Compounds used as CDK4 kinase inhibitors and their applications

Abstract

The present invention relates to compounds used as CDK4 kinase inhibitors and their applications. Specifically, the compounds of the present invention have the structure shown in Formula I, where the definitions of each group and substituent are as described herein. The compounds of the present invention can be used as inhibitors of cyclin-dependent kinases (CDKs), which are used for the treatment or prevention of proliferative diseases (e.g., cancer), and in particular for the regulation and treatment of related diseases caused by the abnormal activity of cyclin-dependent kinases (CDKs). [Formula 1]

Description

[Technical Field]

[0001] The present invention relates to the medical technology field, in particular to compounds used as CDK4 kinase inhibitors and their application in modulating CDK4 kinase activity or in CDK4-related diseases, particularly cancer. [Background technology]

[0002] Cyclin-dependent kinases (CDKs) belong to the serine / threonine kinase family and bind to corresponding cyclins to form active dimeric complexes, which exert physiological functions, causing cell growth and proliferation. Currently, more than 20 CDKs have been discovered, which can be classified into two categories based on their functions: CDKs that regulate the cell cycle and CDKs that regulate cell transcription. CDKs 1-6 and 14-18 are involved in cell cycle regulation, while CDKs 7-13 and 19-20 are involved in cellular transcription regulation. It has now been demonstrated that CDK inhibitors can be used to treat cancer.

[0003] CDK4 and CDK6 regulate the cell cycle from G1 to S phase after binding to cyclin D. Abnormalities in the cyclin D-CDK4 / 6-Rb pathway have been reported to be associated with the development of drug resistance to endocrine therapy. Currently, various CDK4 / 6 inhibitors, such as palbociclib, ribociclib, and abemaciclib, are approved for the treatment of hormone receptor (HR)-positive, human epidermal growth factor 2 (HER2)-negative late-stage or metastatic breast cancer in combination with endocrine therapy. However, hematologic and / or gastrointestinal toxic side effects, such as neutropenia, frequently occur during CDK4 / 6 inhibitor treatment, leading to discontinuation or intermittent dosing and significantly impacting the therapeutic efficacy and compliance of the drug. Current research data suggest that cyclin D3-CDK6 activity may be involved in these side effects. Considering the toxic side effects of current CDK4 / 6 dual target point inhibitors, the development of selective CDK4 inhibitors may improve safety and therapeutic efficacy. Summary of the Invention [Problem to be solved by the invention]

[0004] The present invention provides novel compounds that have CDK4 kinase inhibitory activity and have superior pharmacodynamic and pharmacokinetic properties. [Means for solving the problem]

[0005] A first aspect of the present invention provides a compound for use as a CDK4 kinase inhibitor, said compound being a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotope or prodrug thereof: [ka]

[0006] where: X1 is selected from the group consisting of N, CR3; R1 is selected from the group consisting of H, CF3, F, Cl, Br, a methyl group, an ethyl group, an isopropyl group, and a cyclopropyl group; R2 is selected from the group consisting of H, F, Cl, Br, CF3, CF2H, NH2, and a methyl group; or R1 and R2 together with the C to which they are attached form a 5-membered heteroaryl group containing two N's; R3 is selected from the group consisting of H, CF3, F, Cl, Br, a methyl group, and a cyano group;

[0007] Ring A is [ka] wherein X2 is O or NR;

[0008] X 2-1 N, CR 11 is selected from the group consisting of Ring B is [ka] [ka] is selected from the group consisting of

[0009] wherein each R4 is H, a cyano group, a halogen, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C3-C6 cycloalkyl group, -C(O)NR9R 10 , substituted or unsubstituted -NR m R n are independently selected from the group consisting of Each of R5 and R6 independently represents H, a halogen atom, a hydroxy group, an amino group, [ka] a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C3-C6 cycloalkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted C 1-6 Alkoxy groups, substituted or unsubstituted -NRm R n is selected from the group consisting of

[0010] R7, R 11 are each independently H, substituted or unsubstituted C 1-6 alkyl groups,

[0011] R8 is H, C 1-6 Alkoxy group, halogenated C 1-6 Alkoxy group, -NR m R n , halogenated-NR m R n , a cyano group, a substituted or unsubstituted C 1-6 Alkyl groups, substituted or unsubstituted C 3-6 Cycloalkyl groups, -C(O)NR9R 10 is selected from the group consisting of Each R9, R 10 are each independently H, a halogen atom, a hydroxy group, an amino group, [ka] a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C3-C6 cycloalkyl group, a substituted or unsubstituted phenyl group, -C(O)R 12 , -C(O)OR 13 Alternatively, R and R are selected from the group consisting of 10 together with the N to which they are attached form a substituted or unsubstituted 5- to 7-membered heterocycle, or R or R 10 forms a 5- to 7-membered ring together with R5,

[0012] Each R 14 are each independently H, a halogen atom, a hydroxy group, an amino group, [ka] a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C3-C6 cycloalkyl group, a substituted or unsubstituted phenyl group, or an oxo group; or two R 14together with the C to which they are attached form a C3-C6 cycloalkyl group,

[0013] or R4 and R5 together with the C to which they are attached form a 5- to 7-membered heterocycle containing 1, 2 or 3 heteroatoms selected from N, O and S; R 12 , R 13 are each independently H, substituted or unsubstituted C 1-6 Alkyl groups, substituted or unsubstituted C 3-6 cycloalkyl groups, each R and R' is independently selected from the group consisting of H, a C1-C6 alkyl group, a halogenated C1-C6 alkyl group, a C3-C6 cycloalkyl group, a halogenated C3-C6 cycloalkyl group, and a phenyl group;

[0014] R4, R5, R6, R9, R 10 and R 14 The substitutions described in the above are each independently substituted with 1, 2 or 3 substituents selected from the group consisting of deuterium, halogen, a hydroxy group, an amino group, -N-(C1-C6 alkyl)2, a C1-C6 alkoxy group, a phenyl group and a cyano group; Each R m is H, C 1-6 Alkyl group, C 3-6 Cycloalkyl groups, C 6-10 an aryl group, and a 6- to 10-membered heteroaryl group containing 1, 2, or 3 heteroatoms selected from N, O, and S; Each R n is C 1-6 is an alkyl group,

[0015] Or R m and R n together with the N atom to which they are attached form a 3- to 10-membered N-containing monocyclic or bicyclic heterocyclic group, each m, n, and p is independently selected from the group consisting of 0, 1, 2, 3, 4, and 5; Here, ring A is [ka] When the formula is [ka] is selected from the group consisting of: [Effects of the Invention]

[0016] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (e.g., in the Examples) can be combined with each other to form new or preferred technical solutions, which will not be repeated here due to space limitations. DETAILED DESCRIPTION OF THE INVENTION

[0017] As a result of extensive and thorough research, the present inventors have unexpectedly discovered a class of compounds with excellent CDK4 kinase inhibitory activity. Furthermore, the compounds have excellent inhibitory activity and selectivity against CDK4 kinase, and have superior pharmacodynamic / pharmacokinetic properties. Based on this, the present invention has been completed.

[0018] In another preferred example, X1 is selected from the group consisting of N and CR3; R1 is selected from the group consisting of H, CF3, F, Cl, Br, a methyl group, an ethyl group, an isopropyl group, and a cyclopropyl group; R2 is selected from the group consisting of H, CF3, F, Cl, Br, and a methyl group; R3 is selected from the group consisting of H, CF3, F, Cl, Br, a methyl group, and a cyano group;

[0019] Ring A is [ka] wherein:

[0020] X 2-1 N, CR 11 is selected from the group consisting of R4 is H, substituted or unsubstituted C 1-6 Alkyl groups, substituted or unsubstituted C 3-6 Cycloalkyl groups, -C(O)NR9R 10 , substituted or unsubstituted -NR m R n is selected from the group consisting of Each R5 is H, substituted or unsubstituted C 1-6 Alkyl groups, substituted or unsubstituted C 1-6 Alkoxy groups, substituted or unsubstituted C 3-6 Cycloalkyl groups, substituted or unsubstituted -NR m R n are independently selected from the group consisting of Each R6 is independently a halogen, a substituted or unsubstituted C 1-6 Alkyl groups, substituted or unsubstituted C 3-6 cycloalkyl groups,

[0021] R7, R 11 are each independently H, substituted or unsubstituted C 1-6 alkyl groups, R8 is H, C 1-6 Alkoxy group, halogenated C 1-6 Alkoxy group, -NR m R n , halogenated-NR m R n , a cyano group, a substituted or unsubstituted C 1-6 Alkyl groups, substituted or unsubstituted C 3-6 Cycloalkyl groups, -C(O)NR9R 10 is selected from the group consisting of

[0022] Each R9 and R 10 are each independently H, substituted or unsubstituted C 1-6 Alkyl groups, substituted or unsubstituted C 3-6 Cycloalkyl groups, -C(O)R 12 , -C(O)OR 13 Alternatively, R and R are selected from the group consisting of 10together with the N to which they are attached form a substituted or unsubstituted 5- to 7-membered heterocycle, or R or R 10 forms a 5- to 7-membered ring together with R5, or R4 and R5 together with the C to which they are attached form a 5- to 7-membered heterocycle containing 1, 2 or 3 heteroatoms selected from N, O and S;

[0023] R 12 , R 13 are each independently H, substituted or unsubstituted C 1-6 Alkyl groups, substituted or unsubstituted C 3-6 cycloalkyl groups, The "substituted" groups each independently include deuterium, halogen, a hydroxy group, an amino group, -NR m R n , C 1-6 alkoxy groups; Each R m is H, C 1-6 Alkyl group, C 3-6 Cycloalkyl groups, C 6-10 an aryl group, and a 6- to 10-membered heteroaryl group containing 1, 2, or 3 heteroatoms selected from N, O, and S; Each R n is C 1-6 is an alkyl group,

[0024] each m and n is independently selected from the group consisting of 0, 1, 2, 3, 4, and 5; Ring B is [ka] [ka] is selected from the group consisting of

[0025] Here, ring A is [ka] When the formula is [ka] [ka] is selected from the group consisting of:

[0026] A second aspect of the present invention provides a compound for use as a CDK4 kinase inhibitor, said compound being a compound of formula II, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotopomer or prodrug thereof: [ka] where: X1 is selected from the group consisting of N, CR3;

[0027] R1 is selected from the group consisting of H, CF3, F, Cl, Br, a methyl group, an ethyl group, an isopropyl group, and a cyclopropyl group; R2 is selected from the group consisting of H, F, CF3, CF2H, NH2, and a methyl group; or R1 and R2 together with the C to which they are attached form a 5-membered heteroaryl group containing two N's; R3 is selected from the group consisting of H, CF3, F, Cl, Br, a methyl group, and a cyano group;

[0028] Ring A is [ka] wherein X2 is O or NR;

[0029] Ring B is [ka] [ka] is selected from the group consisting of

[0030] wherein each R4 is independently selected from the group consisting of H, cyano, halogen, substituted or unsubstituted C1-C6 alkyl, and substituted or unsubstituted C3-C6 cycloalkyl; Each R5, R6, R9, R 10 and R 14 are each independently H, a halogen atom, a hydroxy group, an amino group, [ka] oxo group, substituted or unsubstituted C1-C6 alkyl group, substituted or unsubstituted C3-C6 cycloalkyl group, substituted or unsubstituted phenyl group, substituted or unsubstituted C 1-6 Alkoxy groups, substituted or unsubstituted -NR m R n or two R bonded to the same C are selected from the group consisting of 14 together with the C to which they are attached form a C3-C6 cycloalkyl group,

[0031] Or R9, R 10 together with the N to which they are attached, [ka] or [ka] Forming

[0032] Or ring A is [ka] when R4 and R5 together with the ring to which they are attached form a 5- to 7-membered heterocycle containing 1, 2 or 3 heteroatoms selected from N, O and S;

[0033] each R and R' is independently selected from the group consisting of H, a C1-C6 alkyl group, a halogenated C1-C6 alkyl group, a C3-C6 cycloalkyl group, a halogenated C3-C6 cycloalkyl group, and a phenyl group; Each R m is H, C 1-6 Alkyl group, C 3-6 Cycloalkyl groups, C 6-10 an aryl group, and a 6- to 10-membered heteroaryl group containing 1, 2, or 3 heteroatoms selected from N, O, and S; Each R n is C 1-6 is an alkyl group, R4, R5, R6, R9, R 10 and R 14 The substitutions described in the above are each independently substituted with 1, 2 or 3 substituents selected from the group consisting of deuterium, halogen, a hydroxy group, an amino group, -N-(C1-C6 alkyl)2, a C1-C6 alkoxy group, a phenyl group and a cyano group;

[0034] Each m, n, and p is independently selected from the group consisting of 0, 1, 2, 3, and 4. In another preferred embodiment, R1 is selected from the group consisting of H, CF3, F, Cl, Br, a methyl group, an ethyl group, an isopropyl group, and a cyclopropyl group; R2 is selected from the group consisting of H, F, CF3, CF2H, NH2, and a methyl group;

[0035] Ring A is [ka] is selected from the group consisting of

[0036] Ring B is [ka] is selected from the group consisting of

[0037] where: Each R5, R6, R9, R 10 and R 14 are each independently H, a halogen atom, a hydroxy group, an amino group, [ka] selected from the group consisting of substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C3-C6 cycloalkyl groups, and substituted or unsubstituted phenyl groups;

[0038] Or R9, R 10 together with the N to which they are attached, [ka] Forming

[0039] R and R' are each independently selected from the group consisting of H, a C1-C6 alkyl group, a halogenated C1-C6 alkyl group, a C3-C6 cycloalkyl group, a halogenated C3-C6 cycloalkyl group, and a phenyl group; R4, R5, R6, R9, R 10 and R 14 The substitutions described in the above are each independently substituted with 1, 2 or 3 substituents selected from the group consisting of deuterium, halogen, a hydroxy group, an amino group, -N-(C1-C6 alkyl)2, a C1-C6 alkoxy group, a phenyl group and a cyano group;

[0040] Each m, n, and p is independently selected from the group consisting of 0, 1, 2, 3, and 4. In another preferred embodiment, R1 is selected from the group consisting of Cl and Br; R2 is H,

[0041] Ring A is [ka] is selected from the group consisting of

[0042] Ring B is [ka] is selected from the group consisting of

[0043] where: Each R5, R6, R9, R 10 and R 14 are each independently H, a halogen atom, a hydroxy group, an amino group, [ka] selected from the group consisting of substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C3-C6 cycloalkyl groups, and substituted or unsubstituted phenyl groups;

[0044] Or R9, R 10 together with the N to which they are attached, [ka] Forming R and R' are each independently selected from the group consisting of H, a C1-C6 alkyl group, a halogenated C1-C6 alkyl group, a C3-C6 cycloalkyl group, a halogenated C3-C6 cycloalkyl group, and a phenyl group; R5, R6, R9, R 10 and R 14 The substitutions described in the above are each independently substituted with 1, 2 or 3 substituents selected from the group consisting of deuterium, halogen, a hydroxy group, an amino group, -N-(C1-C6 alkyl)2, a C1-C6 alkoxy group, a phenyl group and a cyano group; Each m, n, and p is independently selected from the group consisting of 0, 1, 2, 3, and 4.

[0045] In another preferred embodiment, R1 and R2 together with the C to which they are attached form a 5-membered heteroaryl group containing two N's; Ring A is [ka] is selected from the group consisting of

[0046] Ring B is [ka] [ka] is selected from the group consisting of

[0047] wherein each R4 is independently selected from the group consisting of H, a substituted or unsubstituted C1-C6 alkyl group, and a substituted or unsubstituted C3-C6 cycloalkyl group; Each R5, R6, R9, R 10 and R 14 are each independently H, a halogen atom, a hydroxy group, an amino group, [ka] selected from the group consisting of substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C3-C6 cycloalkyl groups, and substituted or unsubstituted phenyl groups;

[0048] R and R' are each independently selected from the group consisting of H, a C1-C6 alkyl group, a halogenated C1-C6 alkyl group, a C3-C6 cycloalkyl group, a halogenated C3-C6 cycloalkyl group, and a phenyl group; R4, R5, R6, R9, R 10 and R 14 The substitutions described in the above are each independently substituted with 1, 2 or 3 substituents selected from the group consisting of deuterium, halogen, a hydroxy group, an amino group, -N-(C1-C6 alkyl)2, a C1-C6 alkoxy group, a phenyl group and a cyano group;

[0049] Each m, n, and p is independently selected from the group consisting of 0, 1, 2, 3, and 4. In another preferred embodiment, [ka] teeth, [ka] It has a structure like

[0050] X is selected from the group consisting of N, CR3; R3 is selected from the group consisting of H, CF3, F, Cl, Br, a methyl group, and a cyano group. A third aspect of the present invention provides a compound for use as a CDK4 kinase inhibitor, said compound being a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotope or prodrug thereof: [ka] where:

[0051] X1 is selected from the group consisting of N, CR3; R1 is selected from the group consisting of H, CF3, F, Cl, Br, a methyl group, an ethyl group, an isopropyl group, and a cyclopropyl group; R2 is selected from the group consisting of H, F, CF3, CF2H, NH2, and a methyl group;

[0052] or R1 and R2 together with the C to which they are attached form a 5-membered heteroaryl group containing two N's; R3 is selected from the group consisting of H, CF3, F, Cl, Br, a methyl group, and a cyano group;

[0053] Ring A is [ka] wherein X2 is O or NR;

[0054] Ring B is [ka] [ka] is selected from the group consisting of

[0055] wherein each R4 is independently selected from the group consisting of H, cyano, halogen, substituted or unsubstituted C1-C6 alkyl, and substituted or unsubstituted C3-C6 cycloalkyl; Each R5, R6, R9, R 10 and R 14 are each independently H, a halogen atom, a hydroxy group, an amino group, [ka] selected from the group consisting of substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C3-C6 cycloalkyl groups, and substituted or unsubstituted phenyl groups;

[0056] Or R9, R 10 together with the N to which they are attached, [ka] or [ka] Forming

[0057] each R and R' is independently selected from the group consisting of H, a C1-C6 alkyl group, a halogenated C1-C6 alkyl group, a C3-C6 cycloalkyl group, a halogenated C3-C6 cycloalkyl group, and a phenyl group; R4, R5, R6, R9, R 10 and R 14 The substitutions described in the above are each independently substituted with 1, 2 or 3 substituents selected from the group consisting of deuterium, halogen, a hydroxy group, an amino group, -N-(C1-C6 alkyl)2, a C1-C6 alkoxy group, a phenyl group and a cyano group;

[0058] Each m, n, and p is independently selected from the group consisting of 0, 1, 2, 3, and 4. In another preferred embodiment, R1 is selected from the group consisting of H, CF3, F, Cl, Br, a methyl group, an ethyl group, an isopropyl group, and a cyclopropyl group; R2 is selected from the group consisting of H, F, CF3, CF2H, NH2, and a methyl group;

[0059] Ring A is [ka] is selected from the group consisting of

[0060] Ring B is [ka] [ka] is selected from the group consisting of

[0061] wherein each R4 is independently selected from the group consisting of H, cyano, halogen, substituted or unsubstituted C1-C6 alkyl, and substituted or unsubstituted C3-C6 cycloalkyl; Each R5, R6, R9, R 10 and R 14 are each independently H, a halogen atom, a hydroxy group, an amino group, [ka] selected from the group consisting of substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C3-C6 cycloalkyl groups, and substituted or unsubstituted phenyl groups;

[0062] Or R9, R 10 together with the N to which they are attached, [ka] Forming

[0063] R and R' are each independently selected from the group consisting of H, a C1-C6 alkyl group, a halogenated C1-C6 alkyl group, a C3-C6 cycloalkyl group, a halogenated C3-C6 cycloalkyl group, and a phenyl group; R4, R5, R6, R9, R10 and R 14 The substitutions described in the above are each independently substituted with 1, 2 or 3 substituents selected from the group consisting of deuterium, halogen, a hydroxy group, an amino group, -N-(C1-C6 alkyl)2, a C1-C6 alkoxy group, a phenyl group and a cyano group;

[0064] Each m, n, and p is independently selected from the group consisting of 0, 1, 2, 3, and 4. In another preferred embodiment, R1 is selected from the group consisting of CF3, F, Cl, and Br; R2 is H,

[0065] Ring A is [ka] is selected from the group consisting of

[0066] Ring B is [ka] is selected from the group consisting of

[0067] wherein each R4 is independently selected from the group consisting of H, a substituted or unsubstituted C1-C6 alkyl group, and a substituted or unsubstituted C3-C6 cycloalkyl group; Each R5, R6, R9, R 10 and R 14 are each independently H, a halogen atom, a hydroxy group, an amino group, [ka] selected from the group consisting of substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C3-C6 cycloalkyl groups, and substituted or unsubstituted phenyl groups;

[0068] Or R9, R 10 together with the N to which they are attached, [ka] Forming R and R' are each independently selected from the group consisting of H, a C1-C6 alkyl group, a halogenated C1-C6 alkyl group, a C3-C6 cycloalkyl group, a halogenated C3-C6 cycloalkyl group, and a phenyl group;

[0069] R4, R5, R6, R9, R 10 and R 14 The substitutions described in the above are each independently substituted with 1, 2 or 3 substituents selected from the group consisting of deuterium, halogen, a hydroxy group, an amino group, -N-(C1-C6 alkyl)2, a C1-C6 alkoxy group, a phenyl group and a cyano group; Each m, n, and p is independently selected from the group consisting of 0, 1, 2, 3, and 4.

[0070] In another preferred embodiment, R1 and R2 together with the C to which they are attached form a 5-membered heteroaryl group containing two N's; Ring A is [ka] is selected from the group consisting of

[0071] Ring B is [ka] is selected from the group consisting of

[0072] wherein each R4 is independently selected from the group consisting of H, a substituted or unsubstituted C1-C6 alkyl group, and a substituted or unsubstituted C3-C6 cycloalkyl group; Each R5, R6, R9, R 10 and R 14 are each independently H, a halogen atom, a hydroxy group, an amino group, [ka] selected from the group consisting of substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C3-C6 cycloalkyl groups, and substituted or unsubstituted phenyl groups;

[0073] R and R' are each independently selected from the group consisting of H, a C1-C6 alkyl group, a halogenated C1-C6 alkyl group, a C3-C6 cycloalkyl group, a halogenated C3-C6 cycloalkyl group, and a phenyl group; R4, R5, R6, R9, R 10 and R 14 The substitutions described in the above are each independently substituted with 1, 2 or 3 substituents selected from the group consisting of deuterium, halogen, a hydroxy group, an amino group, -N-(C1-C6 alkyl)2, a C1-C6 alkoxy group, a phenyl group and a cyano group; Each m, n, and p is independently selected from the group consisting of 0, 1, 2, 3, and 4.

[0074] In another preferred embodiment, [ka] teeth, [ka] It has a structure like

[0075] X is selected from the group consisting of N, CR3; R3 is selected from the group consisting of H, CF3, F, Cl, Br, a methyl group, and a cyano group.

[0076] In another preferred embodiment, the compound is selected from the group consisting of: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0077] A fourth aspect of the present invention provides a compound for use as a CDK4 kinase inhibitor, said compound being a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotope or prodrug thereof: [ka]

[0078] where: X1 is selected from the group consisting of N, CR3; R1 is selected from the group consisting of H, CF3, F, Cl, Br, a methyl group, an ethyl group, an isopropyl group, and a cyclopropyl group; R2 is selected from the group consisting of H, CF3, F, Cl, Br, and a methyl group; R3 is selected from the group consisting of H, CF3, F, Cl, Br, a methyl group, and a cyano group;

[0079] Ring A is [ka] wherein:

[0080] X2-1 N, CR 11 is selected from the group consisting of R4 is H, substituted or unsubstituted C 1-6 Alkyl groups, substituted or unsubstituted C 3-6 Cycloalkyl groups, -C(O)NR9R 10 , substituted or unsubstituted -NR m R n , substituted or unsubstituted -NRaR b is selected from the group consisting of Each R5 is H, substituted or unsubstituted C 1-6 Alkyl groups, substituted or unsubstituted C 1-6 Alkoxy groups, substituted or unsubstituted C 3-6 Cycloalkyl groups, substituted or unsubstituted -NRaR b , substituted or unsubstituted -NR m R n are independently selected from the group consisting of

[0081] Each R6 is independently a halogen, a substituted or unsubstituted C 1-6 Alkyl groups, substituted or unsubstituted C 3-6 cycloalkyl groups, R7, R 11 are each independently H, substituted or unsubstituted C 1-6 alkyl groups, R8 is H, C 1-6 Alkoxy group, halogenated C 1-6 Alkoxy group, -NR m R n , halogenated-NR m R n , a cyano group, a substituted or unsubstituted C 1-6 Alkyl groups, substituted or unsubstituted C 3-6 Cycloalkyl groups, -C(O)NR9R 10 is selected from the group consisting of

[0082] Each R9 and R 10 are each independently H, substituted or unsubstituted C 1-6 Alkyl groups, substituted or unsubstituted C 3-6 Cycloalkyl groups, -C(O)R 12, -C(O)OR 13 Alternatively, R and R are selected from the group consisting of 10 together with the N to which they are attached form a substituted or unsubstituted 5- to 7-membered heterocycle, or R or R 10 forms a 5- to 7-membered ring together with R5, or R4 and R5 together with the C to which they are attached form a 5- to 7-membered heterocycle containing 1, 2 or 3 heteroatoms selected from N, O and S;

[0083] R 12 , R 13 are each independently H, substituted or unsubstituted C 1-6 Alkyl groups, substituted or unsubstituted C 3-6 cycloalkyl groups, The "substituted" groups each independently include deuterium, halogen, a hydroxy group, an amino group, -NR m R n , C 1-6 alkoxy groups; Each R m is H, C 1-6 Alkyl group, C 3-6 Cycloalkyl groups, C 6-10 an aryl group, and a 6- to 10-membered heteroaryl group containing 1, 2, or 3 heteroatoms selected from N, O, and S;

[0084] Each R n is C 1-6 is an alkyl group, Each R a is H, C 1-6 Alkyl group, C 3-6 cycloalkyl groups, Each R b is C 3-6 is a cycloalkyl group, Or R a and R b together with the N atom to which they are attached form a 3- to 10-membered N-containing monocyclic or bicyclic heterocyclic group, each m and n is independently selected from the group consisting of 0, 1, 2, 3, 4, and 5;

[0085] Ring B is [ka] [ka] is selected from the group consisting of

[0086] Here, ring A is [ka] When the formula is [ka] is selected from the group consisting of:

[0087] In another preferred embodiment, Ring A is [ka] is selected from the group consisting of Ring B is [ka] is selected from the group consisting of

[0088] where X 2-1 , R4, R5, R6, R7, R8, R9, R 10 , m, n are as defined above. In another preferred embodiment, Ring A is [ka] is selected from the group consisting of

[0089] Ring B is [ka] is selected from the group consisting of where R4, R5, R6, R9, R 10 , m, n are as defined above.

[0090] In another preferred embodiment, Ring A is [ka] is selected from the group consisting of Ring B is [ka] is selected from the group consisting of Here, R5, R6, R9, R 10 , m is as defined above.

[0091] In another preferred embodiment, the compound is selected from the group consisting of: [ka] [ka] [ka] [ka] [ka]

[0092] In another preferred embodiment, the pharmaceutically acceptable salt is an inorganic acid salt or an organic acid salt. In another preferred example, the inorganic acid salt is selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, nitrate, phosphate, and acid phosphate.

[0093] In another preferred example, 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. A fifth aspect of the present invention provides a pharmaceutical composition comprising a safe and effective amount of a compound according to the first aspect of the present invention and a pharmaceutically acceptable carrier.

[0094] A sixth aspect of the present invention provides the use of a compound according to the first aspect of the present invention for use in the preparation of a medicament for use as a CDK4 kinase inhibitor.

[0095] A seventh aspect of the present invention provides the use of a compound according to the first aspect of the present invention for use in the preparation of a medicament for modulating CDK4 kinase activity or for treating a CDK4-related disease. In another preferred embodiment, the CDK4-related disease is selected from the group consisting of inflammation, cancer, cardiovascular disease, infectious disease, immune disease, and metabolic disease. In another preferred embodiment, the cancer is selected from the group consisting of lung cancer, breast cancer, prostate cancer, colorectal cancer, liver cancer, pancreatic cancer, ovarian cancer, leukemia, neuroblastoma, gastric cancer, kidney cancer, esophageal cancer, and uterine cancer.

[0096] In another preferred embodiment, the inflammation is selected from the group consisting of dermatitis, keratitis, conjunctivitis, prostatitis, hepatitis, and enteritis. In another preferred embodiment, the infection is selected from the group consisting of a bacterial infection and a viral infection. In another preferred embodiment, the bacterial infection is selected from the group consisting of a gram-positive bacterial infection, a gram-negative bacterial infection, a mycoplasma infection, and a fungal infection.

[0097] In another preferred embodiment, the viral infection is selected from the group consisting of coronavirus infection, influenza A, influenza B, and avian influenza. In another preferred embodiment, the immune disease is selected from the group consisting of systemic lupus erythematosus, rheumatoid arthritis, scleroderma, and ulcerative colitis.

[0098] 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-.

[0099] 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 and 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 one to four substituents at any position. A "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.

[0100] An "alkylene group" refers to a divalent radical of an 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 and an oxy group attached thereto, where the alkyl group has the definition set forth 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.

[0101] A "thioalkyl group" refers to a carbon in an alkyl group being replaced by S, S(O), or S(O)2. The term "alkenyl group (alone or as part of another group)" refers to an aliphatic group generally having 2 to 20 carbon atoms and containing at least one double bond. In the present invention, a "C2-C6 alkenyl group" refers to an alkenyl group containing 2, 3, 4, 5, or 6 carbon atoms. 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. An "alkenylene group" refers to an alkenyl group having two points of attachment. For example, a "vinylene group" refers to the group -CH=CH-. Alkenylene groups can be unsubstituted or substituted with one or more substituents.

[0102] 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, generally 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.

[0103] 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-. Alkynylene groups can be unsubstituted or substituted with one or more substituents. "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.

[0104] "Aromatic ring system" refers to a monocyclic, bicyclic or polycyclic hydrocarbon ring system in which at least one ring is aromatic. 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 ring systems such as phenyl, naphthyl, and anthryl, 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, naphthyrimino, or tetralyl. In the present invention, aryl groups are preferably C6-C8 12 In the present invention, the aryl group is intended to further include substituted aryl groups.

[0105] An "arylalkyl group" or "aralkyl group" refers to an alkyl group in which an alkyl hydrogen atom is replaced by an aryl group. Aralkyl groups include groups in which one or more hydrogen atoms are replaced by an aryl group, where the aryl and alkyl groups are as defined above. Examples of "arylalkyl groups" or "aralkyl groups" include benzyl, 2-phenylethyl, 3-phenylpropyl, 9-fluorenyl, benzhydryl, and trityl groups.

[0106] An "aryloxy group" refers to an --O-(aryl) group, where the aryl portion is as defined herein. A "heteroalkyl group" refers to a substituted alkyl group having one or more skeletal chain atoms selected from atoms other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, or combinations thereof. Numerical ranges may be given, e.g., a C1-C6 heteroalkyl group refers to the number of carbon atoms in the chain containing from 1 to 6 carbon atoms. For example, the group -CH2OCH2CH3 would be referred to as a "C3" heteroalkyl group. Attachment to the remainder of the molecule can be through a heteroatom or a carbon in the heteroalkyl group chain. A "heteroalkylene group" refers to an optionally substituted divalent alkyl group having one or more skeletal chain atoms selected from atoms other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, or combinations thereof. "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.

[0107] "Carbocyclic group" refers to a monovalent group of a carbon ring system, including, for example, cycloalkyl groups (e.g., cyclopentyl, cyclobutyl, cyclopropyl, cyclohexyl) and cycloalkenyl groups (e.g., cyclopentenyl, cyclohexenyl, cyclopentadienyl).

[0108] "Cycloalkyl group" refers to a monovalent saturated carbocyclyl group consisting of a monocyclic or bicyclic ring 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 hydroxyl 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.

[0109] 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 via a cycloalkyl group. "Heteroaromatic ring system" refers to a monocyclic (e.g., 5- or 6-membered), bicyclic (6- to 12-membered), or polycyclic ring system in which at least one ring is not only aromatic but also contains at least one heteroatom (e.g., N, O, or S), and in which none of the other rings are heterocyclic groups (e.g., as defined below). In certain cases, aromatic heteroatom-containing rings contain 1, 2, 3, or 4 ring heteroatoms within the ring. At least one ring is heteroaromatic, and the remaining rings can be saturated, partially unsaturated, or fully unsaturated.

[0110] A "heteroaryl group" refers to a monocyclic (e.g., 5- or 6-membered), bicyclic (e.g., 8-10-membered), or tricyclic group of 5-12 ring atoms containing 1, 2, or 3 ring heteroatoms selected from N, O, or S, and at least one aromatic ring in which the remaining ring atoms are C, it being understood that the point of attachment of the heteroaryl group must be located on the aromatic ring. Examples of heteroaryl groups include, but are not limited to, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, thienyl, furyl, pyranyl, pyridyl, pyrrolyl, pyrazolyl, pyrimidinyl, quinolinyl, isoquinolinyl, benzofuranyl, benzofuranyl, benzothienyl, benzothiopyranyl, benzimidazolyl, benzoxazolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzopyranyl, indolyl, isoindolyl, triazolyl, triazinyl, quinoxalinyl, purinyl, quinazolinyl, quinolidinyl, naphthyridinyl, pteridinyl, carbazolyl, azepine, diazepine, acridinyl, and the like. A heteroarylene group refers to a heteroaryl group that has two binding sites.

[0111] "Heterocyclic ring system" refers to monocyclic, bicyclic, and polycyclic ring systems in which at least one ring is saturated or partially unsaturated (but 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 the creation of a stable structure, and any ring atom can be optionally substituted.

[0112] "Heterocyclic group" refers to a monovalent radical of a heterocyclic ring system, typically a stable monocyclic (e.g., 3-8 membered, i.e., 3-, 4-, 5-, 6-, 7-, or 8-membered) or bicyclic (e.g., 5-12 membered, i.e., 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered) or polycyclic (e.g., 7-14 membered, i.e., 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-membered) ring, including fused, spiro, and / or bridged ring structures, which may be saturated, partially unsaturated, and which contain carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S. Representative heterocyclic groups include ring systems in which: (1) each ring is non-aromatic and at least one ring contains a heteroatom, such as tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, pyrrolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl; (2) 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-tetrahydroquinolinyl group or a 1,2,3,4-tetrahydroisoquinolinyl group; and (3) at least one ring is non-aromatic and contains a heteroatom, and at least one other ring is aromatic and contains a heteroatom, 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 heterocyclic group having two bonding sites. In the present invention, the heterocyclylene group is preferably bicyclic, one of which 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.

[0113] "Heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclic group, where the heterocyclic group and the alkyl group are as defined above. An "alkylamino group" refers to a group having the structure alkyl-NR-, where R is H or an alkyl, cycloalkyl, aryl, heteroaryl, etc., group, as defined above.

[0114] A "cycloalkylamino group" refers to a group of the formula -NRaRb, where Ra is H, an alkyl group as defined herein, or a cycloalkyl group as defined herein; Rb is a cycloalkyl group as defined herein; or Ra and Rb together with the N atom to which they are attached form a 3-10 membered N-containing monocyclic or bicyclic heterocyclic 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.

[0115] 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 heterocyclic group, as defined above. In the present invention, the term "amide group" refers to a group having the structure -CONRR', where R and R' can independently represent hydrogen, alkyl or substituted alkyl groups, cycloalkyl or substituted cycloalkyl groups, aryl or substituted aryl groups, heterocycles or substituted heterocycles, as defined above. R and R' can be the same or different in dialkylamine fragments.

[0116] In the present invention, 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 groups, cycloalkyl or substituted cycloalkyl groups, aryl or substituted aryl groups, heterocycles or substituted heterocycles, as defined above. R and R' can be the same or different in dialkylamine fragments.

[0117] A "ketocarbonyl group" refers to RC(=O)--, where R is an alkyl group, cycloalkyl group, etc., as described above. 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 heterocyclic group corresponds to a heterocyclylene group, and an alkoxy group corresponds to an alkyleneoxy group. In the present invention, each of the above alkyl groups, alkoxy groups, cycloalkyl groups, heteroalkyl groups, aryl groups, heteroaryl groups, cyclic heteroalkyl groups, alkenyl groups, alkynes, heterocycles, heterocyclic groups, etc. may be substituted or unsubstituted.

[0118] In the present invention, the term "substituted" refers to the replacement of one or more hydrogen atoms of a specific group with a specific substituent. The specific substituent is the corresponding substituent described above or the substituent appearing in each example. Unless otherwise specified, a specific substituted group can have one substituent selected from a specific group at any substitutable position of the group, and the substituent may be the same or different at each position. Those skilled in the art will understand that the combination of substituents contemplated by the present invention is a stable or chemically feasible combination. Typical substitutions include, for example, hydrogen, deuterium, halogen (e.g., monohalogen substituents or polyhalogen substituents such as trifluoromethyl or alkyl groups containing Cl), cyano, nitro, oxo (e.g., ═O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, alkynyl, heterocyclic rings, aromatic rings, 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.d P(=O)NR b R c , N.R. b C(=O)R a , or NR b P(=O)2R e 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 heterocyclic ring, or an aromatic ring, or R b and R c can be taken together with the N atom to form a heterocycle, and R e can independently represent hydrogen, an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, a heterocyclic ring, 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 heterocyclic ring, or an aromatic ring, can be optionally substituted. Examples of the substituents include halogen, a hydroxyl group, a cyano group, a carboxyl group (—COOH), a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C3-C8 cycloalkyl group, a 3-12 membered heterocyclic group, an aryl group, a heteroaryl group, a C1-C8 aldehyde group, a C2-C 10 Acyl groups, C2-C 10 Ester group, amine group, C1-C6 alkoxy group, C1-C 10 Examples include, but are not limited to, sulfonyl groups, and C1-C6 ureido groups.

[0119] "Cyano" refers to the radical -CN. The term "nitro group" refers to -NO2. "Hydroxyl group" refers to -OH. "Amino group" refers to -NH2 or RNH-, where R is a ketocarbonyl group, a sulfonyl group, a sulfonamide group, R a -C(=O)-, Ra R b NC(=O)-, etc., where R a and R b is an alkyl group, a cycloalkyl group, an aryl group, a heteroaryl group, or the like.

[0120] "Halogen (halogenated)" refers to any halogen radical such as -F, -Cl, -Br, or -I. The term "deuteride" refers to a compound obtained by replacing one hydrogen atom (H) or multiple hydrogen atoms (H) in a compound with a deuterium atom (D). In the present invention, "plurality" refers independently to 2, 3, 4, or 5.

[0121] Active ingredient As used herein, the terms "compound of the invention" or "active ingredient of the invention" are used interchangeably to 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.

[0122] The compound of formula I has the structure: [ka]

[0123] Here, the definitions of each group are as described above. Salts that can be formed by the compounds of the present invention also fall within the scope of the present invention. Unless otherwise specified, the compounds of the present invention are understood to include these salts. As used herein, the term "salt" refers to acidic or basic salts formed with inorganic or organic acids and bases. Furthermore, when the compounds of the present invention contain a basic fragment, including but not limited to pyridine or imidazole, and when they contain an acidic fragment, including but not limited to carboxylic acids, zwitterions ("inner salts") 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 in separation or purification steps during the preparation process. The compounds of the present invention can form salts, for example, by reacting Compound I with a certain amount, such as an equivalent amount, of an acid or base, followed by intermediate salting out or lyophilization in an aqueous solution.

[0124] The basic fragment contained in the compound of the present invention includes, but is not limited to, an amine or a pyridine or an imidazole ring, which can form a salt with an organic or inorganic acid. Typical acids that can form salts include acetate (e.g., using acetic acid or a trihaloacetic acid, such as trifluoroacetic acid), adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, cerebellar salt, camphorsulfonic acid, cyclopentanepropionate, diglycolate, lauryl sulfate, ethanesulfonate, fumaric acid, glucoheptonate, glycerophosphate, hemisulfate, These include enanthate, hexanoate, hydrochloride, hydrobromide, hydroiodide, isethionate (e.g., 2-isethionate), lactate, maleate, methanesulfonate, naphthalenesulfonate (e.g., 2-naphthalenesulfonate), nicotinate, nitrate, oxalate, pectate, persulfate, phenylpropionate (e.g., 3-phenylpropionate), phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate (e.g., formed with sulfuric acid), sulfonate, tartrate, sulfocyanate, toluenesulfonate such as p-toluenesulfonate, dodecanoate, and the like.

[0125] Acidic fragments that can be contained in certain compounds of the present invention include, but are not limited to, carboxylic acids, and can form salts with various organic or inorganic bases. Typical salts formed with bases include alkali metal salts such as ammonium salts, 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, hibramine (salts formed with N,N-di(dehydroabietyl)ethylenediamine), N-methyl-D-glucamine, N-methyl-D-glucamide, and t-butylamine, and salts formed with amino acids such as arginine and lysine. Basic nitrogen-containing groups can form quaternary ammonium salts with halides such as small molecule alkyl halides (e.g., chlorides, bromides, and iodides of methyl, ethyl, propyl, and butyl groups), dialkyl sulfates (e.g., dimethyl sulfate, diethyl sulfate, dibutyl sulfate, and dipentyl sulfate), long chain halides (e.g., chlorides, bromides, and iodides of decyl, dodecyl, and tetradecyl groups), and aralkyl halides (e.g., bromides of benzyl and phenyl groups).

[0126] Prodrugs and solvates (or solvates) of the compounds of the invention are also included within their scope. Herein, the term "prodrug" refers to a compound that undergoes a chemical conversion during metabolic or chemical processing to produce the compound, salt, or solvate of the present invention during the treatment of a related disease. The compound of the present invention includes solvates such as hydrates. The compounds, salts or solvates of the present invention may exist in their tautomeric form (for example, as amides and imino ethers), and all such tautomeric forms are part of the present invention.

[0127] All stereoisomers of the compounds (e.g., asymmetric carbon atoms possibly present due to various substitutions), including their enantiomeric and diastereomeric forms, are within the contemplation of the present invention. Individual stereoisomers of the compounds of the present invention may exist simultaneously with other isomers (e.g., possessing specific activity as pure or substantially pure optical isomers) or may be mixtures, such as racemates, or mixtures formed with all or some of the other stereoisomers. The chiral centers of the present invention have two configurations, S or R, as defined by the 1974 proposal of the International Union of Theoretical and Applied Sciences (IUPAC). Racemic forms can be resolved via physical methods, such as fractional crystallization, or separated by derivatization into diastereoisomers or chiral column chromatography. Single optical isomers can be obtained from the racemates by suitable methods, including, but not limited to, conventional methods, such as salt formation with an optically active acid followed by recrystallization. In the compound of the present invention, the weight content of the compound obtained through the sequential preparation, separation, and purification is 90% or more, for example, 95% or more, 99% or more ("highly pure" compound), as described herein. Such "highly pure" compound of the present invention is also used as part of the present invention.

[0128] All configurational isomers of the compounds of this invention are included within their scope, whether in admixture, pure, or highly pure form. The definition of the compounds of this invention includes the two olefin isomers, cis (Z) and trans (E), as well as cis and trans isomers of carbocyclic and heterocyclic rings. Throughout the specification, groups and substituents may be chosen to provide stable fragments and compounds.

[0129] The definitions of specific functional groups and chemical terms are explained in detail below. In the present invention, the chemical elements are as defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. The definitions of specific functional groups are also explained therein. Furthermore, the basic principles of organic chemistry and specific functional groups and reactivity are also explained in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, the entire contents of which are incorporated herein by reference.

[0130] Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms. The present invention includes all compounds, including their 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. According to the present invention, the ratio of isomers contained in an isomeric mixture can vary. For example, a mixture having only two isomers can have combinations such as 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0, and all ratios of isomers are within the scope of the present invention. Similar ratios and ratios of more complex isomeric mixtures that would be readily apparent to one skilled in the art are also within the scope of the present invention.

[0131] The present invention also includes isotopically labeled compounds equivalent to the original compounds disclosed herein.However, in practice, it is common for one or more atoms to be replaced by atoms with different atomic masses or masses.Examples of isotopes that can be included in the compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes, respectively, for example. 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 Compounds of the present invention, or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates thereof, which contain isotopes or other isotopic atoms of the above compounds are within the scope of the present invention. 3 H and 14 Certain isotopically labeled compounds of the present invention, such as radioactive isotopes of C, are useful in drug and substrate tissue distribution studies. 3 H and carbon-14, i.e., 14 C is a preferred choice of isotope because its preparation and detection are relatively simple. Furthermore, deuterium, i.e. 2 Substitution with heavier isotopes such as H may be considered a priority in some cases due to better metabolic stability, which may provide advantages for certain therapies, such as increased half-life in vivo or reduced dosage. Isotopically labeled compounds can be prepared using common methods and schemes disclosed in the examples by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents.

[0132] If a synthesis of a particular enantiomer of a compound of the present invention is designed, it can be prepared by asymmetric synthesis or derivatized with a chiral auxiliary, the resulting diastereomeric mixture separated, and the chiral auxiliary removed to yield the pure enantiomers. Furthermore, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, diastereomeric salts can be formed with an appropriate optically active acid or base, which can then be separated by conventional means, such as preparative crystallization or chromatography, to yield the pure enantiomers.

[0133] As described herein, the compounds of the present invention can be substituted with any number of substituents or functional groups to expand their scope. Generally, whether the term "substituted" appears before or after the term "optionally," a general formula containing a substituent in a composition of the present invention refers to the replacement of a hydrogen radical with the specified structural substituent. When multiple positions in a particular structure are substituted with multiple specified substituents, the substituents may be the same or different at each position. The term "substituted" as used herein includes all permissible substitutions of organic compounds. Broadly speaking, permissible substituents include acyclic, cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds. In the present invention, for example, heteroatom nitrogen can have any of the above-mentioned permissible organic compounds to supplement the hydrogen substituent or valence state. Furthermore, the present invention does not intend to limit the organic compounds in which substitution is permitted in any way. The present invention is considered to be highly suitable for the treatment of diseases in the form of stable compounds with a combination of substituents and variables. The term "stable" as used herein refers to having a stable compound sufficient to maintain the structural integrity of the compound for a sufficient period of time, and preferably to be found to be effective for a sufficient period of time, as used herein for the purposes described above.

[0134] The claims of the present application also include metabolic products of the compounds of the present application and pharmaceutically acceptable salts thereof, as well as prodrugs that can be converted in vivo into the structures of the compounds of the present application and pharmaceutically acceptable salts thereof. In another preferred example, in the compound, any of ring A, ring B, R1, R2, and X1 is a corresponding group in the specific compound.

[0135] Preparation method The following schemes and examples describe methods for preparing compounds of Formula I. Raw materials and intermediates are purchased from commercial sources, prepared by known procedures, or otherwise described. In certain cases, the order of carrying out the steps of the reaction schemes can be changed to facilitate the reaction or avoid unwanted side reaction products.

[0136] 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 configuration of the present invention. The compound of the present invention can be easily prepared by selectively combining various synthetic methods described herein or known in the art, and such combination can be easily carried out by those skilled in the art. In general, in the preparation process, each reaction is carried out in a suitable solvent under inert gas protection at 0 to 150°C, and the reaction time is generally 2 to 24 hours.

[0137] A preferred preparation method is as follows. [ka]

[0138] Step 1: Reacting SM1 and M1 or M2 via palladium-catalyzed coupling or nucleophilic substitution in a solvent (e.g., 1,2-dichloroethane, dioxane, tetrahydrofuran) at 70-120°C to generate SM2; Step 2: M3 and SM2 are reacted in an inert solvent (e.g., DMF, dioxane, ethylene glycol dimethyl ether, N-methylpyrrolidone, tetrahydrofuran, etc.) under basic conditions (e.g., diisopropylethylamine, potassium acetate, DBU, LiHDMS, etc.) or in the presence of a catalyst and a ligand (e.g., Pd(pph3)4, Pd2(dba)3\t-BuXphos, etc.) to produce T (the compound of formula I).

[0139] In each of the above formulas, the definitions of ring A, ring B, R1, R2, and X1 are as described above. Unless otherwise stated, the above starting materials can be purchased from commercial sources or synthesized according to reported literature.

[0140] 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 diseases, infectious diseases, immune diseases, metabolic diseases, and the like. The compound described in general formula I can be used in combination with other drugs known to treat or improve similar pathologies. In the case of combined administration, the administration method and dosage of the original drug can be maintained unchanged, and the compound of formula I can be taken simultaneously or successively. When the compound of formula I is administered simultaneously with one or more other drugs, a pharmaceutical composition containing one or more known drugs and the compound of formula I simultaneously can be preferably used. The combination of drugs also includes administering the compound of formula I and one or more other known drugs during an overlapping period. When the compound of formula I is administered in combination with one or several other drugs, the dose of the compound of formula I or the known drug can be lower than the dose of their sequential administration.

[0141] Drugs or active ingredients that can be used in combination with the compounds according to general formula I include PD-1 inhibitors (e.g., nivolumab, pembrolizumab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT1306, AK105, LZM009 or biosimilars of the above drugs, etc.), PD-L1 inhibitors (e.g., durvalumab, atezolizumab, ), CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F520, GR1405, MSB2311 or biosimilars of the above drugs, etc.), CD20 antibodies (e.g., Rituximab, Obinutuzumab, Ofatumumab, Tositumomab, Ibritumomab, etc.), CD47 antibodies (e.g., Hu5F9-G4, CC-90002, TTI-621, T TI-622, OSE-172, SRF-231, ALX-148, NI-1701, SHR-1603, IBI188, IMM01), ALK inhibitors (e.g., ceritinib, alectinib, brigatinib, lorlatinib, okatinib), PI3K inhibitors (e.g., idelalisib, dactolisib, taselisib, buparlisib) etc.), BTK inhibitors (e.g., Ibrutinib, Tirabrutinib, Acalabrutinib, etc.), EGFR inhibitors (e.g., Afatinib, Gefitinib, Erlotinib, Lapatinib, Dacomitinib, Icotinib, Canertinib, etc.), VEGFR inhibitors (e.g., Sorafenib,Pazopanib, Ribatinib, Cabozantinib, Sunitinib, Donafenib, etc.), HDAC inhibitors (e.g., Givinostat, Droxinostat, Entinostat, Dacinostat, Tacedinaline, etc.), MEK inhibitors (e.g., Selumetinib, ) (AZD6244), trametinib (GSK1120212), PD0325901, U0126, AS-703026, PD184352 (CI-1040), etc.), Akt inhibitors (e.g., MK-2206, Ipatasertib, Capivasertib, Afuresertib, Uprosertib, etc.), mTOR inhibitors (e.g., Vistasertib, etc.), SHP2 inhibitors (e.g., R MC-4630, JAB-3068, TNO155, etc.), IGF-1R inhibitors (e.g., ceritinib, okatinib, linsitinib, BMS-754807, GSK1838705A, etc.), ER antagonists or degraders (e.g., tamoxifen, fulvestrant, etc.), aromatase inhibitors (e.g., letrozole, etc.), BCL2 or BCL-XL inhibitors (e.g., ABT-19 9, ABT-263, etc.), hedgehog inhibitors (e.g., vismodegib, cyclopamine, etc.), chemotherapy drugs (e.g., cisplatin, etoposide, topotecan, etc.), PARP inhibitors (e.g., olaparib, veliparib, rucaparib, etc.), ATR / ATM inhibitors (e.g., ceralasertib,Berzosertib, etc.) or combinations thereof.

[0142] Dosage forms of the pharmaceutical compositions of the present invention include, but are not limited to, injections, tablets, capsules, aerosols, suppositories, films, drop pills, external liniments, controlled- or sustained-release or nanoformulations. 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 2000 mg of the compound / agent of the present invention, more preferably 10 to 1000 mg of the compound / agent of the present invention. Preferably, the "single agent" is one capsule or tablet.

[0143] A "pharmaceutically acceptable vector" 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 be blended with each other without significantly reducing the efficacy of the compounds of the present invention. Some examples of pharmaceutically acceptable vectors 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.

[0144] 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. 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 vector), such as sodium citrate or dicalcium phosphate, or with (a) a filler or compatibilizer, 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; (d) agar, calcium carbonate, potato starch, or the like. The formulation may be mixed with ingredients such as disintegrating agents such as potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate, retarders such as paraffin, absorption accelerators such as quaternary amine compounds, wetting agents such as cetyl alcohol and glyceryl monostearate, adsorbents such as kaolin, and lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, and sodium lauryl sulfate, or mixtures thereof. In capsules, tablets, and pills, the dosage form may also contain buffering agents.

[0145] 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.

[0146] 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. Besides these inert diluents, compositions can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, and perfuming agents.

[0147] 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, or mixtures of these substances. 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.

[0148] 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 vector and any preservatives, buffers, or propellants that may be required. The therapeutic methods of the present invention can be used alone or in combination with other therapeutic procedures or therapeutic agents.

[0149] 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) 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. The present invention further provides a method for preparing a pharmaceutical composition, comprising mixing a pharmaceutically acceptable vector with a compound of formula I according to the present invention or a crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, to form a pharmaceutical composition.

[0150] The present invention further provides a method of treatment comprising administering to a subject in need thereof a compound of formula I as described herein, or a crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as described herein, to inhibit CDK4. Compared with the prior art, the present invention has the following main advantages: (1) The compounds of the present invention have excellent inhibitory potency and selectivity against CDK4 kinase. (2) The compounds of the present invention have less toxicity and side effects. (3) The compounds of the present invention have superior pharmacodynamic and pharmacokinetic properties.

[0151] The present invention will be further described below 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 without specific conditions are generally in accordance with conventional conditions, such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or conditions suggested by the manufacturer. Unless otherwise specified, percentages and parts are calculated by weight. 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.

[0152] Example A1 Synthesis of Compound TA-1 of the Invention: [ka] The synthetic route is as follows: [ka] The experimental process is as follows.

[0153] Phase 1: Under nitrogen gas conditions, SM1 (200 mg, 1.0 eq) was added to a 25 mL three-necked bottle, dissolved in 5 mL of ultra-dry DMF, and placed in an ice-water bath. NaH (32.5 mg, 2.0 eq) was added to the three-necked bottle, and after stirring for 30 minutes, 2-iodopropane (138.2 mg, 2.0 eq) was added. The mixture was then heated to 80 °C and allowed to react. After TLC showed the reaction was complete, the mixture was cooled to room temperature, extracted with saturated NaCl solution and EA, and the organic phase was extracted with water and the organic phase was separated. The organic phase was collected, dried over anhydrous sodium sulfate, concentrated, and then purified by silica gel column chromatography to obtain 100 mg of compound SM2 in a yield of 42.9%.

[0154] 1 H NMR (400MHz, Chloroform-d) δ 7.05(t,J=4.0Hz,1H),7.01(dd,J=8.0,4.0Hz,1H),4.62(p,J=8.0Hz,1H),4.54(s,2H),1.55(d,J=8.0Hz,6H).

[0155] Phase 2: Under nitrogen gas, SM2 (100 mg, 1.0 eq) was placed in a 10 mL reaction tube and dissolved in ultra-dry THF. Borane tetrahydrofuran solution (1.56 ml, 5.0 eq) was added, and the mixture was heated to 70 °C and refluxed. After TLC showed the reaction was complete, the mixture was cooled to room temperature and quenched with an appropriate amount of ice water. The reaction mixture was extracted with saturated NH4Cl solution and EA, and the liquids were separated. The organic phase was dried over anhydrous sodium sulfate and concentrated. After separation and purification by silica gel column chromatography, 82 mg of compound SM3 was obtained in an 86.3% yield. 1 H NMR(400MHz,Chloroform-d)δ 6.64(s,J=4.0Hz,1H),6.58(dd,J=8.0,4.0Hz,1H),4.27-4.21(m,2H),3.99(m,1H),3.25(t,J=4.0Hz,2H),1.18(d,J=8.0Hz,6H).

[0156] Stage 3: Under nitrogen gas conditions, SM3 (82 mg, 1.0 eq), B2Pin2 (98.7 mg, 1.3 eq), Pd(dppf)Cl2 (10.9 mg, 0.05 eq), and KOAc (88.0 mg, 3.0 eq) were sequentially added to a 10 mL reaction tube, 1,4-dioxane was added, the mixture was purged with nitrogen gas, and the temperature was raised to reflux. After the reaction was completed, the mixture was cooled to room temperature. The mixture was extracted with ethyl acetate and water, separated, and the organic phase was dried over anhydrous sodium sulfate and concentrated. After separation and purification by silica gel column chromatography, 50 mg of compound SM4 was obtained in a 52.0% yield. LCMS: [M+H] + =322.4.

[0157] Stage 4: Compound SM4 (265 mg, 1.0 eq), 2,4,5-trichloropyrimidine (196.7 mg, 1.3 eq), Pd(pph3)4 (95.0 mg, 0.1 eq), and sodium carbonate (262.4 mg, 3.0 eq) were added to a 25 mL three-neck bottle, followed by 12 mL of a 3:1 1,4-dioxane / HO mixture. The mixture was purged with nitrogen three times and then heated to reflux. After the reaction was complete, the mixture was cooled to room temperature, extracted with EA and water, and the organic phase was dried over anhydrous sodium sulfate and concentrated. The organic phase was purified by silica gel column chromatography to give 130 mg of compound SM5. LCMS: [M+H] + =342.1, yield 46%.

[0158] Stage 5: Compound SM5 (160 mg, 1.0 eq), (3s,4r)-4-aminooxan-3-ol hydrochloride (93.4 mg, 1.3 eq), and DIPEA (211.6 mg, 3.5 eq) were added to 3.0 mL of DMSO solvent and heated to 90 °C under nitrogen gas protection. After the reaction was completed, the mixture was cooled to room temperature and extracted with saturated sodium chloride solution, water, and EA. The organic phase was dried over anhydrous sodium sulfate and concentrated. After separation and purification by silica gel column chromatography, 75 mg of compound TA-1 was obtained. The yield was 38% and the HPLC purity was 99.4%. LCMS: [M+H] + =423.2.

[0159] 1H NMR(400MHz,Chloroform-d)δ 8.26(s,1H),7.00(d,J=4.0Hz,1H),6.97(dd,J=12.0,4.0Hz,1H),5.22(d,J=8.0Hz,1H), 4.99(s,1H),4.43-4.28(m,2H),4.05(dd,J=12.0,4.0Hz,1H),4.01-3.95(m,1H),3.86-3 .77(m,1H),3.68-3.56(m,1H),3.45(td,J=12.0,4.0Hz,1H),3.29(t,J=4.0,2H),3.17(t ,J=8.0Hz,1H),2.02(d,J=12.0Hz,1H),1.76-1.64(m,2H),1.21(dd,J=8.0,4.0sHz,6H).

[0160] The following compounds are synthesized with reference to the synthesis method of Example A1. [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0161] Example A2 Synthesis of the present compound TA-20: [ka]

[0162] The synthetic route is as follows: [ka] The experimental process is as follows.

[0163] 1. Synthesis of Compound SM2 Under nitrogen gas conditions, compound SM1 (5.97 g, 1.0 eq) was dissolved in 120 mL of DCM, cooled in an ice-water bath, and acetone (10.4 mL, 4.5 eq) and glacial acetic acid (9 mL, 5.0 eq) were added sequentially. The mixture was allowed to react for 30 minutes while maintaining the temperature, and then sodium borohydride acetate (26.6 g, 4.0 eq) was added in batches. After the addition was complete, the mixture was cooled to room temperature and allowed to react. After the reaction was completed, an appropriate amount of ammonium chloride solution was added to quench the reaction, followed by extraction with EA and water, followed by separation. The organic phase was dried over anhydrous sodium sulfate, concentrated, and then purified by silica gel column chromatography to obtain 2.8 g of compound SM2 in a yield of 38.4%.

[0164] 2. Synthesis of compound SM3: Under nitrogen gas conditions, compound SM2 (1.48 g, eq) and pyridine (1.01 g, 2.0 eq) were sequentially added to 15 mL of dichloromethane solvent, and the mixture was placed in an ice-water bath and stirred for 10 minutes. Isobutyryl chloride (2.05 g, eq) was slowly added dropwise, and after the addition was completed, the mixture was heated to 50 °C and reacted. After the reaction was completed, the mixture was extracted with ethyl acetate and water, and the organic phase was dried over anhydrous sodium sulfate and concentrated. After separation and purification by silica gel column chromatography, 1.62 g of compound SM3 was obtained with a yield of 83.9%.

[0165] 3. Synthesis of compound SM4: Under nitrogen gas, compound SM3 (95 mg, eq), bis(pinacolato)diboron (159.6 mg, 2.0 eq), Pd(dppf)Cl2 (11.5 mg, 0.05 eq), and potassium acetate (92.5 mg, 3.0 eq) were sequentially added to a 25 mL three-necked bottle, followed by 5 mL of ultra-dry 1,4-dioxane. The mixture was purged with nitrogen gas three times and heated to reflux. After the reaction was completed, the mixture was cooled to room temperature, extracted with ethyl acetate and water, and the organic phase was dried over anhydrous sodium sulfate and then concentrated to give the crude product containing compound SM4, which was used directly in the next step. LCMS: [M+H] + =350.2.

[0166] 4. Synthesis of compound SM5: Crude compound SM4 (110 mg, 1.0 eq), 2,4,5-trichloropyrimidine (81.7 mg, 1.3 eq), Pd(pph3)4 (39.6 mg, 0.1 eq), and sodium carbonate (109.0 mg, eq) were added sequentially to a 25 mL three-neck bottle. 8 mL of a 3:1 mixture of 1,4-dioxane and water was added, and the mixture was purged with nitrogen gas three times. The mixture was then heated and refluxed. After the reaction was completed, the mixture was cooled to room temperature, extracted with ethyl acetate and water, and the organic phase was dried over anhydrous sodium sulfate and concentrated. The mixture was then purified by silica gel column chromatography to give 43 mg of compound SM5. LCMS: [M+H] + =370.0.

[0167] 5. Synthesis of compound TA-20: Compound SM5 (43 mg, 1.0 eq), (3s,4r)-4-aminooxan-3-ol hydrochloride (23.2 mg, 1.3 eq), and DIPEA (52.5 mg, 3.5 eq) were added to 3.0 mL of DMSO solvent and heated to 90 °C under nitrogen gas protection. After the reaction was completed, the mixture was cooled to room temperature and extracted with saturated sodium chloride solution, water, and EA. The organic phase was dried over anhydrous sodium sulfate and concentrated. After separation and purification by silica gel column chromatography, 25 mg of compound TA-20 was obtained. The yield was 47.9% and the HPLC purity was 99.4%. LCMS: [M+H] + =451.10.

[0168] 1 H NMR(400MHz,Chloroform-d)δ 8.35(s,1H),7.55(d,J=8.0Hz,1H),7.37(s,1H),6.97(dt,J=8.0,2.2Hz,1H),5.30(d,J=6.3Hz,1H),5.03 (p,J=6.8Hz,1H),4.34(s,1H),4.05(dd,J=11.4,4.9Hz,1H),4.02-3.93(m,1H),3.87(tt,J=11.2,5.8Hz,1 H),3.63(tt,J=9.0,4.2Hz,1H),3.46(td,J=11.9,2.3Hz,1H),3.18(t,J=10.6Hz,1H),2.38-2.24(m,1H), 2.13-2.00(m,1H),1.72(td,J=12.1,4.8Hz,1H),1.08(dd,J=7.0,4.3Hz,6H),1.02(dd,J=6.6,2.8Hz,6H).

[0169] The following compounds are synthesized with reference to the synthesis method of Example A2. [ka]

[0170] Example A3 Compound TA-22 synthesized according to the present invention: [ka]

[0171] The synthetic route is as follows: [ka]

[0172] The experimental process is as follows. 1. Synthesis of compound SM2: Under nitrogen gas conditions, add p-bromoanisole SM1 (2.0 g, 1.0 eq) to a dry 50 mL three-neck bottle, add 20 mL of 1,2-dichloroethane to dissolve, place in an ice-water bath, and after the temperature stabilizes, add isobutyryl chloride (1.72 g, 1.5 eq) and anhydrous aluminum chloride (2.84 g, 2.0 eq) sequentially. Return to room temperature and heat to reflux temperature. After liquid chromatography indicates the reaction of the raw materials is complete, cool to room temperature, slowly pour into ice water to quench, and extract with dichloroethane. Separate, dry the organic phase over anhydrous sodium sulfate, concentrate under reduced pressure, and then separate and purify by column chromatography to obtain 2.0 g of a pale yellow oily liquid SM2. The yield is 79%. 1 H NMR(400MHz,Chloroform-d)δ 12.43(s,1H),7.88(d,J=2.4Hz,1H),7.54(dd,J=8.0,2.4Hz,1H),6.91(d,J=8.0Hz,1H),3.54(m,J=8.0Hz,1H),1.25(d,J=8.0Hz,6H).

[0173] 2. Synthesis of compound SM3: Under nitrogen gas conditions, compound SM2 (2.5 g, 1.0 eq) was dissolved in 35 mL of acetone, and ethyl bromoacetate (3.4 mL, 3.0 eq) and potassium carbonate (4.26 g, 3.0 eq) were added sequentially. The reaction was allowed to proceed at room temperature. After TLC showed the disappearance of the raw materials, the reaction was terminated. The mixture was suction filtered under reduced pressure, the filter cake was washed with an appropriate amount of ethyl acetate, extracted with water, and the layers were separated. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. After separation and purification by silica gel column chromatography, 2.16 g of compound SM3 was obtained. [M+H] + =330.9, [M+Na] + =350.9, yield is 80%.

[0174] 3. Synthesis of compound SM4: Under nitrogen gas, compound SM3 (2.16 g, 1.0 eq) was placed in a 50 ml three-neck bottle, and an aqueous solution of sodium carbonate (2.08 g, 3.0 eq) was added. The mixture was then reacted at 90°C for 3 hours. After TLC showed the disappearance of the raw materials, the reaction was terminated. The mixture was cooled to room temperature, quenched with 1 M HCl in an ice-water bath, and the pH was adjusted to 3-4. An appropriate amount of ethyl acetate was added for extraction, and the mixture was separated. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain 1.85 g of a pale yellow solid, SM4. [M+H] + =303.1, [M+Na] + =325.1, yield 94%. 4. Synthesis of compound SM5:

[0175] Under nitrogen gas conditions, compound SM4 (1.8 g, 1.0 eq) was dissolved in 18 ml of acetic anhydride, sodium acetate (2.7 g, 5.5 eq) was added, and the mixture was purged with nitrogen gas three times. The mixture was then reacted at 140 °C overnight. After TLC showed the disappearance of the raw materials, the reaction was stopped and cooled to room temperature. The mixture was extracted with an appropriate amount of ethyl acetate and water, and the organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain 1.01 g of colorless oily compound SM5, with a yield of 71.1%.

[0176] 5. Synthesis of compound SM6: Under nitrogen gas conditions, compound SM5 (200 mg, 1.0 eq) was dissolved in 2 ml of dioxane, and bis(pinacolato)diboron (430 mg, 2.0 eq), Pd(dppf)Cl2 (31 mg, 0.05 eq), and KOAc (250 mg, 3.0 eq) were added in that order. The mixture was purged with nitrogen gas three times and reacted at 80°C overnight. After TLC showed the disappearance of the raw materials, the reaction was stopped and cooled to room temperature. The mixture was extracted with an appropriate amount of ethyl acetate and water, separated, and the organic phase was dried over anhydrous sodium sulfate, concentrated, and used directly in the next step.

[0177] 6. Synthesis of compound SM7: Under nitrogen gas conditions, compound SM6 (crude, 240 mg, 1.0 eq) was dissolved in dioxane / water (10V:2V). 2,4,5-trichloropyrimidine (230 mg, 1.5 eq), Pd(pph3)4 (97 mg, 0.1 eq), and sodium carbonate (267 mg, 3.0 eq) were added sequentially. The atmosphere was purged with nitrogen gas three times and the reaction mixture was allowed to react at 90°C for 4 hours. After TLC showed the disappearance of the raw materials, the reaction was stopped and the mixture was cooled to room temperature. The mixture was extracted with an appropriate amount of ethyl acetate and water, and the organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain 180 mg of colorless oily compound SM7 in a 70% yield.

[0178] 7. Synthesis of compound TA-22: Under nitrogen gas conditions, compound SM7 (180 mg, 1.0 eq) was dissolved in 2 ml of DMSO, and (3S,4R)-4-aminooxacyclohexan-3-ol hydrochloride (135 mg, 1.5 eq) and DIPEA (0.4 ml, 3.5 eq) were added. The mixture was allowed to react overnight at 80 °C. After TLC showed the disappearance of the raw materials, the reaction was stopped and cooled to room temperature. The mixture was extracted with an appropriate amount of ethyl acetate and water, and the organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by thick preparative plate to obtain 54 mg of pale yellow solid compound TA-22, [M+H]. +=388.2, yield 23.9%.

[0179] 1 H NMR(400MHz,Chloroform-d)δ 8.31(s,1H),8.04(d,J=2.0Hz,1H),7.69(dd,J=8.6,1.8Hz,1H),7.54(d,J=8.0Hz,1H),7.4 3(s,1H),5.31(d,J=4.0Hz,1H),5.08(s,1H),4.05(dd,J=12.0,4.0Hz,1H),3.98(dd,J=12. 0,4.0Hz,1H),3.89-3.75(m,1H),3.62(td,J=8.0,4.0Hz,1H),3.44(td,J=12.0,2.0Hz,1H) ,3.25-3.05(m,2H),2.03(dt,J=12.0,4.0Hz,1H),1.74-1.67(m,1H),1.38(d,J=8.0Hz,6H).

[0180] The following compounds are synthesized with reference to the synthesis method of Example A3. [ka]

[0181] Example A4 Synthesis of the compound of the present invention, TA-24: [ka]

[0182] The synthetic route is as follows: [ka]

[0183] The experimental process is as follows. 1. Synthesis of compound SM2: Under nitrogen gas, calcium 4-methyl-2-ketopentanoate (5 g, 1.0 eq) was added to a 250 mL three-necked bottle, glacial acetic acid (100 mL) was slowly added, and pyridinium tribromide (13.4 g, 2.5 eq) was added while stirring, and the mixture was allowed to react at room temperature. After the reaction was completed, most of the acetic acid solvent was removed by concentration under reduced pressure, followed by extraction with an appropriate amount of water and EA. The organic phase was dried over anhydrous sodium sulfate, suction filtered, and concentrated under reduced pressure to obtain the crude product SM2, which was used directly in the next step.

[0184] 2. Synthesis of compound SM3: The crude SM2 (9.0 g) obtained in the previous step was dissolved in absolute ethanol. Concentrated sulfuric acid (1.78 mL, 1.0 eq) was slowly added dropwise to the ethanol solution, and the mixture was heated to reflux under nitrogen gas protection. After the reaction was completed, the mixture was cooled to room temperature, and solid sodium bicarbonate was slowly added directly to the reaction mixture to adjust the pH to approximately 7. Most of the solvent was removed by concentration under reduced pressure, followed by extraction with EA and water, followed by separation. The organic phase was dried over anhydrous sodium sulfate, suction filtered, and concentrated under reduced pressure to remove the organic solvent. The mixture was then separated and purified by silica gel column chromatography to obtain 4.1 g of compound SM3, with a two-step reaction yield of 52%. 1 H NMR(400MHz,Chloroform-d)δ 4.85(d,J=8.0Hz,1H),4.37(q,J=8.0Hz,2H),2.49-2.26(m,1H),1.39(t,J=8.0Hz,3H),1.14(d,J=4.0Hz,3H),1.05(d,J=4.0Hz,3H).

[0185] 3. Synthesis of compound SM4: Compound SM3 (4.0 g, 1.0 eq) was dissolved in ultra-dry 1,4-dioxane (80 mL), and 2-amino-5-bromopyridine (2.9 g, 1.0 eq) and solid sodium bicarbonate (2.8 g, 2.8 eq) were added sequentially. The mixture was heated to reflux and reacted. After the reaction was completed, the mixture was cooled to room temperature, extracted with saturated ammonium chloride solution and EA, and the organic phase was dried over anhydrous sodium sulfate. After suction filtration, the solvent was removed by concentration under reduced pressure. The mixture was separated and purified by silica gel column chromatography to obtain 1.7 g of compound SM4 in a 32.4% yield.

[0186] 1 H NMR(400MHz,Chloroform-d)δ 8.29(d,J=4.0Hz,1H),7.57(dd,J=8.0,4.0Hz,1H),4.45(q,J=7.1Hz,2H),4.28(m,1H),1.48(d,J=8.0Hz,6H),1.44(d,J=8.0Hz,3H).

[0187] 4. Synthesis of compound SM5: Under nitrogen gas, compound SM4 (1.7 g, 1.0 eq) was dissolved in ultra-dry tetrahydrofuran (35 mL), placed in an ice-water bath, and 3.0 M MeMgBr solution (9.1 mL, 5.0 eq) was slowly added dropwise while controlling the temperature. After the addition was complete, the mixture was allowed to warm to room temperature and react. After the reaction was complete, the excess Grignard reagent was quenched with saturated ammonium chloride under ice-water bath conditions, extracted with EA, separated, dried over anhydrous sodium sulfate, suction filtered, and concentrated under reduced pressure to remove the solvent. The mixture was then purified by silica gel column chromatography to obtain 0.8 g of compound SM5 in a 49.4% yield. 1 H NMR(400MHz,Chloroform-d)δ 8.25(dd,J=1.8,0.9Hz,1H),7.45(dd,J=9.5,0.9Hz,1H),7.16(dd,J=9.5,1.8Hz,1H),3.93(hept,J=7.4Hz,1H),1.64(s,7H),1.45(d,J=7.4Hz,6H).

[0188] 5. Synthesis of compound SM6: Under nitrogen gas protection, compound SM5 (0.8 g, 1.0 eq), bis(pinacolato)diboron (1.4 g, 2.0 eq), Pd(dppf)Cl2 (98.5 mg, 0.05 eq), and potassium acetate (0.8 g, 3.0 eq) were added to a dried three-neck flask, followed by the addition of ultra-dry 1,4-dioxane (20 mL) and the mixture was heated to reflux. After the reaction was completed, the mixture was cooled to room temperature, extracted with Ea and water, separated, dried over anhydrous sodium sulfate, suction filtered, and concentrated under reduced pressure to obtain a crude product containing SM6.

[0189] 6. Synthesis of compound SM7: Under nitrogen gas protection, compound SM6 (theoretical value: 0.93 g, 1.0 eq), Pd(pph3)4 (0.31 g, 0.1 eq), 2,4-dichloro-5-fluoropyrimidine (0.58 g, 1.3 eq), and sodium carbonate (0.86 g, 3.0 eq) were added to a dried three-neck flask, and a mixture of ultra-dry 1,4-dioxane and water (26 mL, v / v = 10:3) was added. The mixture was heated to reflux and reacted. After the reaction was completed, the mixture was cooled to room temperature, extracted with Ea and water, separated, dried over anhydrous sodium sulfate, suction filtered, and concentrated under reduced pressure to give 0.4 g of compound SM7. The two-step yield was 41%. LCMS: [M+H] + =366.2.

[0190] 7. Synthesis of compound TA-24: Compound SM7 (0.4 g, 1.0 eq), (3s,4r)-4-aminooxan-3-ol hydrochloride (0.34 g, 2.0 eq), and DIPEA (0.8 mL, 4.0 eq) were added to 8.0 mL of DMSO solvent and heated to 90 °C under nitrogen gas protection. After the reaction was completed, the mixture was cooled to room temperature and extracted with saturated sodium chloride solution, water, and EA. The organic phase was dried over anhydrous sodium sulfate and concentrated. After separation and purification by silica gel column chromatography, 120 mg of compound TA-24 was obtained. The yield was 24.5% and the HPLC purity was 96.5%. LCMS: [M+H] +=430.2.

[0191] 1 H NMR(400MHz,Chloroform-d)δ 9.03(s,1H),8.24(d,J=3.8Hz,1H),7.84(d,J=9.5Hz,1H),7.62(d,J=9.5Hz,1H),5.25(d, J=6.3Hz,1H),4.09(dd,J=11.4,4.9Hz,1H),4.04-3.97(m,2H),3.88(tt,J=11.0,5.5Hz,1H ),3.66(td,J=9.5,4.9Hz,2H),3.49(td,J=11.8,2.3Hz,1H),3.23(dd,J=11.4,9.8Hz,1H) ,2.17-2.06(m,1H),1.73(dd,J=8.6,3.9Hz,2H),1.68(s,6H),1.51(dd,J=7.4,2.2Hz,6H).

[0192] The following compounds are synthesized with reference to the synthesis method of Example A4. [ka] [ka] [ka]

[0193] Example A5 Synthesis of the compound of the present invention, TA-30: [ka] The synthetic route is as follows: [ka] The experimental process is as follows.

[0194] 1. Synthesis of compound SM2: Under nitrogen gas conditions, compound SM1 (0.9 g, 1.0 eq) was dissolved in ultra-dry DMF solvent, placed in an ice-water bath, and sodium hydride solid powder (0.18 g, 1.1 eq) was added in batches. The reaction was allowed to proceed with temperature control for 15 minutes. Iodomethane (0.64 g, 1.1 eq) was added, and after the addition was completed, the reaction was allowed to warm up naturally. After the reaction was completed, the mixture was quenched by adding ice water, extracted with EA, and the organic phase was dried over anhydrous sodium sulfate, suction filtered, concentrated under reduced pressure, and purified by column chromatography to obtain compound SM2 (0.85 g, 89%).

[0195] 2. Synthesis of compound SM3: Under nitrogen gas conditions, compound SM2 (0.85 g, 1.0 eq) was dissolved in ethyl acetate, and 4.0 M hydrochloric acid in dioxane (9 mL, 10.0 eq) was added and reacted at room temperature. After the reaction was completed, the mixture was concentrated under reduced pressure and used directly in the next step. 3. Synthesis of compound SM4: Compound SM3 (0.49 g, 1.0 eq), 2,4,5-trichloropyrimidine (0.67 g, 1.0 eq), and DIPEA (1.9 g, 4.0 eq) were added to isopropanol solvent in sequence, and the mixture was heated to 80°C to react. After the reaction was completed, the mixture was cooled to room temperature, extracted with EA and water, and the layers were separated. The organic phase was dried over anhydrous sodium sulfate, suction filtered, concentrated under reduced pressure, and purified by column chromatography to obtain compound SM4 (0.9 g, 59.4%). LCMS: [M+H] + =280.0.

[0196] 4. Synthesis of compound TA-30: Under nitrogen gas conditions, compound SM4 (0.1 g, 1.0 eq), (3s,4r)-4-aminooxan-3-ol hydrochloride (0.083 g, 1.5 eq), and DIPEA (0.12 g, 2.5 eq) were added to DMSO solvent, and the mixture was heated to 90°C to react. After the reaction was completed, the mixture was cooled to room temperature, extracted with saturated brine, water, and EA, and the layers were separated. The organic phase was dried over anhydrous sodium sulfate, suction filtered, concentrated under reduced pressure, and purified by column chromatography to obtain compound TA-30 (56 mg, 43.4%). LCMS: [M+H] + =361.2, HPLC purity is 99.5%.

[0197] 1 H NMR(400MHz,Chloroform-d)δ 7.85(d,J=2.0Hz,1H),5.02(s,1H),4.80(ddd,J=47.7,7.2,3.8Hz,1H),4.28-4.12(m,1H) ),4.04(dd,J=11.4,5.0Hz,1H),4.01-3.85(m,2H),3.70(dq,J=7.4,5.0,3.7Hz,2H),3.57 (dd,J=9.6,5.0Hz,3H),3.49-3.45(m,3H),3.45-3.28(m,2H),3.15(dd,J=11.4,9.8Hz,1H ),2.12-2.03(m,1H),2.00-1.90(m,1H),1.89-1.74(m,1H),1.66(qd,J=12.1,4.8Hz,1H).

[0198] The following compounds are synthesized with reference to the synthesis method of Example A5. [ka]

[0199] Example A6 Synthesis of the compound of the present invention, TA-32: [ka] The synthetic route is as follows: [ka]

[0200] The experimental process is as follows. 1. Synthesis of compound SM2: SM1 (20.0 g, 1.0 eq) was added to a 1000 ml three-neck bottle and dissolved in DCM (500 ml, 25 V). The bottle was then cooled to -78 °C using liquid nitrogen. DIPEA (110.82 ml, 5.3 eq) was added and stirred for 10 minutes. TfO (25.83 ml, 1.2 eq) was then slowly added and the mixture was warmed to room temperature. TLC showed no remaining starting materials, and the reaction was terminated. The apparatus was placed in an ice-water bath, and the reaction mixture was quenched by slowly adding water (250 ml). The mixture was extracted with DCM and then separated. The organic phase was washed twice with 5% aqueous citric acid, concentrated, and purified by silica gel column chromatography to give 35.58 g of a pale yellow oil, SM2. LCMS: [M+H] + =289, yield 96.4%.

[0201] 2. Synthesis of compound SM3: CuI (1.54 g, 0.066 eq) and Pd(pph3)Cl2 (1.72 g, 0.02 eq) were added to a 1000 mL three-necked bottle. Under N2 protection, a THF solution of SM2 (35.32 g, 1.0 eq) was added, followed by a THF solution of trimethylsilylacetylene (26.0 mL, 1.5 eq) and triethylamine (49.22 mL, 2.89 eq). A total of 500 mL of THF was added, and the mixture was purged with nitrogen gas three times. The reaction was allowed to proceed at room temperature. TLC showed no remaining starting material, and the reaction was terminated. The mixture was extracted with saturated aqueous NH4Cl and ethyl acetate. The organic phase was dried and concentrated, followed by purification by silica gel column chromatography to give 30.66 g of a brown oil, SM3, in a 95% yield.

[0202] 3. Synthesis of compound SM4: SM3 (30.66 g, 1.0 eq) was dissolved in THF / MEOH (600 ml, 10V:10V) and placed in a 1000 ml three-necked bottle. 1 M aqueous lithium hydroxide solution (10.9 g, 2.0 eq) was added and the mixture was reacted at 50 °C under nitrogen gas protection. TLC showed that no raw materials remained, and the reaction was terminated. The mixture was cooled to room temperature. After concentrating the mixture to a certain extent, it was extracted with ethyl acetate and water. The aqueous phase was retained and adjusted to acidic pH with 2 M HCl. After extraction with ethyl acetate, the organic phase was dried and concentrated to give 15.3 g of an orange-yellow solid, SM4, in an 86.6% yield.

[0203] 4. Synthesis of compound SM5: SM4 (15.3 g, 1.0 eq), NH4Cl (30.04 g, 5.0 eq), and HATU (64.07 g, 1.5 eq) were added to a 1000 ml three-necked bottle, followed by 1,4-dioxane (300 ml) and DIPEA (58.7 ml, 3.0 eq). The mixture was reacted at room temperature under nitrogen gas protection. TLC showed that no raw materials remained, and the reaction was terminated. The mixture was suction filtered through diatomaceous earth, the filter cake was washed with an appropriate amount of DCM, and the mixture was extracted with DCM and water. The organic phase was dried and concentrated, and the mixture was separated and purified by silica gel column chromatography to obtain 18.7 g of a yellow solid, SM5. LCMS: [M+H] + =136.00, yield is 95%.

[0204] 5. Synthesis of compound SM6: SM5 (18.6 g, 1.0 eq) was added to a 2000 ml three-necked bottle, and a 2.0 M dimethylamine ethanol solution (688 ml, 10.0 eq) was added. Under nitrogen gas protection, the temperature was slowly raised to 80 °C. Since a large amount of gas was generated at the beginning of the reaction, the temperature was lowered appropriately or the condensed water flow was increased. When TLC showed that no raw materials remained, the reaction was terminated. The mixture was cooled to room temperature. The system was directly concentrated, and separated and purified by silica gel column chromatography to obtain 13.6 g of a yellow-brown solid SM6. LCMS: [M+H] + =136.30, yield 73%.

[0205] 6. Synthesis of compound SM7: SM6 (520 mg, 1.0 eq) was added to a 50 ml three-necked bottle, and DMF (10 ml) was added to dissolve it. After purging with nitrogen gas three times, the bottle was cooled to 0 °C in an ice-water bath, and 60% NaH (313 mg, 1.2 eq) was added in batches. The reaction was allowed to proceed at 0 °C for 30 minutes. Under nitrogen gas protection, CHCl (0.292 ml, 1.2 eq) was slowly added to the system, and the system was then allowed to return to room temperature. TLC showed that no raw materials remained, and the reaction was terminated. Ice water was added to the system to quench the reaction. The system was extracted with an appropriate amount of ethyl acetate and water, and the organic phase was dried and concentrated. The organic phase was separated and purified by silica gel column chromatography to obtain 344 mg of a white solid, SM7. LCMS: [M+H] + =150.30, yield is 59.9%.

[0206] 7. Synthesis of compound SM8: SM7 (344 mg, 1.0 eq) was added to a 100 mg bottle, dissolved in 10 ml of ACN, and then NBS (493 mg, 1.2 eq) was added and the mixture was reacted at room temperature under nitrogen gas protection. TLC showed that no raw material remained, and the reaction was terminated. Extraction was performed with ethyl acetate and water, and the organic phase was dried and concentrated. The mixture was separated and purified by silica gel column chromatography to obtain 400 mg of a white solid, SM8. LCMS: [M+H] + =150.30, yield 76.2%.

[0207] 8. Synthesis of compound SM9: SM8 (400 mg, 1.0 eq), bis(pinacolato)diboron (950 mg, 2.0 eq), Pd(dppf)Cl2 (68 mg, 0.05 eq), and KOAc (550 mg, 3.0 eq) were sequentially added to a 100 ml three-necked bottle. After flushing with nitrogen gas three times, 1,4-dioxane (10 ml) was added and the reaction was heated to 90 °C. TLC showed that no raw materials remained, and the reaction was terminated. The reaction was cooled to room temperature. Extraction was performed with ethyl acetate and water, and the organic phase was dried and concentrated. Separation and purification were performed by silica gel column chromatography to obtain 150 mg of a white solid, SM9. LCMS: [M+H] + =276.5, yield is 29%.

[0208] 9. Synthesis of compound SM10: SM9 (150 mg, 1.0 eq) was added to a 50 ml three-necked bottle, and 1,4-dioxane / HO (10V:3V) was added. Sodium carbonate (174 mg, 3.0 eq) and 2,4,5-trichloropyrimidine (0.082 ml, 1.3 eq) were added. The mixture was purged with nitrogen gas three times. Pd(pph3)4 (63 mg, 0.1 eq) was added, and the mixture was purged with nitrogen gas three times. The mixture was heated to 100 °C and reacted for 3 hours. TLC showed that no raw material remained, and the reaction was completed. The mixture was cooled to room temperature. Extraction was performed with ethyl acetate and water. The organic phase was dried and concentrated, and the mixture was separated and purified by silica gel column chromatography to obtain 60 mg of a white solid, SM10. LCMS: [M+H] + =298.5, yield 37.3%.

[0209] 10. Synthesis of compound TA-32: SM10 (60 mg, 1.0 eq) was dissolved in DMSO (2 ml), (3S,4R)-4-aminooxacyclohexan-3-ol hydrochloride (47 mg, 1.5 eq) was added, and DIPEA (0.145 ml, 4.0 eq) was added. The mixture was heated to 90°C under nitrogen gas protection and reacted. TLC showed that no raw material remained, and the reaction was completed. The mixture was cooled to room temperature. Extraction was performed with ethyl acetate and water, and the organic phase was dried and concentrated. The mixture was separated and purified by silica gel column chromatography to obtain 37 mg of white solid TA-32. LC-MS: [M+H] + =377.0, yield 44%. 1 H NMR(400MHz,Chloroform-d)δ 8.27(s,1H),7.53(s,1H),4.05(dd,J=12.0,4.0Hz,1H),4.00-3.94(m,1H),3.86-3.77(m,1H),3.64(t,J=8.0Hz, 2H),3.60(s,3H),3.46(td,J=12.0,2.4Hz,1H),3.18(dd,J=12.0,8.0Hz,1H),2.96(m,1H),2.88(t,J=8.0Hz,3H).

[0210] Example A7 Compound TA-33 synthesized in the present invention: [ka]

[0211] The synthetic route is as follows: [ka]

[0212] The experimental process is as follows. 1. Synthesis of compound SM7: SM6 (5 g, 1.0 eq) (see Synthetic Route 1, Steps 1 to 5) was added to a 250 ml three-neck bottle, dissolved in 50 ml of acetic acid, and liquid bromine (2.35 ml, 1.2 eq) was added. The mixture was allowed to react at room temperature for 2 hours under nitrogen gas. TLC showed that no raw materials remained, and the reaction was terminated. After concentration under reduced pressure, the mixture was separated and purified by silica gel column chromatography to obtain 7.25 g of a yellow solid, SM7. LCMS: [M+H] + =213.9 / 216.1, yield 91.5%.

[0213] 2. Synthesis of compound SM8: SM7 (5 g, 1.0 eq) was added to a 250 ml three-neck bottle, followed by silver carbonate (9.0 g, 1.4 eq). 150 ml of dichloromethane was added, and the mixture was purged with nitrogen gas three times. Iodomethane (15 ml, 10 eq) was added, and the reaction was continued at 37°C for 3 hours. TLC showed that no raw materials remained, and the reaction was terminated. The mixture was cooled to room temperature. The mixture was suction filtered through diatomaceous earth, and the filter cake was washed with an appropriate amount of dichloromethane. The filtrate was concentrated under reduced pressure, followed by separation and purification by silica gel column chromatography to obtain 3.47 g of a white solid, SM8, in a 65% yield.

[0214] 3. Synthesis of compound SM9: SM8 (3.0 g, 1.0 eq), bis(pinacolato)diboron (8.34 g, 2.5 eq), Pd(dppf)Cl2 (480 mg, 0.05 eq), and KOAc (3.9 g, 3.0 eq) were sequentially added to a 100 ml three-necked bottle. After flushing with nitrogen gas three times, 1,4-dioxane (40 ml) was added and the reaction was heated to 90 °C. TLC showed that no raw materials remained, and the reaction was completed. The reaction was cooled to room temperature. Extraction was performed with ethyl acetate and water, and the organic phase was dried and concentrated. Separation and purification were performed by silica gel column chromatography to obtain 3.9 g of white solid SM9. LCMS: [M+H] + =276.00, yield is 100%.

[0215] 4. Synthesis of compound SM10: SM9 (350 mg, 1.0 eq) was added to a 50 ml three-necked bottle, and 1,4-dioxane / HO (10V:3V) was added. Sodium carbonate (405 mg, 3.0 eq) and 2,4,5-trichloropyrimidine (0.19 ml, 1.3 eq) were added. The mixture was purged with nitrogen gas three times. Pd(pph3)4 (147 mg, 0.1 eq) was added, and the mixture was purged with nitrogen gas three times. The mixture was heated to 100 °C and reacted for 3 hours. TLC showed that no raw material remained, and the reaction was completed. The mixture was cooled to room temperature. Extraction was performed with ethyl acetate and water. The organic phase was dried and concentrated, and the mixture was separated and purified by silica gel column chromatography to obtain 100 mg of a white solid, SM10. LCMS: [M+H] + =295.9 / 297.9, yield is 26.6%.

[0216] 5. Synthesis of compound TA-33: SM10 (100 mg, 1.0 eq) was dissolved in DMSO (2 ml), (3S,4R)-4-aminooxacyclohexan-3-ol hydrochloride (78 mg, 1.5 eq) was added, and DIPEA (0.24 ml, 4.0 eq) was added. Under nitrogen gas protection, the temperature was raised to 90 °C and the reaction was carried out overnight. TLC showed that no raw materials remained, and the reaction was completed. The reaction was cooled to room temperature. Extraction was carried out with ethyl acetate and water, and the organic phase was washed twice with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, and then separated and purified by silica gel column chromatography to obtain 68 mg of white solid TA-33. LCMS: [M+H] + =377.10, yield 53.5%.

[0217] 1H NMR(400MHz,Chloroform-d)δ 8.29(s,1H),8.15(s,1H),5.35-5.22(m,1H),4.81(m,1H),4.01(m,5H),3.79(m,1H),3.60(m,1H),3.44(t,J= 12.0Hz,1H), 3.15(t,J=8.0Hz,1H),2.99(m,2H),2.89(d,J=4.0Hz,3H),2.18-2.07(m,2H),2.06-1.98(m,1H). The following compounds are synthesized with reference to the synthesis methods of Examples A6 and A7. [ka] [ka] [ka]

[0218] Example A8 Synthesis of the compound of the present invention, TA-39: [ka] The experimental process is as follows. Under nitrogen gas conditions, 5-[(4-methylpiperazin-1-yl)methyl]pyridin-2-amine (100 mg, 1.0 eq) was dissolved in 3 mL of tetrahydrofuran solvent and cooled to 0 °C in an ice-water bath. 1.0 M LiHDMS in tetrahydrofuran solution (0.73 mL, 1.5 eq) was slowly added and the mixture was allowed to react for 30 minutes while maintaining the temperature. Compound SM1 was then added and the mixture was allowed to react for 30 minutes while maintaining the temperature. After the completion of the reaction was monitored by TLC, an appropriate amount of ice water was added to quench the reaction. The mixture was extracted with ethyl acetate and water, and the layers were separated. The organic phase was dried over anhydrous sodium sulfate, suction filtered, concentrated, and purified by silica gel column chromatography to obtain 50 mg of compound TA-39. LCMS: [M+H] + =450.5, HPLC purity is 98.31%.

[0219] 1 H NMR (400 MHz, Chloroform-d) δ 8.12(d,J=12.0Hz,1H),8.10(d,J=1.6Hz,1H),7.56(dd,J=8.0,1.6Hz,1H),7.3 6(d,J=12.0Hz,1H),6.83(d,J=8.0Hz,1H),4.78(dt,J=48.0,4.0Hz,1H),4.21- 4.07(m,1H),3.92(brs,1H),3.60(m,2H),3.49(s,2H),3.46(s,3H),3.44-3.35 (m,1H),2.83(s,4H),2.69(s,4H),2.55(s,3H),2.03(m,1H),1.88-1.79(m,1H). The following compounds are synthesized with reference to the synthesis method of Example A8. [ka]

[0220] Example A9 Synthesis of the compound of the present invention, TA-32: [ka]

[0221] The synthetic route is as follows: [ka]

[0222] The experimental process is as follows. Phase 1: SM1 (20.0 g, 1.0 eq) was added to a 1000 ml three-neck bottle and dissolved in DCM (500 ml, 25 V). The bottle was then cooled to -78 °C using liquid nitrogen. DIPEA (110.82 ml, 5.3 eq) was added and stirred for 10 minutes. TfO (25.83 ml, 1.2 eq) was then slowly added and the mixture was warmed to room temperature. TLC showed no remaining starting materials, and the reaction was terminated. The apparatus was placed in an ice-water bath, and the reaction mixture was quenched by slowly adding water (250 ml). The mixture was extracted with DCM and then separated. The organic phase was washed twice with 5% aqueous citric acid, concentrated, and purified by silica gel column chromatography to give 35.58 g of a pale yellow oil, SM2. LCMS: [M+H] + =289, yield 96.4%.

[0223] Phase 2: CuI (1.54 g, 0.066 eq) and Pd(pph3)Cl2 (1.72 g, 0.02 eq) were added to a 1000 mL three-necked bottle. Under N2 protection, a THF solution of SM2 (35.32 g, 1.0 eq) was added, followed by trimethylsilylacetylene (26.0 mL, 1.5 eq) and triethylamine (49.22 mL, 2.89 eq) in THF. A total of 500 mL of THF was added, and the mixture was purged with nitrogen gas three times. The reaction was allowed to proceed at room temperature. TLC showed no remaining starting material, and the reaction was terminated. The mixture was extracted with saturated aqueous NH4Cl and ethyl acetate. The organic phase was dried and concentrated, followed by purification by silica gel column chromatography to give 30.66 g of a brown oil, SM3, in a 95% yield.

[0224] Stage 3: SM3 (30.66 g, 1.0 eq) was dissolved in THF / MEOH (600 ml, 10V:10V) and placed in a 1000 ml three-necked bottle. 1 M aqueous lithium hydroxide solution (10.9 g, 2.0 eq) was added and the mixture was reacted at 50 °C under nitrogen gas protection. TLC showed that no raw materials remained, and the reaction was terminated. The mixture was cooled to room temperature. After concentrating the mixture to a certain extent, it was extracted with ethyl acetate and water. The aqueous phase was retained and adjusted to acidic pH with 2 M HCl. After extraction with ethyl acetate, the organic phase was dried and concentrated to give 15.3 g of an orange-yellow solid, SM4, in an 86.6% yield.

[0225] Stage 4: SM4 (15.3 g, 1.0 eq), NH4Cl (30.04 g, 5.0 eq), and HATU (64.07 g, 1.5 eq) were added to a 1000 ml three-necked bottle, followed by 1,4-dioxane (300 ml) and DIPEA (58.7 ml, 3.0 eq). The mixture was reacted at room temperature under nitrogen gas protection. TLC showed that no raw materials remained, and the reaction was terminated. The mixture was suction filtered through diatomaceous earth, the filter cake was washed with an appropriate amount of DCM, and the mixture was extracted with DCM and water. The organic phase was dried and concentrated, and the mixture was separated and purified by silica gel column chromatography to obtain 18.7 g of a yellow solid, SM5. LCMS: [M+H] + =136.00, yield is 95%.

[0226] Stage 5: SM5 (18.6 g, 1.0 eq) was added to a 2000 ml three-necked bottle, and a 2.0 M dimethylamine ethanol solution (688 ml, 10.0 eq) was added. Under nitrogen gas protection, the temperature was slowly raised to 80 °C. Since a large amount of gas was generated at the beginning of the reaction, the temperature was lowered appropriately or the condensed water flow was increased. When TLC showed that no raw materials remained, the reaction was terminated. The mixture was cooled to room temperature. The system was directly concentrated, and separated and purified by silica gel column chromatography to obtain 13.6 g of a yellow-brown solid SM6. LCMS: [M+H] + =136.30, yield 73%.

[0227] Stage 6: SM6 (520 mg, 1.0 eq) was added to a 50 mL three-necked bottle, and DMF (10 ml) was added to dissolve it. After purging with nitrogen gas three times, the bottle was cooled to 0 °C in an ice-water bath, and 60% NaH (313 mg, 1.2 eq) was added in batches. The reaction was allowed to proceed at 0 °C for 30 minutes. Under nitrogen gas protection, CHCl (0.292 ml, 1.2 eq) was slowly added to the system, and the system was then allowed to return to room temperature. TLC showed that no raw materials remained, and the reaction was terminated. Ice water was added to the system to quench the reaction. The system was extracted with an appropriate amount of ethyl acetate and water, and the organic phase was dried and concentrated. The organic phase was separated and purified by silica gel column chromatography to obtain 344 mg of a white solid, SM7. LCMS: [M+H] + =150.30, yield is 59.9%.

[0228] Stage 7: SM7 (344 mg, 1.0 eq) was added to a 100 mg bottle, dissolved in 10 mL of acetonitrile, and then NBS (493 mg, 1.2 eq) was added. The mixture was then reacted at room temperature under nitrogen gas protection. TLC showed that no raw material remained, and the reaction was terminated. The mixture was extracted with ethyl acetate and water, and the organic phase was dried and concentrated. The mixture was separated and purified by silica gel column chromatography to obtain 400 mg of a white solid, SM8. LCMS: [M+H] + =150.30, yield 76.2%.

[0229] Stage 8: SM8 (400 mg, 1.0 eq), bis(pinacolato)diboron (950 mg, 2.0 eq), Pd(dppf)Cl2 (68 mg, 0.05 eq), and KOAc (550 mg, 3.0 eq) were sequentially added to a 100 mL three-necked bottle. After flushing with nitrogen gas three times, 1,4-dioxane (10 mL) was added and the reaction was heated to 90 °C. TLC showed that no raw materials remained, and the reaction was completed. The reaction was cooled to room temperature. Extraction was performed with ethyl acetate and water, and the organic phase was dried and concentrated. Separation and purification were performed by silica gel column chromatography to obtain 150 mg of a white solid, SM9. LCMS: [M+H] + =276.5, yield is 29%.

[0230] Stage 9: SM9 (150 mg, 1.0 eq) was added to a 50 mL three-necked bottle, and 1,4-dioxane and HO (10V:3V) were added. Sodium carbonate (174 mg, 3.0 eq) and 2,4,5-trichloropyrimidine (0.082 mL, 1.3 eq) were added. The mixture was purged with nitrogen gas three times. Pd(pph3)4 (63 mg, 0.1 eq) was added, and the mixture was purged with nitrogen gas three times. The mixture was heated to 100 °C and reacted for 3 h. TLC showed that no raw material remained, and the reaction was completed. The mixture was cooled to room temperature. Extraction was performed with ethyl acetate and water. The organic phase was dried and concentrated, and the mixture was separated and purified by silica gel column chromatography to give 60 mg of a white solid, SM10. LCMS: [M+H] + =298.5, yield 37.3%.

[0231] Stage 10: SM10 (60 mg, 1.0 eq) was dissolved in DMSO (2 ml), (3S,4R)-4-aminooxacyclohexan-3-ol hydrochloride (47 mg, 1.5 eq) was added, and DIPEA (0.145 mL, 4.0 eq) was added. The mixture was heated to 90°C under nitrogen gas protection. TLC showed that no raw material remained, and the reaction was completed. The mixture was cooled to room temperature. Extraction was performed with ethyl acetate and water, and the organic phase was dried and concentrated. The mixture was separated and purified by silica gel column chromatography to obtain 37 mg of white solid TA-32. LC-MS: [M+H] + =377.0, yield 44%.

[0232] 1 H NMR(400MHz,Chloroform-d)δ 8.27(s,1H),7.53(s,1H),4.05(dd,J=12.0,4.0Hz,1H),4.00-3.94(m,1H),3.86-3.77(m,1H),3.64(t,J=8.0Hz, 2H),3.60(s,3H),3.46(td,J=12.0,2.4Hz,1H),3.18(dd,J=12.0,8.0Hz,1H),2.96(m,1H),2.88(t,J=8.0Hz,3H).

[0233] Example B1 Synthesis of Compound TB-1 of the Invention: [ka] The synthetic route is as follows: [ka]

[0234] The experimental process is as follows. Phase 1: Compound SM1 (1.0 g, 1.0 eq) was dissolved in ultra-dry tetrahydrofuran, cooled in an ice-water bath, and solid cesium carbonate (1.37 g, 1.0 eq) was added. Isopropylamine (0.25 g, 1.0 eq) was added dropwise with stirring. After the addition was complete, the reaction was allowed to warm up naturally and monitored for completion by TLC. The solid was removed by suction filtration, the filter cake was washed with an appropriate amount of EA, extracted with water, and the layers were separated. The organic phase was dried over anhydrous sodium sulfate, suction filtered, concentrated under reduced pressure, and purified by column chromatography to give a yellow solid SM2 (750 mg, 64.7%). 1 H NMR (400MHz, Chloroform-d) δ 6.76(t,J=1.9Hz,1H),6.57(dd,J=10.9,2.0Hz,1H),3.73(dq,J=13.0,6.5Hz,1H),1.31(d,J=6.3Hz,6H).

[0235] Phase 2: Compound SM2 (0.75 g, 1.0 eq) was dissolved in a mixed solvent of absolute ethanol and water (v:v=4:1), and iron powder (0.91 g, 6.0 eq) and solid ammonium chloride (0.29 g, 2.0 eq) were added sequentially. The mixture was heated to 90°C and reacted. After the reaction was completed, most of the solvent was removed by concentration under reduced pressure. The mixture was extracted with saturated sodium bicarbonate solution and EA, and the layers were separated. The organic phase was dried over anhydrous sodium sulfate, suction filtered, concentrated under reduced pressure, and purified by column chromatography to obtain compound SM3 (0.5 g, 74.7%). 1 H NMR (400MHz, Chloroform-d) δ 6.64(dd,J=9.4,2.1Hz,1H),6.53(t,J=1.8Hz,1H),3.56(p,J=6.3Hz,1H),3.50(s,1H),3.15(s,2H),1.23(d,J=6.2Hz,6H).

[0236] Phase 3: Compound SM3 (1.3 g, 1.0 eq) and CDI (2.2 g, 2.5 eq) were successively dissolved in ultra-dry DMF solvent, heated to 110 °C, and reacted. The reaction completion was monitored by TLC, cooled to room temperature, extracted with EA and water, and the layers were separated. The organic phase was dried over anhydrous sodium sulfate, suction filtered, concentrated under reduced pressure, and purified by column chromatography to obtain compound SM4 (1.2 g, 83.3%). 1 H NMR (400MHz, Chloroform-d) δ 9.82(s,1H),7.08(s,1H),7.02(dd,J=8.0,4.0Hz,1H),4.70(m,1H),1.53(d,J=8.0Hz,6H).

[0237] Stage 4: Compound SM4 (1.2 g, 1.0 eq) was dissolved in dry toluene, phosphorus oxychloride (7.1 g, 1.0 eq) was added, and the mixture was heated to 90°C and reacted for 2 days. After the reaction was completed, the mixture was cooled to room temperature, quenched by pouring into ice water, extracted with EA, and the layers were separated. The organic phase was dried over anhydrous sodium sulfate, suction filtered, concentrated under reduced pressure, and purified by column chromatography to obtain compound SM5 (1.2 g, 94%). 1 H NMR (400MHz, Chloroform-d) δ 7.45(d,J=2.0Hz,1H),7.14(dd,J=8.0,2.0Hz,1H),4.88(m,1H),1.64(d,J=8.0Hz,6H).

[0238] Stage 5: Compound SM5 (1.23 g, 1.0 eq) was dissolved in ultra-dry DMF, and dimethylamine hydrochloride (3.5 g, 10.0 eq) and triethylamine (8.8 g, 20.0 eq) were added sequentially. The mixture was heated to 110°C and reacted. After the reaction was completed, the mixture was cooled to room temperature, extracted with EA and water, and the layers were separated. The organic layer was dried over anhydrous sodium sulfate, suction filtered, concentrated under reduced pressure, and purified by column chromatography to give compound SM6 (1.2 g, 94.5%). LCMS: [M+H] + =299.9, 301.8.

[0239] Stage 6: Under nitrogen gas protection, compound SM6 (0.27 g, 1.0 eq), bis(pinacolato)diboron (0.46 g, 2.0 eq), Pd(dppf)Cl2 (33 mg, 0.05 eq), and potassium acetate (0.26 g, 3.0 eq) were sequentially added to a dry 50 mL three-necked bottle, and the bottle was purged with nitrogen gas three times. Ultra-dry 1,4-dioxane solvent was added, and the mixture was heated to reflux. After the reaction was completed, the mixture was cooled to room temperature, extracted with Ea and water, and the layers were separated. The organic phase was dried over anhydrous sodium sulfate, suction filtered, concentrated under reduced pressure, and purified by column chromatography to obtain compound SM7 (0.3 g, 97%). LCMS: [M+H] + =348.3.

[0240] Stage 7: Under nitrogen gas protection, compound SM7 (0.39 g, 1.0 eq), 2,4,5-trichloropyrimidine (0.27 g, 1.3 eq), tetrakistriphenylphosphine palladium (0.13 g, 0.1 eq), and solid sodium carbonate (0.36 g, 3.0 eq) were sequentially added to a 50 mL three-necked bottle, and a mixture of 1,4-dioxane and water (v:v=10:3) was added. The mixture was purged with nitrogen gas three times, heated to reflux, and after the reaction was completed, the mixture was cooled to room temperature, extracted with Ea and water, and the liquids were separated. The organic phase was dried over anhydrous sodium sulfate, suction filtered, concentrated under reduced pressure, and separated and purified by column chromatography to obtain compound SM8 (0.2 g, 49%). LCMS: [M+H] + =368.2.

[0241] Stage 8: Under nitrogen gas conditions, compound SM8 (0.17 g, 1.0 eq), (3s,4r)-4-aminooxan-3-ol hydrochloride (0.14 g, 2.0 eq), and DIPEA (0.24 g, 4.0 eq) were added to DMSO solvent in order, and the mixture was heated to 90°C for reaction. After the reaction was completed, the mixture was cooled to room temperature, extracted with saturated brine, water, and EA in order, and the layers were separated. The organic phase was dried over anhydrous sodium sulfate, suction filtered, concentrated under reduced pressure, and purified by column chromatography to obtain compound TB-1 (90 mg, 43.3%). The HPLC purity was 99.7%. LCMS: [M+H] + =449.4. 1 H NMR (400 MHz, Chloroform-d) δ 8.30(s,1H),7.71(d,J=1.4Hz,1H),7.41(dd,J=11.4,1.4Hz,1H),5.29(d,J=6.0 Hz,1H),4.98(s,1H),4.68(h,J=7.0Hz,1H),4.02(ddd,J=27.1,11.7,4.7Hz,2H), 3.92-3.77(m,1H),3.63(td,J=9.5,4.9Hz,1H),3.46(td,J=11.9,2.2Hz,1H),3.1 7(dd,J=11.4,9.8Hz,1H),2.98(s,6H),2.07(s,1H),1.62(dd,J=7.0,1.9Hz,6H).

[0242] The following compounds are synthesized with reference to the synthesis method of Example B1. [ka] [ka] [ka] [ka] [ka] [ka]

[0243] Example B2 Synthesis of the compound of the present invention, TB-16: [ka] The synthetic route is as follows: [ka]

[0244] The experimental process is as follows. Synthesis of compound TB-16 Under nitrogen gas protection, 5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-amine (180 mg, 1.5 eq) was dissolved in 4 mL of ultra-dry tetrahydrofuran, placed in an ice-water bath, and a 1 M solution of LiHDMS in tetrahydrofuran (0.81 mL, 1.5 eq) was added dropwise. The mixture was incubated in the ice-water bath for 30 minutes. Compound SM1 (100 mg, 1.0 eq) was added and the mixture was incubated. After the reaction was completed, the mixture was extracted with Ea and water, separated, and the organic phase was dried over anhydrous sodium sulfate, suction filtered, and concentrated under reduced pressure. After preparative separation and purification, 120 mg of compound TB-16 was obtained. The HPLC purity was 98.14%, and the yield was 82.0%. LCMS: [M+H] + =552.5.

[0245] 1 H NMR(400MHz,Chloroform-d)δ 8.53(s,1H),8.47(s,1H),8.36-8.32(d,J=8.0Hz,1H),8.21(d,J=4.0Hz,1H),7.80(d,J=1.6Hz,1H),7.57(dd,J=8.0,4.0Hz,1H),7.48(dd, J=12.0,1.6Hz,1H),4.65(p,J=8.0Hz,1H),3.48(s,2H),2.94(s,6H),2.73(m,8H),1.58(d,J=8.0Hz,6H),1.25(t,J=6Hz,3H),1.19(m,2H).

[0246] The following compounds are synthesized with reference to the synthesis method of Example B2. [ka] [ka] [ka]

[0247] Example B3 Synthesis of the compound of the present invention, TB-23: [ka] The synthetic route is as follows: [ka]

[0248] The experimental process is as follows. Phase 1: Compound SM1 (1.5 g, 1.0 eq) was dissolved in a mixed solvent of aqueous ammonia and methanol (45 mL, v:v=2:1), heated to 110 °C in a sealed autoclave, and reacted for 24 hours. After the reaction was completed, the mixture was cooled to room temperature, and the reaction solvent was concentrated under reduced pressure. The mixture was then directly separated and purified by silica gel column chromatography to obtain 1.1 g of compound SM2. The yield was 78.6%. LCMS: [M+H] + =272.0,274.0.

[0249] Phase 2: In an ice-water bath, compound SM2 (170 mg, 1.0 eq) was dissolved in 2 mL of ultra-dry THF solvent, and then triethylamine (316 mg, 5.0 eq) and 4-chlorobutyryl chloride (221 mg, 2.5 eq) were added sequentially. The reaction was maintained in an ice-water bath. After the reaction was completed, the mixture was extracted with EA and water, and the liquids were separated. The organic phase was dried over anhydrous sodium sulfate and suction filtered. The filtrate was concentrated under reduced pressure, and then separated and purified by silica gel column chromatography to obtain 180 mg of compound SM3. The yield was 76.6%. LCMS: [M+H] + =376.1, 378.1.

[0250] Phase 3: Compound SM3 (1.1 g, 1.0 eq) was dissolved in 22 mL of ultra-dry DMF solvent under ice-water bath conditions, and solid NaOH (0.21 g, 1.8 eq) was added. The mixture was stirred in an ice bath and reacted. After the reaction was completed, the mixture was extracted with saturated ammonium chloride and EA, and the liquid was separated. The organic phase was dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated under reduced pressure. The mixture was then purified by silica gel column chromatography to give 340 mg of compound SM4. The yield was 34%. LCMS: [M+H] + =340.1, 342.1.

[0251] Stage 4: Under nitrogen gas protection, compound SM4 (360 mg, 1.0 eq), bis(pinacolato)diboron (537 mg, 2.0 eq), Pd(dppf)Cl2 (38.7 mg, 0.05 eq), and potassium acetate (311 mg, 3.0 eq) were sequentially added to a dry 50 mL three-necked bottle, and the bottle was purged with nitrogen gas three times. Ultra-dry 1,4-dioxane solvent was added, and the mixture was heated to reflux. After the reaction was completed, the mixture was cooled to room temperature, extracted with Ea and water, and the layers were separated. The organic phase was dried over anhydrous sodium sulfate, suction filtered, concentrated under reduced pressure, and purified by column chromatography to obtain compound SM5 (310 mg, 75.6%). LCMS: [M+H] + =388.3.

[0252] Stage 5: Under nitrogen gas protection, compound SM5 (310 mg, 1.0 eq), 2,4,5-trichloropyrimidine (200 mg, 1.5 eq), tetrakistriphenylphosphine palladium (92.5 mg, 0.1 eq), and solid sodium carbonate (254.5 mg, 3.0 eq) were sequentially added to a 50 mL three-necked bottle, and 13 mL of a mixture of 1,4-dioxane and water (v:v=10:3) was added. The mixture was purged with nitrogen gas three times, heated to reflux, and after the reaction was completed, the mixture was cooled to room temperature, extracted with Ea and water, and the liquids were separated. The organic phase was dried over anhydrous sodium sulfate, suction filtered, concentrated under reduced pressure, and purified by column chromatography to obtain compound SM6 (240 mg, 73.6%). LCMS: [M+H] + =408.1.

[0253] Stage 6: Under nitrogen gas conditions, compound SM6 (180 mg, 1.0 eq), (3s,4r)-4-aminooxan-3-ol hydrochloride (102 mg, 1.5 eq), and DIPEA (228 mg, 4.0 eq) were sequentially added to 3 mL of DMSO solvent, and the mixture was heated to 90°C for reaction. After the reaction was completed, the mixture was cooled to room temperature, extracted sequentially with saturated brine, water, and EA, and the layers were separated. The organic phase was dried over anhydrous sodium sulfate, suction filtered, concentrated under reduced pressure, and purified by column chromatography to obtain compound TB-23 (120 mg, 56.0%). The HPLC purity was 96.75%. LCMS: [M+H] + =489.4. 1H NMR(400MHz,Chloroform-d)δ 8.32(s,1H),7.88(d,J=1.2Hz,1H),7.45(dd,J=12.0,1.2Hz,1H),5.33(d,J=8.0Hz,1H),4.82(s ,1H),4.61(m,1H),4.11(t,J=8.0Hz,3H),4.05(dd,J=12.0,4.0Hz,1H),3.98(dd,J=12.0,4.0Hz ,1H),3.92-3.79(m,1H),3.63(td,J=8.0,4.0Hz,1H),3.46(td,J=12.0,2.0Hz,1H),3.17(t,J=8 .0,1H),2.63(t,J=8.0Hz,2H),2.32(p,J=8.0Hz,2H),1.78-1.69(m,2H),1.68(d,J=8.0Hz,6H). The following compounds are synthesized with reference to the synthesis method of Example B3.

[0254] Example B4 Synthesis of the compound of the present invention, TB-36: [ka] The synthetic route is as follows: [ka]

[0255] The experimental process is as follows. Phase 1: Under nitrogen gas protection, Int-1 (200 mg, 1.0 eq), N-methyl-3-aminobenzenesulfonamide (136.0 mg, 1.5 eq), cesium carbonate (476.5 mg, 3.0 eq), and Xantphos Pd G2 catalyst (21.6 mg, 0.05 eq) were added to a 25 mL three-neck bottle. 10 mL of ultra-dry 1,4-dioxane was added, and the mixture was purged with nitrogen gas three times. The mixture was then heated to reflux and the reaction mixture was cooled to room temperature. The mixture was extracted with Ea and water, and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure after suction filtration. The isomers were separated by preparative chromatography to give compound TB-36 (20 mg, 7.3%). The HPLC purity was 97.18%. LCMS: [M+H] + =561.0. 1 H NMR(400MHz,Chloroform-d)δ 8.51(s,1H),8.25(t,J=2.0Hz,1H),8.03(d,J=1.3Hz,1H),7.84(d,J=8.3Hz,1H),7.62-7.43(m,4H),4.79(p,J=6.9Hz, 1H),4.66(t,J=7.7Hz,2H),4.51(q,J=5.4Hz,1H),4.40(t,J=7.7Hz,2H),2.69(d,J=5.4Hz,3H),1.72(d,J=6.9Hz,6H).

[0256] The following compounds are synthesized with reference to the synthesis method of Example B4. [ka] [ka] [ka]

[0257] Example B5 Synthesis of the present compound TB-40: [ka]

[0258] The synthetic route is as follows: [ka]

[0259] The experimental process is as follows. Phase 1: Compound SM1 (5.0 g, 1.0 eq) was dissolved in ultra-dry tetrahydrofuran solvent, placed in an ice-water bath, and solid cesium carbonate (17.1 g, 2.5 eq) was added. 3-Chloropropylamine hydrochloride (2.7 g, 1.0 eq) was added with stirring. After the addition was complete, the reaction was allowed to warm to room temperature. The reaction was monitored by TLC, and the solid was removed by suction filtration. The filter cake was washed with an appropriate amount of EA, extracted with water, and the layers were separated. The organic phase was dried over anhydrous sodium sulfate, suction filtered, concentrated under reduced pressure, and purified by column chromatography to give a yellow solid SM2 (4.7 g, 71.9%). 1 H NMR(400MHz,Chloroform-d)δ 7.35(s,1H),6.81(t,J=2.0Hz,1H),6.64(dd,J=12.0,2.0Hz,1H),3.67(t,J=4.0Hz,2H),3.46(q,J=8.0Hz,2H),2.16(p,J=8.0Hz,H).

[0260] Phase 2: Compound SM2 (4.3 g, 1.0 eq) was dissolved in a mixture of methanol and water (v:v=4:1), iron powder (3.9 g, 5.0 eq) and solid ammonium chloride (1.5 g, 2.0 eq) were added, and the mixture was heated to reflux. After monitoring the completion of the reaction by TLC, the mixture was cooled to room temperature, suction filtered, the filter cake was washed with an appropriate amount of EA, and the filtrate was concentrated under reduced pressure to remove most of the solvent. The mixture was extracted with saturated sodium bicarbonate solution and EA, and the organic phase was dried over anhydrous sodium sulfate, suction filtered, concentrated under reduced pressure, and purified by column chromatography to give compound SM3 (2.0 g, 51.4%).

[0261] Phase 3: Compound SM3 (1.3 g, 1.0 eq) and CDI (2.2 g, 2.5 eq) were dissolved in ultra-dry DMF solvent sequentially, heated to 90 °C, and reacted. The reaction completion was monitored by TLC, cooled to room temperature, extracted with EA and water, and the layers were separated. The organic phase was dried over anhydrous sodium sulfate, suction filtered, concentrated under reduced pressure, and purified by column chromatography to obtain compound SM4 (1.2 g, 83.3%).

[0262] Stage 4: Compound SM4 (4.0 g, 1.0 eq) was dissolved in dry toluene, and phosphorus oxychloride (36 mL, 30.0 eq) was added. The mixture was heated to reflux for 2 days. After monitoring the completion of the reaction by TLC, the mixture was cooled to room temperature, poured into ice water to quench, extracted with EA, and the layers were separated. The organic layer was dried over anhydrous sodium sulfate, suction filtered, concentrated under reduced pressure, and purified by column chromatography to give compound SM5 (137 mg, 24.9%). LCMS: [M+H] + =325.3, 327.3.

[0263] Stage 5: Compound SM5 (1.25 g, 1.0 eq) is added to 60 mL of a 30% methylamine ethanol solution, and the mixture is heated to 60°C to react. After the reaction is complete, the mixture is cooled to room temperature, concentrated under reduced pressure to remove most of the solvent, extracted with saturated brine and EA, and the layers are separated. The organic phase is dried over anhydrous sodium sulfate, suction filtered, concentrated, and separated and purified by silica gel column chromatography to obtain compound SM6 (500 mg, 48.9%). 1 H NMR(400MHz,Chloroform-d)δ 6.98(dd,J=10.0,1.7Hz,1H),6.93(d,J=1.7Hz,1H),3.93(t,J=6.2Hz,2H),3.48-3.31(m,2H),3.22(s,3H),2.26(p,J=6.0Hz,2H).

[0264] Stage 6: Under nitrogen gas protection, compound SM6 (0.26 g, 1.0 eq), bis(pinacolato)diboron (0.46 g, 2.0 eq), Pd(dppf)Cl2 (34 mg, 0.05 eq), and potassium acetate (0.27 g, 3.0 eq) were sequentially added to a dry 50 mL three-neck bottle. The bottle was purged with nitrogen gas three times, and ultra-dry 1,4-dioxane solvent was added. The mixture was heated to reflux and the reaction mixture was monitored for completion by TLC. After cooling to room temperature, the mixture was extracted with Ea and water, and the organic phase was dried over anhydrous sodium sulfate, suction filtered, concentrated under reduced pressure, and purified by column chromatography to give compound Int-1 (0.21 g, 69.3%). LCMS: [M+H] + =332.6.

[0265] Stage 7: Under nitrogen gas protection, compound Int-1 (0.21 g, 1.0 eq), 2,4,5-trichloropyrimidine (0.21 g, 2.0 eq), tetrakistriphenylphosphine palladium (71.5 mg, 0.1 eq), and solid sodium carbonate (0.2 g, 3.0 eq) were sequentially added to a 50 mL three-neck bottle, and a mixture of 1,4-dioxane and water (v:v = 10:3) was added. The mixture was purged with nitrogen gas three times and heated to reflux. After monitoring the completion of the reaction by TLC, the mixture was cooled to room temperature, extracted with Ea and water, and the layers were separated. The organic phase was dried over anhydrous sodium sulfate, suction filtered, concentrated under reduced pressure, and purified by column chromatography to give compound Int-2 (0.13 g, 59.2%). LCMS: [M+H] + =352.5.

[0266] Stage 8: Under nitrogen gas conditions, compound Int-2 (100 mg, 1.0 eq), (3s,4r)-4-aminooxan-3-ol hydrochloride (87.2 mg, 2.0 eq), and DIPEA (0.2 mL, 4.0 eq) were added to DMSO solvent and heated to 90 °C for reaction. After the reaction was completed, the mixture was cooled to room temperature, extracted with saturated brine, water, and EA, and the organic phase was separated. The organic phase was dried over anhydrous sodium sulfate, suction filtered, concentrated under reduced pressure, and purified by filtration to obtain compound TB-40 (50 mg, 40.7%). The HPLC purity was 91.7%. LCMS: [M+H] + =433.4. 1H NMR (400 MHz, Chloroform-d) δ 8.25(s,1H),7.42(dd,J=11.8,1.2Hz,1H),7.32(d,J=1.2Hz,1H),5.27(d,J=6.0 Hz,1H),5.12(s,1H),4.05(m,2H),4.00(t,J=6.0Hz,2H),3.89-3.77(m,1H),3.6 2(td,J=9.6,4.8Hz,1H),3.50-3.43(m,1H),3.42(t,J=5.6Hz,2H),3.26(s,3H), 3.24-3.14(m,1H),2.28(p,J=5.8Hz,2H),2.09-1.98(m,1H),1.70-1.64(m,1H).

[0267] The following compounds are synthesized with reference to the synthesis method of Example B5. [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] Example B6 Compounds synthesized according to the present invention: [ka] The experimental process is as follows. Synthesis of compound TB-98 The synthetic route is as follows: [ka]

[0268] The experimental process is as follows. Phase 1: Compound SM1 (7.7 g, 1.0 eq) was dissolved in ultra-dry tetrahydrofuran solvent, placed in an ice-water bath, and solid cesium carbonate (31.8 g, 3.0 eq) was added. (S)-3-aminobutyric acid methyl ester hydrochloride (5.0 g, 1.0 eq) was added with stirring. After the addition was complete, the reaction was allowed to warm to room temperature. The reaction was monitored for completion by TLC, and the solid was removed by suction filtration. The filter cake was washed with an appropriate amount of EA, extracted with water, and the layers were separated. The organic phase was dried over anhydrous sodium sulfate, suction filtered, concentrated under reduced pressure, and purified by column chromatography to give yellow solid SM2 (6.7 g, 61.5%). LCMS: [M+H] + =335.2, 337.2.

[0269] Phase 2: Compound SM2 (6.7 g, 1.0 eq) was dissolved in a mixed solvent of methanol and water (v:v=4:1), iron powder (6.7 g, 6.0 eq) and solid ammonium chloride (2.1 g, 2.0 eq) were added, and the mixture was heated to reflux. After monitoring the completion of the reaction by TLC, the mixture was cooled to room temperature, suction filtered, the filter cake was washed with an appropriate amount of EA, and the filtrate was concentrated under reduced pressure to remove most of the solvent. The mixture was extracted with saturated sodium bicarbonate solution and EA, and the layers were separated. The organic phase was dried over anhydrous sodium sulfate, suction filtered, concentrated under reduced pressure, and purified by column chromatography to give compound SM3 (5.5 g, 90.0%). LCMS: [M+H] + =305.1, 307.1.

[0270] Stage 3: Compound SM3 (5.5 g, 1.0 eq) and CDI (4.4 g, 1.5 eq) were dissolved in ultra-dry DMF solvent successively, and the temperature was raised to 50° C. to react. The completion of the reaction was monitored by TLC, and the mixture was cooled to room temperature, extracted with EA and water, and the layers were separated. The organic phase was dried over anhydrous sodium sulfate, suction filtered, concentrated under reduced pressure, and purified by column chromatography to obtain compound SM4 (5.4 g, 90.4%). LCMS: [M+H] + =331.2, 333.1.

[0271] Stage 4: Compound SM4 (5.4 g, 1.0 eq) was dissolved in phosphorus oxychloride (18.2 mL, 12.0 eq), and the temperature was raised to 100°C for 12 hours. After monitoring the completion of the reaction by TLC, the mixture was cooled to room temperature, poured into ice water to quench, extracted with EA, and the layers were separated. The organic layer was dried over anhydrous sodium sulfate, suction filtered, concentrated under reduced pressure, and purified by column chromatography to obtain compound SM5 (5.2 g, 91.2%). LCMS: [M+H] + =349.0, 351.1.

[0272] Stage 5: Compound SM5 (1.9 g, 1.0 eq) was added to 50 mL of 30% methylamine ethanol solution, and the reaction was maintained in an ice-water bath. After the reaction was completed, most of the solvent was removed by concentration under reduced pressure, and the mixture was extracted with saturated brine and EA, and the layers were separated. The organic phase was dried over anhydrous sodium sulfate, then suction filtered, concentrated, and purified by silica gel column chromatography to obtain compound SM6 (1.7 g, 89.4%). LCMS: [M+H] + =348.1, 350.1.

[0273] Stage 6: Compound SM6 (1.5 g, 1.0 eq) was dissolved in 50 mL of ultra-dry tetrahydrofuran solvent, cooled in an ice-water bath, and 60% NaH powder was added in batches. After the addition was complete, the mixture was allowed to react for 3 hours while maintaining the temperature. After the reaction was completed, the mixture was cooled to 0 °C and quenched by adding an appropriate amount of ice water. The mixture was extracted with saturated brine and EA, and the organic phase was separated. The organic phase was dried over anhydrous sodium sulfate, suction filtered, concentrated, and purified by silica gel column chromatography to give compound SM7 (811 mg, 60.5%). LCMS: [M+H] + =312.1, 314.0.

[0274] Stage 7: Under nitrogen gas protection, compound SM7 (811 mg, 1.0 eq), bis(pinacolato)diboron (1.32 g, 2.0 eq), Pd(dppf)Cl2 (95.1 mg, 0.05 eq), and potassium acetate (764.7 mg, 3.0 eq) were sequentially added to a dry 50 mL three-neck bottle. The bottle was purged with nitrogen gas three times, and ultra-dry 1,4-dioxane solvent was added. The mixture was heated to reflux and the reaction mixture was monitored for completion by TLC. The reaction mixture was then cooled to room temperature, extracted with Ea and water, and the layers were separated. The organic phase was dried over anhydrous sodium sulfate, suction filtered, concentrated under reduced pressure, and purified by column chromatography to give compound SM8 (890 mg, 95.4%). LCMS: [M+H] + =360.3.

[0275] Stage 7: Under nitrogen gas protection, compound SM8 (150 mg, 1.0 eq), 2,4,5-trichloropyrimidine (115 mg, 1.5 eq), tetrakistriphenylphosphine palladium (48.3 mg, 0.1 eq), and solid sodium carbonate (66.4 mg, 1.5 eq) were sequentially added to a 50 mL three-neck bottle, and a mixture of 1,4-dioxane and water (v:v=10:3) was added. The mixture was purged with nitrogen gas three times and heated to reflux. After monitoring the completion of the reaction by TLC, the mixture was cooled to room temperature, extracted with EA and water, and the layers were separated. The organic phase was dried over anhydrous sodium sulfate, suction filtered, concentrated under reduced pressure, and purified by column chromatography to give compound SM9 (120 mg, 75.5%). LCMS: [M+H] + =380.1.

[0276] Stage 8: Under nitrogen gas conditions, compound SM9 (150 mg, 1.0 eq), (3s,4r)-4-aminooxan-3-ol hydrochloride (121.2 mg, 2.0 eq), and DIPEA (0.28 mL, 4.0 eq) were added to NMP solvent and heated to 90 °C for reaction. After the reaction was completed, the mixture was cooled to room temperature, extracted with saturated brine, water, and EA, and the organic phase was separated. The organic phase was dried over anhydrous sodium sulfate, suction filtered, concentrated under reduced pressure, and purified by filtration to obtain compound TB-98 (76 mg, 40.7%). The HPLC purity was 99.38%. LCMS: [M+H] + =461.3. 1H NMR(400MHz,Chloroform-d)δ 8.32(s,1H),7.53(s,1H),7.48(d,J=11.4Hz,1H),5.32(d,J=6.0Hz,1H),4.75(p,J=6.9H z,1H),4.05(dd,J=11.5,5.0Hz,1H),3.99(dd,J=11.7,4.1Hz,1H),3.90-3.80(m,1H),3. 67(dt,J=8.5,4.5Hz,1H),3.63(d,J=4.9Hz,1H),3.60(s,3H),3.46(ddd,J=14.1,9.8,2. 2Hz, 2H), 3.27-3.14 (m, 2H), 2.11-1.99 (m, 1H), 1.76-1.69 (m, 1H), 1.47 (d, J = 6.7Hz, 3H).

[0277] The following compounds are synthesized with reference to the synthesis method of Example B6. [ka] [ka]

[0278] Test Example 1: Enzyme activity test Hereinafter, biological activity tests will be carried out on some of the compounds in the above examples and comparative examples. The biological activity test experiment process is as follows:

[0279] 1. Kinase activity test: IC for CDK4 and CDK6 kinases for test compounds 50 Detect the value. [Table 1] [Table 2]

[0280] (3) Research design (1) Preparation of compounds: (i) A test compound is prepared as a 0.5 mM DMSO solution, and at the same time, a positive control drug, Palbociclib, is also prepared as a 0.5 mM DMSO solution. (ii) Dilute three-fold to obtain 10 different concentrations of the compound solution. (2) Enzyme measurement: (i) Prepare a 1.3x enzyme solution containing the enzyme, substrate, and cofactors as shown below. (ii) Add 15 μL of 1.3× enzyme solution to each well and incubate at room temperature for 30 minutes. (iii) The reaction is initiated by adding 5 μL of 4×ATP solution, and each test well contains the components listed in the table, with a final volume of 20 μL. (iv) After incubation for 150 minutes, the reaction is stopped by adding 75 μL of a buffer solution (containing 0.5 M EDTA). (v) Read and analyze the data for each test well using EZ. (3) Data analysis: Calculate the inhibition rate using the readout conversion ratio (CR) according to the following formula: Wells treated with DMSO serve as positive controls, and wells without enzyme serve as negative controls. %(inhibition rate)=100-100×((CRPC-CRSample) / (CRPC-CRNC)).

[0281] [Table 3] The above detection results in the inhibitory activity IC of the test sample against CDK4 and CDK6 kinases. 50 Values ​​(nM) are as shown in Table 1.

[0282] [Table 4-1] [Table 4-2] [Table 4-3]

[0283] As can be seen from Table 1, in vitro bioactivity screening showed that, using palbociclib as a control, the compounds synthesized according to the present invention all have excellent inhibitory ability against CDK4 kinase, and also have excellent selectivity for the kinase activity of CDK4 and CDK6, which may significantly reduce hematological and other side effects caused by CDK6 inhibition. Therefore, it is expected that the compounds synthesized according to the present invention will be further developed as drugs used to regulate CDK4 kinase activity or treat CDK4-related diseases.

[0284] Test Example 2: Cell Antiproliferation Experiment 1. Experimental materials and devices: Human breast cancer cells MCF-7, ovarian cancer cells A2780, and human mantle cell lymphoma cells JEKO-1. DMEM medium (Bio-Channel), DMSO (dimethyl sulfoxide), MTT (thiazolyl blue), 0.25% EDTA-trypsin (Tripsin digestion solution), 1x PBS (phosphate buffer solution, pH 7.2), 96-well plates (Corning), fetal bovine serum (FBS), 10,000 U / mL penicillin G / streptomycin, high-speed refrigerated centrifuge (EPPENDORF 5810R), and enzyme immunoassay system (Tecan Spark).

[0285] 2. Experimental preparation: 1. Cell Plating A) Tumor cells are cultured in DMEM (containing high glucose, 10% FBS, and 100 U / mL penicillin-G / streptomycin) under conditions of 37°C, 5% CO2, and saturated humidity to 80-90% confluency. B) Removing the medium from a 10 cm culture dish C) Wash the cells once with 10 ml of 1x PBS. D) Add 4 ml of 0.25% EDTA-trypsin, place in a 37°C, 5% CO2 incubator for 5 minutes to digest with trypsin, transfer to a 15 ml centrifuge tube, and centrifuge at 200 g for 5 minutes. Discard the supernatant to obtain a cell pellet. E) Resuspend in 4 ml of DMEM medium, count the cells and adjust to 50,000 cells / ml. F) Add 100 μL of the cell suspension to each well of a 96-well plate and culture overnight in a 37°C, 5% CO2 incubator.

[0286] 2. Compound Treatment Compound dilution A) Preparation of gradient dilutions of test compounds: Test compounds are prepared to a 1 mM stock solution. Then, 1.5 μl of the stock solution is dissolved in 1.5 ml of DMSO-free medium, and diluted 3-fold with 0.1% DMSO medium to obtain a total of 9 concentrations. The concentrations of the compounds after dilution are as follows: 333.33nM, 111.11nM, 37.03nM, 12.35nM, 4.15nM, 1.37nM, 0.46nM, 0.15nM B) After thorough mixing, 100 μL of each compound solution was taken and replaced with the culture medium in the cell culture plate, with four duplicate wells for each concentration. C) The cells are transferred to an incubator and incubated for 5 days.

[0287] 3.MTT detection A) Remove the cell culture plate and add 10 μL of 5 mg / mL MTT in a biosafety cabinet. B) Return the cell culture plate to the incubator and continue to incubate for 3 hours. C) The cell culture plate was removed, the culture medium was removed, 100 μL of isopropanol (containing 0.4 mM HCl and 0.1% NP-40) was added, and the plate was shaken at room temperature for 30 minutes. D) Select a wavelength of 570 nm using the TECAN enzyme immunoassay device and measure the absorbance value.

[0288] 4. Data Analysis Calculate the % Cell Viability using the following formula: %Cell Viability=100%×(Lum_Sample-Lum_LC) / (Lum_HC-Lum_LC) Lum_HC: Readout of cells from the 0.1% DMSO control group Lum_Sample: Readout of compound-treated cells Lum_LC: Blank medium readout IC obtained by curve fitting using GraphPad Prism 8 software 50 The values ​​(unit: nM) are as shown in Table 2, where A / B / C represent the following: A≦500nM, 500nM<B≦2000nM、C> It is 2000nM.

[0289] [Table 5-1] [Table 5-2] [Table 5-3]

[0290] As can be seen from Table 2, in vitro bioactivity screening showed that the compounds synthesized by the present invention all have excellent inhibitory abilities against human breast cancer cells MCF-7, ovarian cancer cells A2780, and human mantle cell lymphoma cells JEKO-1.

[0291] Test Example 3: Preclinical rat pharmacokinetic study 1. Experimental materials and devices: Healthy adult SD rats, male, 6-8 weeks old, weighing 200-300g. EDTA-Na2 anticoagulant. Analytical balance, animal scale, magnetic stirrer, refrigerated centrifuge, single-channel manual pipette, etc. 2. Experimental process: 1. Drug Preparation Approximately 10 mg of test sample was accurately weighed, dissolved in 5% DMSO after conversion, and then sonicated with 10% solutol HS-15 and 85% saline, and mixed uniformly with a vortex to obtain a solution with a concentration of 1 mg / mL, which was freshly prepared before use. Transfer a 0.2 mL sample to a 1.5 mL centrifuge tube and store at -80 °C for analysis of the concentration of the dosing solution.

[0292] 2. Animal Preparation The animals are housed in rat cages and fasted (for at least 10 hours) from the day before the test, but are allowed to drink water. On the day of the test, each animal is weighed and its tail is marked. A blank blood sample is taken before administration. Blood is collected from the tail vein.

[0293] 3. Administration Route of administration: oral gavage (po) Dosage: 10 mg / kg Dosage volume: 10 mL / kg Procedure: Hold the rat upright with your left hand wearing a bite-resistant glove, insert a No. 16 oral gavage needle into the mouth and throat, feeling for any obvious resistance, and inject the drug into the stomach.

[0294] 4. Sample Collection Before administration and 0.5, 1, 2, 4, 6, 8, 12, and 24 hours after administration, 0.1 ml of whole blood was collected from the test animals into an EDTA-Na2 anticoagulant tube, inverted 3-4 times to mix evenly, centrifuged at 10,000 g for 5 minutes at 4°C to separate the plasma, and stored at -80°C for testing. Blood was collected from the tail vein. The specific procedure involves securing the rat in a restrainer, ensuring its tail is completely exposed, wiping the rat's tail with alcohol so that the skin absorbs the alcohol and achieves significant venous dilation. Select an appropriate vein on either side and insert the needle approximately one-third of the way from the tip of the tail. Use an insulin syringe, inserting the needle with the beveled side facing up. As soon as the needle pierces the skin, it should be parallel to the skin. This allows the needle to slide smoothly through the vein with minimal resistance, and blood should be felt returning to the syringe. This allows approximately 0.1-0.2 ml of whole blood to be drawn into the vein. After removing the needle, apply pressure to stop the bleeding.

[0295] 3. Sample analysis: Preparation of standard curve: Place 25 μL of blank rat plasma in a centrifuge tube, add 25 μL of prepared standard series solution (prepared in methanol), add 200 μL of internal standard solution (prepared in methanol), vortex for 2 minutes to mix evenly, and centrifuge at 10,000 g for 10 minutes at 4°C. Processing of unknown plasma samples: 25 μL of drug-containing plasma from each rat was collected, 25 μL of methanol and 200 μL of internal standard solution were added sequentially, and the mixture was vortexed for 2 minutes to homogenize, followed by centrifugation at 10,000 g for 10 minutes at 4°C. The supernatant was collected and subjected to LC / MS / MS detection.

[0296] 4. Data Processing A quantitative detection method for the test compound was established using Shimadzu liquid chromatograph and Triple Quad™ 6500+AB mass spectrometry. The unchanged drug concentration in plasma was measured. The blood drug concentration-time curve was plotted, and the main pharmacokinetic parameters were calculated using the non-compartmental model of Winnonlin Phoenix software. The detailed data are shown in Table 3. [Table 6] As can be seen from Table 3, the PK test screening shows that all the compounds synthesized according to the present invention have excellent pharmacokinetic properties. 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 for use as a CDK4 kinase inhibitor, comprising: The compound is a compound of Formula I, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotope, or prodrug thereof: 【Chemical 1】 where: X １ is N,CR ３ is selected from the group consisting of R １ is H,CF ３ , F, Cl, Br, a methyl group, an ethyl group, an isopropyl group, and a cyclopropyl group; R ２ are H, F, Cl, Br, and CF ３ , C.F. ２ H, N.H. ２ , methyl groups; Or R １ and R ２ together with the C to which they are attached form a 5-membered heteroaryl group containing two N's, R ３ is H,CF ３ , F, Cl, Br, a methyl group, a cyano group; Ring A is 【Chemistry 2】 wherein X is selected from the group consisting of ２ is O or NR, X ２－１ is N,CR １１ is selected from the group consisting of Ring B is 【Chemistry 3-1】 【Chemistry 3-2】 is selected from the group consisting of Here, each R ４ is H, a cyano group, a halogen, a substituted or unsubstituted C １ -C ６ alkyl group, substituted or unsubstituted C ３ -C ６ Cycloalkyl group, —C(O)NR ９ R １０ , substituted or unsubstituted -NR ｍ R ｎ are independently selected from the group consisting of Each R ５ , R ６ are each independently H, a halogen atom, a hydroxy group, an amino group, 【Chemistry 4】 Substituted or unsubstituted C １ -C ６ alkyl group, substituted or unsubstituted C ３ -C ６ a cycloalkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted C １－６ an alkoxy group, a substituted or unsubstituted —NR ｍ R ｎ is selected from the group consisting of R ７ , R １１ are each independently H, substituted or unsubstituted C １－６ alkyl groups, R ８ is H, C １－６ Alkoxy group, halogenated C １－６ Alkoxy group, —NR ｍ R ｎ , halogenated -NR ｍ R ｎ , a cyano group, a substituted or unsubstituted C １－６ alkyl group, substituted or unsubstituted C ３－６ Cycloalkyl group, —C(O)NR ９ R １０ is selected from the group consisting of Each R ９ , R １０ are each independently H, a halogen atom, a hydroxy group, an amino group, 【Chemistry 5】 Substituted or unsubstituted C １ -C ６ alkyl group, substituted or unsubstituted C ３ -C ６ a cycloalkyl group, a substituted or unsubstituted phenyl group, —C(O)R １２ , -C(O)OR １３ or R ９ and R １０ together with the N to which they are attached form a substituted or unsubstituted 5- to 7-membered heterocycle, or R ９ or R １０ Either of these is R ５ together with the 5- to 7-membered ring, Each R １４ are each independently H, a halogen atom, a hydroxy group, an amino group, 【Chemistry 6】 Substituted or unsubstituted C １ -C ６ alkyl group, substituted or unsubstituted C ３ -C ６ a cycloalkyl group, a substituted or unsubstituted phenyl group, an oxo group, or two R １４ together with the C to which they are bound, ３ -C ６ forming a cycloalkyl group, Or R ４ and R ５ form together with the C to which they are attached a 5- to 7-membered heterocycle containing 1, 2 or 3 heteroatoms selected from N, O, S, R １２ , R １３ are each independently H, substituted or unsubstituted C １－６ alkyl group, substituted or unsubstituted C ３－６ cycloalkyl groups, Each R and R' is independently H, C １ -C ６ Alkyl groups, halogenated C １ -C ６ Alkyl group, C ３ -C ６ Cycloalkyl groups, halogenated C ３ -C ６ selected from the group consisting of cycloalkyl groups and phenyl groups; R ４ , R ５ , R ６ , R ９ , R １０ and R １４ The substitutions described above are each independently deuterium, halogen, a hydroxy group, an amino group, -N-(C １ -C ６ alkyl) ２ , C １ -C ６ substituted by one, two or three substituents selected from the group consisting of an alkoxy group, a phenyl group and a cyano group; Each R ｍ is H, C １－６ Alkyl group, C ３－６ Cycloalkyl group, C ６－１０ aryl groups, and 6-10 membered heteroaryl groups containing 1, 2 or 3 heteroatoms selected from N, O and S; Each R ｎ is C １－６ is an alkyl group, Or R ｍ and R ｎ together with the N atom to which they are attached form a 3- to 10-membered N-containing monocyclic or bicyclic heterocyclic group, each m, n, and p is independently selected from the group consisting of 0, 1, 2, 3, 4, and 5; Here, ring A is 【Chemistry 7】 When the formula is 【Chemistry 8】 The compound used as a CDK4 kinase inhibitor is selected from the group consisting of:

2. X １ is N,CR ３ is selected from the group consisting of R １ is H,CF ３ , F, Cl, Br, a methyl group, an ethyl group, an isopropyl group, and a cyclopropyl group; R ２ is H,CF ３ , F, Cl, Br, and a methyl group; R ３ is H,CF ３ , F, Cl, Br, a methyl group, a cyano group; Ring A is 【Chemistry 9】 wherein: X ２－１ is N,CR １１ is selected from the group consisting of R ４ is H, substituted or unsubstituted C １－６ alkyl group, substituted or unsubstituted C ３－６ Cycloalkyl group, —C(O)NR ９ R １０ , substituted or unsubstituted -NR ｍ R ｎ is selected from the group consisting of Each R ５ is H, substituted or unsubstituted C １－６ alkyl group, substituted or unsubstituted C １－６ Alkoxy group, substituted or unsubstituted C ３－６ Cycloalkyl groups, substituted or unsubstituted -NR ｍ R ｎ are independently selected from the group consisting of Each R ６ are each independently a halogen, a substituted or unsubstituted C １－６ alkyl group, substituted or unsubstituted C ３－６ cycloalkyl groups, R ７ , R １１ are each independently H, substituted or unsubstituted C １－６ alkyl groups, R ８ is H, C １－６ Alkoxy group, halogenated C １－６ Alkoxy group, —NR ｍ R ｎ , halogenated -NR ｍ R ｎ , a cyano group, a substituted or unsubstituted C １－６ alkyl group, substituted or unsubstituted C ３－６ Cycloalkyl group, —C(O)NR ９ R １０ is selected from the group consisting of Each R ９ and R １０ are each independently H, substituted or unsubstituted C １－６ alkyl group, substituted or unsubstituted C ３－６ cycloalkyl group, —C(O)R １２ , -C(O)OR １３ or R ９ and R １０ together with the N to which they are attached form a substituted or unsubstituted 5- to 7-membered heterocycle, or R ９ or R １０ Either of these is R ５ together with the 5- to 7-membered ring, Or R ４ and R ５ form together with the C to which they are attached a 5- to 7-membered heterocycle containing 1, 2 or 3 heteroatoms selected from N, O, S, R １２ , R １３ are each independently H, substituted or unsubstituted C １－６ alkyl group, substituted or unsubstituted C ３－６ cycloalkyl groups, The "substituted" groups each independently include deuterium, halogen, a hydroxy group, an amino group, -NR ｍ R ｎ , C １－６ alkoxy groups; Each R ｍ is H, C １－６ Alkyl group, C ３－６ Cycloalkyl group, C ６－１０ aryl groups, and 6-10 membered heteroaryl groups containing 1, 2 or 3 heteroatoms selected from N, O and S; Each R ｎ is C １－６ is an alkyl group, each m and n is independently selected from the group consisting of 0, 1, 2, 3, 4, and 5; Ring B is 【Chemistry 10-1】 【Chemistry 10-2】 is selected from the group consisting of Here, ring A is 【Chemistry 11】 When the formula is 【Chemistry 12-1】 【Chemistry 12-2】 characterized in that the compound is selected from the group consisting of The compound of claim 1.

3. A compound for use as a CDK4 kinase inhibitor, comprising: The compound is a compound of Formula II, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotope, or prodrug thereof: 【Chemistry 13】 where: X １ is N,CR ３ is selected from the group consisting of R １ is H,CF ３ , F, Cl, Br, a methyl group, an ethyl group, an isopropyl group, and a cyclopropyl group; R ２ H, F, CF ３ , C.F. ２ H, N.H. ２ , methyl groups; Or R １ and R ２ together with the C to which they are attached form a 5-membered heteroaryl group containing two N's, R ３ is H,CF ３ , F, Cl, Br, a methyl group, a cyano group; Ring A is 【Chemistry 14】 wherein X is selected from the group consisting of ２ is O or NR, Ring B is 【Chemistry 15-1】 【Chemistry 15-2】 is selected from the group consisting of Here, each R ４ is H, a cyano group, a halogen, a substituted or unsubstituted C １ -C ６ alkyl group, substituted or unsubstituted C ３ -C ６ independently selected from the group consisting of cycloalkyl groups; Each R ５ , R ６ , R ９ , R １０ and R １４ are each independently H, a halogen atom, a hydroxy group, an amino group, 【Chemistry 16】 oxo group, substituted or unsubstituted C １ -C ６ alkyl group, substituted or unsubstituted C ３ -C ６ a cycloalkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted C １－６ an alkoxy group, a substituted or unsubstituted —NR ｍ R ｎ or two R bonded to the same C are selected from the group consisting of １４ together with the C to which they are bound, ３ -C ６ forming a cycloalkyl group, Or R ９ , R １０ together with the N to which they are attached, 【Chemistry 17】 or 【Chemistry 18】 Forming Or ring A is 【Chemistry 19】 If R ４ and R ５ together with the ring to which they are attached form a 5- to 7-membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N, O, S; Each R and R' is independently H, C １ -C ６ Alkyl groups, halogenated C １ -C ６ Alkyl group, C ３ -C ６ Cycloalkyl groups, halogenated C ３ -C ６ selected from the group consisting of cycloalkyl groups and phenyl groups; Each R ｍ is H, C １－６ Alkyl group, C ３－６ Cycloalkyl group, C ６－１０ aryl groups, and 6-10 membered heteroaryl groups containing 1, 2 or 3 heteroatoms selected from N, O and S; Each R ｎ is C １－６ is an alkyl group, R ４ , R ５ , R ６ , R ９ , R １０ and R １４ The substitutions described above are each independently deuterium, halogen, a hydroxy group, an amino group, -N-(C １ -C ６ alkyl) ２ , C １ -C ６ substituted by one, two or three substituents selected from the group consisting of an alkoxy group, a phenyl group and a cyano group; The compound for use as a CDK4 kinase inhibitor, wherein each of m, n, and p is independently selected from the group consisting of 0, 1, 2, 3, and 4.

4. R １ is H,CF ３ , F, Cl, Br, a methyl group, an ethyl group, an isopropyl group, and a cyclopropyl group; R ２ H, F, CF ３ , C.F. ２ H, N.H. ２ , methyl groups; Ring A is 【Chemistry 20】 is selected from the group consisting of Ring B is 【Chemistry 21-1】 【Chemistry 21-2】 is selected from the group consisting of where: Each R ５ , R ６ , R ９ , R １０ and R １４ are each independently H, a halogen atom, a hydroxy group, an amino group, 【Chemical Formula 22】 Substituted or unsubstituted C １ -C ６ alkyl group, substituted or unsubstituted C ３ -C ６ cycloalkyl groups, and substituted or unsubstituted phenyl groups; Or R ９ , R １０ together with the N to which they are attached, 【Chemical 23】 Forming R and R' are each independently H, C １ -C ６ Alkyl groups, halogenated C １ -C ６ Alkyl group, C ３ -C ６ Cycloalkyl groups, halogenated C ３ -C ６ selected from the group consisting of cycloalkyl groups and phenyl groups; R ４ , R ５ , R ６ , R ９ , R １０ and R １４ The substitutions described above are each independently deuterium, halogen, a hydroxy group, an amino group, -N-(C １ -C ６ alkyl) ２ , C １ -C ６ substituted by one, two or three substituents selected from the group consisting of an alkoxy group, a phenyl group and a cyano group; Each m, n, and p is independently selected from the group consisting of 0, 1, 2, 3, and 4. The compound of claim 3.

5. R １ is selected from the group consisting of Cl, Br, R ２ is H, Ring A is 【Chemistry 24】 is selected from the group consisting of Ring B is 【Chemistry 25】 is selected from the group consisting of where: Each R ５ , R ６ , R ９ , R １０ and R １４ are each independently H, a halogen atom, a hydroxy group, an amino group, 【Chemical 26】 Substituted or unsubstituted C １ -C ６ alkyl group, substituted or unsubstituted C ３ -C ６ cycloalkyl groups, and substituted or unsubstituted phenyl groups; Or R ９ , R １０ together with the N to which they are attached, 【Chemical 27】 Forming R and R' are each independently H, C １ -C ６ Alkyl groups, halogenated C １ -C ６ Alkyl group, C ３ -C ６ Cycloalkyl groups, halogenated C ３ -C ６ selected from the group consisting of cycloalkyl groups and phenyl groups; R ５ , R ６ , R ９ , R １０ and R １４ The substitutions described above are each independently deuterium, halogen, a hydroxy group, an amino group, -N-(C １ -C ６ alkyl) ２ , C １ -C ６ substituted by one, two or three substituents selected from the group consisting of an alkoxy group, a phenyl group and a cyano group; Each m, n, and p is independently selected from the group consisting of 0, 1, 2, 3, and 4. The compound of claim 3.

6. R １ and R ２ together with the C to which they are attached form a 5-membered heteroaryl group containing two N's, Ring A is 【Chemical Formula 28】 is selected from the group consisting of Ring B is 【Chemistry 29-1】 【Chemistry 29-2】 is selected from the group consisting of Here, each R ４ is H, substituted or unsubstituted C １ -C ６ alkyl group, substituted or unsubstituted C ３ -C ６ independently selected from the group consisting of cycloalkyl groups; Each R ５ , R ６ , R ９ , R １０ and R １４ are each independently H, a halogen atom, a hydroxy group, an amino group, 【Chemistry 30】 Substituted or unsubstituted C １ -C ６ alkyl group, substituted or unsubstituted C ３ -C ６ cycloalkyl groups, and substituted or unsubstituted phenyl groups; R and R' are each independently H, C １ -C ６ Alkyl groups, halogenated C １ -C ６ Alkyl group, C ３ -C ６ Cycloalkyl groups, halogenated C ３ -C ６ selected from the group consisting of cycloalkyl groups and phenyl groups; R ４ , R ５ , R ６ , R ９ , R １０ and R １４ The substitutions described above are each independently deuterium, halogen, a hydroxy group, an amino group, -N-(C １ -C ６ alkyl) ２ , C １ -C ６ substituted by one, two or three substituents selected from the group consisting of an alkoxy group, a phenyl group and a cyano group; Each m, n, and p is independently selected from the group consisting of 0, 1, 2, 3, and 4. The compound of claim 3.

7. 【Chemical 31】 teeth, 【Chemical 32】 It has a structure like X is N, CR ３ is selected from the group consisting of R ３ is H,CF ３ , F, Cl, Br, a methyl group, and a cyano group. The compound of claim 6.

8. A compound for use as a CDK4 kinase inhibitor, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotope or prodrug thereof, A compound used as a CDK4 kinase inhibitor, characterized in that the compound is selected from the group consisting of: a compound ... 【Table 1】 【Table 2】 【Table 3】 【Table 4】 【Table 5】 【Table 6】 【Table 7】 【Table 8】 【Table 9】 【Table 10】 【Table 11】 【Table 12】 【Table 13】

9. 1. A pharmaceutical composition comprising: A pharmaceutical composition comprising a safe and effective amount of a compound according to any one of claims 1 to 8 and a pharmaceutically acceptable carrier.

10. Use of the compound according to any one of claims 1 to 8, 9. Use of the compound according to any one of claims 1 to 8 for the preparation of a medicament for modulating CDK4 kinase activity or treating a CDK4-related disease, wherein the disease is selected from the group consisting of inflammation, cancer, cardiovascular disease, infectious disease, immune disease, and metabolic disease.

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