Compound used as CDK4 protein kinase inhibitor and use thereof

Abstract

The present invention relates to a compound used as a CDK4 protein kinase inhibitor and the use thereof. Further disclosed are a preparation method for the compound and the use thereof in the prevention and / or treatment of CDK4-related diseases.

Description

Compounds useful as inhibitors of CDK4 protein kinases and uses thereof TECHNICAL FIELD

[0001] The present invention relates to the field of medicine, in particular to novel compounds useful as inhibitors of CDK4 protein kinases, and their use in modulating CDK4 protein kinase activity or treating CDK4-associated cell proliferative diseases and conditions, particularly cancer. BACKGROUND

[0002] Protein kinases regulate a variety of biological functions, including DNA replication, transcription, translation, cell cycle progression, energy metabolism, migration, and cell growth, making them ideal targets for the treatment of proliferative diseases and conditions, including cancer. There is a continuing need for novel compounds that can selectively inhibit protein kinase activity and are effective as therapeutic anti-proliferative agents.

[0003] Cyclin-dependent kinases (CDKs) belong to the family of serine / threonine kinases, which exert their physiological functions through forming active dimeric complexes with corresponding cyclins, leading to cell growth and proliferation. More than 20 CDKs have been discovered, which can be classified into two major categories according to their main functions: CDKs that regulate cell cycle and CDKs that regulate cell transcription. Among them, CDK1-CDK6 and CDK14-CDK18 and their cyclin partners (e.g., Cyclins A, B, D1, D2, D3, E, F, etc.) are involved in the regulation of cell cycle progression and are considered as cell cycle regulators; while CDK7-CDK13 and CDK19-CDK20 and their cyclin partners (e.g., Cyclins C, H, K, L1, L2, T1, T2, etc.) are involved in the regulation of cell transcription and are considered as transcription regulators. CDKs are thus involved in the regulation of cell cycle control, apoptosis, differentiation, and transcription, and it has now been demonstrated that CDK inhibitors can be used for the treatment of a variety of diseases, including cancer.

[0004] CDK4 and CDK6 are involved in the regulation of cell cycle from G1 to S phase after binding with Cyclin D. It is reported that the abnormality of CyclinD-CDK4 / 6-Rb pathway is associated with the drug resistance progress of endocrine therapy. At present, a variety of CDK4 / 6 inhibitors such as palbociclib, ribociclib, abemaciclib, etc. have been approved for marketing, and are used in combination with endocrine therapy for the treatment of hormone receptor (HR) positive, human epidermal growth factor 2 (HER2) negative advanced or metastatic breast cancer. However, during the treatment with CDK4 / 6 inhibitors, hematological toxicities such as neutropenia and / or gastrointestinal side effects often occur, thereby leading to drug discontinuation or intermittent administration, which seriously affects the efficacy and compliance of the drug. At present, research data shows that the activity of Cyclin D3-CDK6 may be related to these side effects. In view of the toxic side effects of the current CDK4 / 6 dual-target inhibitors, the development of selective CDK4 inhibitors may have better safety and efficacy. SUMMARY

[0005] One or more embodiments of the present application provide a compound of Formula I, Formula II or Formula III, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotopically enriched compound, deuterated compound, metabolite or prodrug thereof,

[0006] wherein

[0007] X1is selected from N and CR5;

[0008] X2is selected from N and CR6;

[0009] R1is selected from H, deuterium, cyano, C 1-6 alkyl, nitro, -COC 1-8 alkyl, -COOH, -C(O)NRR', -C(O)OC 1-6 alkyl, -OR 101 , C 6-10 aryl, 5-8 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O and S, 5-8 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S, -OC(O)NRR', -NRC(O)OC 1-6 alkyl; the C 1-6 alkyl, C 6-10 aryl, 5-8 membered heterocyclyl, 5-8 membered heteroaryl are each independently optionally substituted with one or more R groups; or

[0010] or R1and X1together form a 5-8 membered cycloalkyl, a 5-8 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or a 5-8 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; each of said 5-8 membered cycloalkyl, 5-8 membered heterocyclyl, 5-8 membered heteroaryl is independently optionally substituted with one or more substituents selected from deuterium, halogen, cyano, amino, hydroxyl, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, and oxo (=0), C 1-6 cycloalkyl, haloC 1-6 cycloalkyl, C 1-6 cyclohydroxyalkyl, and C 1-6 cycloalkoxy;

[0011] R2is selected from H, C 1-6 alkyl, hydroxy-substituted C 1-6 alkyl, haloC 1-6 alkyl, C 3-8 cycloalkyl, haloC 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, 3-8 membered heterocycloalkyl containing 1, 2, or 3 heteroatoms selected from N, O, or S, or 5-8 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, or S, said C 1-6 alkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, 3-8 membered heterocycloalkyl, and 5-8 membered heteroaryl are each independently optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, C 1-4 alkyl, haloC 1-4 alkyl, C 1-4 hydroxyalkyl, and C 1-4 alkoxy;

[0012] or R2and X1together form a 5-8 membered cycloalkyl, a 5-8 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or a 5-8 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; each of said 5-8 membered cycloalkyl, 5-8 membered heterocyclyl, 5-8 membered heteroaryl is independently optionally substituted with one or more substituents selected from deuterium, halogen, cyano, amino, hydroxyl, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, and oxo (=0), C 1-6 cycloalkyl, haloC1-6 cycloalkyl, C 1-6 Cyclohydroxyalkyl and C 1-6 Cycloalkoxy;

[0013] R3 is selected from H, halogen, cyano, C. 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl, C 2-6 alkenyl or C 2-6 alkynyl group;

[0014] R4 is selected from

[0015] R5 is selected from H, halogen, hydroxyl, C. 1-6 Alkyl, C 3-8 cycloalkyl, halogenated C 1-6 Alkyl, Halogenated C 3-8 Cycloalkyl, amino, -C(O)H, -C(O)C 1-8 Alkyl, -C(O)OC 1-8 Alkyl, -OC(O)C 1-8 Alkyl, -OC(O)OC 1-8 Alkyl, C 1-6 Alkyl group, -COO-C 1-6 Alkyl, -CO-C 1-6 Alkyl, Halogenated C 1-6 alkoxy- or hydroxy-substituted C 1-6 Alkyl, -C 1-4 Alkyl-OC 1-4 Alkyl, 5-8 membered heterocyclic alkyl containing 1, 2 or 3 heteroatoms selected from N, O and S, and optional halogen-substituted 5-8 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S, or R1 and R5 forming a 5-7 membered heterocycle containing O, N or S.

[0016] R6 is selected from H, halogen, cyano, C. 1-6 Alkyl and halogenated C 1-6 alkyl;

[0017] R7 is selected from C 1-6 Alkyl, C 3-8 cycloalkyl groups and -NH2;

[0018] R and R' are each independently selected from H, deuterium, halogen, cyano, hydroxyl, C 1-6 Alkyl, hydroxyl substituted C 1-6 Alkyl, C 3-8 cycloalkyl, halogenated C 1-6 Alkyl, Halogenated C 3-8 cycloalkyl, -CO-C 1-6 Alkyl, C 1-6alkyl, -SO2CH3, C 1-6 alkyl, -SO2CH3, C 6-10 aryl, 5-8 membered heterocycloalkyl containing 1, 2, or 3 heteroatoms selected from N, O, and S;

[0019] R 101 selected from: C 1-6 alkyl, phenyl, 5-8 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, 5-8 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; each C 1-6 alkyl, phenyl, 5-8 membered heterocyclyl and 5-8 membered heteroaryl are each independently optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, C 1-4 alkyl, haloC 1-4 alkyl, C 1-4 hydroxyalkyl and C 1-4 alkoxy;

[0020] each m is independently selected from 0, 1, 2, 3, 4, 5, and 6.

[0021] In one or more embodiments, the -C(O)OC 1-6 alkyl is -COO-C(CH3)3.

[0022] In one or more embodiments, the haloC 1-6 alkyl is CF3.

[0023] In one or more embodiments, the R3 is halogen; the halogen is Cl, Br.

[0024] In one or more embodiments, the R3 is halogen; the halogen is F, Cl, Br, I.

[0025] In one or more embodiments, the C 1-6 alkyl is methyl, ethyl, isopropyl.

[0026] In one or more embodiments, the C 1-6 alkoxy is -O-methyl.

[0027] In one or more embodiments, the -COO-C 1-6 alkyl is -COO-C(CH3)3.

[0028] In one or more embodiments, the R6 is halogen; the halogen is F, Cl, Br, I.

[0029] In one or more embodiments, the R and R’ are each independently halogen; the halogen is F, Cl, Br, I.

[0030] In one or more embodiments, X1is CR5; R5is selected from H, halogen, hydroxyl, C 1-6 alkyl, C 3-8 cycloalkyl, halogenated C 1-6 alkyl, halogenated C 3-8 cycloalkyl, amino, -C(O)H, -C(O)C 1-8 alkyl, -C(O)OC 1-8 alkyl, -OC(O)C 1- 8alkyl, -OC(O)OC 1-8 alkyl, C 1-6 alkoxy, -COO-C 1-6 alkyl, -CO-C 1-6 alkyl, halogenated C 1-6 alkoxy, hydroxyl substituted C 1-6 alkyl, 5-8 membered heterocycloalkyl containing 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S, and 5-8 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S, optionally substituted with halogen, or R1and R5form a 5-7 membered heterocyclic ring containing O, N, or S; preferably, R5is selected from H, methyl, and hydroxyl substituted t-butyl.

[0031] In one or more embodiments, the R5is halogen; the halogen is F, Cl, Br, I.

[0032] In one or more embodiments, the R5is C 1-6 alkyl, C 1-6 alkyl is methyl, ethyl, isopropyl.

[0033] In one or more embodiments, the R5is halogenated C 1-6 alkyl, halogenated C 1-6 alkyl is CF3.

[0034] In one or more embodiments, the R5is C 1-6 alkoxy, C 1-6 alkoxy is -O-methyl.

[0035] In one or more embodiments, the R5is -COO-C 1-6 alkyl, -COO-C 1-6 alkyl is -COO-C(CH3)3.

[0036] In one or more embodiments, the X2is N.

[0037] In one or more embodiments, the R1is selected from H, cyano, nitro, -COC 1-8alkyl, -COOH, -C(O)NRR', -C(O)OC 1-6 alkyl, 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S, -OC(O)NRR', -NRC(O)OC 1-6 alkyl.

[0038] In one or more embodiments, said R1is selected from H, deuterium, cyano, nitro, -COC 1-4 alkyl, -COOH, -C(O)NRR', -C(O)OC 1-4 alkyl (such as -COO-C(CH3)3), phenyl, 5-6 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O and S, -OR 101 , 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S, -OC(O)NRR', -NRC(O)OC 1-6 alkyl; said phenyl, heterocyclyl, heteroaryl is optionally substituted with one or more of deuterium, halogen (preferably F), cyano, hydroxyl, C 1-4 alkyl (preferably methyl), haloC 1-4 alkyl (preferably trifluoromethyl), C 1-4 hydroxyalkyl, C 1-4 alkoxy (preferably methoxy) and oxo (=O).

[0039] In one or more embodiments, R1may form together with X1a 5-6 membered cycloalkyl, 5-6 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O and S or 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S; said 5-6 membered cycloalkyl, 5-6 membered heterocyclyl, 5-6 membered heteroaryl is optionally substituted with 1, 2, 3 or 4 of deuterium, halogen, cyano, amino, hydroxyl, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy and oxo (=O), C 1-6 cycloalkyl, haloC 1-6 cycloalkyl, C 1-6 cyclohydroxyalkyl and C 1-6 cycloalkoxy.

[0040] In one or more embodiments, R1may be taken together with X1to form a 6-membered cycloalkyl, a 5-6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or a 5-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; said 6-membered cycloalkyl, 5-6 membered heterocyclyl, 5-membered heteroaryl optionally substituted with 1, 2, 3, or 4 of deuterium, halogen, cyano, amino, hydroxyl, C 1-4 alkyl, haloC 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, and oxo (=0), C 1-4 cycloalkyl, haloC 1-4 cycloalkyl, C 1-4 cyclohydroxyalkyl, and C 1-4 cycloalkoxy.

[0041] In one or more embodiments, said R1is selected from -C(O)OC 1-6 alkyl, -C(O)OC 1-6 alkyl is -COO-C(CH3)3.

[0042] In one or more embodiments, R1is selected from: C 1-4 alkyl, -COC 1-8 alkyl, -C(O)NRR', cyano, nitro, phenyl, or a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; R, R' are each independently selected from H, deuterium, C 1-6 alkyl, or hydroxyl substituted C 1-6 alkyl; said C 1-4 alkyl, phenyl, and heteroaryl are optionally further substituted with deuterium, cyano, halogen, C 1-3 alkyl, or haloC 1-3 alkyl. In one or more embodiments, said R1is selected from -COCH3, cyano, nitro,

[0043] said R and R' are as described above.

[0044] In one or more embodiments, R2is selected from H, C 1-4 alkyl, hydroxyl substituted C 1-4 alkyl, haloC 1-4 alkyl (such as CF3), C 3-6 cycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 6-8 heteroaryl; said C1-4 alkyl, C 3-6 cycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 6-8 aryl, heterocycloalkyl and heteroaryl are each optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, C 1-3 alkyl, haloC 1-3 alkyl, C 1-3 hydroxyalkyl and C 1-3 alkoxy.

[0045] In one or more embodiments, R2may form together with X1a 5-6 membered cycloalkyl, a 5-6 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O and S, or a 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S; said 5-6 membered cycloalkyl, 5-6 membered heterocyclyl, 5-6 membered heteroaryl is optionally substituted with 1, 2, 3 or 4 of the following groups: deuterium, halogen, cyano, amino, hydroxyl, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy and oxo (=0), C 1-6 cycloalkyl, haloC 1-6 cycloalkyl, C 1-6 cyclohydroxyalkyl and C 1-6 cycloalkoxy.

[0046] In one or more embodiments, R2may form together with X1a 6 membered cycloalkyl, a 5-6 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O and S, or a 5 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S; said 6 membered cycloalkyl, 5-6 membered heterocyclyl, 5 membered heteroaryl is optionally substituted with 1, 2, 3 or 4 of the following groups: deuterium, halogen, cyano, amino, hydroxyl, C 1-4 alkyl, haloC 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy and oxo (=0), C 1-4 cycloalkyl, haloC 1-4 cycloalkyl, C 1-4 cyclohydroxyalkyl and C 1-4 cycloalkoxy.

[0047] In one or more embodiments, R2is selected from C 1-4 alkyl or C 3-6 cycloalkyl.

[0048] In one or more embodiments, R2is selected from methyl, ethyl, isopropyl, cyclopropyl, and -CD3.

[0049] In one or more embodiments, R3is selected from H, F, CI, Br, cyclopropyl, and cyano.

[0050] In one or more embodiments, R4is selected from

[0051] In one or more embodiments, the compound is selected from any one of the following general formulae:

[0052] Z1, Z2, Z3, Z4are each independently selected from -C=0, -CR 102 R 102 , -NR 103 , O, or S;

[0053] V1, V2, V3, V4are each independently selected from CR 102 or N;

[0054] each R 102 , R 103 is each independently selected from H, deuterium, halogen, cyano, hydroxyl, C 1-4 alkyl, haloC 1- 4alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy;

[0055] In one or more embodiments, each R 102 , R 103 is each independently selected from H, deuterium, or methyl.

[0056] In one or more embodiments, the compound is selected from any one of the following general formulae:

[0057] each R 102 , R 103 is each independently selected from: H, deuterium, halogen, cyano, hydroxyl, C 1-4 alkyl, haloC 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy; or, each R 102 , R 103 is each independently selected from: H, deuterium, or methyl;

[0058] u1or U1is 0, 1, 2, 3, or 4; u2or U2is 0, 1, or 2; u3or U3is 0, 1, 2, 3, 4, 5, or 6; u4or U4is 0, 1, 2, 3, or 4; u5or U5is 0, 1, 2, 3, 4, 5, 6, 7, or 8.

[0059] In one or more embodiments, the compound is:

[0060] wherein,

[0061] X1is selected from CR5or N, R5is selected from H, C 1-4 alkyl, C 1-4 alkoxy or hydroxy substituted C 1-4 alkyl, C 1-4 alkyl-O-C 1- 4alkyl;

[0062] X2is selected from N;

[0063] R1is selected from: -COC 1-8 alkyl, -C(O)NRR', cyano or nitro; R, R' are each independently selected from H, deuterium, C 1-6 alkyl or hydroxy substituted C 1-6 alkyl;

[0064] R2is selected from C1-4alkyl or cyclopropyl, said C1-4alkyl, cyclopropyl being optionally further substituted with deuterium or hydroxy;

[0065] R3is selected from F, Cl, Br, cyclopropyl or cyano;

[0066] R4is selected from:

[0067] In one or more embodiments, the compound is:

[0068] wherein,

[0069] X1is selected from CR5, R5is selected from H, C 1-4 alkyl, C 1-4 alkoxy or hydroxy substituted C 1-4 alkyl, C 1-4 alkyl-O-C 1-4 alkyl;

[0070] X2is selected from N;

[0071] R1is selected from: C 1-4 alkyl, -COC 1-8 alkyl, phenyl, 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S; said C 1-4 alkyl, phenyl and heteroaryl being optionally further substituted with deuterium, cyano, halogen, C 1-3 alkyl or halogenated C 1-3 alkyl;

[0072] R2is selected from C1-4alkyl or cyclopropyl;

[0073] R3is selected from Cl or Br;

[0074] R4is selected from:

[0075] In one or more embodiments, the C 1-6 alkyl is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl.

[0076] In one or more embodiments, the halogen is F, Cl, Br, or I.

[0077] In one or more embodiments, the haloC 1-6 alkyl is CF3.

[0078] In one or more embodiments, the halogen is F, Cl, Br, or I.

[0079] In one or more embodiments, the C 1-6 alkoxy is -O-methyl.

[0080] In one or more embodiments, the -COO-C 1-6 alkyl is -COO-C(CH3)3.

[0081] Preferably, the -C(O)OC 1-6 alkyl is -COO-C(CH3)3.

[0082] In one or more embodiments, the C 1-4 alkyl is methyl.

[0083] In one or more embodiments, the haloC 1-4 alkyl is trifluoromethyl.

[0084] In one or more embodiments, the C 1-4 alkoxy is methoxy.

[0085] One or more embodiments of the present application provide a compound of Formula I’, Formula II’, or Formula III’, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotopologue, deuterated compound, metabolite, or prodrug thereof,

[0086] wherein

[0087] X1is selected from N and CR5;

[0088] X2is selected from N and CR6;

[0089] R1is selected from H, cyano, -COO 1-8alkyl, -COOH, -C(O)NRR', -C(O)OC 1-6 alkyl (e.g., -COO-C(CH3)3), heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, -OC(O)NRR', -NRC(O)OC 1- 6alkyl;

[0090] R2is selected from H, C 1-6 alkyl, haloC 1-6 alkyl (e.g., CF3), C 3-8 cycloalkyl, haloC 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, or C 6-10 aryl;

[0091] R3is selected from H, halo (e.g., Cl, Br), C 1-6 alkyl, haloC 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl;

[0092] R4is selected from

[0093] R5is selected from H, halo (e.g., F, Cl, Br, I), hydroxyl, C 1-6 alkyl (e.g., methyl, ethyl, isopropyl), C 3-8 cycloalkyl, haloC 1-6 alkyl (e.g., CF3), haloC 3-8 cycloalkyl, amino, -C(O)H, -C(O)C 1-8 alkyl, -C(O)OC 1-8 alkyl, -OC(O)C 1-8 alkyl, -OC(O)OC 1-8 alkyl, C 1-6 alkoxy (e.g., -O-methyl), -COO-C 1-6 alkyl (e.g., -COO-C(CH3)3), -CO-C 1-6 alkyl, haloC 1-6 alkoxy, hydroxyl substituted C 1-6 alkyl, 5-8 membered heterocycloalkyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and 5-8 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, optionally substituted with halo, or R1and R5form a 5-7 membered heterocyclic ring containing O, N, or S;

[0094] R6is selected from H, halo (e.g., F, Cl, Br, I), cyano, C 1-6 alkyl, and haloC 1-6alkyl;

[0095] R7is selected from C 1-6 alkyl, C 3-8 cycloalkyl, and -NH2;

[0096] R and R' are each independently selected from H, halogen (such as F, Cl, Br, I), cyano, hydroxyl, C 1-6 alkyl, C 3-8 cycloalkyl, haloC 1-6 alkyl (such as CF3), haloC 3-8 cycloalkyl, -CO-C 1-6 alkyl, C 1-6 alkoxy (such as -O-methyl), amino, -COOH, -CONH2, -COO-C 1-6 alkyl, -SO2CH3, C 6-10 aryl, 5-8 membered heterocycloalkyl containing 1, 2, or 3 heteroatoms selected from N, O, and S;

[0097] m is each independently selected from 0, 1, 2, 3, 4, 5, and 6.

[0098] In one or more embodiments, the compound is selected from:

[0099] One or more embodiments of the present application provide the use of a compound of the present application in the manufacture of a medicament for the prevention and / or treatment of a CDK4 kinase-mediated disease.

[0100] One or more embodiments of the present application provide a compound of the present application for use as a medicament.

[0101] One or more embodiments of the present application provide a compound of the present application for use in a medicament for the prevention and / or treatment of a CDK4 kinase-mediated disease.

[0102] One or more embodiments of the present application provide a compound of the present application for use in the prevention and / or treatment of inflammation, cancer, cardiovascular diseases, infectious diseases, immunological diseases, and metabolic diseases.

[0103] One or more embodiments of the present application provide a method of preventing and / or treating a CDK4 kinase-mediated disease, comprising administering to a subject in need thereof a compound of the present application.

[0104] One or more embodiments of the present application provide a method of preventing and / or treating inflammation, cancer, cardiovascular disease, infectious disease, immunological disease, and metabolic disease, comprising administering to a subject in need thereof a compound of the present application.

[0105] In one or more embodiments, the CDK4 kinase-mediated disease is selected from the group consisting of inflammation, cancer, cardiovascular disease, infectious disease, immunological disease, and metabolic disease.

[0106] In one or more embodiments, 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, uterine cancer, liposarcoma.

[0107] One or more embodiments of the present application provide use of a compound of the present application in the manufacture of a CDK4 kinase inhibitor.

[0108] One or more embodiments of the present application provide a method of preparing a compound of the present application, comprising:

[0109] In the first step: in a solvent, a coupling or nucleophilic substitution reaction is carried out by palladium catalysis, wherein a compound of formula SM1 reacts with a compound of formula S1 at 70-120°C to form a compound of formula SM2;

[0110] In the second step: in a solvent, a coupling or nucleophilic substitution reaction is carried out by palladium catalysis under basic conditions, wherein a compound of formula SM2 reacts with a compound of formula S2 to obtain product T;

[0111] wherein R1, R2, R3, R4, X1, X2 are as described above.

[0112] In one or more embodiments, in the first step, the solvent is 1,4-dioxane, tetrahydrofuran, 1,2-dichloroethane.

[0113] In one or more embodiments, in the second step, the solvent is 1,4-dioxane, tetrahydrofuran, toluene, N,N-dimethylformamide, dimethyl sulfoxide, N-methyl pyrrolidone.

[0114] One or more embodiments of the present application provide a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present application and a pharmaceutically acceptable carrier.

[0115] In one or more embodiments, the dosage form of the pharmaceutical composition is selected from the group consisting of an injection, a tablet, a capsule, an aerosol, a suppository, a film, a dripping pill, an external liniment, a controlled release preparation, a sustained release preparation, and a nano preparation.

[0116] One or more embodiments of the present application provide a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present application and another therapeutic agent.

[0117] In one or more embodiments, the therapeutic agent is an anti-cancer drug.

[0118] In one or more embodiments, the dosage form of the pharmaceutical composition is selected from the group consisting of an injection, a tablet, a capsule, an aerosol, a suppository, a film, a dripping pill, an external liniment, a controlled release preparation, a sustained release preparation, and a nano preparation.

[0119] One or more embodiments of the present application provide use of a pharmaceutical composition of the present application in the manufacture of a medicament for preventing and / or treating a CDK4 kinase-mediated disease.

[0120] One or more embodiments of the present application provide a pharmaceutical composition of the present application for use as a medicament.

[0121] One or more embodiments of the present application provide a pharmaceutical composition of the present application for use in a medicament for preventing and / or treating a CDK4 kinase-mediated disease.

[0122] One or more embodiments of the present application provide a pharmaceutical composition of the present application for use in preventing and / or treating inflammation, cancer, a cardiovascular disease, an infectious disease, an immunological disease, and a metabolic disease.

[0123] One or more embodiments of the present application provide a method of preventing and / or treating a CDK4 kinase-mediated disease, comprising administering a pharmaceutical composition of the present application to a subject in need thereof.

[0124] One or more embodiments of the present application provide a method of preventing and / or treating inflammation, cancer, a cardiovascular disease, an infectious disease, an immunological disease, and a metabolic disease, comprising administering a pharmaceutical composition of the present application to a subject in need thereof.

[0125] It should be understood that, within the scope of the present application, each of the technical features described above and each of the technical features specifically described hereinafter (e.g., in the Examples) can be combined with each other to constitute a new or preferred technical scheme. Due to the limited space, no further elaboration is made here. DETAILED DESCRIPTION

[0126] The present inventors have made extensive and intensive studies, and found a compound having good CDK4 protein kinase inhibitory activity, which has excellent inhibitory activity on CDK4 protein kinase and has better pharmacodynamics / pharmacokinetics performance. On this basis, the present application is completed.

[0127] The terms

[0128] Unless specifically indicated otherwise, the following terms as used in the present application (including the specification and claims) have the definitions given below.

[0129] When a substituent is described by a conventional chemical formula written from left to right, the substituent also equally includes a chemically equivalent substituent resulting from writing the structural formula from right to left. By way of example, -CH2O- is equivalent to -OCH2-.

[0130] As used herein, the term "alkyl" in a group "-" or represents the point of attachment of the group to the rest of the compound or molecule.

[0131] "Alkyl", alone or as part of other groups, means a straight-chain or branched saturated hydrocarbon group of from 1 to 12 carbon atoms (i.e., C 1-12 alkyl). For example, alkyl is C 1-6 alkyl (i.e., an alkyl group containing 1, 2, 3, 4, 5, or 6 carbon atoms). Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, t-butyl, pentyl, n-hexyl, octyl, and the like. Unless otherwise indicated, alkyl in the present application is intended to include substituted alkyl groups, i.e., one or more positions in the alkyl group are substituted, especially 1-4 substituents, which can be substituted at any position. Unless otherwise indicated, "substituted alkyl" in the present application includes haloalkyl. As used herein, "haloalkyl" means an alkyl group as defined herein in which one or more hydrogens are replaced by the same or different halogen. Haloalkyl is preferably C 1-6 haloalkyl, more preferably C 1-6 haloalkyl. Examples of haloalkyl include -CH2Cl, -CH2CF3, -CH2CCl3, perfluoroalkyl (e.g., -CF3), and the like.

[0132] "Alkoxy", alone or as part of other groups, means an alkyl group as defined above having an oxy group attached thereto, having the structure alkylO-. Preferably, alkoxy is C 1-6 alkoxy (i.e., -OC 1-6alkyl). Alkoxy includes, but is not limited to, methoxy, ethoxy, propyloxy, t-butyloxy, and the like. "Haloalkoxy" means a group of the formula -OR, wherein R is a haloalkyl group, as defined herein. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, 2,2,2-trifluoroethoxy, and the like.

[0133] "Thioalkyl" means an alkyl group in which a carbon is replaced by S, S(O), or S(O)2.

[0134] "Alkenyl", alone or as part of another group, means an aliphatic group containing at least one double bond, generally from 2 to 20 carbon atoms (i.e., C 2-20 alkenyl). For example, alkenyl is C 2-6 alkenyl (i.e., alkenyl groups containing 2, 3, 4, 5, or 6 carbon atoms). Alkenyl groups include, but are not limited to, for example, ethylenyl, propylenyl, butylenyl, 1-methyl-2-buten-1-yl, and the like. Unless defined otherwise, in the present application, alkenyl also includes substituted alkenyl groups.

[0135] "Alkynyl", alone or as part of another group, means a straight or branched chain hydrocarbon chain containing two or more carbon atoms and characterized by having one or more triple bonds, generally from 2 to 20 carbon atoms (i.e., C 2-20 alkynyl). For example, alkynyl is C 2-6 alkynyl (i.e., alkynyl groups having 2, 3, 4, 5, or 6 carbon atoms). Alkynyl groups include, but are not limited to, ethynyl, propargyl, and 3-hexynyl. One of the triple-bond carbons can optionally be the point of attachment of the alkynyl substituent. Unless defined otherwise, in the present application, alkynyl also includes substituted alkynyl groups.

[0136] "Aliphatic group" means a straight chain, branched chain, or cyclic hydrocarbon group that is either saturated or unsaturated, such as alkyl, alkenyl, and alkynyl.

[0137] "Aryl ring system" or "aryl ring" means a monocyclic, bicyclic, or polycyclic ring system in which at least one ring is aromatic. For example, "aryl ring system" or "aryl ring" has from 6 to 12 ring atoms (i.e., C 6-12 aromatic ring. Examples of aryl rings include benzene, naphthalene, anthracene, and the like.

[0138] "Aryl", alone or as part of another group, means a monovalent radical of an aryl ring system (aryl ring). Representative aryl groups include fully aromatic ring systems, such as phenyl, naphthyl, and anthryl; and ring systems in which an aromatic carbon ring is fused with one or more non-aromatic carbon rings, such as indanyl, phthalimidyl, naphthimidyl, or tetrahydronaphthyl, and the like. For example, aryl is C 6-10 aromatic ring. Examples of aryl rings include benzene, naphthalene, anthracene, and the like.

[0139] "Aryloxy" means an -O-(aryl) group wherein the aryl moiety is as defined above.

[0140] "Aryloxy" means an -O-(aryl) group wherein the aryl moiety is as defined above.

[0141] "Heteroalkyl" means an alkyl group in which one or more of the carbon atoms are replaced by a heteroatom selected from oxygen, nitrogen, sulfur, phosphorus, or combinations thereof. Numerical ranges for heteroalkyl groups, for example, can be given as having 1 to 6 carbon atoms, i.e., C1-C6heteroalkyl. 1-6 Heteroalkyl refers to the number of carbons in the chain, which includes 1 to 6 carbon atoms. For example, a -CH2OCH2CH3group is referred to as a "C3" heteroalkyl. Attachment to the rest of the molecule can be through a heteroatom or carbon in the heteroalkyl chain.

[0142] "Carbocyclic ring system" or "carbocycle" means a monocyclic, bicyclic or polycyclic hydrocarbon ring system in which each ring is completely saturated or contains one or more units of unsaturation, but which is not aromatic, and wherein all rings are carbon rings. Preferably, the "carbocyclic ring system" or "carbocycle" has 6-12 ring atoms, i.e., C6-Ci2carbocycle. 6-12 Carbocyclic ring system" or "carbocycle" means a monocyclic, bicyclic or polycyclic hydrocarbon ring system in which each ring is completely saturated or contains one or more units of unsaturation, but which is not aromatic, and wherein all rings are carbon rings. Preferably, the "carbocyclic ring system" or "carbocycle" has 6-12 ring atoms, i.e., C6-Ci2carbocycle. 6-12 Carbocyclic ring system" or "carbocycle" means a monocyclic, bicyclic or polycyclic hydrocarbon ring system in which each ring is completely saturated or contains one or more units of unsaturation, but which is not aromatic, and wherein all rings are carbon rings. Preferably, the "carbocyclic ring system" or "carbocycle" has 6-12 ring atoms, i.e., C6-Ci2carbocycle.

[0143] "Cycloalkyl" refers to a monovalent saturated carbocyclic radical which is either monocyclic or bicyclic, for example, having from 3 to 8 ring carbon atoms (i.e., C3-C8cycloalkyl). Unless otherwise specified, cycloalkyl groups can be optionally substituted by one or more substituents. Preferably, the substituents of the cycloalkyl group can be independently hydroxy, alkyl, alkoxy, halo, haloalkyl, amino, mono- or di-alkylamino. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. 3- "Cycloalkyl" refers to a monovalent saturated carbocyclic radical which is either monocyclic or bicyclic, for example, having from 3 to 8 ring carbon atoms (i.e., C3-C8cycloalkyl). Unless otherwise specified, cycloalkyl groups can be optionally substituted by one or more substituents. Preferably, the substituents of the cycloalkyl group can be independently hydroxy, alkyl, alkoxy, halo, haloalkyl, amino, mono- or di-alkylamino. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

[0144] "Cycloalkoxy" refers to a group of the formula -OR wherein R is cycloalkyl as defined herein. Exemplary cycloalkoxy groups include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.

[0145] A "heteroaromatic ring system" or "heteroaromatic ring" refers to a monocyclic (e.g., 5- or 6-membered), bicyclic (5, 6, 7, 8-membered), or polycyclic system in which at least one ring is an aromatic ring containing at least one heteroatom (e.g., N, O, or S) as a ring atom and the remaining ring atoms are all carbon. In some cases, the aromatic ring containing at least one heteroatom may contain 1, 2, 3, or 4 heterocyclic atoms. Apart from aromatic rings containing at least one heteroatom as a ring atom, the remaining rings in a "heteroaromatic ring system" or "heteroaromatic ring" may be saturated, partially unsaturated, or fully unsaturated rings.

[0146] "Heteroaryl," alone or as part of other groups, refers to a monovalent group of a "heteroary ring system" or "heteroary ring" as defined above. The junction of the heteroaryl group should be located on the aromatic ring. Examples of heteroaryl groups include, but are not limited to: imidazole, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiazolyl, pyrazinyl, thiophene, furanyl, pyranyl, pyridinyl, pyrroleyl, pyrazolyl, pyrimidinyl, quinolinyl, isoquinolinyl, benzofuranyl, benzofuranyl, benzothiophene, benzothiaranyl, benzoimidazolyl, benzooxazolyl, benzooxadiazolyl, benzothiazolyl, benzothiazolyl, benzopyranyl, indole, isindole, triazolyl, triazinyl, quinoxolinyl, purine, quinazolinyl, quinazinyl, naphthidyl, pteridinyl, carbazole, and azazolyl. basalt, diazoxide Acridine, acridine, etc. A heteroaryl group is a heteroaryl group as defined above that has two linking sites. Unless otherwise defined, heteroaryl groups include substituted or unsubstituted forms.

[0147] A "heterocyclic system" or "heterocyclic ring" refers to a monocyclic, bicyclic, or polycyclic system (e.g., 3-8-membered, i.e., 3-, 4-, 5-, 6-, 7-, or 8-membered), wherein at least one ring is saturated or partially unsaturated (but non-aromatic) and the ring contains at least one (e.g., 1, 2, or 3) heteroatoms selected from O, N, and S as ring atoms. Heterocyclic systems or heterocyclic rings can be attached to side groups at any heteroatom or carbon atom, resulting in a stable structure, and any ring atom can optionally be substituted.

[0148] "Heterocyclic alkyl" refers to a heterocyclic system or heterocyclic group, usually a stable monocyclic, bicyclic, or tricyclic (e.g., 3-8 members, i.e., 3, 4, 5, 6, 7, or 8 members), including fused ring, spirocyclic, and / or bridged ring structures, which are saturated and contain a carbon atom and one, two, three, or four heteroatoms independently selected from N, O, and S as ring atoms.

[0149] In this invention, "ester group" refers to having a -C(O)-OR or RC(O)-O- structure, wherein R independently represents hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group, as defined above.

[0150] In the present application, the term "amido" refers to a group bearing the structure -CONRR', where R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R and R' in the dialkylamine fragment can be the same or different.

[0151] In the present application, the term "sulfonamido" refers to a group bearing the structure -SO2NRR', where R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R and R' in the dialkylamine fragment can be the same or different.

[0152] "Ketone carbonyl" refers to R-C(=O)-, where R is alkyl, cycloalkyl, etc., as described above.

[0153] When a substituent is a non-terminal substituent, it is an alkyl group, for example, corresponds to an alkylene group, a cycloalkyl group corresponds to an alkylenecycloalkyl group, a heterocyclyl group corresponds to an alkyleneheterocyclyl group, an alkoxy group corresponds to an alkylenoxy group, etc.

[0154] In the present application, each of the above-mentioned alkyl, alkoxy, cycloalkyl, heteroalkyl, aryl, heteroaryl, cycloheteroalkyl, alkenyl, alkyne, heterocycle, heterocyclyl, etc., can be substituted or unsubstituted.

[0155] In the present application, the term "substituted" refers to replacement of one or more hydrogen atoms on a specified group with a specified substituent. The specified substituents are those described in the foregoing, or those appearing in each of the embodiments. Unless otherwise specified, a substituted group can have one substituent selected from a specified group at any substitutable position on the group, which can be the same or different at each position. Those skilled in the art will appreciate that combinations of substituents contemplated by the present application are those that result in stable or chemically feasible compounds. Typical substitutions include, but are not limited to, one or more of the following: hydrogen, deuterium, halogen (e.g., a monohalogen substituent or a polyhalogen substituent, the latter such as trifluoromethyl or an alkyl group containing Cl3), cyano, nitro, oxo (e.g., =0), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, alkynyl, heterocycle, aryl, OR a , SR a , S(=O)R e , S(=O)2R e , P(=O)2R e , S(=O)2OR e , P(=O)2OR e , NR b R c , NRb S(=O)2R e , NR b P(=O)2R e , S(=O)2NR b R c , P(=O)2NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , NR b C(=O)OR e , NR d C(=O)NR b R c , NR d S(=O)2NR b R c , NR d P(=O)2NR b R c , NR b C(=O)R a , or NR b P(=O)2R e , wherein R a may independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, alkynyl, heterocycle, or aryl, R b , R c and R d may independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocycle, or aryl, or R b and R c together with the N atom can form a heterocycle; and R e may independently represent hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, heterocycle, or aryl. The above typical substituents, such as alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl, can be optionally substituted. The substituents are exemplified by, but not limited to, halogen, hydroxyl, cyano, carboxyl (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, aryl, heteroaryl, C1-C8 aldehydo, C2-C 10 acyl, C2-C 10 ester, amine, C1-C6 alkoxy, C1-C 10 sulfonyl, and C1-C6 ureido, etc.

[0156] "Cyano" means -CN.

[0157] "nitro" means -NO2.

[0158] "hydroxy" means -OH.

[0159] "amino" means -NH2or RNH-, where R is keto carbonyl, sulfonyl, sulfonamide, R a -C(=O)-, R a R b N-C(=O)-, and the like, where R a and R b are alkyl, cycloalkyl, aryl, or heteroaryl, and the like.

[0160] "halogen (halo)" means any halogen radical, for example, -F, -Cl, -Br, or -I.

[0161] "deuterated" means a compound in which one hydrogen atom (H) or multiple hydrogen atoms (H) are replaced by deuterium atom (D).

[0162] In the present invention, the term "plurality" independently means greater than 1, for example, 2, 3, 4, 5.

[0163] It should be understood that when a group is simultaneously present in a plurality of different positions of a compound, its definition in each position is independent of each other and can be the same or different. That is, the term "selected from" has the same meaning as the term "each independently selected from".

[0164] Active ingredient

[0165] As used herein, the term "compound of the present invention" or "active ingredient of the present invention" can be used interchangeably to mean a compound of Formula I, Formula II, or Formula III, or a pharmaceutically acceptable salt, hydrate, solvate, isotopically- enriched compound (e.g., deuterated compound), metabolite, or prodrug thereof. The term also includes racemates, optical isomers.

[0166] The compound of Formula I, Formula II, or Formula III is shown below:

[0167] R1, R2, R3, R4, X1, X2are defined as above.

[0168] In one or more embodiments, R1, R2, R3, R4, X1, X2are each independently a specific group corresponding to a specific compound of the present invention.

[0169] Prodrugs and solvates (or solvates) of the compounds of the present invention are also within the scope of the present invention.

[0170] The term "prodrug" as used herein refers to a compound which, upon administration, is metabolized or chemically converted into a compound, salt, or solvate of the present application in the treatment of a disease of interest. The compounds of the present application include solvates, such as hydrates.

[0171] The compounds, salts, or solvates of the present application can exist in tautomeric forms (e.g., amide and imine ether). All such tautomers are intended to be encompassed within the scope of the present application.

[0172] All stereoisomers (e.g., those that result from the presence of an asymmetric carbon atom in the compounds of the present application) are intended to be encompassed within the scope of the present application. The compounds of the present application can be present in the form of one or more stereoisomers independently of other stereoisomers. For example, a particular optical isomer can have special activity, either as a pure or substantially pure optical isomer. The chiral centers of the present application have the S or R configuration as defined by the International Union of Pure and Applied Chemistry (IUPAC) Recommendations of 1974. The racemic forms can be resolved by physical methods, such as fractional crystallization, or by separation of diastereomeric salts, or by chromatography on chiral columns. The individual optical isomers can be obtained from the racemates by conventional methods, including but not limited to, the traditional method of resolving the racemates with an optically active acid, followed by recrystallization.

[0173] The compounds of the present application are obtained by preparation, isolation, and purification, and are present in a weight amount of equal to or greater than 90%, for example, equal to or greater than 95%, equal to or greater than 99% ("very pure") as described in the text. Such "very pure" compounds of the present application are also intended to be encompassed by the present application.

[0174] All configurational isomers of the compounds of the present application are intended to be encompassed within the scope of the present application, whether in admixture, pure, or very pure form. The definition of the compounds of the present application includes both cis (Z) and trans (E) isomers of alkenes, as well as cis and trans isomers of carbocyclic and heterocyclic rings.

[0175] Throughout the specification, groups and substituents are chosen by one of ordinary skill in the art to provide stable moieties and compounds.

[0176] The definitions of specific functional groups and chemical terms are described in more detail below. For purposes of the present application, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional group terms are used as generally understood in the art. thThe definitions of specific functional groups are also described in Ed. In addition, the principles of organic chemistry and the specific functional groups and reactivity are illustrated in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, the entire contents of which are incorporated herein by reference.

[0177] Certain compounds of the present application can exist in particular geometric or stereoisomeric forms. The present application contemplates all such isomers, including cis, and trans isomers, R and S enantiomers, diastereomers, (D) and (L) isomers, racemic mixtures and other mixtures thereof. Additionally, an asymmetric carbon atom can represent a substituent group, such as an alkyl group. All isomers and mixtures thereof are contemplated by the present application.

[0178] According to the present application, mixtures of isomers can contain a variety of ratios of isomers. For example, mixtures of only two isomers can have the following combinations: 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0, and all ratios of isomers are within the scope of the present application. Similar ratios, as would be readily understood by one of ordinary skill in the art, and ratios for more complex mixtures of isomers are also within the scope of the present application.

[0179] The present application also includes isotopically-labelled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl. The present application also includes the prodrugs, salts, and solvates of the compounds of the present application and the compounds of the present application containing certain isotopic substitutions as set forth above. Certain isotopically-labeled compounds of the present application, for example, 3 H, and 14 C, are useful in drug and substrate tissue distribution assays. Tritiated, i.e.,3 H and carbon-14, i.e. 14 C, are easier to make and detect. Carbon-14 is preferred among the isotopes. Furthermore, substitution with heavier isotopes such as deuterium, i.e. 2 H, can afford advantages in some therapies, such as increased half-life or reduced dosage, and are therefore preferred in some cases. Isotopically-labeled compounds can generally be prepared by conventional techniques known to those skilled in the art.

[0180] If one desires to design a synthesis of a specific enantiomer of a compound of the application, it can be prepared by asymmetric synthesis, or derivatized with a chiral auxiliary, separating the resulting diastereomeric mixture, and then removing the chiral auxiliary to yield the pure enantiomer. Alternatively, if the molecule contains an acidic functional group, such as an amino acid, or a basic functional group, such as a carboxylic acid, one can form a diastereomeric salt with a suitable optically active acid or base, and then separate the desired enantiomer by crystallization or chromatography, and then remove the counterion to yield the pure enantiomer.

[0181] As described herein, the compounds of the application can be expanded to include any number of substituents or functional groups. In general, the term "substituted" whether preceded by the term "optionally" or not, is intended to refer to the general formula of the compounds of the application, wherein the indicated structure is replaced with the indicated substituent. When multiple instances of a particular structure are substituted with multiple instances of a particular substituent, each instance of the substituent can be the same or different. In a broad sense, the permissible substituents include noncyclic, cyclic, branched, unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic organic compounds. In the present application, for example, the heteroatom nitrogen can have a hydrogen substituent or any permissible organic compound as described above to complete its valence. Furthermore, the present application is not intended to be limited in any way by any means of permissible substitution of organic compounds. The present application contemplates combinations of substituents and variables in a manner that is chemically

[0182] Metabolites of compounds of the present application and pharmaceutically acceptable salts thereof, and those compounds which exist in un-ionized enteric coated form, can be

[0183] Pharmaceutical compositions and methods of administration

[0184] The pharmaceutical compositions described herein are useful for the prevention and / or treatment of inflammatory diseases, cancer, cardiovascular diseases, infectious diseases, immune diseases, metabolic diseases.

[0185] The compounds of Formula I, Formula II, or Formula III can be used in combination with other agents known to be effective in the treatment or amelioration of similar conditions. When administered in combination, the original dosage regimen for the previously known agent can be maintained while the compound of Formula I, Formula II, or Formula III is administered either concurrently or sequentially with the previously known agent. When the compound of Formula I, Formula II, or Formula III is administered concurrently with the other agent(s), a pharmaceutical composition containing both the compound of Formula I, Formula II, or Formula III and the other agent(s) can be used. Pharmaceutical combinations also include administration of the compound of Formula I, Formula II, or Formula III and the other agent(s) within overlapping time periods. When the compound of Formula I, Formula II, or Formula III is administered in combination with the other agent(s), the dosage of the compound of Formula I, Formula II, or Formula III or the other agent(s) can be lower than that usually used when these are used singly.

[0186] The drugs or active ingredients that can be combined with the compounds described in Formula I, Formula II, or Formula III include, but are not limited to, PD-1 inhibitors (such as nivolumab, pembrolizumab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT1306, AK105, LZM 009, or biosimilars of the above drugs, etc.), PD-L1 inhibitors (such as 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 (such as rituximab, obinutuzumab, ofatumumab, tositumomab, ibritumomab, etc.), CD47 antibodies (such as Hu5F9-G4, CC-90002, TTI-621, TTI-622, OSE-172, SRF-231, ALX-148, NI-1701, SHR-1603, IBI188, IMM01), ALK inhibitors (such as ceritinib, alectinib, brigatinib, lorlatinib, osimertinib), PI3K inhibitors (such as idelalisib, Dactolisib, Taselisib, Buparlisib, etc.), BTK inhibitors (such as Ibrutinib, Tirabrutinib, Acalabrutinib, etc.), EGFR inhibitors (such as Afatinib, Gefitinib, Erlotinib, Lapatinib, Dacomitinib, Egfrinib, Canertinib, etc.), VEGFR inhibitors (such as Sorafenib, Pazopanib, Raveurbib, Cabozantinib, Sunitinib, Dornafinib, etc.), HDAC inhibitors (such as Givinostat, Droxinostat, Entinostat, Dacsitst, Tacedinaline, etc.), CDK inhibitors (such as Palbociclib, Ribociclib, Abemaciclib, Lerociclib, etc.), MEK inhibitors (such as Selumetinib (AZD6244), Trametinib (GSK1120212), PD0325901, U0126, AS-703026, PD184352 (CI-1040), etc.), Akt inhibitors (such as MK-2206, Ipatasertib, Capivasertib, Afuresertib, Uprosertib, etc.), mTOR inhibitors (such as Vistusertib, etc.), SHP2 inhibitors (such as RMC-4630, JAB-3068, TNO155, etc.), IGF-1R inhibitors (such as Ceritinib, Oclatentinib, linsitinib, BMS-754807, GSK1838705A, etc.), ER antagonists or degraders (such as Tamoxifen, Fulvestrant, etc.), aromatase inhibitors (such as Letrozole, etc.), BCL2 or BCL-XL inhibitors (such as ABT-199, ABT-263, etc.), Hedgehog inhibitors (such as vismodegib, cyclopamine, etc.), chemotherapy drugs (such as cisplatin, etoposide, topotecan, etc.), PARP inhibitors (such as Olaparib, Veliparib, Rucaparib, etc.), ATR / ATM inhibitors (such as Ceralasertib, Berzosertib, etc.), or combinations thereof.

[0187] Dosage forms of the pharmaceutical composition of the present application include, but are not limited to, injections, tablets, capsules, aerosols, suppositories, films, dripping pills, external liniments, controlled- or sustained-release forms, or nano-preparations.

[0188] The pharmaceutical composition of the present application comprises a safe and effective amount of the compound of the present application or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier. The "safe and effective amount" means an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Generally, the pharmaceutical composition contains 1-2000 mg of the compound of the present application per dose, more preferably, 10-1000 mg of the compound of the present application per dose. Preferably, the "one dose" is one capsule or tablet.

[0189] The "pharmacologically acceptable carrier" means one or more compatible solid or liquid filler or gel materials that are suitable for human use and must be of sufficient purity and sufficiently low toxicity. "Compatible" here means that the components of the composition are capable of being combined with the compound of the present application and with each other in the composition, without any significant degradation to the efficacy of the compound. Examples of the pharmacologically acceptable carrier 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.), polyhydric alcohols (e.g., propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (e.g., Tween 20®, Tween 80®, Span 20®, Span 80®, etc.), wetting agents (e.g., sodium dodecyl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0190] The administration of the compound or the pharmaceutical composition of the present application is not particularly limited, and representative administration methods include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular, or subcutaneous), and topical administration.

[0191] ​Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert excipient (or carrier) such as sodium citrate or dicalcium phosphate, or with such excipients as (a) fillers or extenders, e.g., starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, e.g., hydroxymethylcellulose, alginic acid, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (c) humectants, e.g., glycerol; (d) disintegrating agents, e.g., agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solution retarders, e.g., paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) moisturizing agents, e.g., glycerol and sorbitol; (h) respiration accelerators, e.g., high-oleic acid cottonseed oil; and (i) lubricants, e.g., magnesium stearate, calcium stearate, stearic acid, glyceryl monostearate, sodium stearyl fumarate, and talc. In the case of capsules, tablets, and pills, the dosage forms can also comprise buffering agents.

[0192] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, e.g., enteric coatings and other materials well known in the art. They can optionally contain opacifying agents, and can also be of a composition that they release the active compound or compounds in a certain part of the digestive tract. Examples of embedding compositions that can be used are polymeric substances and waxes. The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0193] Liquid dosage forms for oral administration include pharmaceutically-acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the liquid dosage forms can contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as, for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and the like, as well as mixtures thereof.

[0194] Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0195] Suspensions, in addition to the active compounds, can contain suspending agents, as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, and sodium carbomate, among others.

[0196] Compositions for parenteral injection can include physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.

[0197] Dosage forms for topical administration of a compound of this application include ointments, powders, sprays, and inhalers. The active component is admixed with a carrier, which can be a sterile, physiologically acceptable carrier, and any buffers, preservatives or propellants as can be required.

[0198] The therapeutic methods of this application can be employed, alone or in combination with other treatments or therapeutic agents.

[0199] When a pharmaceutical composition is used, a safe and effective amount of a compound of this application is administered to a mammal (e.g., human) in need of treatment, wherein the amount is a pharmaceutically effective amount, and for a human of 60 kg body weight, the amount is usually 1-2000 mg, preferably 50-1000 mg, per day. The specific dose will vary depending on the route of administration, the health condition of the patient, and the like, which are within the skill of the skilled practitioner.

[0200] The present application also provides a method of preparing a pharmaceutical composition, comprising the step of mixing a pharmaceutically acceptable carrier with a compound of Formula I, Formula II or Formula III, or a crystal form, a pharmaceutically acceptable salt, a hydrate or a solvate thereof, to form a pharmaceutical composition.

[0201] The present application also provides a method of treatment, comprising the step of administering to a subject in need thereof a compound of Formula I, Formula II or Formula III, or a crystal form, a pharmaceutically acceptable salt, a hydrate or a solvate thereof, or a pharmaceutical composition as described herein, for inhibiting CDK4 protein kinase.

[0202] In one or more embodiments, the present application has at least one of the following features compared to the prior art:

[0203] (1) The compound of the present application has excellent inhibitory ability on CDK4 protein kinase;

[0204] (2) The compound of the present application has lower toxic side effects;

[0205] (3) The compound of the present application has better pharmacodynamics and pharmacokinetics.

[0206] Preparation method

[0207] Methods for preparing compounds of Formula I, Formula II, or Formula III are described in the following schemes and examples. Starting materials and intermediates are purchased from commercial sources, prepared by known procedures, or otherwise described. In some cases, the order of carrying out the steps of the reaction schemes can be varied to facilitate the reaction or to avoid unwanted side products.

[0208] The preparation of compounds of Formula I, Formula II, or Formula III of the present application is described in more detail below, but these specific methods are not to be construed as limiting the present application. The compounds of the present application can also be made by any other means, optionally combining various synthetic methods described in this specification or known in the art, as can be readily determined by one skilled in the art.

[0209] Generally, in the preparation schemes, each reaction is usually carried out in a suitable solvent under an inert gas atmosphere at a temperature from 0 to 150 °C, and the reaction time is usually 2 to 24 hours.

[0210] General preparation methods are as follows:

[0211] In the first step: SM1 and S1 are reacted by palladium-catalyzed coupling or nucleophilic substitution in a solvent (e.g., 1,4-dioxane, tetrahydrofuran, 1,2-dichloroethane) at 70-120 °C to form SM2;

[0212] In the second step: SM2 and S2 are reacted by palladium-catalyzed coupling or nucleophilic substitution under basic conditions in a solvent (e.g., 1,4-dioxane, tetrahydrofuran, toluene, N,N-dimethylformamide, dimethyl sulfoxide, N-methyl pyrrolidone) to form product T.

[0213] In the above formulas, R1, R2, R3, R4, X1, and X2 are as defined above.

[0214] Unless otherwise specified, the above starting materials can be purchased commercially or synthesized according to reported literature.

[0215] Examples

[0216] The present application is further illustrated by the following examples. It is to be understood that these examples are merely illustrative of the present application and do not in any way limit the scope of the application.

[0217] The following examples were carried out under conventional conditions unless otherwise specified, such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or as recommended by the manufacturer. Percentages and parts are by weight unless otherwise specified.

[0218] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. Methods and materials similar or equivalent to those described herein can be used in the practice of the present application. The exemplary methods and materials described herein are illustrative only and not intended to be limiting.

[0219] The technical solutions of the present application are further described below, but the protection scope of the present application is not limited thereto.

[0220] Example 1

[0221] Compound T-1

[0222] The synthesis process is as follows:

[0223] The experimental process is as follows:

[0224] First step:

[0225] Compound 1 (800 mg, 1.0 e.q.) was dissolved in 20 mL of DCM solvent and cooled to 0°C in an ice water bath, then 1 mol / L of Et2AlCl (23 mL, 5.0 e.q.) was added dropwise, and after half an hour of reaction, acetyl chloride (2 mL, 7.5 e.q.) dissolved in 10 mL of DCM solvent was added, and the reaction was allowed to naturally warm to room temperature under nitrogen protection. After the raw material was completely reacted as monitored by TLC, the reaction was stopped, quenched with an appropriate amount of ice water, then extracted with ethyl acetate and water, and the organic phase was dried with anhydrous sodium sulfate, then filtered and concentrated to remove the solvent, and then purified by silica gel column chromatography to obtain compound 2 (740 mg, 77.3%), LCMS: [M+H] = 255.8, 258.0. +

[0226] 1 H NMR (400 MHz, DMSO-d6) δ 12.34 (s, 1H), 8.36 (d, J = 3.0 Hz, 1H), 7.50 (d, J = 1.6 Hz, 1H), 7.15 (dd, J = 10.5, 1.6 Hz, 1H), 2.47 (s, 3H).

[0227] Second step:

[0228] ​Compound 2 (740 mg, 1.0 e.q.), iodine isopropyl (0.58 ml, 2.0 e.q.) and potassium hydroxide (324 mg, 2.0 e.q.) were added into a dry 100 mL three-necked flask, 10 mL of dimethyl sulfoxide solvent was added, and the reaction was heated to 50°C for 4 hours under nitrogen protection. After the raw material was completely reacted by TLC monitoring, the reaction was stopped and returned to room temperature. Extraction was performed with ethyl acetate and water. The organic phase was dried with anhydrous sodium sulfate, then filtered and concentrated to remove the solvent. Compound 3 (800 mg, 92.9%) was obtained after purification by silica gel column chromatography. LCMS: [M+H] + = 298.0, 300.0.

[0229] Step 3:

[0230] Compound 3 (800 mg, 1.0 e.q.), bis(pinacolato)diboron (1.4 g, 2.0 e.q.), Pd(dppf)Cl2 (96 mg, 0.05 e.q.) and potassium acetate (800 mg, 3.0 e.q.) were added into a dry 100 mL three-necked flask under nitrogen protection, and nitrogen was replaced three times. 20 mL of ultra-dry 1,4-dioxane solvent was added, and the reaction was heated to reflux for 3 hours. After the raw material was completely reacted by TLC monitoring, the reaction was stopped and returned to room temperature. Extraction was performed with ethyl acetate and water. The organic phase was dried with anhydrous sodium sulfate, then filtered and concentrated to remove the solvent. Compound 4 (800 mg, 86.1%) was obtained after purification by silica gel column chromatography. LCMS: [M+H] + = 346.4.

[0231] Step 4:

[0232] Compound 4 (800 mg, 1.0 e.q.), 2,4,5-trichloropyrimidine (637 mg, 1.5 e.q.), tetrakis(triphenylphosphine)palladium (134 mg, 0.05 e.q.) and sodium carbonate solid (738 mg, 3.0 e.q.) were added into a 100 mL three-necked flask under nitrogen protection, 1,4-dioxane and water (V1:V2=10:3) were added and nitrogen was replaced three times, then the reaction was heated to reflux for 3 hours. After the raw material was completely reacted by TLC monitoring, the reaction was stopped and returned to room temperature. Extraction was performed with ethyl acetate and water. The organic phase was dried with anhydrous sodium sulfate, then filtered and concentrated to remove the solvent. Compound 5 (700 mg, 82.5%) was obtained after purification by silica gel column chromatography. LCMS: [M+H] + = 366.1.

[0233] Step 5:

[0234] To a 10 mL microwave reaction tube was added compound 5 (100 mg, 1.0 e.q.), (3s,4r)-4-aminooxan-3-ol hydrochloride (89 mg, 2.0 e.q.), DIPEA (0.2 ml, 4.0 e.q.) and NMP solvent (2 mL) in sequence, and heated to 130 °C by microwave for half an hour. After TLC monitoring the reaction was complete, extraction was performed with EA and water, the organic phase was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The target compound T-1 (80 mg, 65.5%) was obtained by silica gel column chromatography, with a HPLC purity of 96.2%, LCMS: [M+H] + = 447.2.

[0235] 1 H NMR (400 MHz, Chloroform-d) δ 8.33 (s, 1H), 8.02 (s, 1H), 7.76 7.71 (m, 1H), 7.50 - 7.42 (m, 1H), 5.35 (d, J = 6.1 Hz, 1H), 4.72 (p, J = 6.7 Hz, 1H), 4.06 (dd, J = 11.4, 4.9 Hz, 1H), 3.99 (dd, J = 11.9, 4.6 Hz, 1H), 3.86 (tt, J = 10.9, 5.3 Hz, 1H), 3.64 (td, J = 9.5, 4.9 Hz, 1H), 3.47 (td, J = 11.9, 2.2 Hz, 1H), 3.18 (t, J = 10.6 Hz, 1H), 2.68 (d, J = 2.7 Hz, 3H), 2.06 (dt, J = 13.0, 3.2 Hz, 1H), 1.73 (td, J = 12.3, 4.7 Hz, 2H), 1.61 (d, J = 6.7 Hz, 6H).

[0236] Referring to the synthetic method of Example 1, the following compounds were synthesized:

[0237] Example 2

[0238] Compound T-69

[0239] The synthesis process is as follows:

[0240] First step:

[0241] To a 20 mL flask, was added compound 1 (1.0 g, 1.0 e.q.), sodium tert-butoxide (658 mg, 1.5 e.q.) and cuprous iodide (1.22 g, 1.5 e.q.) sequentially under nitrogen atmosphere and heated to 50 °C for 16 h. After the completion of the reaction as monitored by TLC, the reaction was stopped, cooled to room temperature and concentrated directly for purification by silica gel column chromatography to yield compound 2 (680 mg, 46 %), LCMS: [M+H] = 346.2, 348.2. + = 346.2, 348.2.

[0242] Second Step:

[0243] To a 50 mL flask, was added compound 2 (680 mg, 1.0 e.q.), iron powder (660 mg, 6.0 e.q.) and ammonium chloride solid (210 mg, 2.0 e.q.) sequentially under nitrogen atmosphere and added 12 mL of absolute ethanol and 3 mL of water, heated to 70 °C for 4 h. After the completion of the reaction as monitored by TLC, the reaction was stopped, cooled to room temperature, filtered and the cake was washed with ethyl acetate and extracted with water. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to yield compound 3 (565 mg, 91.1 %), LCMS: [M+H] = 316.2, 318.2. + = 316.2, 318.2.

[0244] Third Step:

[0245] To a 10 mL flask, was added compound 3 (360 mg, 1.0 e.q.), 2H-pyrane-3,5(4H,6H)-dione (145 mg, 1.1 e.q.) and p-toluenesulfonic acid hydrate (22 mg, 0.1 e.q.) sequentially under nitrogen atmosphere and heated to reflux for 8 h. After the completion of the reaction as monitored by TLC, the reaction was stopped, cooled to room temperature and extracted with ethyl acetate and saturated sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in DMSO and added L-proline (26.6 mg, 0.2 e.q.), potassium hydroxide (259 mg, 4.0 e.q.) and cuprous iodide (22 mg, 0.1 e.q.) sequentially and heated to 90 °C for 16 h. After the completion of the reaction as monitored by TLC, the reaction was stopped, cooled to room temperature and extracted with ethyl acetate and water. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to yield compound 4 (200 mg, 61.9 %), LCMS: [M+H] = 284.2, 286.2. + = 284.2, 286.2.

[0246] Fourth Step:

[0247] Compound 4 (200 mg, 1.0 e.q.), bis(pinacolato)diboron (357.6 mg, 2.0 e.q.), Pd(dppf)Cl2(28.8 mg, 0.05 e.q.) and potassium acetate (207 mg, 3.0 e.q.) were added into a dry 50 mL three-neck flask under nitrogen protection, nitrogen was replaced for three times, 5 mL of super dry 1,4-dioxane solvent was added, and the reaction was heated to reflux for 12 hours. After the raw material was completely reacted by TLC monitoring, the reaction was stopped, and the temperature was returned to room temperature. Extraction was performed with ethyl acetate and water, the organic phase was dried with anhydrous sodium sulfate, then filtered and concentrated to remove the solvent, and the target compound 5 (180 mg, 77.3%) was obtained by silica gel column chromatography, LCMS: [M+H] + = 332.2.

[0248] Fifth step:

[0249] Compound 5 (180 mg, 1.0 e.q.), 2,4,5-trichloropyrimidine (120.0 mg, 1.2 e.q.), tetrakis(triphenylphosphine)palladium (31.4 mg, 0.05 e.q.) and sodium carbonate solid (172.8 mg, 3.0 e.q.) were added into a 50 mL three-neck flask under nitrogen protection, 1,4-dioxane (4 mL) and water (1 mL) were added and nitrogen was replaced for three times, then the reaction was heated to reflux for 16 hours. After the raw material was completely reacted by TLC monitoring, the reaction was stopped, and the temperature was returned to room temperature. Extraction was performed with ethyl acetate and water, the organic phase was dried with anhydrous sodium sulfate, then filtered and concentrated to remove the solvent, and the target compound 6 (105 mg, 55.0%) was obtained by silica gel column chromatography, LCMS: [M+H] + = 352.1.

[0250] Sixth step:

[0251] Compound 6 (100 mg, 1.0 e.q.), (3s,4r)-4-aminooxan-3-ol hydrochloride (65.4 mg, 1.5 e.q.), DIPEA (73.3 mg, 2.0 e.q.) and NMP solvent (2 mL) were added into a 10 mL microwave reaction tube, and the reaction was heated at 130°C for 40 minutes. After the reaction was completed by TLC monitoring, extraction was performed with ethyl acetate and water, the organic phase was dried with anhydrous sodium sulfate, then concentrated under reduced pressure, and the target compound T-69 (45.0 mg, 36.6%) was obtained by silica gel column chromatography, HPLC purity was 98.31%, LCMS: [M+H] + = 433.2.

[0252] 1 H NMR (400 MHz, DMSO-d 6δ 8.43 (s, 1H), 8.00 (s, 1H), 7.51 (s, 2H), 5.21 (s, 2H), 4.95 (d, J = 5.5 Hz, 1H), 4.79 (s, 1H), 4.21 (s, 2H), 3.81 (d, J = 11.4 Hz, 4H), 3.51 (s, 1H), 3.04 (t, J = 10.4 Hz, 1H), 1.97 (s, 1H), 1.59 (d, J = 6.7 Hz, 7H).

[0253] Referring to the synthesis method of Example 3, the following compounds were synthesized:

[0254] Example 3

[0255] Compound T-161

[0256] The synthesis process is as follows:

[0257] The experimental process is as follows:

[0258] First step:

[0259] Under nitrogen conditions, compound 1 (5.0 g, 1.0 e.q.) was dissolved in dry 50 mL of toluene solvent, then at room temperature, dichlorosulfoxide liquid (12.6 g, 5.0 e.q.) was slowly added dropwise, and after mixing, the temperature was raised to reflux for 2 hours. After the reaction was completed, the solvent was directly concentrated and evaporated under reduced pressure to obtain compound 2, which was directly used in the next step of the reaction.

[0260] Second step:

[0261] Under nitrogen conditions, compound 2 (4.5 g, 1.0 e.q.) and cuprous iodide (168 mg, 0.05 e.q.) were sequentially added to 90 mL of super-dry tetrahydrofuran solvent, and the temperature was lowered to about -15°C, then isopropyl magnesium chloride Grignard reagent (8.8 mL, 1.0 e.q.) was slowly added dropwise, and the reaction was continued for 1 hour, then the temperature was slowly raised to room temperature and the reaction was continued for 16 hours. After the reaction was completed, a proper amount of ice water was added to quench, extracted with ethyl acetate and water, the organic phase was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and compound 3 (4.0 g, 86.2%) was obtained by silica gel column chromatography separation and purification, LCMS: [M+H] = 263.2, 265.1. +

[0262] Third step:

[0263] ​Compound 3 (4.0 g, 1.0 e.q.) was dissolved in 80 mL of ethylene glycol solvent under nitrogen condition, then 10 mL of hydrazine hydrate was added, and the temperature was raised to 160°C for 10 hours. After the reaction was completed, it was cooled to room temperature, extracted with dichloromethane and water, the organic phase was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 4 (3.0 g, 76.9%), LCMS: [M+H] + = 257.1, 259.2.

[0264] Fourth step:

[0265] Compound 4 (0.5 g, 1.0 e.q.) was dissolved in DMSO under nitrogen condition, then potassium carbonate solid (0.81 g, 3.0 e.q.) and 2-bromo-5-(difluoromethyl)-1,3,4-thiadiazole (0.62 g, 1.5 e.q.) were added in turn, and the temperature was raised to 80°C for 12 hours. After the reaction was completed, it was cooled to room temperature, extracted with ethyl acetate and water, the organic phase was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and then purified by silica gel column chromatography to obtain compound 5 (0.4 g, 52.6%), LCMS: [M+H] + = 391.2, 393.2.

[0266] Fifth step:

[0267] Compound 5 (0.4 g, 1.0 e.q.), pinacol diboronic acid (0.52 g, 2.0 e.q.), Pd(dppf)Cl2(37.0 mg, 0.05 e.q.) and potassium acetate (300 mg, 3.0 e.q.) were added in turn to a dry 50 mL three-necked flask under nitrogen protection, replaced with nitrogen three times, added 5 mL of super dry 1,4-dioxane solvent, and the temperature was raised to reflux for 12 hours. After the TLC monitoring of the raw material reaction was completed, the reaction was stopped, and the temperature was restored to room temperature, extracted with ethyl acetate and water, the organic phase was dried with anhydrous sodium sulfate, then filtered and concentrated to remove the solvent, and then purified by silica gel column chromatography to obtain compound 6 (320 mg, 71.4%), LCMS: [M+H] + = 439.2.

[0268] Sixth step:

[0269] Compound 6 (300 mg, 1.0 e.q.), 2,4,5-trichloropyrimidine (150.7 mg, 1.2 e.q.), tetrakis triphenylphosphine palladium (39.5 mg, 0.05 e.q.) and sodium carbonate solid (217.8 mg, 3.0 e.q.) were added to a 50 mL three-necked flask under nitrogen protection, 1,4-dioxane (4 mL) and water (1 mL) were added and nitrogen was replaced for three times, then the temperature was raised to reflux for 16 hours. After TLC monitoring, the reaction was stopped when the raw material was completely reacted, and the reaction was cooled to room temperature. Ethyl acetate and water were used for extraction and separation, and the organic phase was dried with anhydrous sodium sulfate. After filtration and concentration, the solvent was removed, and the compound 7 (200 mg, 63.6%) was obtained by silica gel column chromatography. LCMS: [M+H] + = 459.1.

[0270] Step 6:

[0271] Compound 7 (200 mg, 1.0 e.q.), (3s,4r)-4-aminooxan-3-ol hydrochloride (100 mg, 1.5 e.q.), DIPEA (112 mg, 2.0 e.q.) and NMP solvent (2 mL) were added to a 10 mL microwave reaction tube in turn, and heated at 130°C for 40 minutes. After TLC monitoring, the reaction was completely reacted, and the reaction was cooled to room temperature. Ethyl acetate and water were used for extraction and separation, and the organic phase was dried with anhydrous sodium sulfate. After filtration and concentration, the solvent was removed, and the target compound T-161 (60.1 mg, 25.6%) was obtained by silica gel column chromatography. HPLC purity was 99.35%, LCMS: [M+H] + = 540.3.

[0272] 1 H NMR (400 MHz, DMSO-d6) δ 8.47 (s, 1H), 8.26 (s, 1H), 7.91 (d, J = 12.1 Hz, 1H), 7.57 (t, J = 53.1 Hz, 2H), 4.96 (d, J = 5.4 Hz, 1H), 3.83 (dq, J = 11.4, 7.1, 5.6 Hz, 3H), 3.53 (h, J = 6.9 Hz, 1H), 3.05 (t, J = 10.4 Hz, 1H), 1.99 (d, J = 20.6 Hz, 1H), 1.44 (d, J = 6.9 Hz, 10H), 1.36 - 1.26 (m, 2H).

[0273] The following compounds were synthesized according to the synthetic method of Example 4:

[0274] Test Example 1 Enzyme activity test

[0275] The following experiments tested the bioactivity of the compounds in the above examples and the comparative examples.

[0276] The bioactivity test procedure is as follows:

[0277] 1. Kinase activity test:

[0278] CDK4 and CDK6 kinase IC50 assays were performed on the test compounds. 50 Value detection.

[0279] (I) Reagent Information

[0280] (II) Equipment Information

[0281] (III) Research Design

[0282] (1) Compound preparation:

[0283] ① Prepare a 0.5 mM DMSO solution of the test compound and a 0.5 mM DMSO solution of the positive control drug Palbociclib.

[0284] ② The compound was diluted three times to obtain 10 different concentrations of the compound solution.

[0285] (2) Perform enzyme assay:

[0286] ① As shown below, prepare a 1.3× enzyme solution containing enzyme, substrate and cofactor.

[0287] ② Add 15 μL of 1.3× enzyme solution to each well and incubate at room temperature for 30 minutes.

[0288] ③ Add 5 μL of 4×ATP solution to start the reaction. Each test well contains the components listed in the list, and the final volume is 20 μL.

[0289] ④Incubate for 150 minutes, then add 75 μL of buffer (containing 0.5 M EDTA) to stop the reaction.

[0290] ⑤ Use EZ to read and analyze the data from each test well.

[0291] (3) Data Analysis:

[0292] The suppression percentage is calculated using the following formula, based on the concern ratio (CR):

[0293] The wells treated with DMSO were used as positive control, and the wells without enzyme were used as negative control.

[0294] % (inhibition percentage) = 100 - 100 x ((CRPC-CR Sample ) / (CRPC-CRNC)).

[0295] Through the above detection, the IC 50 (nM) value of the tested sample on CDK4, CDK6 kinase is shown in Table 1.

[0296] Table 1

[0297] From the above table, through in vitro biological activity screening, with Palbociclib as a control, the compound synthesized in the application has good inhibitory ability on CDK4 kinase, and the kinase activity of CDK4 and CDK6 has very good selectivity, so it is very likely to reduce the hematological side effects caused by the inhibition of CDK6, and is expected to be further developed into a drug for regulating CDK4 kinase activity or treating CDK4 related diseases.

[0298] Test Example 2 Cell Anti-proliferation Experiment

[0299] I. Experimental materials and equipment:

[0300] Human breast cancer cells MCF-7, ovarian cancer cells A2780, DMEM culture medium (Bio-Channel), DMSO (dimethyl sulfoxide), MTT (thiazolyl blue), 0.25% EDTA-tripsin (trypsin digestion solution), 1x PBS (phosphate buffer, pH 7.2), 96-well plate (Corning), fetal bovine serum (FBS), 10,000 U / mL penicillin-G / streptomycin, high-speed refrigerated centrifuge (EPPENDORF 5810R), enzyme-linked immunoassay instrument (Tecan Spark).

[0301] II. Experimental preparation:

[0302] 1. Cell plating

[0303] A) The tumor cells were cultured in DMEM (high sugar, containing 10% FBS and 100 U / mL penicillin-G / streptomycin) at 37°C, 5% CO2 and saturated humidity to 80-90% density.

[0304] B) Remove the culture medium in the 10 cm culture dish;

[0305] C) rinse the cells once with 10 ml 1 x PBS;

[0306] D) add 4 ml 0.25% EDTA-trypsin and incubate for 5 minutes at 37°C in a 5% CO2incubator, transfer to a 15 ml centrifuge tube and centrifuge at 200g for 5 minutes, discard the supernatant to obtain the cell pellet;

[0307] E) resuspend with 4 ml DMEM medium, count and adjust to 50,000 cells / ml.

[0308] F) add the cell suspension to a 96-well plate at a volume of 100 μL per well and incubate overnight at 37°C in a 5% CO2incubator.

[0309] 2. Compound treatment

[0310] Compound dilution

[0311] A) prepare a gradient dilution of the test compound: prepare a 1 mM stock solution of the test compound. Then dissolve 1.5 μl of the stock solution in 1.5 ml of DMSO-free medium and perform a 3-fold serial dilution in 0.1% DMSO medium, resulting in 9 concentrations. The concentrations after dilution are as follows:

[0312] 333.33 nM, 111.11 nM, 37.03 nM, 12.35 nM, 4.15 nM, 1.37 nM, 0.46 nM, 0.15 nM;

[0313] B) after thorough mixing, replace the medium in the cell culture plate with 100 μL of the compound solution per well, in quadruplicate for each concentration;

[0314] C) transfer the cells to the incubator and incubate for 5 days.

[0315] 3. MTT assay

[0316] A) remove the cell culture plate and add 10 μL of 5 mg / ml MTT in a biological safety cabinet;

[0317] B) return the cell culture plate to the incubator and continue incubation for 3 hours;

[0318] C) remove the cell culture plate and replace the medium with 100 μL of isopropanol containing 0.4 mM HCl and 0.1% NP-40, and incubate on a shaker at room temperature for 30 minutes;

[0319] D) measure the absorbance values on a TECAN ELISA reader at a wavelength of 570 nm.

[0320] 4. Data analysis

[0321] Cell Viability (%) was calculated using the following formula:

[0322] Cell Viability (%) = 100% x (Lum_Sample - Lum_LC) / (Lum_HC - Lum_LC)

[0323] Lum_HC: 0.1% DMSO control cell reading;

[0324] Lum_Sample: cell reading with compound added;

[0325] Lum_LC: blank media reading;

[0326] IC50values (in nM) were obtained by curve fitting using GraphPad Prism 8 software. 50

[0327] As shown in Table 2.

[0328] Table 2

[0329] From Table 2, it can be seen that the compound of the present application has excellent anti-proliferative activity on breast cancer cells and ovarian cancer cells. Preclinical rat pharmacokinetic test

[0330] I. Experimental materials and equipment:

[0331] Healthy adult SD rats, male, 6-8 weeks old, weighing 220-280 grams, purchased from Vintone Lifescience Technologies Limited. EDTA-Na2 anticoagulant. Analytical balance, animal weight scale, magnetic stirrer, refrigerated centrifuge, single-channel manual pipette, etc.

[0332] II. Experimental process:

[0333] 1. Drug preparation

[0334] Accurately weigh about 10 mg of the sample to be tested, dissolve in 5% DMSO after conversion, then add 10% solutol HS-15 and 85% physiological saline, ultrasonic, vortex and mix well to obtain a solution with a concentration of 1 mg / mL; freshly prepared before use.

[0335] Take 0.2 mL of sample in a 1.5 mL centrifuge tube and store at -80°C for drug solution concentration analysis.

[0336] 2. Animal preparation

[0337] ​Animals were housed in rat cages and fasted for at least 10 hours starting the day before the experiment, but water was allowed. On the day of the experiment, each animal was weighed and marked on its tail. Blank blood samples were collected before drug administration. Blood was collected via tail vein.

[0338] 3. Administration

[0339] Route of administration: Oral gavage (po)

[0340] Dosage: 10 mg / kg

[0341] Dosage volume: 10 mL / kg

[0342] Procedure: Hold the rat upright with your left hand wearing a bite-proof glove. Insert a 16-gauge gavage needle into the throat through the mouth. Once you feel no obvious resistance, insert the needle and then inject the medication into the stomach.

[0343] 4. Sample collection

[0344] Whole blood (0.1 ml) was collected from the test animals before administration and at 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, and 24 h after administration into EDTA-Na2 anticoagulant tubes. The tubes were inverted 3-4 times to mix thoroughly, and the plasma was separated by centrifugation at 10000g for 5 min at 4℃. The plasma was then stored at -80℃ for analysis. Blood was collected via tail vein.

[0345] Specific procedure: Fix the rat in a restraint device, ensuring its tail is fully exposed. Wipe the rat's tail with alcohol to allow the skin to absorb the alcohol, resulting in significant venous dilation. Select suitable veins from both sides and insert the needle approximately one-third of the way from the tail tip. Use an insulin syringe, inserting the needle with the bevel facing upwards. Immediately after feeling the skin pierce, move the needle horizontally. You should feel minimal resistance as the needle slides through the vein, and you should see blood return in the syringe. This indicates the needle is in the vein. Draw approximately 0.1-0.2 ml of whole blood. After removing the needle, apply pressure to stop the bleeding.

[0346] III. Sample Analysis:

[0347] Preparation of standard curve: Take 25 μL of rat blank plasma into centrifuge tubes, add 25 μL of prepared standard series solution (prepared with methanol), then add 200 μL of internal standard solution (prepared with methanol), vortex to mix for 2 min, and centrifuge at 10000g for 10 min at 4℃.

[0348] Unknown plasma sample processing: Take 25 μL of drug-containing rat plasma, add 25 μL of methanol and 200 μL of internal standard solution sequentially, vortex to mix for 2 min, and centrifuge at 10000g for 10 min at 4℃. Take the supernatant for LC / MS / MS detection.

[0349] IV. Data Processing

[0350] The quantitative detection method of the test compound was established by Shimadzu liquid phase and Triple Quad TM 6500+AB mass spectrometry. The concentration of the original drug in the plasma was determined. The blood concentration-time curve was drawn, and the main pharmacokinetic parameters were calculated by using the non-compartment model in the winnonlin Phoenix software. The detailed data are shown in Table 3.

[0351] Table 3

[0352] From Table 3, it can be known that the compounds of the present application all have excellent pharmacokinetic performance.

[0353] All the documents mentioned in the present application are cited as references in the present application, just like each document is cited as a reference individually. In addition, it should be understood that various modifications or changes can be made to the present application by those skilled in the art after reading the above teaching of the present application, and these equivalent forms also fall within the scope defined by the claims attached to the present application.

Claims

1. A compound of Formula I, Formula II, or Formula III, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotopologue, deuteride, metabolite, or prodrug thereof, wherein X1is selected from N and CR5; X2is selected from N and CR6; R1is selected from H, deuterium, cyano, C 1-6 alkyl, nitro, -COC 1-8 alkyl, -COOH, -C(O)NRR', -C(O)OC 1-6 alkyl, -OR 101 , C 6-10 aryl, 5-8 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O and S, 5-8 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S, -OC(O)NRR', -NRC(O)OC 1-6 alkyl; each R is independently selected from H, halo, C 1-6 alkyl, C 6-10 aryl, 5-8 membered heterocyclyl, 5-8 membered heteroaryl, each independently optionally substituted with one or more R groups; or or R1and X1together form a 5-8 membered cycloalkyl, 5-8 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5-8 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; each of said 5-8 membered cycloalkyl, 5-8 membered heterocyclyl, 5-8 membered heteroaryl is independently optionally substituted with one or more deuterium, halogen, cyano, amino, hydroxyl, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, and oxo (=0), C 1-6 cycloalkyl, haloC 1-6 cycloalkyl, C 1-6 cyclohydroxyalkyl, and C 1-6 cycloalkoxy; R2is selected from H, C 1-6 alkyl, hydroxy-substituted C 1-6 alkyl, halo-substituted C 1-6 alkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2- alkynyl, C 6-10 aryl, 3-8 membered heterocycloalkyl containing 1, 2, or 3 heteroatoms selected from N, O, or S, or 5-8 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, or S; each of said C 1-6 alkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, 3-8 membered heterocycloalkyl, and 5-8 membered heteroaryl are each independently optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, C 1-4 alkyl, halo-substituted C 1-4 alkyl, C 1-4 hydroxyalkyl, and C 1-4 alkoxy; or R2and X1together form a 5-8 membered cycloalkyl, 5-8 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or 5-8 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; each of said 5-8 membered cycloalkyl, 5-8 membered heterocyclyl, 5-8 membered heteroaryl is independently optionally substituted with one or more deuterium, halogen, cyano, amino, hydroxyl, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, and oxo (=0), C 1-6 cycloalkyl, haloC 1-6 cycloalkyl, C 1-6 cyclohydroxyalkyl, and C 1-6 cycloalkoxy; R3is selected from H, halogen, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, halogenated C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl; R4is selected from R5is selected from H, halo, hydroxyl, C 1-6 alkyl, C 3-8 cycloalkyl, halo C 1-6 alkyl, halo C 3-8 cycloalkyl, amino, -C(O)H, -C(O)C 1-8 alkyl, -C(O)OC 1-8 alkyl, -OC(O)C 1-8 alkyl, -OC(O)OC 1-8 alkyl, C 1-6 alkoxy, -COO-C 1-6 alkyl, -CO-C 1-6 alkyl, halo C 1-6 alkoxy, hydroxyl substituted C 1-6 alkyl, -C 1-4 alkyl-O-C 1-4 alkyl, 5-8 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O and S, and 5-8 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S; R6is selected from H, halo, cyano, C 1-6 alkyl, and haloC 1-6 alkyl; R7is selected from C 1-6 alkyl, C 3-8 cycloalkyl, and -NH2; R and R' are each independently selected from H, deuterium, halogen, cyano, hydroxyl, C 1-6 alkyl, hydroxy-substituted C 1-6 alkyl, C 3-8 cycloalkyl, halogenated C 1-6 alkyl, halogenated C 3-8 cycloalkyl, -CO-C 1-6 alkyl, C 1-6 alkoxy, amino, oxo (=0), -COOH, -CONH2, -COO-C 1-6 alkyl, -SO2CH3, C 6-10 aryl, 5-8 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O and S; R 101 selected from C 1-6 alkyl, phenyl, 5-8 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O and S, 5-8 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O and S; each of said C 1-6 alkyl, phenyl, 5-8 membered heterocyclyl and 5-8 membered heteroaryl is independently optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, C 1-4 alkyl, halogenoC 1-4 alkyl, C 1-4 hydroxyalkyl and C 1-4 alkoxy; m is each independently selected from 0, 1, 2, 3, 4, 5, and 6; Preferably, said C 1-6 alkyl is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl or t-butyl; Preferably, said haloC 1-6 alkyl is CF3; Preferably, the halogen is F, Cl, Br, or I; Preferably, said C 1-6 alkoxy is -O-methyl; Preferably, said -COO-C 1-6 alkyl is -COO-C(CH3)3.

2. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotopically enriched compound, deuterated compound, metabolite, or prodrug thereof, wherein X1 is CR5; R5 is selected from the group consisting of H, halogen, hydroxyl, C 1-6 alkyl, C 3-8 ycloalkyl, halogenated C 1-6 alkyl, halogenated C 3-8 ycloalkyl, amino, -C(O)H, -C(O)C 1- 8alkyl, -C(O)OC 1-8 alkyl, -OC(O)C 1-8 alkyl, -OC(O)OC 1-8 alkyl, C 1-6 alkoxy, -COO-C 1-6 alkyl, -CO-C 1-6 alkyl, halogenated C 1-6 alkoxy, hydroxyl substituted C 1-6 alkyl, 5-8 membered heterocycloalkyl containing 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S, and 5-8 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S, optionally substituted with halogen, or R1 and R5 form a 5-7 membered heterocyclic ring containing O, N, or S; preferably, R5 is selected from the group consisting of H, methyl, and hydroxyl substituted t-butyl.

3. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotopologue, deuterated analog, metabolite, or prodrug thereof, wherein X2is N.

4. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotopologue, deuterated product, metabolite, or prodrug thereof, selected from any one of the following general formulae: Z1, Z2, Z3, Z4are each independently selected from -C=0, -CR 102 R 102 , -NR 103 , O or S; V1and V2are each independently selected from CR 102 or N each R 102 , R 103 is each independently selected from H, deuterium, halogen, cyano, hydroxyl, C 1-4 alkyl, haloC 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy; preferably, each R 102 , R 103 is each independently selected from H, deuterium or methyl.

5. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotopically enriched compound, deuterated compound, metabolite, or prodrug thereof, wherein R1is selected from H, deuterium, cyano, nitro, -COC 1-8 alkyl, -COOH, -C(O)NRR’, -C(O)OC 1-6 alkyl, phenyl, 5-6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, -OR 101 , 5-8 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, -OC(O)NRR’, -NRC(O)OC 1-6 alkyl; said phenyl, 5-6 membered heterocyclyl, 5-8 membered heteroaryl is optionally substituted with one or more deuterium, halogen, cyano, hydroxyl, C 1-4 alkyl, haloC 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, and oxo (=O); R 101 selected from 5-6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S or 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; each of said 5-6 membered heterocyclyl, 5-6 membered heteroaryl is optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, C 1-4 alkyl, haloC 1-4 alkyl; Preferably, R1is selected from -COCH3, cyano, nitro, each of said R and R’ is independently as described in claim 1; Preferably, said -C(O)OC 1-6 alkyl is -COO-C(CH3)3; Preferably, the halogen is F; The C 1-4 alkyl is methyl; said haloC 1-4 alkyl is trifluoromethyl; The C 1-4 Alkoxy is methoxy.

6. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotopically enriched compound, deuterated compound, metabolite, or prodrug thereof, wherein R2is selected from the group consisting of methyl, ethyl, isopropyl, cyclopropyl, and -CD3.

7. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotopologue, deuterated analog, metabolite, or prodrug thereof, wherein R3is selected from H, F, Cl, Br, cyclopropyl, and cyano.

8. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotopologue, deuterated product, metabolite, or prodrug thereof, wherein R4is selected from 9. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotopologue, deuterated product, metabolite, or prodrug thereof, which is: wherein, X1is selected from CR5or N, R5is selected from H, C 1-4 alkyl, C 1-4 alkoxy or hydroxy substituted C 1-4 alkyl, C 1-4 alkyl-O-C 1-4 alkyl; X2is selected from N; R1is selected from: -COC 1-8 alkyl, -C(O)NRR', cyano, or nitro; R, R' are each independently selected from H, deuterium, C 1-6 alkyl, or hydroxy-substituted C 1-6 alkyl; R2is selected from C 1-4 alkyl or cyclopropyl, said C 1-4 each R2is independently selected from C1-6alkyl, C3-6cycloalkyl, each of which is independently optionally further substituted by deuterium or hydroxyl; R3is selected from F, Cl, Br, cyclopropyl, or cyano; R4is selected from R is independently selected from H, deuterium, and C 1-6 alkyl; R7is C 1-6 alkyl.

10. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotopologue, deuterated product, metabolite, or prodrug thereof, which is: wherein, X1is selected from CR5, R5is selected from H, C 1-4 alkyl, C 1-4 alkoxy or hydroxy substituted C 1-4 alkyl, C 1-4 alkyl-O-C 1-4 alkyl; X2is selected from N; R1is selected from: C 1-4 alkyl, -CO 1-8 alkyl, phenyl, 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; each of which is independently and optionally further substituted by deuterium, cyano, halogen, C 1-4 alkyl, phenyl, and heteroaryl are each independently and optionally further substituted by deuterium, cyano, halogen, C 1-3 alkyl or haloC 1-3 alkyl; R2is selected from C 1-4 alkyl or cyclopropyl; R3is selected from Cl or Br; R4is selected from:

11. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotopologue, deuterated product, metabolite, or prodrug thereof, selected from any one of the following formulae: R2is selected from C 1-4 alkyl; X2is selected from N; R3is selected from Cl; R4is selected from each R 102 , R 103 is each independently selected from H, deuterium, halogen, cyano, hydroxyl, C 1-4 alkyl, haloC 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy; preferably, each R 102 , R 103 is each independently selected from H, deuterium or methyl; u1is 0, 1, 2, 3, or 4; u2is 0, 1, or 2; U3is 0, 1, 2, 3, 4, 5, or 6; u4or U4is 0, 1, 2, 3, or 4; U5is 0, 1, 2, 3, 4, 5, 6, 7, or 8.

12. A compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotopically enriched compound, deuterated compound, metabolite, or prodrug thereof, wherein the compound is selected from:

13. Use of a compound of any one of claims 1-12 in the manufacture of a medicament for the prevention and / or treatment of a CDK4 kinase-mediated disease; preferably, the CDK4 kinase-mediated disease is selected from the group consisting of inflammation, cancer, cardiovascular disease, infectious disease, immunological disease, and metabolic disease; more preferably, 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, uterine cancer, liposarcoma.

14. Use of a compound of any one of claims 1-12 in the manufacture of a CDK4 kinase inhibitor.

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