparation method is as follows. Method 1: [ka] Step 1: Compound SM2 is mixed with diisopropylethylamine and n-butanol to obtain a mixture, the mixture is cooled to -20°C, compound SM1 is added to react, the mixture is then warmed to room temperature, and stirred overnight. After that, the solvent of the reaction system is removed, ethyl acetate and water are added to the residue, and the layers are separated. The organic phase is taken out, the solvent is removed, and the mixture is separated and purified to obtain M1. Step 2: Compound M1 is mixed with compound SM3, p-toluenesulfonic acid monohydrate, and n-butanol to obtain a mixture, the mixture is heated to 120°C, and reacted overnight. The solvent in the reaction mixture is removed, and ethyl acetate and aqueous sodium bicarbonate solution are added to the residue, followed by layer separation. The organic phase is taken out, the solvent is removed, and the mixture is separated and purified to obtain M2. Step 3: Compounds M2 and SM4 are amide-coupled with a coupling agent such as HATU, stirred overnight at room temperature, extracted with water and ethyl acetate, the organic phase is removed, the solvent is removed, and compound T (i.e., the compound of formula I) is obtained by separation and purification.

[0081] Method 2: [ka] Step 1: Compound SM2 is mixed with diisopropylethylamine and n-butanol to obtain a mixture, the mixture is cooled to -20°C, compound SM1 is added to react, the mixture is then warmed to room temperature, and stirred overnight. After that, the solvent of the reaction system is removed, ethyl acetate and water are added to the residue, and the layers are separated. The organic phase is taken out, the solvent is removed, and the mixture is separated and purified to obtain M1. Step 2: Compound M1 is mixed with compound SM3, p-toluenesulfonic acid monohydrate, and n-butanol to obtain a mixture, the mixture is heated to 120°C, and reacted overnight. The solvent in the reaction mixture is removed, and ethyl acetate and aqueous sodium bicarbonate solution are added to the residue, followed by layer separation. The organic phase is taken out, the solvent is removed, and the mixture is separated and purified to obtain M2. Step 3: The hydroxy group of compound M2 is oxidized to an aldehyde, which is then subjected to reductive ammoniation with SN4 under the conditions of sodium borohydride acetate. After the reaction is completed at room temperature, compound T is obtained by separation and purification.

[0082] Unless otherwise stated, the starting materials mentioned above can be purchased through commercial channels or synthesized according to reported literature.

[0083] Pharmaceutical compositions and methods of administration The pharmaceutical compositions according to the present invention are used to prevent and / or treat diseases such as inflammation, cancer, cardiovascular disease, infection, immune disorders, metabolic disorders, and the like.

[0084] The compounds described in general formula I can be used in combination with other drugs known to treat or improve similar conditions. When administered in combination, the administration method and dosage of the original drug remain unchanged, but the compound of formula I is administered simultaneously or subsequently. When the compound of formula I is taken simultaneously with one or more other drugs, a pharmaceutical composition containing one or more known drugs and the compound of formula I can be preferably used. The combination of drugs also includes the administration of the compound of formula I and one or more other known drugs during overlapping periods. When the compound of formula I is used in combination with one or more other drugs, the dose of the compound of formula I or the known drug can be lower than the dose of the compound alone.

[0085] Drugs or active ingredients that can be used in combination with the compounds described in general formula I include, but are not limited to, gefitinib, erlotinib, icotinib, lapatinib, XL647, NVP-AEE-788, ARRY-334543, vandetanib, PF00299804, cetuximab, panitumumab, pertuzumab, zalutumumab, nimotuzumab, MDX-214, CDX-110, IMC-11F8, CNF2024, tanspiromycin, aspiramycin, IPI-504, NVP-AUY922.

[0086] Dosage forms of the pharmaceutical compositions of the present invention include, but are not limited to, injections, tablets, capsules, aerosols, suppositories, films, pills, topical applications, controlled or sustained release formulations or nanoformulations.

[0087] The pharmaceutical composition of the present invention contains a safe and effective amount of the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or vector. Here, "safe and effective amount" refers to an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1 to 2,000 mg of the compound / agent of the present invention, more preferably 10 to 1,000 mg of the compound / agent of the present invention. Preferably, the "single agent" is a single capsule or tablet.

[0088] "Pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid fillers or gel substances that must be of sufficient purity and sufficiently low toxicity to be suitable for human use. "Compatibility" refers to the ability of the components of the composition to blend with each other without significantly reducing the efficacy of the compounds of the present invention. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., Tween®), wetting agents (e.g., sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0089] The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0090] 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 (a) a filler or extender, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) a binder, such as hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) a humectant, such as glycerin; or (d) agar, calcium carbonate, potato starch, or the like. The pharmaceutical composition is mixed with ingredients such as disintegrating agents such as flour or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate, (I) dissolution buffers such as paraffin, (f) absorption promoters such as quaternary amine 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 lauryl sulfate, or mixtures thereof. In capsules, tablets, and pills, the dosage form may also contain buffering agents.

[0091] Solid dosage forms such as tablets, sugar pills, capsules, pills, and granules can be prepared with coatings and shell materials, such as enteric coatings and other materials known in the art. They can contain opacifying agents, and the release of the active compound or compounds of such compositions can be delayed in a specific part of the digestive tract. Examples of embedding materials that can be used include polymeric substances and waxes. If necessary, the active compound can be formed into microcapsules with one or more of the above-mentioned excipients.

[0092] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, the liquid dosage form can contain an inert diluent conventionally used in the art, such as water or other solvents, and solubilizers and emulsifiers, such as 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.

[0093] Besides these inert diluents, compositions can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, and perfuming agents.

[0094] In addition to the active compound, suspensions may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and dehydrated sorbitan esters, microcrystalline cellulose, aluminum methoxide, and agar-agar, or mixtures of these substances.

[0095] Compositions for parenteral injection can include 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 vehicles, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0096] Dosage forms of the compounds of the present invention used for topical administration include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0097] The therapeutic methods of the present invention can be used alone or in combination with other therapeutic procedures or therapeutic agents.

[0098] When a pharmaceutical composition is used, a safe and prevalent amount of the compound of the present invention is administered to a mammal (e.g., a human or mouse) in need of treatment, and the dosage at the time of administration is the considered effective dose. For a person weighing 60 kg, the daily dose is usually 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dosage must also take into account factors such as the route of administration and the patient's health condition, all of which are within the skill of a skilled physician.

[0099] The present invention further provides a method for preparing a pharmaceutical composition, comprising mixing a pharmaceutically acceptable carrier with a compound of general formula I according to the present invention or a crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, to form a pharmaceutical composition.

[0100] The present invention further provides a method of treatment comprising administering to a subject in need thereof a compound of formula I as described in the present invention, or a crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as described in the present invention, to inhibit EGFR.

[0101] Compared with the prior art, the present invention has the following advantages: (1) The compounds of the present invention have excellent inhibitory activity against one or more types of activating or resistant mutations of EGFR, and have excellent inhibitory effects against three specific types of EGFR mutations, such as H1975 (T790M / L858R), HCC827 (19DEL), and PC-9 (19DEL). (2) The compounds of the present invention can be used to treat EGFR-sensitive mutant cancers. (3) The compounds of the present invention can be applied in cases of sequential resistance caused by current EGFR treatments. (4) The compounds of the present invention have excellent degradation ability against EGFR proteins. In particular advantageous examples of the present invention, degradation of 80% or more can be achieved for both H1975 and HCC827.

[0102] Hereinafter, the present invention will be further explained in conjunction with specific examples. It should be understood that these examples are used only to illustrate the present invention and do not limit the scope of the present invention. In the following examples, experimental methods for which no specific conditions are given are generally those described in, for example, Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1999). b or Laboratory Press, 1989), or according to conventional conditions, or conditions suggested by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0103] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those familiar to those skilled in the art. Furthermore, any methods and materials similar or equivalent to those described herein can all be applied to the methods of the present invention. The preferred implementation methods and materials described herein are used for demonstration purposes only.

[0104] Example 1 Compounds synthesized according to the present invention: [ka]

[0105] The experimental process is as follows. 1. Synthesis of intermediate M1 The synthetic route is as follows: [ka] Synthesis of intermediate M1 M1: Add 7.8 mmol of compound SM2 to a 100 ml single-neck bottle, add 3 ml of diisopropylethylamine and 30 ml of n-butanol to obtain a mixture, use a cold bath to cool the mixture to -20 ° C, slowly add compound SM1 (13.8 mmol), after the addition is completed, react at low temperature for 1 hour, remove the cold bath and warm to room temperature, stir overnight, evaporate the solvent to dryness under reduced pressure, add the residue to 100 ml of ethyl acetate (EA), add 50 ml of water to wash twice, evaporate the organic phase to dryness, separate the residue by column chromatography (eluent is ethyl acetate: petroleum ether = 1:30 (volume ratio)) to obtain intermediate M1.

[0106] 2. Synthesis of intermediate M2 The synthetic route is as follows: [ka] In a 100 mL three-neck flask, 700 mg of M1, 663 mg of SM3, and 663 mg of p-toluenesulfonic acid monohydrate were dissolved in 3 mL of n-butanol, heated to 110° C., and reacted overnight. The reaction was monitored by TLC until completion, and the solvent was removed by rotary evaporation. The residue was added with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, spin-dried, and subjected to column chromatography to obtain 800 mg of intermediate M2. LC-MS [M+1]: 441.

[0107] 3. Synthesis of intermediate SM4 The synthetic route is as follows: [ka]

[0108] 1. Synthesis of Compound 2 In a 250 mL three-neck 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 PdCl2dppf were mixed uniformly and purged with nitrogen gas. The mixture was heated to 80°C and reacted overnight. The reaction was monitored by TLC until completion. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, spin-dried, and separated by column chromatography to obtain 5.8 g of compound 2. LC-MS [M+1]: 275.

[0109] 2. Synthesis of Compound 3 In a 100 ml three-neck 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, heated to 100 °C, and reacted overnight. The reaction was monitored by TLC until completion. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, spin-dried, and separated by column chromatography to obtain 3.6 g of compound 3. LC-MS [M+1]: 386.

[0110] 3. Synthesis of Compound 4 Add 3.6g of compound 2, 0.72g of palladium carbon, and 36ml of absolute ethanol to a high-pressure reactor, adjust the hydrogen gas pressure to 0.7Mpa, react for two days, suction filter, and remove the solvent on a rotary evaporator to obtain 1.2g of compound 4. LC-MS [M+1]: 388.

[0111] 4. Synthesis of Compound 5 Add 1.2 g of compound 4 to a 100 ml single-neck flask, add 30 ml of methanol to dissolve, add 4 M hydrochloric acid in dioxane dropwise in a cold water bath, and react at 40 °C for 2 hours after the addition is complete. Remove the solvent using a rotary evaporator to obtain 1.4 g of compound 5. LC-MS [M+1]: 288.

[0112] 5. Synthesis of Compound 6 In a 100ml single-neck bottle, 0.8g of compound 5, 8ml of N,N-dimethylformamide, N,N-diisopropylethylamine, and t-butyl bromoacetate were added and stirred overnight at room temperature. The reaction was confirmed to be complete by TLC, and the mixture was extracted with ethyl acetate and water. The organic phase was dried, filtered, and then subjected to column chromatography to obtain 300mg of compound 6. LC-MS [M+1]: 402.

[0113] 6. Synthesis of Compound SM4 In a 100 ml single-neck bottle, 100 mg of compound 6 was added to 1 ml of dichloromethane, and 1.6 ml of trifluoroacetic acid was added dropwise. The mixture was stirred at room temperature overnight. The reaction was confirmed to be complete by TLC, and the solvent was removed by rotary evaporation to obtain 150 mg of SM4. LC-MS [M-1]: 344.

[0114] 4. Synthesis of Compound T-01 [ka]

[0115] The synthetic route is as follows: In a 50mL round-bottom flask, compound M2 and SM3 are dissolved in 2mL of N,N-dimethylformamide, cooled to 0°C in an ice-water bath, N,N-diisopropylethylamine and HATU are added under stirring, and the reaction is carried out in an ice-water bath under nitrogen gas protection for 1 hour, and the temperature is allowed to rise to room temperature naturally. The completion of the reaction is detected by TLC, and the reaction is extracted with ethyl acetate and water. The organic phase is dried, filtered, and then subjected to column chromatography to obtain 100mg of compound T-01. LC-MS [M+1]: 739.

[0116] The following compounds are synthesized according to the method of Example 1: [ka] [ka] [ka] [ka] [ka] [ka]

[0117] Example 2 Compounds synthesized according to the present invention: [ka]

[0118] The experimental process is as follows. 1. Synthesis of intermediate M1 The synthetic route is as follows: [ka] Intermediate M1 is synthesized with reference to the method in Example 1.

[0119] 2. Synthesis of intermediate M2 The synthetic route is as follows: [ka]

[0120] 1. Synthesis of Compound 2 In a 100 mL single-neck bottle, 500 mg of M1, 465 mg of 4-fluoro-2-methoxy-5-nitroaniline, and 475 mg of p-toluenesulfonic acid monohydrate were dissolved in 3 mL of n-butanol, heated to 110° C., and reacted overnight. The reaction was monitored by TLC until completion, and the solvent was removed by rotary evaporation. The residue was added with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, spin-dried, and subjected to column chromatography to obtain 750 mg of compound 2. LC-MS [M+1]: 391.

[0121] 2. Synthesis of Compound 3 In a 100ml single-neck bottle, 700mg of compound 2, 667mg of N-boc piperazine, and 694mg of DIPEA were dissolved in 10.5ml of DMAC, heated to 110°C, and reacted for 18 hours. The solvent was removed using a rotary evaporator, and the residue was added with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, spin-dried, and subjected to column chromatography to obtain 1.1g of compound 3. LC-MS [M+1]: 557.

[0122] 3. Synthesis of Compound 4 In a 100ml single-neck bottle, 1.0g of compound 3, 950mg of ammonium chloride, and 700mg of zinc powder were dispersed in 6ml of a 5:1 ethanol:water mixture. The mixture was heated to reflux and reacted for 18 hours. The solvent was removed using a rotary evaporator, water was added to the residue, and the pH was adjusted to 7-8 with a small amount of saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, spin-dried, and subjected to column chromatography to obtain 900mg of a brown solid, compound 4. LC-MS [M+1]: 527.

[0123] 4. Synthesis of Compound 5 In a 50ml single-neck bottle, 200mg of compound 4 and 0.15ml of triethylamine were dissolved in 1.6ml of tetrahydrofuran. The mixture was cooled to 0°C in an ice-water bath, and a diluted solution of 46.5mg of acetic anhydride and 0.4ml of tetrahydrofuran was slowly added dropwise. After the addition was complete, the mixture was allowed to react at room temperature for 2 hours. The disappearance of the raw materials was monitored by TLC. After the reaction was complete, the reaction solution was spin-dried to obtain compound 5. LC-MS [M+1]: 568.

[0124] 5. Synthesis of intermediate M2 In a 50ml single-neck bottle, 300mg of compound 5 was dissolved in 2ml of tetrahydrofuran. The reaction solution was cooled to 0°C in an ice-water bath, and 1ml of 4M HCl / dioxane was slowly added dropwise. After the addition was complete, the reaction was allowed to proceed at room temperature for 2 hours. The disappearance of the raw material was monitored by TLC. After the reaction was complete, the reaction solution was spin-dried to obtain M2. LC-MS [M+1]: 468.

[0125] 3. Synthesis of Compound T-05 The synthetic route is as follows: [ka]

[0126] In a 50 mL round-bottom flask, compound M2 and SM3 were dissolved in 2 mL of N,N-dimethylformamide, cooled to 0°C in an ice-water bath, and N,N-diisopropylethylamine and HATU were added with stirring. The reaction was carried out in an ice-water bath under nitrogen gas protection for 1 hour, and the temperature was allowed to rise to room temperature. The completion of the reaction was confirmed by TLC, and the mixture was extracted with ethyl acetate and water. The organic phase was dried, filtered, and then subjected to column chromatography to obtain 100 mg of compound T-05. LC-MS [M+1]: 796.

[0127] The following compounds are synthesized according to the method of Example 2: [ka] [ka]

[0128] Example 3 Compounds synthesized according to the present invention: [ka]

[0129] The experimental process is as follows. 1. Synthesis of intermediate M1 The synthetic route is as follows: [ka] Intermediate M1 is synthesized with reference to the method in Example 1.

[0130] 2. Synthesis of intermediate M2 The synthetic route is as follows: [ka]

[0131] 1. Synthesis of Compound 2 In a 250 mL three-neck flask, 5 g of 5-fluoro-2-nitroanisole, 11.8 g of 1-Boc-4-(piperidin-4-yl)-piperazine, and 11.3 g of dIpea are dissolved in 50 mL of DMAC, heated to 110° C., and reacted overnight. The reaction is monitored by TLC until completion, and water is added, extracted with ethyl acetate, dried over anhydrous sodium sulfate, spin-dried, and subjected to column chromatography to obtain 11 g of compound 2. LC-MS [M+1]: 421.

[0132] 2. Synthesis of Compound 3 In a 100ml single-neck bottle, 1.0g of compound 3, 1.26g of ammonium chloride, and 800mg of zinc powder were dispersed in 6ml of a 5:1 ethanol:water mixture, heated to reflux, and reacted for 18 hours. TLC showed the disappearance of the starting material, and the solvent was removed using a rotary evaporator. Water was added to the residue, and the pH was adjusted to 7-8 with a small amount of saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, spin-dried, and subjected to column chromatography to obtain 900mg of a brown solid, compound 3. LC-MS [M+1]: 391.

[0133] 3. Synthesis of intermediate M2 In a 10 ml microwave tube, 500 mg of M1, 300 mg of compound 3, and 292 mg of p-toluenesulfonic acid monohydrate are dissolved in 5 ml of n-butanol, heated in a microwave at 120 °C for 20 minutes, and monitored by TLC until the reaction is complete. The solvent is removed by rotary evaporation, and the residue is added with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, spin-dried, and subjected to column chromatography to obtain 350 mg of intermediate M2. LC-MS [M+1]: 496.

[0134] 3. Synthesis of Compound T-07 The synthetic route is as follows: [ka]

[0135] In a 50mL round-bottom flask, compound M2 and SM3 were dissolved in 2mL of N,N-dimethylformamide, cooled to 0°C in an ice-water bath, and N,N-diisopropylethylamine and HATU were added under stirring. The reaction was carried out in an ice-water bath under nitrogen gas protection for 1 hour, and the temperature was allowed to rise to room temperature. The completion of the reaction was confirmed by TLC, and the mixture was extracted with ethyl acetate and water. The organic phase was dried, filtered, and then subjected to column chromatography to obtain 50mg of compound T-07. LC-MS [M+1]: 822.

[0136] The following compounds are synthesized according to the method of Example 3: [ka] [ka] [ka] [ka] [ka] [ka]

[0137] Example 4 Compounds synthesized according to the present invention: [ka] T-126 The experimental process is as follows. 1. Synthesis of intermediate M1 The synthetic route is as follows: [ka] Intermediate M1 is synthesized with reference to the method in Example 1.

[0138] 2. Synthesis of intermediate M2 The synthetic route is as follows: [ka]

[0139] 1. Synthesis of Compound 2 In a 100 mL three-neck flask, 1.0 g of 5-fluoro-2-nitroanisole, 4.26 g of 2,6-diazaspiro[3.3]heptane-2-carboxylic acid t-butyl ester oxalate, and 5 mL of DIPEA were dissolved in 10 mL of DMAC, heated to 110° C., and reacted overnight. The reaction was monitored by TLC until completion, followed by the addition of water, extraction with ethyl acetate, drying over anhydrous sodium sulfate, spin-drying, and column chromatography to obtain 4.0 g of compound 2.

[0140] 2. Synthesis of Compound 3 In a 100ml single-neck bottle, 4.0g of compound 3, 6.1g of ammonium chloride, and 4.5g of zinc powder were dispersed in 24ml of a 5:1 ethanol:water mixture, heated to reflux, and reacted for 18 hours. TLC showed the disappearance of the starting material, and the solvent was removed using a rotary evaporator. Water was added to the residue, and the pH was adjusted to 7-8 with a small amount of saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, spin-dried, and subjected to column chromatography to obtain 3.0g of brown solid compound 3. LC-MS [M+1]: 320.

[0141] 3. Synthesis of Compound 4 In a 50ml single-neck bottle, 100mg of M1 and 150mg of compound 3 were dissolved in 5ml of tetrahydrofuran. Under nitrogen gas protection, 3.5mg of Ruhos-Pd-G3 catalyst and 60mg of sodium t-butoxide were added, and the mixture was refluxed for 15 hours. The reaction was monitored by TLC until completion, and the solvent was removed by rotary evaporation. The residue was added with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, spin-dried, and subjected to column chromatography to obtain 50mg of compound 4. LC-MS [M+1]: 523.

[0142] 4. Synthesis of intermediate M2 In a 50ml single-neck bottle, add 50mg of compound 4, 50mg of 50wt% aqueous tetrafluoroboric acid solution, and 2ml of tetrahydrofuran. Heat at 30°C for 2 hours. LC-MS indicates the reaction is complete. After removing the solvent on a rotary evaporator, adjust the pH to 7-8 with saturated aqueous sodium bicarbonate solution. Extract the aqueous phase with ethyl acetate, dry the organic layer, filter, spin-dry, and then separate by column chromatography to obtain intermediate M2, 45mg. LC-MS [M+1]: 423.

[0143] 3. Synthesis of Compound T-126 The synthetic route is as follows: [ka]

[0144] In a 50mL round-bottom flask, compound M2 and SM3 are dissolved in 2mL of N,N-dimethylformamide, cooled to 0°C in an ice-water bath, and N,N-diisopropylethylamine and HATU are added under stirring. Under nitrogen gas protection, the reaction is carried out in an ice-water bath for 1 hour, and the temperature is allowed to rise to room temperature. The completion of the reaction is detected by TLC, and the reaction is carried out by extraction with ethyl acetate and water. The organic phase is dried, filtered, and then subjected to column chromatography to obtain 50mg of compound T-126. LC-MS [M+1]: 752.

[0145] 1H NMR(400MHz,DMSO-d6)δ 10.79(s,1H),8.64(s,1H),8.02(s,1H),7.85(s,1H),7.66(d,J=8.0Hz,2H ),7.38(d,J=8.4Hz,1H),7.24(t,J=7.8Hz,2H),7.05(t,J=7.4Hz,1H),6.9 7(d,J=8.3Hz,2H),6.62(d,J=8.2Hz,2H),6.12(d,J=2.4Hz,1H),5.94(dd, J=8.5,2.4Hz,1H),5.71(d,J=7.8Hz,1H),4.42(s,2H),4.31-4.23(m,1H),4 .11(s,2H),3.96(s,3H),3.74(s,3H),2.89(s,1H),2.74(ddd,J=17.3,11. 9,5.3Hz,2H),2.60(s,1H),2.56(s,1H),2.15-2.04(m,2H),2.00(q,J=7.3H z,1H),1.87(tt,J=12.2,6.1Hz,2H),1.72(s,4H),1.34-1.27(m,2H),1.16 (dd,J=11.0,6.5Hz,2H),1.06(q,J=7.5,7.0Hz,1H),0.85(t,J=6.5Hz,1H).

[0146] The following compounds are synthesized according to the method of Example 4. [ka]

[0147] Example 5 Compounds synthesized according to the present invention: [ka]

[0148] The experimental process is as follows. 1. The synthesis route is as follows: [ka]

[0149] 1. Synthesis of Compound 2 In a 50 mL single-neck flask, 300 mg (1.0 eq.) of compound 1, 164.55 mg (1.2 eq.) of N-Boc-4-piperidinecarbaldehyde, and 158.37 mg (3.0 eq.) of sodium acetate were added to a mixture of 4 mL of ethanol and 2 mL of DCM and stirred at room temperature for 2 hours. The reaction was monitored by TLC until completion, indicating the formation of a reaction intermediate. 121.35 mg (3.0 eq.) of sodium cyanoborohydride was added and stirred overnight at room temperature. The disappearance of the starting material was confirmed by LCMS, indicating the complete formation of the desired product (LC-MS [M+1]: 650). The reaction mixture was directly stirred on 1 g of silica gel (100 mesh-200 mesh) and purified by column chromatography (EA of PE: 0%-80%) to obtain the desired product 2 (200 mg, yellow solid). LC-MS [M+1]: 650.

[0150] 2. Synthesis of Compound 3 In a 50 ml single-neck bottle, 510 mg (1.0 eq.) of compound 2 was dissolved in a mixture of THF (5 ml) and MeOH (2 ml), and HCl / dioxane (2 ml) was added and stirred at room temperature for 4 hours. The reaction was monitored for completion by LCMS, and the reaction solution was directly evaporated to dryness and used in the next step. LC-MS [M+1]: 550.

[0151] 3. Synthesis of Compound 4 In a 50 mL single-neck flask, 510 mg (1.0 eq) of compound 3 and 157.39 mg (1.2 eq) of p-fluoronitrobenzene were dissolved in 5 mL of DMAC and refluxed at 120 °C for 2 h. The reaction was monitored by LCMS until completion. The reaction was cooled to room temperature, diluted with ethyl acetate, extracted with water, dried over anhydrous sodium sulfate, spin-dried, and the sample was stirred on 1 g of silica gel (100 mesh-200 mesh) and purified by column chromatography (PE EA: 0%-50%) to obtain the desired product 4 (220 mg, yellow solid). LC-MS [M+1]: 671.

[0152] 4. Synthesis of Compound 5 In a 50 mL round-bottom flask, compound 4 (220 mg, 1.0 eq) was dissolved in 4 mL of ethanol, and 128.06 mg (6.0 eq.) of zinc powder, 174 mg of ammonium chloride (10.0 eq.), and 1 mL of water were added. The reaction mixture was refluxed at 90 °C overnight. LCMS confirmed the reaction was complete. The reaction mixture was directly stirred on 500 mg of silica gel (100 mesh to 200 mesh) and purified by column chromatography (MeOH in DCM: 0% to 20%) to obtain the desired product 5 (220 mg, yellow solid). LC-MS [M+1]: 641.

[0153] 5. Synthesis of Compound T-85 In a 50 mL single-neck flask, 220 mg (1.0 eq) of compound 5 and 198 mg (3.0 eq) of 3-bromopiperidine-2,6-dione were dissolved in 4 mL of DMF and refluxed at 80 °C for 12 hours. The reaction was monitored by LCMS until completion. The reaction was cooled to room temperature, diluted with ethyl acetate, extracted with water, dried over anhydrous sodium sulfate, spin-dried, and the sample was stirred on 500 mg of silica gel (100 mesh-200 mesh) and purified by column (MeOH in DCM: 0%-20%) to give the desired product TM (120 mg, brown solid). HPLC yield: 89%. The final product TM (i.e., T-85) (10 mg, green solid, HPLC yield: 95.53%) was obtained. LC-MS [M+1]: 752.3. 1H NMR(400MHz,DMSO-d6)δ 11.83(s,1H),10.78(s,1H),8.79(s,1H),8.34(s,1H),8.16(s,1H),8.09(s,1H),7.42(s,1H),7.35(d,J= 8.5Hz,1H),7.14(t,J=7.6Hz,2H),6.77(d,J=8.5Hz,2H),6.68-6.57(m,3H),6.51(dd,J=8.9,2.5Hz,1H), 5.38(d,J=7.3Hz,1H),4.60(t,J=5.4Hz,1H),4.19(dt,J=11.8,6.5Hz,1H),3.75(s,3H),3.53-3.37(m,17 H),3.18(s,4H),2.68(s,4H),2.38-2.20(m,4H),2.15-2.06(m,2H),1.81(d,J=12.6Hz,3H),1.64(s,2H).

[0154] The following compounds are synthesized according to the method of Example 5: [ka]

[0155] Example 6 Compounds synthesized according to the present invention: [ka]

[0156] The experimental process is as follows. 1. The synthesis route is as follows: [ka]

[0157] 1. Synthesis of Compound 2 In a 50 mL single-neck flask, 500 mg (1.0 eq.) of compound 1, 412 mg (1.1 eq.) of N-Boc-4-piperazine, and 520 mg (2.0 eq.) of DIPEA were dissolved in DMAC and stirred at 90 °C for 4 h. The reaction was monitored for completion by LCMS. The reaction mixture was cooled to room temperature, diluted with EA, and then separated by adding HO. The aqueous phase was extracted with EA (10 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was passed through a 2 g silica gel (100 mesh - 200 mesh) column. The EA content in PE was 0% to 45% (EA in PE from 0% to 80%). The desired product 2 (630 mg, yellow solid) was obtained. LC-MS [M+1]: 416.27.

[0158] 2. Synthesis of Compound 3 Compound 2 (200 mg, 1.0 eq) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (120 mg, 1.2 eq) were dissolved in dioxane in a 50 mL single-neck bottle. Potassium carbonate (133 mg, 2.0 eq), Pd(dppf)Cl (7 mg, 0.02 eq), and HO (0.5 mL) were added. The atmosphere was purged with N three times and the mixture was stirred at 100 °C under nitrogen gas protection for 12 h. The reaction was monitored for completion by LCMS. The reaction mixture was cooled to room temperature, diluted with EA, and separated with HO. The aqueous phase was extracted with EA (5 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was stirred over 600 mg of silica gel (100 mesh to 200 mesh) and purified by column chromatography (EA of PE is 0% to 70%) to obtain the desired product 3 (202 mg, yellow solid). LC-MS [M+1]: 418.2.

[0159] 3. Synthesis of Compound 4 In a 50 mL round-bottom flask, compound 3 (202 mg, 1.0 eq.) was dissolved in 2 mL of ethanol, and zinc powder (154 mg, 6.0 eq.), ammonium chloride (315 mg, 10.0 eq.), and water (0.4 mL) were added. The reaction mixture was refluxed at 90 °C overnight. Completion of the reaction was confirmed by LCMS. The reaction mixture was directly stirred and loaded onto 500 mg of silica gel (100 mesh to 200 mesh) and purified by column chromatography (EA of PE: 0% to 75%) to obtain the desired product 4 (127 mg, yellow oil). LC-MS [M+1]: 388.2.

[0160] 4. Synthesis of Compound 5 In a 50 mL microwave tube, compound 4 (127 mg, 1.0 eq) and 1-(2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)ethan-1-one (92.2 mg, 1.0 eq) were dissolved in 2 mL of n-butanol, and p-toluenesulfonic acid monohydrate (75 mg, 1.2 eq) was added. The mixture was heated in a microwave at 120 °C for 20 min. The reaction was confirmed to be complete by LCMS. The reaction mixture was adjusted to pH > 7 with saturated aqueous sodium bicarbonate. Extracted with DCM, the organic phase was washed with saturated brine, and dried over anhydrous sodium sulfate. The sample was stirred on 500 mg of silica gel (100 mesh to 200 mesh) and purified by column chromatography (MeOH in DCM: 0% to 20%) to give the desired product 5 (100 mg, brown solid). LC-MS [M+1]: 533.03.

[0161] 5. Synthesis of Compound TM In a 50 mL round-bottom flask, compound 1 (50 mg, 1.0 eq), 2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)acetic acid (57 mg, 1.2 eq, equivalent purity 68%) was dissolved in 2 mL of N,N-dimethylformamide, and the mixture was cooled to 0°C in an ice-water bath. N,N-diisopropylethylamine (24 mg, 2.0 eq) and HATU (43 mg, 1.2 eq) were added under stirring, and the mixture was reacted in an ice-water bath under nitrogen gas protection for 1 hour, and then allowed to warm to room temperature. The reaction was confirmed to be complete by TLC, and the mixture was extracted with ethyl acetate and water. The organic phase was dried, filtered, and then subjected to column chromatography to obtain 50 mg of compound TM (i.e., T-233). LC-MS [M+1]: 860. 1 H NMR(400MHz,Chloroform-d)δ 11.97(s,1H),8.85(d,J=8.3Hz,1H),8.27(s,1H),8.16(s,1H),8.13-8.03(m,1H),7.98(s,1H),7.95-7.86(m,1H) ,7.53(d,J=7.6Hz,1H),7.38(s,2H),7.08(d,J=8.0Hz,2H),6.97(s,2H),6.76-6.54(m,3H),4.66(s,1H),4.05(d, J=12.6Hz,1H),3.88(d,J=20.4Hz,6H),3.73(s,4H),3.28(s,2H),3.03(d,J=10.8Hz,2H),2.98-2.87(m,4H),2.85 (d,J=3.8Hz,1H),2.81-2.74(m,1H),2.72(s,3H),2.55(d,J=13.0Hz,1H),2.44(s,1H),2.28(s,2H),1.80(s,2H).

[0162] Example 7 Compounds synthesized according to the present invention: [ka]

[0163] The experimental process is as follows. 1. The synthesis route is as follows: [ka]

[0164] 1. Synthesis of Compound 2 In a 50 mL three-neck flask, 230 mg (1.0 eq.) of compound 1, cuprous cyanide (64.37 mg, 1.3 eq.), and cuprous iodide (137 mg, 1.3 eq.) were added to 2.3 mL of DMF and stirred at 150 °C for 4 h. The reaction was monitored for completion by LCMS. The reaction mixture was cooled to room temperature, filtered, and the filtrate was diluted with EA. H2O was added and the mixture was allowed to stand. The aqueous phase was extracted with EA (10 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by column chromatography (PE EA content: 0%-40%) on 600 mg of silica gel (100 mesh-200 mesh) to give the desired product 2 (140 mg, yellow solid). LC-MS [M+1]: 362.

[0165] 2. Synthesis of Compound 3 In a 50 mL round-bottom flask, compound 2 (140 mg, 1.0 eq.) was dissolved in 2 mL of ethanol, and zinc powder (123 mg, 6.0 eq.), ammonium chloride (251 mg, 10.0 eq.), and water (0.4 mL) were added. The reaction mixture was refluxed at 90 °C for 4 hours. Completion of the reaction was confirmed by LCMS. The reaction mixture was directly stirred and loaded onto 500 mg of silica gel (100 mesh-200 mesh) and purified by column chromatography (PE EA: 0%-30%) to obtain the desired product 3 (30 mg, white solid). LC-MS [M+1]: 332.

[0166] 3. Synthesis of Compound 4 In a 10 mL microwave tube, compound 4 (30 mg, 1.0 eq) and 1-(2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)ethan-1-one (26 mg, 1.0 eq) were dissolved in 1 mL of n-butanol, and p-toluenesulfonic acid monohydrate (21 mg, 1.2 eq) was added. The mixture was heated in a microwave at 120 °C for 20 min. The reaction was confirmed to be complete by LCMS. The reaction mixture was adjusted to pH > 7 with saturated aqueous sodium bicarbonate. Extracted with DCM, the organic phase was washed with saturated brine, and dried over anhydrous sodium sulfate. The sample was stirred on 200 mg of silica gel (100 mesh to 200 mesh) and purified by column chromatography (MeOH in DCM is 0% to 10%) to give the desired product 4 (17 mg, yellow solid). LC-MS [M+1]: 477.

[0167] 4. Synthesis of Compound TM In a 50 mL round-bottom flask, compound 1 (20 mg, 1.0 eq), 2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)acetic acid (30 mg, 1.2 eq, equivalent purity 68%) was dissolved in 2 mL of N,N-dimethylformamide, and the mixture was cooled to 0 ° C in an ice-water bath. N,N-diisopropylethylamine (15 mg, 2.0 eq) and HATU (18 mg, 1.2 eq) were added with stirring, and the mixture was reacted in an ice-water bath under nitrogen gas protection for 1 hour, and then allowed to warm to room temperature. The reaction was confirmed to be complete by TLC, and the mixture was extracted with ethyl acetate and water. The organic phase was dried, filtered, and then subjected to column chromatography to obtain 15 mg of compound TM (i.e., T-282). LC-MS [M+1]: 805.

[0168] Example 8 Compounds synthesized according to the present invention: [ka]

[0169] The experimental process is as follows. 1. Synthesis of intermediate M1 The synthetic route is as follows: [ka]

[0170] 1. Synthesis of Compound SM2 In a 250 mL three-neck flask, 5 g of o-nitrobenzoic acid and 19 g of dIpea were dissolved in 25 mL of DMF, and the mixture was purged with N2 three times. The ice bath was then cooled to 0 °C. 19 g of dIpea, 3 g of a 30% methylamine solution in methanol, and 13.6 g of HATU were added in that order, and the reaction was continued overnight. The reaction was monitored by TLC until completion. Water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated NaCl solution, dried over anhydrous sodium sulfate, spin-dried, and subjected to column chromatography to obtain 6 g of crude product Compound 2. LC-MS [M+1]: 181.

[0171] 2. Synthesis of Compound SM3 In a 250ml three-neck bottle, 6.0g of compound SM2, 14.7g of ammonium chloride, and 10.8g of zinc powder were dispersed in 55ml of a 5:1 mixture of ethanol and water, heated to reflux, and reacted for 18 hours. TLC showed the disappearance of the raw material, and the solvent was removed using a rotary evaporator. Water was added to the residue, and the pH was adjusted to 7-8 with a small amount of saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, spin-dried, and subjected to column chromatography to obtain 3.3g of solid compound SM3. LC-MS [M+1]: 151.

[0172] 3. Synthesis of intermediate M1 In a 100ml three-necked bottle, 950mg of SM3, 1.16g of 2,4,5-trichloropyrimidine, and 4g of dIpea were dissolved in 10ml of isopropanol, and the mixture was reacted at 80°C overnight. The reaction was monitored by TLC until completion, and the solvent and water were evaporated on a rotary evaporator. The mixture was extracted with ethyl acetate, and the organic phase was washed with saturated NaCl solution, dried with anhydrous sodium sulfate, spin-dried, and subjected to column chromatography to obtain 570mg of intermediate M1. LC-MS [M+1]: 342.

[0173] 2. Synthesis of Compound T-184 The synthetic route is as follows: [ka]

[0174] 1. Synthesis of Compound M2 In a 10 ml microwave tube, 200 mg of M1, 190 mg of 4-(4-amino-3-methoxyphenyl)piperazine-1-carboxylic acid tert-butyl ester, and 135 mg of p-toluenesulfonic acid monohydrate were dissolved in 3 ml of isopropanol and heated in a microwave at 120° C. for 20 minutes. The reaction was monitored by TLC until completion, and the reaction solution was transferred to a 125 ml separatory funnel, water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated NaCl solution, dried over anhydrous sodium sulfate, spin-dried, and subjected to column chromatography to obtain 130 mg of intermediate M2. LC-MS [M+1]: 512.

[0175] 2. Synthesis of Compound T-184 In a 50ml round-bottom flask, 130mg of compound M2, 147mg of 60% SM3 are dissolved in 4ml of N,N-dimethylformamide, cooled to 0°C in an ice-water bath, and 164mg of N,N-diisopropylethylamine and 116mg of HATU are added under stirring, and reacted in an ice-water bath under nitrogen gas protection for 1 hour, and allowed to warm to room temperature naturally. The reaction is confirmed to be complete by TLC, and extracted with ethyl acetate and water. The organic phase is dried, filtered, and then subjected to column chromatography to obtain 50mg of compound T-184. LC-MS [M+1]: 796. 1H NMR(400MHz,DMSO-d6)δ 11.61(s,1H),10.79(s,1H),8.73(d,J=4.9Hz,1H),8.60(s,1H),8.19(s,1H),8.11(s,1H),7.69(d,J=7.9Hz,1H),7.44(d,J=8.5 Hz,1H),7.32(s,1H),7.02(t,J=7.6Hz,1H),6.95(d,J=8.1Hz,2H),6.71(d,J=2.4Hz,1H),6.62-6.50(m,4H),5.67(d,J=7.5Hz,1 H),4.26(dq,J=12.1,5.9,5.3Hz,1H),3.78(s,4H),3.63(s,2H),3.22(s,3H),3.12(s,2H),2.94(s,3H),2.79(d,J=4.4Hz,3H),2 .75-2.66(m,2H),2.58(d,J=4.4Hz,1H),2.33(s,2H),2.13-2.05(m,3H),1.84(dd,J=12.1,4.4Hz,2H),1.70(s,3H),1.60(s,3H).

[0176] Following the method of Example 8, the following compounds are synthesized: [ka]

[0177] Example 9 Compounds synthesized according to the present invention: [ka]

[0178] The synthetic route is as follows: [ka]

[0179] 1. Synthesis of SM2: In a 50 ml single-neck bottle, 1.36 g of 2,4-dichloropyrimidine, 691 mg of AlCl3, and 10 ml of DCE were added, the mixture was purged with nitrogen gas, heated to 80 °C, and maintained for 30 minutes. 400 mg of N-methylindole was added, and the mixture was allowed to react overnight. The reaction was monitored for completion by TLC, followed by the addition of water, extraction with DCM, and drying with anhydrous sodium sulfate. The sample was stirred and subjected to column chromatography to obtain 700 mg of SM2. LC-MS [M+1]: 244.

[0180] 2. Synthesis of SM3: In a 10 ml microwave tube, 400 mg of SM2, 306.2 mg of 4-fluoro-2-methoxy-5-nitroaniline, and 376.2 mg of p-toluenesulfonic acid monohydrate were dissolved in 4 ml of n-butanol, heated in a microwave at 120 °C for 20 minutes, monitored for reaction completion by TLC, adjusted to basic by adding saturated sodium bicarbonate, dichloromethane, filtered, and dried the filter cake to give 439 mg of intermediate SM3. LC-MS [M+1]: 394.

[0181] 3. Synthesis of SM4: In a 50 ml single-neck bottle, 339 mg of SM3 and 195 mg of methyl(2-(methylamino)ethyl)amino group were dissolved in 5 ml of DMAC, 332 mg of DIEA was added, the mixture was purged with nitrogen gas, heated to 120 °C, and reacted overnight. The reaction was monitored for completion by TLC, water was added, extracted with EA, dried over anhydrous sodium sulfate, and the sample was stirred and subjected to column chromatography to obtain 417 mg of SM4. LC-MS [M+1]: 562.

[0182] 4. Synthesis of SM5: In a 50 ml single-neck bottle, 417 mg of SM4 was dissolved in 5 ml of methanol and 2 ml of THF, 41.7 mg of Pd / C was added, the atmosphere was purged with hydrogen gas, and the reaction was carried out at room temperature for 4 hours. The reaction was monitored for completion by TLC, filtered, and the sample was stirred and subjected to column chromatography to obtain 360 mg of SM5. LC-MS [M+1]: 532.

[0183] 5. Synthesis of SM6: In a 50 ml single-neck bottle, 360 mg of SM5 was dissolved in 5 ml of dichloromethane, purged with nitrogen gas, cooled to 0°C, 102.7 mg of triethylamine and 67.5 mg of acryloyl chloride were added, and the mixture was allowed to warm to room temperature overnight. TLC was used to monitor the reaction of most of the raw materials. Water was added, extracted with DCM, dried over anhydrous sodium sulfate, and the sample was stirred and subjected to column chromatography to obtain 263 mg of SM6. LC-MS [M+1]: 586.

[0184] 6. Synthesis of SM7: In a 50 ml single-neck bottle, 263 mg of SM6 was dissolved in 3 ml of dichloromethane, purged with nitrogen, cooled to 0°C, 3 ml of trifluoroacetic acid was added, and the mixture was allowed to warm to room temperature and react for 30 minutes. The reaction was monitored for completion by LC-MS, and the mixture was directly spun dry. The theoretical yield was 218 mg of SM7. LC-MS [M+1]: 486.

[0185] 7. Synthesis of SM8: In a 50 ml single-neck bottle, 150 mg of SM7 was dissolved in 2 ml of DMF, purged with nitrogen gas, cooled to 0°C, 200 mg of DIEA and 66.3 mg of t-butyl bromoacetate were added, and the mixture was allowed to warm to room temperature and react overnight. The reaction was monitored for completion by TLC, water was added, extracted with EA, dried over anhydrous sodium sulfate, and the sample was stirred and subjected to column chromatography to obtain 151 mg of SM8. LC-MS [M+1]: 600.

[0186] 8. Synthesis of SM9: In a 50 ml single-neck bottle, 150 mg of SM8 was dissolved in 2 ml of dichloromethane, purged with nitrogen, cooled to 0° C., added with 2 ml of trifluoroacetic acid, returned to room temperature, and reacted for 4 hours. The reaction completion was monitored by LC-MS, and the mixture was directly spun dry. The theoretical yield was 136 mg of SM9. LC-MS [M+1]: 544.

[0187] 9. Synthesis of TM: In a 50 ml single-neck bottle, 60 mg of SM9, 36 mg of 2,6-piperidinedione, 3-[[4-(4-piperidine)phenyl]amino] were dissolved in 3 ml of DMF and 99.8 mg of DIEA, purged with nitrogen gas, cooled to 0 °C, 54.6 mg of HAtu was added, and the mixture was allowed to warm to room temperature and react for 3 hours. The reaction was monitored for completion by TLC, water was added, extracted with EA, dried over anhydrous sodium sulfate, and the sample was stirred and subjected to column chromatography on a large plate to obtain 63 mg of TM (i.e., T-237). LC-MS [M+1]: 813.

[0188] 1 H NMR(400MHz,Chloroformed)δ 9.78(s,1H),9.37(s,1H),8.97(s,1H),8.31(d,J=5.3Hz,1H),8.00(d,J=7.6Hz,1H),7.84(d,J=19.1Hz,1H) ,7.66(s,1H),7.36-7.28(m,1H),7.22(s,1H),7.14(d,J=5.3Hz,2H),6.87(d,J=7.8Hz,2H),6.71(s,1H),6. 44(dd,J=33.4,11.0Hz,4H),5.73-5.61(m,1H),4.62(d,J=13.1Hz,1H),4.52(s,1H),3.89(s,5H),3.82(s,3 H),2.98(d,J=15.8Hz,4H),2.75(d,J=18.4Hz,2H),2.62(s,5H),2.60-2.09(m,8H),1.78(d,J=28.7Hz,4H).

[0189] The following compounds are synthesized according to the method of Example 9: [ka]

[0190] Example 10 Compounds synthesized according to the present invention: [ka]

[0191] The synthetic route is as follows: Synthesis of intermediate SM1: [ka]

[0192] 1. Synthesis of Compound 2 Add 120 mg of compound 1 to a 100 ml single-neck flask, add 30 ml of methanol to dissolve, cool, add 4 M hydrochloric acid in dioxane dropwise in a cold water bath, and react at 40 °C for 2 hours after the addition is complete. Remove the solvent using a rotary evaporator to obtain 140 mg of compound 2. LC-MS [M+1]: 329.

[0193] 2. Synthesis of Compound 3 In a 100ml single-neck bottle, add 80mg of compound 2, 8ml of N,N-dimethylformamide, N,N-diisopropylethylamine, and t-butyl bromoacetate, and stir overnight at room temperature. The reaction was confirmed to be complete by TLC, and the mixture was extracted with ethyl acetate and water. The organic phase was dried, filtered, and then subjected to column chromatography to obtain 30mg of compound 3, with LC-MS [M+1]: 443.

[0194] 3. Synthesis of Compound SM1 In a 100 ml single-neck bottle, 100 mg of compound 6 and 1 ml of dichloromethane were added, and 1.6 ml of trifluoroacetic acid was added dropwise. The mixture was stirred at room temperature overnight, and the reaction was confirmed to be complete by TLC. The solvent was removed by rotary evaporation to obtain 150 mg of compound 4 (i.e., SM1). LC-MS [M-1]: 385.

[0195] 4. Synthesis of Compound T-15 The synthetic route is as follows: [ka] In a 50mL round-bottom flask, compound M2 and SM1 are dissolved in 2mL of N,N-dimethylformamide, cooled to 0°C in an ice-water bath, and N,N-diisopropylethylamine and HATU are added under stirring. Under nitrogen gas protection, the reaction is carried out in an ice-water bath for 1 hour, and the temperature is allowed to rise to room temperature. The completion of the reaction is detected by TLC, and the reaction is extracted with ethyl acetate and water. The organic phase is dried, filtered, and then subjected to column chromatography to obtain 100mg of compound T-15. LC-MS [M+1]: 780.

[0196] Following the method of Example 10, the following compounds are synthesized: [ka] [ka] [ka] [ka]

[0197] Example 11 Compounds synthesized according to the present invention: [ka]

[0198] The synthetic route is as follows: Synthesis of intermediate SM1: [ka] The synthetic route is as follows: [ka]

[0199] 1. Synthesis of Compound 2 Add 200 mg of compound 1 to a 50 ml three-neck bottle, add 4 ml of DMF, stir to dissolve, cool to 0-5°C, slowly add 30 mg of sodium hydride, and stir for 30 minutes while maintaining the temperature at 0°C. Add 0.034 ml of iodomethane, keep warm, and stir for 30 minutes. TLC shows the disappearance of the starting material and the formation of a new spot. Purify and separate the compound using a column to obtain 30 mg of compound 2. LC-MS: [M+H]: 416.

[0200] 2. Synthesis of Compound 3 In a 50 ml single-neck bottle, 30 mg of compound 2 and 1 ml of dichloromethane were added, and 0.5 ml of trifluoroacetic acid was added dropwise. The mixture was stirred at room temperature overnight, and the reaction was confirmed to be complete by TLC. The solvent was removed by rotary evaporation to obtain 20 mg of compound 3 (i.e., SM1). LC-MS [M-1]: 360.

[0201] Synthesis of Compound T-352 [ka] In a 50ml round-bottom flask, compound M2 and SM1 are dissolved in 2ml of N,N-dimethylformamide, cooled to 0°C in an ice-water bath, and N,N-diisopropylethylamine and HATU are added under stirring, and reacted in an ice-water bath under nitrogen gas protection for 1 hour, and then allowed to warm to room temperature naturally. The reaction is confirmed to be complete by TLC, and extracted with ethyl acetate and water. The organic phase is dried, filtered, and then subjected to column chromatography to obtain 16mg of compound T-352, LC-MS [M+1]: 828. HNMR: 1H NMR(400MHz,DMSO-d6)δ 8.44(s,1H),8.33(s,1H),8.28(s,1H),7.50(s,2H),7.38(d,J=8.5Hz,1H),7.26(d,J=7.9Hz,2H),7.09( t,J=7.5Hz,1H),6.98(d,J=8.0Hz,2H),6.72-6.58(m,3H),6.38(s,1H),5.80(d,J=7.7Hz,1H),4.35(ddd ,J=11.9,7.7,4.9Hz,1H),3.77(s,3H),3.66(s,4H),3.16(d,J=30.3Hz,5H),2.99(s,3H),2.91-2.65(m, 3H), 2.09(dt,J=12.9,4.6Hz,1H),1.99(s,1H),1.89(ddt,J=24.1,12.2,6.5Hz,5H),1.32-1.20(m,3H).

[0202] Example 12 Compounds synthesized according to the present invention: [ka]

[0203] The synthetic route is as follows: [ka]

[0204] Synthesis of compound 2 Add 230 mg of compound 1 to a 50 ml single-mouth bottle, add 3 ml of 1,2-dichloroethane to dissolve, add 0.3 ml of triethylamine, and add 150 mg of p-nitrophenyl chloroformate. Allow to react at room temperature for 3 hours, detect the completion of the reaction by TLC, and directly purify by column to obtain 250 mg of compound 2.

[0205] Synthesis of Compound T-344 Add 110 mg of compound 2 to a 10 ml reaction tube, add 0.2 ml of DMF to dissolve, add 0.1 ml of triethylamine, and add 100 mg of intermediate M2. Heat to 80 °C and react overnight. After separation and purification, 10 mg of compound T-344 was obtained. LC-MS [M+1]: 766. 1 H NMR(400MHz,DMSO-d6)δ 8.76(s,0H),8.12(d,J=15.5Hz,1H),7.92(s,1H),7.73-7.54(m,1H),7.32(dd,J=8.5,7.3Hz,1H),7.18-7.08(m,1H),6.72(d,J=2.6H z,1H),6.47(dd,J=8.8,2.6Hz,1H),3.83(s,2H),3.69-3.54(m,2H),3.25-3.09(m,2H),2.56(p,J=1.8Hz,2H),1.29(d,J=5.7Hz,1H).

[0206] Following the method of Example 12, the following compounds are synthesized: [ka]

[0207] Example 13 Compounds synthesized according to the present invention: [ka]

[0208] The synthetic route is as follows: [ka] Synthesis of intermediate SM1

[0209] Synthesis of compound 2 Add 1.0g of compound 1 to a 50ml single-mouth bottle, add 10ml of DMF to dissolve, add 1.13g of N-Boc piperazine and 3.28g of DIEA, cool to 0°C, add 2.31g of HATU, allow to warm to room temperature, stir for 2 hours, check the reaction completion by TLC, add water to quench the reaction, extract with ethyl acetate, combine the organic phases and pass through a column to obtain 2.63g of compound 2.

[0210] Synthesis of compound 3 Add 2.63 g of compound 2, 5 ml of methanol, and 5 ml of tetrahydrofuran to a 50 ml single-neck bottle, add 263 mg of palladium-carbon catalyst, and flush with a hydrogen balloon three times before sealing and reacting overnight. The completion of the reaction was detected by TLC, and the palladium-carbon was removed by suction filtration. The reaction solution was spin-dried to obtain 2.56 g of compound 3.

[0211] Synthesis of intermediate SM1 In a 10 ml microwave tube, 500 mg of compound 3, 471.6 mg of intermediate M1, and 284 mg of p-toluenesulfonic acid monohydrate are dissolved in 5 ml of n-butanol, heated in a microwave at 120 °C for 20 minutes, monitored for reaction completion by TLC, adjusted to basic by adding saturated sodium bicarbonate, dichloromethane, filtered, and the filter cake is dried to give 150 mg of intermediate SM1. LC-MS [M+1]: 516.

[0212] Synthesis of Compound T-329 [ka] In a 50ml round-bottom flask, 150mg of compound SM1 and 378mg of M2 are dissolved in 3ml of N,N-dimethylformamide, cooled to 0°C in an ice-water bath, N,N-diisopropylethylamine and HATU are added under stirring, reacted in an ice-water bath under nitrogen gas protection for 1 hour, allowed to warm to room temperature, and the reaction is confirmed to be complete by TLC. Extracted with ethyl acetate and water, the organic phase is dried, filtered, and then subjected to column chromatography to obtain 24mg of compound T-329, LC-MS [M+1]: 843.

[0213] Following the method of Example 13, the following compounds are synthesized: [ka]

[0214] Example 14 Compounds synthesized according to the present invention: [ka]

[0215] The synthetic route is as follows: [ka]

[0216] Synthesis of compound 2: 200 mg of compound 1 was weighed into a reaction bottle, and 70 mg of 2-bromoethanol, 0.6 ml of DIEA, and 10 ml of acetonitrile were added to dissolve the compound. The mixture was heated to 70 °C under nitrogen gas protection and reacted for 3 hours. LC-MS showed the disappearance of the raw material, and the mixture was purified by column chromatography to obtain 300 mg of compound 2. M+H: 498.

[0217] Synthesis of compound 3 In an ice-water bath, 0.15 ml of triethylamine is added to a 5 ml DMF solution of 300 mg of compound 2, and 63 mg of methylsulfonyl chloride is slowly added dropwise. After the addition is complete, the mixture is stirred at room temperature for 4 hours, and the raw material is detected to have almost disappeared by TLC. After separation by column, 150 mg of compound 3 is obtained.

[0218] Synthesis of Compound T-182 To a solution of 130 mg of compound 3 in 5 ml of acetonitrile, add 0.5 ml of DIEA, add 80 mg of M2, and then heat to 70 ° C under nitrogen gas protection and react overnight. After separation and purification, 15 mg of compound T-182 is obtained. LC-MS: [M + H]: 766. HNMR: 1H NMR(400MHz,DMSO-d6)δ11.87(s,1H),10.84(s,1H),8.82(s,1H),8.39(s,1H) ,8.27-7.87(m,2H),7.42(d,J=28.1Hz,2H),7.18(s,1H),7.00(s,2H),6.64(t, J=29.8Hz,4H),5.75(s,1H),4.32(s,1H),3.79(s,3H),3.23(s,5H),2.93(s,2 H),2.74(q,J=24.7,23.0Hz,10H),2.14(s,2H),1.98-1.65(m,5H),1.27(s,3H)

[0219] Following the method of Example 14, the following compounds are synthesized: [ka]

[0220] Example 15 Compounds synthesized according to the present invention: [ka]

[0221] The experimental process is as follows. 1. Synthesis of intermediate M1 The synthetic route is as follows: [ka]

[0222] 1. Synthesis of Compound 2 In a 100 mL single-neck flask, 2 g of 5-chloro-2-nitrobenzoic acid methyl ester, 3.62 g of Zn powder, and 5 g of NH4Cl were dissolved in 20 mL of EtOH and 4 mL of EtOH, and the mixture was heated to 90°C and reacted overnight. The reaction was monitored by TLC until completion, and the reaction solution was directly spun dry. The sample was stirred and subjected to column chromatography to obtain 445 mg of compound 2. LC-MS [M+1]: 186.

[0223] 2. Synthesis of Compound 3 In a 100 ml three-necked bottle, add 8 ml of MeMgCl, cool to -40 °C, add 445 mg of compound 2 dissolved in 15 mL of Et O dropwise, return to room temperature and react for 1 hour, TLC shows the disappearance of the raw material, quench with a small amount of saturated aqueous sodium bicarbonate solution, extract with ethyl acetate, dry with anhydrous sodium sulfate, spin-dry, and apply to column chromatography to obtain 378 mg of compound 3. LC-MS [M+1]: 186.

[0224] 3. Synthesis of intermediate M1 In a 100ml single-neck bottle, 278mg of compound 3, 276mg of SM2, and 290mg of DIPEA were dissolved in 4mL of isopropanol, and the mixture was reacted overnight at 40°C. The reaction was monitored by TLC until completion, and the mixture was quenched with a small amount of saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, spin-dried, and subjected to column chromatography to obtain 437mg of intermediate M1. LC-MS [M+1]: 332.

[0225] 2. Synthesis of intermediate M2 The synthetic route is as follows: [ka] In a 10 ml microwave tube, 144 mg of M1, 147 mg of 4-(N-Boc-piperazin-1-yl)-2-methoxyaniline, and 99 mg of p-toluenesulfonic acid monohydrate were dissolved in 2 ml of n-butanol and heated in a microwave at 120° C. for 20 minutes. The reaction was monitored by TLC until completion, quenched with a small amount of saturated aqueous sodium bicarbonate solution, added with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, spin-dried, and subjected to column chromatography to give 150 mg of intermediate M2. LC-MS [M+1]: 503.

[0226] 3. Synthesis of Compound T-243 The synthetic route is as follows: [ka]

[0227] In a 50 mL round-bottom flask, 150 mg of compound M2 and 114 mg of SM4 are dissolved in 3 mL of N,N-dimethylformamide, cooled to 0°C in an ice-water bath, and N,N-diisopropylethylamine and HATU are added under stirring. Under nitrogen gas protection, the reaction is carried out in an ice-water bath for 1 hour, and the temperature is allowed to rise to room temperature, and the reaction is carried out for 4 hours. The completion of the reaction is detected by TLC, and the reaction is carried out by extracting with dichloromethane and water, and the organic phase is dried and subjected to column chromatography to obtain 33 mg of compound T-243, LC-MS [M+1]: 831. 1 H NMR(400MHz,DMSO-d6)δ 10.77(s,1H),10.45(d,J=6.3Hz,1H),8.23(d,J=8.7Hz,1H),8.16-7.98(m,2H),7.43(d,J=8.6Hz,1H),7.24(d,J=2.4Hz,1H),7.14(d ,J=8.8Hz,1H),6.94(d,J=8.3Hz,2H),6.69(d,J=2.5Hz,1H),6.59(d,J=8.2Hz,2H),6.52(dd,J=8.7,2.5Hz,1H),6.31(d,J=8.1Hz,1H) ,5.65(d,J=7.5Hz,1H),4.25(dt,J=11.4,5.8Hz,1H),3.79-3.76(m,3H),3.63(s,1H),3.51(d,J=0.9Hz,2H),3.32(s,6H),3.21(s,4H) ,3.12(s,2H),2.93(d,J=10.8Hz,2H),2.08(d,J=12.2Hz,2H),1.85(dq,J=19.5,7.4,6.2Hz,1H),1.70(d,J=12.0Hz,2H),1.51(s,7H).

[0228] Following the method of Example 15, the following compounds are synthesized: [ka]

[0229] Example 16 Compounds synthesized according to the present invention: [ka]

[0230] The experimental process is as follows. 1. Synthesis of intermediate M1 The synthetic route is as follows: [ka]

[0231] 1. Synthesis of Compound SM2 In a 100 mL three-neck flask, 1 g of o-nitrophenol and 7 g of cesium carbonate were dissolved in 10 mL of acetone, and the mixture was purged with N2 three times. The ice bath was set to 0°C, and 928 mg of dimethylcarbamoyl chloride was added dropwise. The mixture was allowed to warm naturally and reacted for 48 hours. The reaction was monitored by TLC until completion. Water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated NaCl solution, dried with anhydrous sodium sulfate, spin-dried, and subjected to column chromatography to obtain 6 g of crude compound SM2. LC-MS [M+1]: 211.

[0232] 2. Synthesis of Compound SM3 In a 100ml three-neck bottle, 900mg of compound SM2, 2.2g of ammonium chloride, and 1.7g of zinc powder were dispersed in 12ml of a 5:1 mixture of ethanol and water, heated to reflux, and reacted for 18 hours. TLC showed the disappearance of the starting material, and the solvent was removed using a rotary evaporator. Water was added to the residue, and the pH was adjusted to 7-8 with a small amount of saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, spin-dried, and subjected to column chromatography to obtain 500mg of wine-red oily compound SM3. LC-MS [M+1]: 181.

[0233] 3. Synthesis of intermediate M1 In a 100ml three-necked bottle, 500mg of SM3, 286mg of 2,4,5-trichloropyrimidine, and 403.2mg of DIPEA were dissolved in 5ml of n-butanol, and the mixture was allowed to react overnight at room temperature. The reaction was monitored by TLC until completion, and the solvent and water were evaporated on a rotary evaporator. The mixture was extracted with ethyl acetate, and the organic phase was washed with saturated NaCl solution, dried over anhydrous sodium sulfate, spin-dried, and subjected to column chromatography to obtain 260mg of intermediate M1. LC-MS [M+1]: 327.

[0234] 2. Synthesis of Compound T-370 The synthetic route is as follows: [ka]

[0235] 1. Synthesis of Compound M2 In a 10 ml microwave tube, 150 mg of M1, 125 mg of 4-(4-amino-3-methoxyphenyl)piperazine-1-carboxylic acid tert-butyl ester, and 105 mg of p-toluenesulfonic acid monohydrate were dissolved in 2 ml of n-butanol and heated in a microwave at 120° C. for 20 minutes. The reaction was monitored by TLC until completion. The reaction solution was transferred to a 125 ml separatory funnel, water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated NaCl solution, dried over anhydrous sodium sulfate, spin-dried, and subjected to column chromatography to obtain 130 mg of intermediate M2. LC-MS [M+1]: 498.

[0236] 2. Synthesis of Compound T-152 In a 50ml round-bottom flask, 130mg of compound M2 and 225mg of 40% SM3 were dissolved in 3ml of N,N-dimethylformamide, cooled to 0°C in an ice-water bath, and 168mg of N,N-diisopropylethylamine and 119mg of HATU were added under stirring, and the mixture was reacted in an ice-water bath under nitrogen gas protection for 1 hour, and then allowed to warm to room temperature. The reaction was confirmed to be complete by TLC, and the mixture was extracted with ethyl acetate and water. The organic phase was dried, filtered, and then subjected to column chromatography to obtain 100mg of final compound T-152. LC-MS [M+1]: 825. 1 H NMR(400MHz,DMSO-d6)δ 10.79(s,1H),8.41(s,1H),8.08(s,1H),7.65(dt,J=10.4,3.4Hz,3H),7.28-7.15(m,3H),6.95(d,J=8.1Hz,2 H),6.69-6.55(m,3H),6.37(d,J=8.8Hz,1H),5.68(d,J=7.4Hz,1H),4.26(dt,J=12.1,6.6Hz,1H),3.79(s,3H) ),3.72(s,2H),3.62(s,2H),3.33(s,2H),3.15(d,J=6.0Hz,2H),3.06(s,2H),2.81(d,J=3.1Hz,6H),2.65-2. 52(m,4H),2.33(q,J=1.9Hz,1H),2.16-2.03(m,2H),1.85(qd,J=12.2,4.6Hz,2H),1.72(s,2H),1.61(s,2H).

[0237] Example 17 Compounds synthesized according to the present invention: [ka]

[0238] The experimental process is as follows. Synthesis of intermediate SM5 [ka]

[0239] 1. Synthesis of SM2: In a 50 ml single-neck bottle, 500 mg of N-methyl-2-nitroaniline and 1 g of TEA were dissolved in 5 ml of dichloromethane, purged with nitrogen gas, cooled to 0 °C, 5.2 g of acetyl chloride was added, and the mixture was allowed to warm to room temperature and react for 2 hours. Completion of the reaction was monitored by TLC. Water was added, and the mixture was extracted with EA, dried over anhydrous sodium sulfate, and the sample was stirred and subjected to column chromatography to obtain 613 mg of SM2. LC-MS [M+1]: 195.

[0240] 2. Synthesis of SM3: In a 50 ml single-neck bottle, 790 mg of SM2, 2.16 g of ammonium chloride, and 1.59 g of zinc powder were dispersed in 6 ml of a 5:1 mixture of ethanol and water, heated to reflux, and reacted for 18 hours. TLC showed the disappearance of the starting material, and the solvent was removed using a rotary evaporator. Water was added to the residue, and the pH was adjusted to 7-8 with a small amount of saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, spin-dried, and subjected to column chromatography to obtain 412 mg of SM3. LC-MS [M+1]: 165.

[0241] 3. Synthesis of SM4: In a 50 ml single-neck bottle, 150 mg of SM3, 168 mg of 2,4,5-trichloropyrimidine, 177 mg of DIEA, and 3 ml of isopropanol were added, purged with nitrogen gas, heated to 100 °C, and reacted overnight. The reaction was monitored for completion by TLC, water was added, extracted with EA, dried over anhydrous sodium sulfate, and the sample was stirred and subjected to column chromatography to obtain 98 mg of SM4. LC-MS [M+1]: 311.

[0242] 4. Synthesis of SM5: In a 10 ml microwave tube, 98 mg of SM4, 97 mg of the intermediate, and 72 mg of p-toluenesulfonic acid monohydrate are dissolved in 2 ml of n-butanol, heated in a microwave at 120° C. for 20 minutes, monitored for reaction completion by TLC, adjusted to basic by adding saturated sodium bicarbonate, extracted with dichloromethane, dried over anhydrous sodium sulfate, and the sample is stirred and subjected to column chromatography to give 94 mg of SM5. LC-MS [M+1]: 482.

[0243] 5. Synthesis of TM: [ka] In a 50 ml single-neck bottle, 94 mg of SM5, 135 mg of intermediate 2 were dissolved in 2 ml of DMF and 126 mg of DIEA, purged with nitrogen gas, cooled to 0 ° C, 97 mg of HAtu was added, and the mixture was allowed to warm to room temperature and react for 3 hours. The reaction was monitored for completion by TLC, water was added, extracted with EA, dried over anhydrous sodium sulfate, the sample was stirred, and subjected to column chromatography on a large plate to obtain 82 mg of TM (i.e., T-206). LC-MS [M+1]: 809.

[0244] 1H NMR(400MHz,DMSO-d6)δ 10.78(s,1H),8.36(s,1H),8.06(d,J=4.5Hz,1H),7.81-7.66(m,2H),7.43(d,J=8.6Hz,1H),7.37(d,J=7.7Hz,2H),7. 28(t,J=7.4Hz,1H),6.95(d,J=8.1Hz,2H),6.68-6.55(m,3H),6.32(d,J=8.9Hz,1H),5.66(d,J=7.5Hz,1H),4.25(ddd, J=11.7,7.5,4.8Hz,1H),3.75(d,J=10.6Hz,5H),3.61(s,2H),3.22(s,2H),3.14(s,2H),3.05(s,2H),2.99(s,3H),2. 94(s,2H),2.80-2.68(m,2H),2.33(s,1H),2.25-2.03(m,4H),1.92-1.79(m,2H),1.71(s,5H),1.58(d,J=12.7Hz,2H).

[0245] Following the method of Example 17, the following compounds are synthesized: [Table 1]

[0246] Example 18 Compounds synthesized according to the present invention: [ka]

[0247] The experimental process is as follows. 1. Synthesis of intermediate M1 The synthetic route is as follows: [ka]

[0248] 1. Synthesis of Compound 2 A 100 mL three-neck flask was charged with 4 mL of ultra-dry THF, and the mixture was purged with N2 three times. 2.25 mL of MeMgCl was then added. The ice bath was then cooled to 0 °C, and 200 mg of 2-amino-5-methoxybenzonitrile was dissolved in 2 mL of ultra-dry THF and slowly poured into the flask. The mixture was allowed to warm to room temperature and react overnight. The ice bath was then cooled to 0 °C again, and 20 mL of saturated aqueous NH4Cl was added dropwise. After the addition was complete, the mixture was allowed to cool to room temperature and stirred rapidly for 30 minutes. TLC was used to monitor the formation of a new spot in the reaction. The reaction mixture was then added with water, extracted with dichloromethane, dried over anhydrous sodium sulfate, and subjected to column chromatography to give 26 mg of compound 2. LC-MS [M+1]: 166.

[0249] 2. Synthesis of intermediate M1 In a 50 ml single-neck bottle, 26 mg of compound 2, 32 mg of SM2, and 31 mg of DIPEA were dissolved in 2 ml of isopropanol and reacted at 80 ° C overnight. The reaction was monitored by TLC until completion, quenched with a small amount of saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, spin-dried, and subjected to column chromatography to obtain 25 mg of intermediate M1. LC-MS [M+1]: 312.

[0250] 2. Synthesis of intermediate M2 The synthetic route is as follows: [ka] In a 10 ml microwave tube, 25 mg of M1, 28 mg of 4-(N-Boc-piperazin-1-yl)-2-methoxyaniline, and 19 mg of p-toluenesulfonic acid monohydrate were dissolved in 2 ml of n-butanol and heated in a microwave at 120° C. for 20 minutes. The reaction was monitored by TLC until completion, quenched with a small amount of saturated aqueous sodium bicarbonate solution, added with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, spin-dried, and subjected to column chromatography to give 27 mg of intermediate M2. LC-MS [M+1]: 483.

[0251] 3. Synthesis of Compound T-249 The synthetic route is as follows: [ka] In a 50 mL round-bottom flask, 27 mg of compound M2 and 32 mg of SM4 are dissolved in 2 mL of N,N-dimethylformamide, cooled to 0°C in an ice-water bath, and N,N-diisopropylethylamine and HATU are added under stirring. Under nitrogen gas protection, the reaction is carried out in an ice-water bath for 1 hour, and the temperature is naturally raised to room temperature, and the reaction is carried out for 4 hours. The completion of the reaction is detected by TLC, and the reaction is carried out by extracting with dichloromethane and water, and the organic phase is dried and subjected to column chromatography to obtain 13 mg of compound T-249. LC-MS [M+1]: 810. 1 H NMR(400MHz,DMSO-d6)δ 11.42(s,1H),10.84(s,1H),8.68(s,1H),8.28(s,1H),8.18(s,1H),7.58(d,J=3.0Hz,1H),7.46(d,J=8.6Hz,1H),7.09(d,J=9.3Hz, 1H),7.01(d,J=8.1Hz,2H),6.78(d,J=2.5Hz,1H),6.70-6.57(m,3H),5.73(d,J=7.6Hz,1H),4.32(dt,J=12.1,6.4Hz,1H),3.87(s,3 H),3.83(s,3H),3.70(s,2H),3.57(s,1H),3.30(s,2H),3.21(s,2H),3.04(s,2H),2.74(s,3H),2.65(d,J=4.4Hz,1H),2.16(dt,J=1 3.0,4.5Hz,2H),1.92(tt,J=12.0,5.9Hz,2H),1.79(s,2H),1.68(s,2H),1.54(s,1H),1.40(d,J=4.2Hz,1H),1.24(t,J=7.2Hz,1H).

[0252] Example 19 Compounds synthesized by reference: 1. See WO2021 / 127561A1(R1) of C4 Company. [ka] Control Compound 1 (R1, Example 5)

[0253] 2. See BeiGeneWO2022 / 012622A1(R2). [ka] Control Compound 2 (R2, Example 113) [ka] Control Compound 3 (R2, Example 128)

[0254] Compounds tested for cell growth inhibitory activity: Test Example 1: Cell proliferation inhibition experiment 2.1. Experimental Phase: Experimental materials and equipment: H1975 has an EGFR:L858R / T790M double mutation, PC-9 has an EGFR exon 19 deletion, and HCC827 has an exon 19 deletion mutation. Cell Counting-Lite 2.0, trypsin-EDTA, 37°C, CO2 incubator, cell counter, EnVision serial number 1050454.

[0255] 2. Experimental preparation: 1. Plating in 96-well plates A) Log-phase cells are digested with trypsin-EDTA, culture medium is added to stop the reaction, and the mixture is mixed evenly with a pipette to prepare a cell suspension. B) Measure the cell concentration using VI-cell and prepare a cell suspension of 15,000 to 25,000 cells per mL according to the experimental purpose and cell characteristics. C) After preparing the cell suspension, mix gently and evenly, and add 100 μL per well so that the test cell density is 1500-2500 cells per well.

[0256] 2. Compound Treatment Compound dilution A) Weigh out approximately 2 mg of compound and calculate the volume of DMSO required according to the formula: mass of compound (mg) x purity of compound (%) / molecular weight of compound x 1000. B) The inoculated cell culture plate is placed in an incubator and cultured for approximately 24 hours, after which a concentration gradient compound is added. C) 10 mM compound stock solution was diluted to 50 mM with medium and the 50 mM compound solution was added sequentially to column 2 of a deep well plate, followed by 375 μl of 0.5% DMSO-containing medium in columns 3 through 11. D) Gradient dilution: Take 125 μL of solution from column 2 and add it to column 3, mix evenly, then take 125 μL of solution from column 3 and add it to column 4, and repeat this process up to column 10. E) Using a multichannel pipette, 25 µL of compound was taken from the deep-well plate and added to a 96-well culture plate. Each compound was replicated three times on the 96-well plate. Finally, a 1:4 concentration gradient was formed on the 96-well plate, with the highest concentration being 10,000 Nm.

[0257] 3. Add CTG and read A) The 96-well plate was cultured in an incubator for 72 hours, and the effects of the compounds were observed using an inverted microscope. 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.

[0258] 4. Data Analysis Calculate the cell viability (%Cell Viability) using the following formula: %Cell VIabIlIty=100%×(Lum_Sample-Lum_LC ) / (Lum_HC-Lum_LC ) Lum_HC: Readings from 0.1% DMSO control cells Lum_Sample: Readings from cells spiked with compound Lum_LC: Blank medium reading IC50 values ​​are obtained by curve fitting using GraphPad Prism8 software.

[0259] As shown in Table 2, where AA≦10 nM, 10 nM <A≦100nM、100nM<B<1000nM、C≧1000nM。 [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4]

[0260] As can be seen from Table 2, the compounds of the present invention have very excellent inhibitory effects against H1975 (human lung adenocarcinoma cells), PC-9 (human lung cancer cells), and HCC827 (human non-small cell lung cancer cells).

[0261] [Table 3]

[0262] As can be seen from Table 3, the inhibitory effects on H1975 (human lung adenocarcinoma cells), PC-9 (human lung cancer cells), and HCC827 (human non-small cell lung cancer cells) are better than those of the compounds from C4 and BeiGene.

[0263] At the same time, we tested the biological activity of our compounds against EGFR non-classical mutation cell lines, and found that the compounds of the present invention have excellent inhibitory effects against mutations such as exon 20 insertion mutations, L861Q, DEL19-G724S, and L858R-L792H.

[0264] Test Example 2: EGFR PROTAC in a Cell Western Experiment 1. Experimental Materials HCC827 cell culture medium is purchased from Corning. The cell line HCC827 is purchased from BNCC and contains EGF R e Ceptor(D38B1)XP R a bbit mAb antibody and β-Actin (8H10D10) Mouse mAb antibody are purchased from CST, IRDye 800CW, IRDye 680RD, and Intercept blocking solution (PBS) are purchased from Licor, Triton-100 is purchased from Sigma, and 96-well black cell culture imaging microwell plates are purchased from Agilent.

[0265] 2. Experimental Method 1) Count the HCC827 cells and inoculate them into a 96-well black cell culture imaging microwell plate at a cell density of 40,000 cells per well, at 100 μl per well. Incubate in a carbon dioxide incubator overnight. 2) Day 1: Add gradient dilutions of the test compound (starting concentration 3 μM, nine concentrations, 1:3 dilutions, 2 duplicate wells) to the culture plate cells. The final concentration of DMSO is 0.5%. A blank control is DMSO without compound. Place the culture plate in a cell incubator and incubate for 16 hours.

[0266] 3) Remove the culture medium from the 96-well plates using a pipette, add 200 μl of PBS to each well, and shake for 5 minutes to remove any residual medium. After removing the PBS, quickly add 150 μl of fresh fixation buffer (3.7% paraformaldehyde) to fix the cells and incubate at room temperature for 20 minutes. 4) Remove the fixation buffer and wash with 200 μl of Triton elution buffer (0.3% Triton-100) four times for 5 minutes each on a shaker.

[0267] 5) Add 150 μl of LI-COR Odyssey Blocking Solution, shake gently on a shaker, and incubate at room temperature for 1.5 hours. 6) When blocking the samples, use the antibody dilution buffer to prepare the primary antibodies EGFR and Actin at a ratio of 1:300. Discard the blocking solution and add the diluted primary antibodies (total volume 50 μl / each well). Cover the cell plate and incubate overnight at 4°C. 7) Wash the cell plate 4 times with PBS + Triton X-100 for 5 minutes each time.

[0268] 8) Dilute the fluorescently labeled secondary antibodies IRDyeR680RD and IRDyeR800CW with the antibody dilution buffer (ratio 1:600, total volume 50 μl / each well), and then incubate for 1 hour at room temperature in the dark. 9) Wash the cells in the cell plate 4 times with PBS + Triton X-100 for 5 minutes each time.

[0269] 3. Calculation After completely absorbing the PBS, place it upside down on the Bio-rad imager. Select the multiple exposure program, select IRDye 680RD Blot for the first channel, and select IRDye 800CW Blot for the second channel. Open the image with the software Image StudIo Lite Ver5.2 and analyze the signal values of each well, and the signal values of EGFR and Actin will be shown. The blank group is the DMSO group. For EGFR / Actin, calculate the EGFR value of the corresponding sample well, and the degradation rate = 100 - 100 × EGFRsignal / DMSOsignal. Use Prism software and the three-parameter method to calculate the DC50 and Dmax of EGFR protein degradation.

[0270] As shown in Table 4, for DC50, AA ≤ 10 nM, 10 nM < A ≤ 100 nM, 100 nM < B < 1000 nM, C ≥ 1000 nM, and for Dmax, 70% ≤ A ≤ 100%, 50% ≤ B < 70%, C < 50%, and NA has not been tested.

Table 4-1

Table 4-2

[0271] [Table 5]

[0272] As can be seen from Table 5, the decomposition effect of the compounds of the present invention on HCC827 is superior to that of the control compound.

[0273] All documents mentioned in this application are incorporated by reference in this application as if each document were incorporated by reference individually. Furthermore, after reading the above teachings of the present invention, those skilled in the art will be able to make various changes or modifications to the present invention, and these equivalents will also fall within the scope defined by the appended claims of this application.

Claims

1. A compound comprising: The compound is a compound of Formula I, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, or isotopic compound thereof: 【Chemical 1】 where: L is, 【Chemistry 2】 and A is, 【Chemistry 3】 is selected from the group consisting of B is, 【Chemistry 4】 is selected from the group consisting of In each formula, Each X １ , X ２ are each independently selected from the group consisting of CR and N; Each X ３ are each independently NH; each Ar is independently a phenyl group or a substituted phenyl group, and 【Chemistry 5】 and X is selected from the group consisting of ４ is NR, and the substituted phenyl group is １－６ Alkyl group, C １－６ Halogenated alkyl groups, hydroxy-substituted C １－６ Alkyl group, C １－６ Alkylamino group, C １－６ Alkoxy group, C １－６ Halogenated alkoxy group, —NR ９ C(O)R １０ , —OC(O)NR ９ R １０ , -NR ９ C(O)OR １０ , —C(O)NR ９ R １０ , methanesulfonyl group, —NR ９ methanesulfonyl group, 【Chemistry 6】 -CO-C １－６ Alkyl group, —C(═O)O—C １－６ Alkyl groups, and —CO—C １－６ having 1, 2, 3 or 4 substituents selected from the group consisting of halogenated alkyl groups; Each R １ are independently hydrogen, halogen, and C １－６ selected from the group consisting of halogenated alkyl groups; Each R ２ , R ３ are each independently H, halogen, or C １－６ Alkyl group, C ３－６ Cycloalkyl group, C １－６ Alkylamino group, C １－６ Alkoxy group, C １－６ Halogenated alkoxy group, C １－６ Halogenated alkyl group, C ３－６ Halogenated cycloalkyl groups, -NR ９ C(O)R １０ , —C(O)NR ９ R １０ and unsubstituted or C １－６ alkyl-substituted 5-10 membered heteroaryl groups containing 1, 2, or 3 heteroatoms selected from N, O, or S; Each R ４ are independently １－６ Alkyl groups, and C １－６ selected from the group consisting of halogenated alkyl groups; Each R ５ does not exist, Each R6 is independently H, halogen, C １－６ Alkyl groups, and C １－６ selected from the group consisting of halogenated alkyl groups; Each R 7 is H Each R ９ are independently H, C １－６ Alkyl groups, and C １－６ selected from the group consisting of halogenated alkyl groups; Each R １０ are independently H, C １－６ Alkyl group, C ２－６ alkenyl groups, and C １－６ selected from the group consisting of halogenated alkyl groups; each m, n, and q is independently selected from the group consisting of 0, 1, 2, 3, 4, and 5; Each R １１ , R １２ are each independently H, C １－６ Alkyl groups, and C １－６ selected from the group consisting of halogenated alkyl groups; Each R １３ are independently H, halogen, C １－６ Alkyl groups, and C １－６ selected from the group consisting of halogenated alkyl groups, and Each R is independently H, and C １－６ The compound is characterized in that it is selected from the group consisting of alkyl groups.

2. Ar is 【Chemistry 7】 is selected from the group consisting of Here, X ４ is NR, Each R １１ are independently H, C １－６ Alkyl groups, and C １－６ selected from the group consisting of halogenated alkyl groups; Each R １２ are independently １－６ Alkyl groups, and C １－６ selected from the group consisting of halogenated alkyl groups; Each R １３ are independently halogen, and q is selected from the group consisting of 0, 1, 2, 3, 4, and 5; R is as defined in claim 1. The compound of claim 1.

3. A is, 【Chemistry 8】 is selected from the group consisting of Here, R １ is selected from the group consisting of chlorine, trifluoromethyl, and bromine; Ar is 【Chemistry 9】 is selected from the group consisting of Each R ３ are independently H, halogen, C １－６ Alkyl group, C １－６ Halogenated alkyl groups, and —NR ９ C(O)R １０ is selected from the group consisting of Each R １２ are independently １－６ Alkyl groups, and C １－６ selected from the group consisting of halogenated alkyl groups; Each R １３ are independently halogen; q is selected from the group consisting of 0, 1, 2, 3, 4, and 5; X ４ , R ２ , R ４ , R ７ , R ８ , R ９ , R １０ , R １１ , R ５ , X １ , X ２ , m are as defined in claim 1 The compound of claim 1.

4. B is, 【Chemistry 10】 wherein R ７ , R １１ , m are as defined in claim 1 The compound of claim 1.

5. below: 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 【Chemistry 18】 【Chemistry 19】 【Chemistry 20】 【Chemical 21】 【Chemical 22】 【Chemical 23】 【Chemistry 24】 【Chemistry 25】 【Chemical 26】 【Chemical 27】 【Chemical Formula 28】 【Chemical Formula 29】 【Chemistry 30】 【Chemical 31】 【Chemical 32】 【Chemical 33】 【Chemical 34】 【Chemistry 35】 or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, or isotopic compound thereof, characterized in that:

6. The pharmaceutically acceptable salt is an inorganic acid salt or an organic acid salt, the inorganic acid salt is selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, nitrate, phosphate, and acid phosphate; The organic acid salt is 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. The compound of claim 1.

7. 1. A pharmaceutical composition comprising:

10. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.

8. Use of the compound of claim 1 or a pharmaceutical composition comprising the same, 1) Preparation of a medicament for modulating EGFR kinase activity or for treating EGFR-related diseases; and 2) The above use, characterized in that it is used for a purpose selected from the group consisting of the preparation of a drug for degrading EGFR protein.

9. The use according to claim 8, characterized in that the EGFR-related disease is selected from the group consisting of inflammation, cancer, cardiovascular disease, infection, immune disease and metabolic disease.

10. The use of claim 8, wherein the EGFR protein is an EGFR mutant protein selected from the group consisting of DEL19, L858R, L858R / T790M, L858R / C797S, DEL19 / T790M / C797S, L858R / T790M / C797S, exon 20 insertion mutation, L861Q, DEL19-G724S, and L858R-L792H.

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