Compound functioning as CDK4 protein kinase inhibitor and use thereof

Abstract

The present invention relates to a compound functioning as a CDK4 kinase inhibitor and to the use thereof. Specifically, the compound of the present invention has a chemical structure as represented by formula I or formula II, wherein each group and substituent are defined as described in the description. The compound of the present invention can function as an inhibitor of cyclin-dependent kinases (CDK) to treat or prevent proliferative diseases (such as cancer) and especially to regulate and treat related diseases caused by abnormal CDK4 activity.

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 a novel class of 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, CDKs 1-6 and 14-18 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 CDKs 7-13 and 19-20 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 CDKs 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 a selective CDK4 inhibitor may have better safety and efficacy. SUMMARY

[0005] The present application provides a CDK4 protein kinase inhibitory activity compound with novel structure and excellent activity.

[0006] In a first aspect, the present application provides a compound having the structure of Formula I or Formula II, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotopically enriched compound, or prodrug thereof,

[0007] wherein:

[0008] is selected from the group consisting of -N=C(R6)-, -N=N-, -C(R6)=C(R6)-, -CO-NH-, -COO-, -S-C(R6)(R7)-, -O-C(R6)(R7)-, and -N(R8)-C(R6)(R7)-;

[0009] is selected from the group consisting of -N=C(R6)-, -N=N-, -C(R6)=C(R6)-, -CO-NH-, -COO-, -S-C(R6)(R7)-, -O-C(R6)(R7)-, and -N(R8)-C(R6)(R7)-;

[0010] each Z is independently selected from the group consisting of N, CR9;

[0011] m is selected from 0, 1, 2, 3, 4, 5, and 6;

[0012] each R is independently selected from the group consisting of H, halogen (such as F, Cl, Br, I), cyano, hydroxyl, amino, C 1-6 alkyl (such as methyl, ethyl, isopropyl), C 2-6 alkenyl, C 2-6alkynyl, C 3-8 cycloalkyl, haloC 1-6 alkyl (e.g., CF3), haloC 3-8 cycloalkyl, -CO-C 1-6 alkyl, C 1-6 alkoxy (e.g., -O-methyl), C 1-6 haloalkoxy (e.g., -O-CF3), -COOH, -CONH2, -COO-C 1-6 alkoxy (e.g., -COO-C(CH3)3), hydroxy-substituted C 1-6 alkyl, methylsulfonyl, C 6-10 aryl, 5-8 membered heterocycloalkyl containing 1, 2, or 3 heteroatoms selected from N, O, or S, or 5-10 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, or S; and one or more hydrogens on said groups are independently optionally substituted with a member selected from the group consisting of halogen, cyano, hydroxyl, C 1-4 alkyl, haloC 1-4 alkyl, C 1-4 hydroxyalkyl and C 1-4 alkoxy-substituted;

[0013] R1and R2are each independently selected from the group consisting of H, halogen (e.g., F, Cl, Br, I), hydroxyl, C 1-6 alkyl (e.g., methyl, ethyl, isopropyl), haloC 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, haloC 1-6 alkyl (e.g., CF3), amino, ketone carbonyl, C 1-6 alkoxy (e.g., -O-methyl), C 1-6 haloalkoxy (e.g., -O-CF3), -COO-C 1-6 alkoxy (e.g., -COO-C(CH3)3), -CO-C 1-6 alkyl, C 1-6 haloalkoxy, hydroxy-substituted C 1-6 alkyl, C 6-10 aryl, 5-8 membered heterocycloalkyl containing 1, 2, or 3 heteroatoms selected from N, O, or S, or 5-10 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, or S; and one or more hydrogens on said groups are independently optionally substituted with a member selected from the group consisting of halogen, cyano, hydroxyl, C 1-4 alkyl, haloC 1-4 alkyl, C 1-4 hydroxyalkyl and C 1-4 alkoxy-substituted;

[0014] R3is each independently selected from the group consisting of H, C 1-6 alkyl (e.g., methyl, ethyl, isopropyl), haloC1-6 alkyl, C 3-8 cycloalkyl (e.g. cyclopropyl), halo-C 3-8 cycloalkyl, -C 1-3 alkyl-C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl;

[0015] R4is each independently selected from the group consisting of H, halogen (e.g. F, Cl, Br), C 2-6 alkynyl (e.g. ethynyl, propynyl), cyano, C 1-6 alkyl (e.g. methyl, ethyl), C 1-6 haloalkyl (e.g. CF3), C 1-6 alkoxy (e.g. methoxy), C 1-6 haloalkoxy (e.g. -O-CF3), C 3-6 cycloalkyl (e.g. cyclopropyl);

[0016] R5is each independently selected from the group consisting of:

[0017] wherein,

[0018] R6and R7are each independently selected from the group consisting of H, halogen, cyano, C 1-6 alkyl (e.g. methyl, ethyl, isopropyl), C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl (e.g. cyclopropyl), hydroxy, amino, C 1-6 alkoxy (e.g. methoxy), -COO-C 1-6 alkoxy (e.g. ), -CO-C 1-6 alkyl (e.g. ), C 1-6 haloalkyl (e.g. CF3), C 1-6 haloalkoxy (e.g. -O-CF3), C 6-10 aryl, hydroxy-substituted C 1-6 alkyl, 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S, 5-10 membered heterocycloalkyl, 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S, 5-10 membered heteroaryl;

[0019] R8is each independently selected from the group consisting of H, C 1-6 alkyl (e.g. methyl, ethyl, isopropyl), C 2-6 alkenyl, C 2-6 alkynyl, -COO-C 1-6 alkoxy (e.g. ), -CO-C 1-6 alkyl or haloalkyl (e.g. ), -CO-C 3-6 cycloalkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, -C 1-3 alkyl-C 3-8 cycloalkyl, hydroxy-substituted C 1-6 alkyl, -CONH-C 1-6 alkyl, C 3-6 cycloalkyl, 5-8 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O or S, C 6-10 aryl, 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S; wherein each of said alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, heterocyclyl, heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, -C(=O)-C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, -N(C 1-6 alkyl)2;

[0020] each R9is independently selected from the group consisting of H, halogen (such as F, Cl, Br), cyano, C 1-6 alkyl (such as methyl, ethyl), C 1-6 haloalkyl (such as CF3), C 1-6 alkoxy (such as methoxy), C 1-6 haloalkoxy, C 3-6 cycloalkyl (such as cyclopropyl);

[0021] R 10 each is independently selected from the group consisting of C 1-6 alkyl (such as methyl, ethyl, isopropyl), -C 1-3 alkyl-C 3-8 cycloalkyl, C 3-8 cycloalkyl (such as cyclopropyl), -NH2.

[0022] In another preferred embodiment,

[0023] is selected from the group consisting of -N=C(R6)- and -N=N-;

[0024] is selected from the group consisting of -N=C(R6)-, -CO-NH-, -S-C(R6)(R7)-, -O-C(R6)(R7)- and -N(R8)-C(R6)(R7)-;

[0025] Z is selected from the group consisting of N, CR9(preferably, Z is N);

[0026] R is selected from the group consisting of H, halogen (e.g. F, Cl, Br, I), cyano, hydroxy, amino, C 1-6 alkyl (e.g. methyl, ethyl, isopropyl), C 3-8 cycloalkyl, halo-C 1-6 alkyl (e.g. CF3), hydroxy-substituted C 1-4 alkyl, halo-C 3-8 cycloalkyl, -CO-C 1- 6alkyl, C 1-6 alkoxy (e.g. -O-methyl), -COOH, -CONH2, -COO-C 1-6 alkoxy (e.g. -COO-C(CH3)3), methylsulfonyl, C 6-10 aryl, 5-8 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S;

[0027] R1and R2are selected from the group consisting of H, halogen (e.g. F, Cl, Br, I), hydroxy, C 1-6 alkyl (e.g. methyl, ethyl, isopropyl), C 3-8 cycloalkyl, halo-C 1-6 alkyl (e.g. CF3), amino, keto-carbonyl, C 1-6 alkoxy (e.g. -O-methyl), -COO-C 1- alkoxy (e.g. -COO-C(CH3)3), -CO-C 1-6 alkyl, C 1-6 haloalkoxy, hydroxy-substituted C 1-6 alkyl, 5-8 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S, 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S;

[0028] R3is selected from the group consisting of H, C 1-6 alkyl (e.g. methyl, ethyl, isopropyl), C 3-8 cycloalkyl (e.g. cyclopropyl);

[0029] R4is selected from the group consisting of H, halogen (e.g. F, Cl, Br), C 2-6 alkynyl;

[0030] R5is selected from the group consisting of:

[0031] m, R6, R7, R8and R9are as defined in the application.

[0032] In another preferred embodiment, in formula I, X is N and Y is CR6, or X is CR6and Y is N; preferably R6is selected from the group consisting of H, halogen, cyano, hydroxy, C 1-6 alkyl (e.g. methyl, ethyl, isopropyl), C3-6 cycloalkyl (e.g. cyclopropyl), C 1-6 alkoxy (e.g. methoxy), -COO-C 1-6 alkoxy (e.g. ), -CO-C 1-6 alkyl (e.g. ), C 1-6 haloalkyl (e.g. CF3), C 1-6 haloalkoxy (e.g. -O-CF3).

[0033] In another preferred embodiment, m is 0; in another preferred embodiment, m is 1; preferably R is selected from the group consisting of H, halogen, cyano, hydroxy, C 1-6 alkyl (e.g. methyl, ethyl, isopropyl), C 3-6 cycloalkyl (e.g. cyclopropyl), C 1-6 alkoxy (e.g. methoxy), -COO-C 1-6 alkoxy (e.g. ), -CO-C 1-6 alkyl (e.g. ), C 1-6 haloalkyl (e.g. CF3), C 1-6 haloalkoxy (e.g. -O-CF3), hydroxy substituted C 1-6 alkyl (e.g. -COH(CH3)2).

[0034] In another preferred embodiment, in formula I, X is N and Y is CR6, or X is CR6 and Y is N; R6 is selected from the group consisting of H, F, Cl, Br, cyano, hydroxy, methyl, ethyl, isopropyl, cyclopropyl, methoxy, CF3, -O-CF3;

[0035] In another preferred embodiment, m is 0 or 1;

[0036] In another preferred embodiment, R is selected from the group consisting of H, F, Cl, Br, cyano, hydroxy, methyl, ethyl, isopropyl, hydroxy substituted isopropyl, hydroxy substituted isobutyl, cyclopropyl, methoxy, CF3, -O-CF3.

[0037] In another preferred embodiment, in formula II, is selected from the group consisting of -N=C(R6)-, -CO-NH-, -S-C(R6)(R7)- and O-C(R6)(R7)-; preferably R6 and R7 are each independently selected from the group consisting of H, halogen, cyano, hydroxy, C 1-6 alkyl (e.g. methyl, ethyl, isopropyl), C 3-6 cycloalkyl (e.g. cyclopropyl), C 1-6 alkoxy (e.g. methoxy), -COO-C 1-6Alkoxy (e.g.) ), -CO-C 1-6 Alkyl (e.g.) C 1-6 Halogenated alkyl groups (such as CF3), C 1-6 Halogenated alkoxy groups (e.g., -O-CF3); preferably, R6 and R7 are H.

[0038] In another preferred embodiment, in formula II, -N = C(R6)-, -CO-NH-, -SC(R6)(R7)-, and OC(R6)(R7)-; in another preferred embodiment, R6 and R7 are each independently selected from the group consisting of: H, halogen, cyano, hydroxyl, methyl, ethyl, isopropyl, cyclopropyl, methoxy, - CF3, -O-CF3; preferably, R6 and R7 are H;

[0039] In another preferred embodiment, R1 and R2 are each independently selected from the group consisting of: H, F, Cl, Br, hydroxyl, methyl, ethyl, isopropyl, and CF3.

[0040] In another preferred embodiment, in equation I, -N = C(R6)-, where R6 is as defined in this invention, preferably selected from the group consisting of: H, halogens, cyano groups, C 1-3 Alkyl groups (such as methyl, ethyl, isopropyl), -CO-C 1-3 Alkyl (e.g.) ) and C 1-3 Halogenated alkyl groups (such as CF3).

[0041] In another preferred embodiment, in formula II, It is -CO-NH- or -COO-.

[0042] In another preferred embodiment, R is selected from the group consisting of: H, halogens (such as F, Cl, Br, I), cyano, hydroxyl, amino, C. 1-6 Alkyl groups (such as methyl, ethyl, isopropyl), C 3-8 cycloalkyl, halogenated C 1-6 Alkyl groups (such as CF3), halogenated C 3-8 cycloalkyl, -CO-C 1- 6-alkyl, C 1-6 Alkoxy groups (such as -O-methyl), -COOH, -CONH2, -COO-C 1-6 Alkyl groups (such as -COO-C(CH3)3), methanesulfonyl groups, C 6-10 Aryl, 5-8 membered heterocyclic alkyl containing 1, 2 or 3 heteroatoms selected from N, O or S.

[0043] In another preferred embodiment, R is selected from the group consisting of: H, halogen, cyano, C.1-3 alkyl (e.g. methyl, ethyl, isopropyl), -CO-C 1-3 alkyl (e.g. methyl, ethyl, isopropyl), -CO-C alkyl (e.g. methyl, ethyl, isopropyl), -CO-C 1-3 haloalkyl (e.g. CF3).

[0044] In another preferred embodiment, R1and R2are each independently selected from the group consisting of H, halogen (e.g. F, Cl, Br, I), hydroxy, C 1-6 alkyl (e.g. methyl, ethyl, isopropyl), -CO-C 1-6 alkyl (e.g. methyl, ethyl, isopropyl), -CO-C

[0045] In another preferred embodiment, R3is each independently selected from the group consisting of H, C 1-6 alkyl (e.g. methyl, ethyl, isopropyl), -CO-C 1-6 alkyl (e.g. methyl, ethyl, isopropyl), -CO-C 3-6 cycloalkyl, halo-C 3-6 cycloalkyl, -C 1-2 alkyl-C 3-6 cycloalkyl, preferably R3is each independently selected from the group consisting of methyl, ethyl, isopropyl, cyclopropyl; more preferred R3is isopropyl.

[0046] In another preferred embodiment, R4is each independently selected from the group consisting of H, halogen (e.g. F, Cl, Br), cyano, C 1-6 alkyl (e.g. methyl, ethyl), -CO-C 1-3 haloalkyl (e.g. CF3), -CO-C 1-3 haloalkoxy (e.g. -O-CF3), preferably each independently selected from halogen, more preferred R4is Cl.

[0047] In another preferred embodiment, R9is each independently selected from the group consisting of H, halogen (e.g. F, Cl, Br), cyano, C 1-6 alkyl (e.g. methyl, ethyl), -CO-C 1-6 haloalkyl (e.g. CF3).

[0048] In another preferred embodiment, R 10 is selected from the group consisting of C 1-3 alkyl (e.g. methyl, ethyl, isopropyl), -CO-C 1-3 alkyl-C 3-6 cycloalkyl, -CO-C 3-6 cycloalkyl (e.g. cyclopropyl).

[0049] In another preferred embodiment, R5is selected from the group consisting of: preferably is

[0050] In another preferred embodiment, m = 0.

[0051] In another preferred embodiment, m = 1.

[0052] In another preferred embodiment, R, R1, R2, R3, R4, R5, X, Y, Z, m are each independently optionally the specific group corresponding to any specific compound of the present application.

[0053] In another preferred embodiment, the compound is selected from the group consisting of:

[0054] In another preferred embodiment, the pharmaceutically acceptable salt is an inorganic acid salt or an organic acid salt.

[0055] The inorganic acid salt is selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, nitrate, phosphate, acid phosphate.

[0056] The organic acid salt is selected from the group consisting of formate, acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, malonate, fumarate, maleate, lactate, malate, citrate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, salicylate, picrate, glutamate, ascorbate, camphorate, camphorsulfonate.

[0057] In a second aspect, the present application provides a pharmaceutical composition comprising a prophylactically and / or therapeutically effective amount of a compound of the first aspect of the present application, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotopologue or prodrug thereof, and a pharmaceutically acceptable carrier.

[0058] In a third aspect, the present application provides use of a compound of the first aspect of the present application, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotopologue or prodrug thereof, in the manufacture of a CDK4 protein kinase inhibitor.

[0059] In a fourth aspect, the present application provides use of a compound of the first aspect of the present application, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotopologue or prodrug thereof, or a pharmaceutical composition of the second aspect of the present application, in the manufacture of a medicament for preventing or treating a CDK4 related disease.

[0060] In another preferred embodiment, the CDK4 related disease is selected from the group consisting of inflammation, cancer, cardiovascular disease, infection, immunological disease, metabolic disease.

[0061] In another preferred embodiment, the cancer is selected from the group consisting of breast cancer, endometrial cancer, ovarian cancer, vaginal cancer, fallopian tube cancer, cervical cancer, kidney cancer, bladder cancer, urothelial cancer, urethral cancer, prostate cancer, testicular cancer, colorectal cancer, sarcoma, bone cancer, multiple myeloma, leukemia, rhabdomyoma, leiomyoma, fibroma, lipoma, teratoma, laryngeal cancer, nasopharyngeal cancer, oral cancer, lung cancer, lymphoma, mesothelioma, small intestine cancer, stomach cancer, esophageal cancer, pancreatic cancer, liver cancer, bile duct cancer, biliary tract cancer, gallbladder cancer, peritoneal cancer, thymus cancer, central nervous system tumor, retinoblastoma, glioblastoma multiforme, neurofibroma, glioma, neuroblastoma, melanoma, skin cancer, basal cell carcinoma, squamous cell carcinoma, thyroid cancer, head and neck cancer, brain cancer, salivary gland cancer, and gastrointestinal stromal tumor.

[0062] In another preferred embodiment, the cancer is selected from the group consisting of lung cancer, breast cancer, prostate cancer, colorectal cancer, liver cancer, pancreatic cancer, ovarian cancer, leukemia, neuroblastoma, gastric cancer, renal cancer, esophageal cancer, uterine cancer, liposarcoma.

[0063] It should be understood that, within the scope of the present application, all combinations between the above-mentioned technical features of the present application and the technical features specifically described hereinafter (e.g., in the examples) can be interchanged, thereby constituting new or preferred technical solutions. Due to the limited space, they will not be listed one by one here. DETAILED DESCRIPTION

[0064] The present inventors have made extensive and in-depth research, and unexpectedly found a class of compounds with novel structure and excellent CDK4 protein kinase inhibitory activity. In addition, the compounds have excellent inhibitory activity on CDK4 protein kinase and better pharmacodynamics / pharmacokinetic performance. On this basis, the present application is completed.

[0065] TERMS

[0066] Unless specifically indicated otherwise, the following terms as used in the present application (including the specification and claims) have the definitions given below.

[0067] 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. For example, -CH2O- is included in -OCH2-.

[0068] As used herein, a bond represented by in a group indicates the position at which the group is attached to the rest of the compound or molecule.

[0069] As used herein, indicates a bond or absence.

[0070] "Alkyl," alone or as part of another group, refers to a straight or branched saturated hydrocarbon chain of one to twelve carbon atoms (i.e., C 1-12 alkyl groups). Preferably, the alkyl group is a C 1-6 alkyl group (i.e., an alkyl group containing one, two, three, four, five, or six carbon atoms), more preferably a C 1-4 alkyl group (i.e., an alkyl group containing one, two, three, or four 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, dodecyl, and the like. Unless otherwise indicated, alkyl groups in the present application are also intended to include substituted alkyl groups, that is, alkyl groups in which one or more positions substituted, especially 1-4 substituents, can be substituted at any position. Unless otherwise indicated, "substituted alkyl" includes haloalkyl groups in the present application. As used herein, "haloalkyl" refers to an alkyl group as defined herein in which one or more hydrogens are replaced by the same or different halogen. Preferably, the haloalkyl group is a C 1-6 haloalkyl group, more preferably a C 1-6 haloalkyl group. Examples of haloalkyl groups include -CH2Cl, -CH2CF3, -CH2CCI3, perfluoroalkyl (e.g., -CF3), and the like. "Hydroxy-substituted C 1-6 alkyl" refers to a C 1-6 alkyl group substituted with at least one hydroxyl group, preferably one or two, the alkyl group being as defined above; preferably the hydroxy-substituted alkyl group is -CH2OH, -CH2CH2OH, -CHOHCH3, -COH(CH3)2.

[0071] "Alkylene" refers to a divalent group of an alkyl group as defined herein, for example, -CH2-, -CH2CH2-, and -CH2CH2CH2-.

[0072] "Alkoxy," alone or as part of another group, refers to an alkyl group as defined herein having an oxy group attached thereto, having the structure alkylO-, wherein alkyl is as defined above. Preferably, the alkoxy group is a C 1-6 alkoxy group (i.e., -OC 1- 6alkyl group). Alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, t-butoxy, and the like. "Haloalkoxy" refers to the 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. "Thioalkyl" refers to an alkyl group in which a carbon is replaced by S, S(O), or S(O)2.

[0073] "Alkenyl," alone or as part of another group, refers to an aliphatic group of at least one double bond, generally from two to twenty carbon atoms (i.e., C 2-20alkenyl). Alkenyl is preferably C 2-6 alkenyl (i.e., alkenyl groups containing 2, 3, 4, 5, or 6 carbon atoms). Alkenyl includes, but is not limited to, for example, vinyl, propenyl, butenyl, 1 -methyl-2-buten- 1 -yl, and the like. Unless otherwise defined, in the present invention, alkenyl also includes substituted alkenyl groups.

[0074] "Alkenylene" refers to an alkenyl group as previously defined having two points of attachment, for example, "vinylene" denotes the group -CH=CH-. Alkenylene is preferably C 2-6 alkenylene (i.e., alkenylene groups containing 2, 3, 4, 5, or 6 carbon atoms). Unless otherwise defined, alkenylene can be in the unsubstituted form or a substituted form having one or more substituents.

[0075] "Alkynyl", alone or as part of another group, refers to a straight or branched hydrocarbon chain, typically having from 2 to 20 carbon atoms (i.e., C 2-20 alkynyl). Alkynyl is preferably C 2-6 alkynyl (i.e., alkynyl groups having 2, 3, 4, 5, or 6 carbon atoms). Alkynyl includes, but is not limited to, ethynyl, propynyl, and 3-hexynyl. One of the triple-bond carbons can optionally be the point of attachment of the alkynyl substituent. Unless otherwise defined, in the present invention, alkynyl also includes substituted alkynyl groups.

[0076] "Alkynylene" refers to an alkynyl group as previously defined having two points of attachment. For example, "ethynylene" denotes the group: -C≡C-. Alkynylene is preferably C 2-6 alkynylene (i.e., alkynylene groups containing 2, 3, 4, 5, or 6 carbon atoms). Unless otherwise defined, alkynylene can be in the unsubstituted form or a substituted form having one or more substituents. "Aliphatic group" refers to straight chain, branched or cyclic hydrocarbon groups including saturated and unsaturated groups such as alkyl, alkenyl and alkynyl groups.

[0077] "Aromatic ring system" or "aromatic ring" refers to a monocyclic, bicyclic or polycyclic hydrocarbon ring system in which at least one ring is aromatic. Preferably, the "aromatic ring system" or "aromatic ring" has 6-12 ring atoms, i.e., C 6-12 aromatic ring. Examples of aromatic rings include benzene, naphthalene, anthracene, and the like.

[0078] "Aryl", alone or as part of another group, refers to a monovalent group derived from a aromatic ring system (aromatic 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. In the present invention, aryl is preferably C 6-12 aryl. In the present invention, unless otherwise defined, aryl also includes substituted aryl groups.

[0079] "Aryloxy" means -O-(aryl), wherein the aryl moiety is as defined above.

[0080] "Aryloxy" means -O-(aryl), wherein the aryl moiety is as defined above.

[0081] "Heteroalkyl" means an alkyl group in which one or more carbon atoms in the chain are replaced by a skeletal chain atom(s) selected from oxygen, nitrogen, sulfur, phosphorus, or combinations thereof. Numerical ranges, such as C 1-6 Heteroalkyl refers to the number of carbons in the chain, which includes from 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. "Heteroalkylene" means a divalent alkyl group in which one or more carbon atoms in the chain are replaced by a skeletal chain atom(s) selected from oxygen, nitrogen, sulfur, phosphorus, or combinations thereof. Unless otherwise defined, "heteroalkyl" and "heteroalkylene" include both substituted and unsubstituted forms.

[0082] "Carbocyclic ring system" or "carbocyclic ring" means a monocyclic, bicyclic, or polycyclic hydrocarbon ring system in which each ring is fully saturated or contains one or more units of unsaturation, but in which none of the rings are aromatic. Preferably, the "carbocyclic ring system" or "carbocyclic ring" has 6-12 ring atoms, i.e., C 6-12 carbocyclic ring. "Carbocyclyl" means a monovalent radical of a carbocyclic ring system or carbocyclic ring as defined above. Preferably, the carbocyclyl group has 6-12 ring atoms, i.e., C 6-12 carbocyclic ring. "Carbocyclyl" means a monovalent radical of a carbocyclic ring system or carbocyclic ring as defined above. Preferably, the carbocyclyl group has 6-12 ring atoms, i.e., C

[0083] "Cycloalkyl" means a monovalent saturated carbocyclic radical consisting of a single- or bicyclic ring having from 3 to 12 (i.e., C 3-12 cycloalkyl), preferably from 3 to 10 (i.e., C 3-10 cycloalkyl), more preferably from 3 to 8 ring atoms (i.e., C 3-8 cycloalkyl), most preferably 3, 4, 5, or 6 ring atoms (i.e., C 3-6 cycloalkyl). Unless otherwise defined, cycloalkyl can be optionally substituted with one or more substituents. Preferably, the substituents of cycloalkyl can be independently hydroxy, alkyl, alkoxy, halo, haloalkyl, amino, monoalkylamino, or dialkylamino. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

[0084] "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. "Cycloalkylalkyl" or "cycloalkylalkylene" refers to -alkylene(cycloalkyl), wherein cycloalkyl and alkylene are as previously defined. "Cycloalkylalkyl" or "cycloalkylalkylene" is bonded to the parent molecular structure through the alkyl (alkylene) group.

[0085] "Heteroaromatic ring system" or "heteroaromatic ring" refers to a monocyclic (e.g., 5- or 6-membered), bicyclic (6- to 12-membered), or polycyclic system in which at least one ring is an aromatic ring that contains at least one heteroatom (e.g., N, O, or S) as a ring atom and the remaining ring atoms are all carbon. In certain instances, the aromatic ring that contains at least one heteroatom contains 1, 2, 3, or 4 heteroatom ring atoms in the ring. In addition to the aromatic ring that contains at least one heteroatom as a ring atom, the remaining rings in the "heteroaromatic ring system" or "heteroaromatic ring" can be saturated, partially unsaturated, or fully unsaturated rings.

[0086] "Heteroaryl", alone or as part of another group, refers to a monovalent radical of a "heteroaromatic ring system" or "heteroaromatic ring" as defined above. The point of attachment of a heteroaryl group shall be at an aromatic ring. Examples of heteroaryl groups include, but are not limited to: imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, thiophenyl, furanyl, pyranyl, pyridyl, pyrrolyl, pyrazolyl, pyrimidinyl, quinolinyl, isoquinolinyl, benzofuranyl, benzofuranyl, benzothiophenyl, benzothiopyranyl, benzimidazolyl, benzoxazolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzopyranyl, indolyl, isoindolyl, triazolyl, triazinyl, quinoxalinyl, purinyl, quinazolinyl, quinolizinyl, naphthridinyl, pteridinyl, carbazolyl, diazepinyl, diazepinyl, acridinyl, and the like. Heteroaryl groups include substituted and unsubstituted forms, unless otherwise defined. "Heteroaryl", alone or as part of another group, refers to a monovalent radical of a "heteroaromatic ring system" or "heteroaromatic ring" as defined above. The point of attachment of a heteroaryl group shall be at an aromatic ring. Examples of heteroaryl groups include, but are not limited to: imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, thiophenyl, furanyl, pyranyl, pyridyl, pyrrolyl, pyrazolyl, pyrimidinyl, quinolinyl, isoquinolinyl, benzofuranyl, benzofuranyl, benzothiophenyl, benzothiopyranyl, benzimidazolyl, benzoxazolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzopyranyl, indolyl, isoindolyl, triazolyl, triazinyl, quinoxalinyl, purinyl, quinazolinyl, quinolizinyl, naphthridinyl, pteridinyl, carbazolyl, diazepinyl, diazepinyl, acridinyl, and the like. Heteroaryl groups include substituted and unsubstituted forms, unless otherwise defined. "Heteroaryl", alone or as part of another group, refers to a monovalent radical of a "heteroaromatic ring system" or "heteroaromatic ring" as defined above. The point of attachment of a heteroaryl group shall be at an aromatic ring. Examples of heteroaryl groups include, but are not limited to: imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, thiophenyl, furanyl, pyranyl, pyridyl, pyrrolyl, pyrazolyl, pyrimidinyl, quinolinyl, isoquinolinyl, benzofuranyl, benzofuranyl, benzothiophenyl, benzothiopyranyl, benzimidazolyl, benzoxazolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzopyranyl, indolyl, isoindolyl, triazolyl, triazinyl, quinoxalinyl, purinyl, quinazolinyl, quinolizinyl, naphthridinyl, pteridinyl, carbazolyl, diazepinyl, diazepinyl, acridinyl, and the like. Heteroaryl groups include substituted and unsubstituted forms, unless otherwise defined.

[0087] "Heterocyclic ring system" or "heterocyclic ring" refers to monocyclic, bicyclic, and polycyclic ring systems in which at least one ring is saturated or partially unsaturated (but not aromatic) and which contains at least one heteroatom as a ring atom. The heterocyclic ring system or heterocyclic ring can be attached at a pendant group at any heteroatom or carbon atom, which results in a stable structure and any ring atom can be optionally substituted.

[0088] "Heterocyclyl" refers to a monovalent radical of a heterocyclic ring system or heterocyclic ring as previously defined, typically a stable monocyclic (e.g., 3 to 8 membered, i.e., 3, 4, 5, 6, 7, or 8 membered) or bicyclic (e.g., 5 to 12 membered, i.e., 5, 6, 7, 8, 9, 10, 11, or 12 membered) or membered polycyclic ring (e.g., 7 to 14 membered, i.e., 7, 8, 9, 10, 11, 12, 13, or 14), including fused, spiro, and / or bridged ring structures, which is saturated, partially unsaturated, and which contains carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S as ring atoms. Heterocyclyl is preferably 3 to 14 membered, more preferably 3 to 8 membered, and most preferably 4 to 6 membered. Representative heterocyclyl groups include the following ring systems, wherein (1) each ring is non-aromatic and at least one ring contains a heteroatom, for example, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, pyrrolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl; (2) at least one ring is non-aromatic and contains a heteroatom as a ring atom and at least one other ring is an aromatic carbocyclic ring, for example, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl; and (3) at least one ring is non-aromatic and contains a heteroatom and at least one other ring is aromatic and contains a heteroatom, for example, 3,4-dihydro-lH-pyrano[4,3-c]pyridine and 1,2,3,4-tetrahydro-2,6-naphthylene. Heterocyclyl groups can also be referred to as heterocycloalkyl groups when saturated. Heterocyclyl groups can also be referred to as heteroalicyclic groups.

[0089] "Heterocyclylalkyl" refers to an alkyl group substituted with a heterocyclyl group, wherein heterocyclyl and alkyl are as defined above.

[0090] "Alkylamino" refers to a group having the formula -NRaRb, wherein Ra is H or an alkyl group as defined above, and Rb is an alkyl group as defined above.

[0091] "Cycloalkylamino" refers to a group having the formula -NRaRb, wherein Ra is H or a cycloalkyl group as defined above, and Rb is a cycloalkyl group as defined above. a R b wherein R a is H, an alkyl group as defined herein, or a cycloalkyl group as defined herein, and Rb is a cycloalkyl group as defined herein. a and R btogether with the N atom to which it is attached, form a 3-10 membered N-containing monocyclic or bicyclic heterocyclyl group, such as tetrahydropyrrolyl. As used herein, C3-C8cycloalkylamine refers to an amine group containing 3-8 carbon atoms.

[0092] In the present application, "ester" refers to a group having the structure -C(O)-O-R or R-C(O)-O-, wherein R independently represents hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, as defined above.

[0093] In the present application, the term "amido" refers to a group bearing the structure -CONRR', wherein R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R and R' can be the same or different in a dialkylamine moiety.

[0094] In the present application, the term "sulfonamido" refers to a group bearing the structure -SO2NRR', wherein R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R and R' can be the same or different in a dialkylamine moiety.

[0095] "Keto carbonyl" refers to R-C(=O)-, wherein R is alkyl, cycloalkyl, etc., as described above.

[0096] When a substituent is a non-terminal substituent, it is an "alkylene" group, e.g., alkyl corresponds to alkylene, cycloalkyl to cycloalkylene, heterocyclyl to heterocyclylene, alkoxy to alkoxylene, etc.

[0097] 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.

[0098] In the present application, the term "substituted" means that one or more hydrogen atoms on a particular group are replaced with a particular substituent. The particular substituents are those described in the foregoing, or those appearing in the various embodiments. Unless otherwise specified, a substituted group can have at any substitutable position one substituent selected from a particular 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 stable or chemically feasible combinations. Typical substitutions include, but are not limited to, one or more of the following: hydrogen, deuterium, halogen (e.g., monohalogenated substituents or polyhalogenated substituents, the latter such as trifluoromethyl or alkyl groups containing Cl3), cyano, nitro, oxo (e.g., =0), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, alkynyl, heterocycle, aryl, OR, SR, NR2, SiRR', PR2, CCRR', SOR, SO2R, SO2NR2, SO2RR', NRR'SO2R, NRR'CONR2, NRR'CO2R, NRR'COR, NRR'SO2RR', NRR'CO2RR', NRR'CONRR', NRR'CSRR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', NRR'PO2RR', Na SR a S(=O)R e S(=O)2R e P(=O)2R e S(=O)2OR e P(=O)2OR e NR b R c NR b S(=O)2R e NR b P(=O)2R e S(=O)2NR b R c P(=O)2NR b R c C(=O)OR d C(=O)R a C(=O)NR b R c OC(=O)R a OC(=O)NR b R c NR b C(=O)OR e NR d C(=O)NR b R c NR d S(=O)2NR b R c NR d P(=O)2NR b R c NR b C(=O)R a or NR b P(=O)2R e 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; R eIt can independently represent hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, heterocyclic, or aromatic ring. The above-mentioned typical substituents, such as alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aromatic ring, can be optionally substituted. Such substituents include (but are not limited to): halogen, hydroxyl, cyano, carboxyl (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-12 membered heterocyclic, aryl, heteroaryl, C1-C8 aldehyde, C2-C... 10 Acyl group, C2-C 10 Ester group, amino group, C1-C6 alkoxy group, C1-C 10 Sulfonyl groups and C1-C6 urea groups, etc.

[0099] "Cyano" refers to -CN.

[0100] "Nitro" refers to -NO2.

[0101] "Hydroxy group" refers to -OH.

[0102] "Amino" refers to -NH2 or RNH-, where R is a ketone carbonyl group, sulfonyl group, sulfonamide group, or R a -C(=O)-、R a R b NC(=O)- etc., where R a and R b It can be alkyl, cycloalkyl, aryl, or heteroaryl, etc.

[0103] "Halogen (halogenated)" refers to any halogen group, such as -F, -Cl, -Br or -I.

[0104] "Deuterated compounds" refer to compounds in which one or more hydrogen atoms (H) are replaced by deuterium atoms (D).

[0105] In this invention, the term "multiple" independently refers to 2, 3, 4, or 5.

[0106] The structural formula of the carbamate group is -NH-C(=O)-OR, where R is an alkyl, aryl, heteroaryl, etc.

[0107] It should be understood that when a group exists simultaneously at multiple different positions in a compound, its definition at each position is independent and can be the same or different. That is, the term "selected from the following group:" and the term "each independently selected from the following group:" have the same meaning.

[0108] Active ingredients

[0109] As used herein, the terms "compound of the present invention" or "active ingredient of the present invention" are used interchangeably to refer to a compound of Formula I and Formula II, or a pharmaceutically acceptable salt, hydrate, solvate, isotopically enriched compound (e.g., deuterium-enriched compound), or prodrug thereof. The term also includes racemates, optical isomers.

[0110] The compounds of Formula I and Formula II are described by the following structures:

[0111] R, R1, R2, R3, R4, R5, X, Y, Z, m are defined as above.

[0112] In another preferred embodiment, R, R1, R2, R3, R4, R5, X, Y, Z, m are each independently the specific group corresponding to a specific compound of the present invention.

[0113] Salts of the compounds of the present invention are also within the scope of the present invention. Unless otherwise specified, the compounds of the present invention are understood to include salts thereof. The term "salt," as used herein, refers to an acid or base salt formed by reaction of a compound of the present invention with inorganic or organic acids and bases. In addition, when a compound of the present invention contains a basic moiety, including but not limited to a pyridine or imidazole ring, and an acidic moiety, including but not limited to a carboxylic acid, a zwitterion ("inner salt") can be formed, which is included within the scope of the term "salt." Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, e.g., in isolation and purification steps. Salts of the compounds of the present invention can be formed by reacting a compound of Formula I or II with an amount of an acid or base, such as an equivalent amount of acid or base, in a medium such as water, or another solvent, or in a frozen state.

[0114] Compounds of the present invention containing a basic moiety, including but not limited to an amine or pyridine or imidazole ring, can form salts with organic or inorganic acids. Typical acids which can form salts include acetate (e.g., with acetic acid or a trihaloacetic acid, such as trifluoroacetic acid), adipate, alginate, ascorbate, aspartate, benzoate, besylate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrochloride, hydrobromide, hydroiodide, hydroxymethanesulfonate (e.g., 2-hydroxyethanesulfonate), lactate, maleate, methanesulfonate, naphthylenesulfonate (e.g., 2-naphthalenesulfonate), nicotinate, nitrate, oxalate, pectinate, persulfate, phenylpropionate (e.g., 3-phenylpropionate), phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate (e.g., with sulfuric acid), sulfonate, tartrate, thiocyanate, toluenesulfonate such as para-toluenesulfonate, dodecanoate, and the like.

[0115] Certain compounds of the present application can contain acidic moieties, including but not limited to carboxylic acids, which can form salts with a variety of organic and inorganic bases. Typical bases which form salts include ammonium salts, alkali metal salts such as sodium, lithium, potassium salts, alkaline earth metal salts such as calcium, magnesium salts and salts with organic bases (e.g., organic amines) such as benzathines, dicyclohexylamines, ephedrines (salts with N,N-di(dehydroabietyl)ethylenediamine), N-methyl-D-glucamines, N-methyl-D-glucamides, t-butyl amines, and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups can be quaternized with agents such as lower alkyl halides (e.g. methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g. decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyl and phenyl bromides), and others.

[0116] Prodrugs and solvates (or solvates) of the compounds of the present application are also within the scope of the application.

[0117] The term "prodrug" as used herein refers to a compound which, upon administration, is metabolized or chemically converted in the body to form a compound, salt, or solvate of the present application. The compounds of the present application include solvates such as hydrates.

[0118] 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 application.

[0119] All stereoisomers (for example, those which result from the presence of an asymmetric carbon atom) of the compounds of the present application, including but not limited to, enantiomeric forms, and diastereomeric forms, are intended to be encompassed within the scope of the present application. The compounds of the present application can be in the form of a single stereoisomer (e.g., as a pure or substantially pure optical isomer) or as a mixture of two or more stereoisomers, and can be in the form of a racemic mixture or in the form of an enantiomeric or diastereomeric mixture. The chiral centers of the present application have the S or R configuration as defined by the IUPAC Recommendations (1974). The racemic forms can be resolved in physical form by methods known to those skilled in the art, such as, for example, fractional crystallization, or by separation of the diastereomeric forms, or by chromatographic methods using chiral columns. The individual optical isomers can be obtained by the application of the appropriate methods known to those skilled in the art, including but not limited to, the traditional methods of resolution of an enantiomeric pair by using, for example, a salt of an optically active acid such as quinine or quinidine or a salt of an optically active base such as ephedrine.

[0120] The compounds of the present application, obtained by preparation, isolation and purification, have a weight content of equal to or greater than 90%, for example equal to or greater than 95%, equal to or greater than 99% ("very pure" compounds), as described in the text. Such "very pure" compounds of the present application are also part of the present application.

[0121] All configurational isomers of the compounds of the present application are encompassed, 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.

[0122] Throughout the specification, groups and substituents are chosen by one of ordinary skill in the art to provide stable moieties and compounds.

[0123] 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. Additionally, general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, the entire contents of which are incorporated herein by reference. th Ed. Additionally, general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, the entire contents of which are incorporated herein by reference.

[0124] Certain compounds of the present application can exist in particular geometric or stereoisomeric forms. The present application contemplates all such compounds, including cis- and trans-isomers, R- and S- enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures and other mixtures thereof. Additionally, asymmetric carbon atoms can be designated by substituents, such as alkyl groups. All isomers and mixtures thereof are encompassed by the present application.

[0125] According to the present application, mixtures of isomers can have a variety of ratios of isomers. For example, mixtures of only two isomers can have the following compositions: 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0. All ratios of isomers are within the scope of the present application. Similar ratios, as would be 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.

[0126] This invention also includes isotopically labeled compounds, equivalent to the original compounds disclosed herein. However, in practice, it is common for one or more atoms to be replaced by atoms with different atomic weights or mass numbers. Examples of isotopes that can be included in the compounds of this invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine isotopes, respectively as follows: 2 H, 3 H, 13 C 11 C 14 C 15 N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F and 36 Cl. The compounds of this invention, or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates, wherein the isotopes or other isotopic atoms of the aforementioned compounds are all within the scope of this invention. Certain isotopically labeled compounds of this invention, for example... 3 H and 14 Radioactive isotopes of carbon are also included, and are useful in tissue distribution experiments of drugs and substrates. Tritium, i.e. 3 H and carbon-14, i.e. 14 C, their preparation and detection are relatively easy. They are the preferred isotopes. In addition, heavier isotopes such as deuterium are used for substitution. 2 H, due to its excellent metabolic stability, offers advantages in certain therapies, such as increasing half-life or reducing dosage in vivo, and therefore may be preferred in some cases. Isotopically labeled compounds can be prepared using general methods, by replacing the non-isotopic reagent with an readily available isotopically labeled reagent, according to the scheme described in the examples.

[0127] To design the synthesis of a specific enantiomer of the compound of this invention, it can be prepared asymmetrically or derivatized with a chiral auxiliary. The resulting diastereomeric mixture is then separated, and the chiral auxiliary is removed to obtain the pure enantiomer. Alternatively, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, it can be formed with a suitable optically active acid or base to form a diastereomer salt, which is then separated by conventional methods such as separation crystallization or chromatography to obtain the pure enantiomer.

[0128] As described herein, the compounds of the present 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 present application including substituents, is intended to mean that the indicated structure is replaced with the designated 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. The term "substituted" as used herein includes all permissible substituents of organic compounds. In a broad aspect, permissible substituents include acyclic, cyclic, branched, unbranched, carbocyclic, and heterocyclic, aromatic and non-aromatic organic compounds. In the present application, as in heteroatom nitrogen, can have a hydrogen substituent or any permissible organic compound as described above to supplement its valence. Furthermore, the present application is not intended to be limited in any way by any means of permissible substituents of organic compounds. The present application contemplates combinations of substituents and variables in so far as such combinations result in stable compounds useful in the treatment of disease. The term "stable" as used herein, refers to compounds that are sufficiently robust to survive isolation from a reaction mixture, and formulation into an efficacious therapeutic agent. The term is used herein to refer to compounds that are sufficiently robust to survive isolation from a reaction mixture, and formulation into an efficacious therapeutic agent.

[0129] Metabolites of compounds of the present application, which are within the scope of the present application, as well as prodrugs of compounds of the present application, which can be converted under metabolic conditions within the body to the compounds of the present application and their pharmaceutically acceptable salts, are also within the scope of the present application.

[0130] Methods of Preparation

[0131] Methods for preparing compounds of Formula I or Formula II are described in the following schemes and examples. Starting materials and intermediates are either commercially available, prepared by known procedures, or otherwise described. In certain cases, the order of carrying out the steps of the reaction sequences can be varied to facilitate the reaction or to avoid undesired side products.

[0132] The following more specifically describe methods for preparing compounds of the present application having the structure of Formula I or Formula II, but these specific methods are not to be construed as limiting the present application in any way. The compounds of the present application can also be prepared by any other means known to those skilled in the art, optionally combining various synthetic methods described in this specification or known in the art.

[0133] Generally, in the preparation schemes, each reaction is typically carried out in an appropriate solvent under an inert gas atmosphere at a temperature in the range of from 0 to 150°C, and the reaction time is usually from 2 to 24 hours.

[0134] Preferably, the method of preparation is as follows:

[0135] Method:

[0136] Step 1: SM1 and S1 are reacted by palladium-catalyzed coupling or nucleophilic substitution in a solvent (1,4-dioxane, tetrahydrofuran, 1,2-dichloroethane) at 70-120 °C to give

[0137] Step 2: SM2 and S2 are reacted by palladium-catalyzed coupling or nucleophilic substitution in a solvent (1,4-dioxane, tetrahydrofuran, toluene, N,N-dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone) under basic conditions at 70-120 °C to give product T

[0138] In the above formulae, R, R1, R2, R3, R4, R5, X, Y, Z, and m are as defined above.

[0139] Unless otherwise specified, the above starting materials can be purchased commercially or synthesized according to reported literature.

[0140] Pharmaceutical compositions and methods of administration

[0141] The pharmaceutical compositions described herein are used for the prevention and / or treatment of inflammatory diseases, cancer, cardiovascular diseases, infections, immunological diseases, metabolic diseases.

[0142] The compounds of Formula I or II can be used in combination with other drugs known to treat or ameliorate similar conditions. When administered in combination, the original dosage of the other drug or drugs may be reduced, and / or the frequency of administration may be reduced, and / or the dosage of the compound of Formula I or II may be reduced. When the compound of Formula I or II is used in combination with other drugs, the combination of the compound of Formula I or II and other drug(s) can be achieved by:

[0143] The drugs or active ingredients that can be combined with the compounds described in general formula I or formula II 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.

[0144] The dosage form of the pharmaceutical composition of the present application includes, but is not limited to, injection, tablet, capsule, aerosol, suppository, film, drop pill, external liniment, controlled release or sustained release or nano-preparation.

[0145] The pharmaceutical composition of the present application comprises a safe and effective amount of the compound of the present application or its pharmacologically acceptable salt and a pharmacologically acceptable excipient or carrier. The "safe and effective amount" means the 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.

[0146] The "pharmacologically acceptable carrier" means one or more compatible solid or liquid filler or gel material suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components of the composition can be blended with the compound of the present application and among themselves without significantly reducing the efficacy of the compound. Some examples of the pharmacologically acceptable carrier include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyhydric alcohols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium dodecyl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0147] The administration of the compound or pharmaceutical composition of the present application is not particularly limited, and the representative administration methods include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0148] 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 other ingredients as binders, e.g., carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, acacia, and tragacanth; humectants; e.g., glycerol; disintegrating agents, e.g., agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; effervescing mixtures; e.g., sodium bicarbonate; and a combination of two or more of the above ingredients. Tablets can contain suitable binders, e.g., povidone, gelatin, acacia; fillers, e.g., lactose, sugar, mannitol, calcium phosphate; glidants, e.g., colloidal silicon dioxide; and lubricants, e.g., magnesium stearate, stearic acid, and polyethylene glycol. Tablets can also contain suitable flavoring, coloring, and sweetening agents as desired.

[0149] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, e.g., enteric coatings and other coatings 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.

[0150] 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- butanediol, dimethylformamide, and the like, as well as mixtures thereof.

[0151] Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0152] 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.

[0153] 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.

[0154] Dosage forms for topical administration of a compound of this application include ointments, powders, sprays, and inhalants. The active component is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as can be required.

[0155] The therapeutic methods of this application can be employed in admixture with other therapeutic procedures and agents.

[0156] Pharmaceutical compositions are employed in a safe and effective amount, which is a quantity sufficient to deliver a safe and effective amount of a compound of this application to a mammal in need thereof. A safe and effective amount is typically in the range of 1 to 2000 mg, preferably 50 to 1000 mg, per day for a 60 kg person, administered in dosages considered pharmaceutically effective. The precise dosage will depend on the frequency and mode of administration, the age, health and weight of the patient, and the particular compound of this application used.

[0157] 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 or II, or a crystalline form, a pharmaceutically acceptable salt, a hydrate or a solvate thereof, to form a pharmaceutical composition.

[0158] 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 or II, or a crystalline form, a pharmaceutically acceptable salt, a hydrate or a solvate thereof, or a pharmaceutical composition of the present application, for inhibiting CDK4 protein kinase.

[0159] Compared with the prior art, the present application has the following main advantages:

[0160] (1) The compounds of the present application have excellent inhibitory ability on CDK4 protein kinase;

[0161] (2) The compounds of the present application have lower toxic side effects;

[0162] (3) The compounds of the present application have better pharmacodynamics and pharmacokinetics.

[0163] The application will be further described in conjunction with specific examples. It should be understood that these examples are only used to illustrate the application and not used to limit the scope of the application. The experimental methods in the following examples, if not otherwise specified, are generally carried out according to the conventional conditions, such as the conditions described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or the conditions suggested by the manufacturers. Unless otherwise specified, the percentages and parts are calculated by weight.

[0164] 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. In addition, any method and material similar or equivalent to those described herein can be used in the practice of the present application. The preferred methods and materials described herein are illustrative only and not intended to be limiting.

[0165] Examples

[0166] The technical solutions of the present application are further described below, but the protection scope of the present application is not limited thereto.

[0167] Example 1

[0168] The compound synthesized in the present application:

[0169] The experimental process is as follows: synthesis of compound T-1

[0170] The synthesis route is as follows:

[0171] Compound SM 1 (500 mg, 1.0 e.q.), compound SM 2 (647 mg, 1.2 e.q.), tetrakis triphenyl phosphine palladium (143 mg, 0.05 e.q.) and Na2CO3(653 mg, 2.5 e.q.) were placed in a dry 25 mL three-necked flask, 1,4-dioxane and water (V1:V2=10:3) were added and replaced with nitrogen three times, then warmed to reflux for 3 hours. After TLC monitoring, the reaction was stopped, and the temperature was returned 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 SM 3 (700 mg, 95.8%), LCMS: [M+H] + = 297.0, 299.1.

[0172] Second step:

[0173] Compound SM 3 (700 mg, 1.0 e.q.), 1,2-bis(diphenylphosphino)ethane (1130 mg, 1.2 e.q.) were added into a dry 25 mL three-neck flask and 10 mL of 1,2-dichlorobenzene solvent was added, and heated to 170 °C for 30 minutes under nitrogen protection. After TLC monitoring of the complete reaction of the raw material, the reaction was stopped and returned 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 purified by silica gel column chromatography to obtain compound SM 4 (600 mg, 96.5%), LCMS: [M+H] + = 264.9, 266.9.

[0174] Third step:

[0175] Compound SM 4 (0.6 g, 1.0 e.q.) was dissolved in 5 mL of ultra-dry DMF solvent and cooled to 0 °C in an ice water bath, then 60% sodium hydride solid powder (0.2 g, 2.0 e.q.) was added, and the reaction was incubated for half an hour, then isopropyl iodide SM 5 (0.62 mL, 2.5 e.q.) was added, and the temperature was allowed to rise to room temperature. After TLC monitoring of the complete reaction of the raw material, the reaction was stopped and quenched with ice water, then extracted with ethyl acetate and water, the organic phase was dried with anhydrous sodium sulfate, then filtered and concentrated to remove the solvent, and purified by silica gel column chromatography to obtain compound SM 6 (270 mg, 39.1%), LCMS: [M+H] + = 307.0, 309.0.

[0176] Fourth step:

[0177] Compound SM 6 (270 mg, 1.0 e.q.), bis(pinacolato)diboron SM 7 (340 mg, 1.5 e.q.), Pd(dppf)Cl2 (65 mg, 0.1 e.q.) and potassium acetate (260 mg, 3.0 e.q.) were added into a dry 25 mL three-neck flask under nitrogen protection, nitrogen was replaced three times, 10 mL of ultra-dry 1,4-dioxane solvent was added, and heated to reflux for 3 hours. After TLC monitoring of the complete reaction of the raw material, the reaction was stopped and returned 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 purified by silica gel column chromatography to obtain compound SM 8 (300 mg, 96.5%), LCMS: [M+H] + = 355.0.

[0178] Fifth step:

[0179] Under nitrogen protection, compound SM 8 (300 mg, 1.0 e.q.), 2,4,5-trichloropyrimidine SM 9 (234 mg, 1.5 e.q.), tetrakis triphenylphosphine palladium (49 mg, 0.05 e.q.) and sodium carbonate solid (270 mg, 3.0 e.q.) were sequentially added into a 25 mL three-necked flask, 1,4-dioxane and water (V1:V2=10:3) were added and nitrogen was replaced for three times, then the temperature was raised to reflux for 3 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, then filtered and concentrated to remove the solvent. After purification by silica gel column chromatography, compound SM 10 (250 mg, 78.6%) was obtained, LCMS: [M+H] + = 375.2.

[0180] Step 6:

[0181] Into a 10 mL microwave reaction tube, compound SM 10 (80 mg, 1.0 e.q.), (3s,4r)-4-aminooxane-3-ol hydrochloride SM 11 (50 mg, 1.5 e.q.), DIPEA (83 mg, 3.0 e.q.) and NMP solvent (3 mL) were sequentially added, and microwave heating was carried out at 130°C for half an hour. After TLC monitoring, the reaction was completely reacted, and EA and water were used for extraction and separation. The organic phase was dried with anhydrous sodium sulfate, then concentrated under reduced pressure, and the target compound T-1 (40 mg, 41.2%) was obtained after purification by silica gel column chromatography, HPLC purity was 99.3%, LCMS: [M+H] + = 456.3.

[0182] 1 H NMR (400 MHz, DMSO-d6) δ 8.56 (dd, J = 4.5, 1.3 Hz, 1H), 8.44 (s, 1H), 8.24 (d, J = 8.5 Hz, 1H), 8.00 (s, 1H), 7.52 (dd, J = 8.5, 4.6 Hz, 2H), 7.41 (s, 1H), 5.19 (p, J = 6.9 Hz, 1H), 5.04 (d, J = 5.4 Hz, 1H), 3.81 (m, 2H), 3.33 (m, 2H), 3.04 (t, J = 10.4 Hz, 2H), 1.98 (m, 1H), 1.65 (d, J = 6.9 Hz, 6H), 1.51 (m, 1H).

[0183] Referring to the synthesis method of Example 1, the following compounds were synthesized:

[0184] Test Example 1 Enzyme activity test

[0185] The following describes bioactivity tests on some compounds and comparative examples from the above embodiments.

[0186] The bioactivity test procedure is as follows:

[0187] 1. Kinase activity test:

[0188] The test compound was subjected to CDK4 and CDK6 kinase IC50. 50 Value detection.

[0189] (I) Reagent Information

[0190] (II) Equipment Information

[0191] (III) Research Design

[0192] (1) Compound preparation:

[0193] 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.

[0194] ② The compound was diluted three times to obtain 10 different concentrations of the compound solution.

[0195] (2) Perform enzyme assay:

[0196] ① As shown below, prepare a 1.3x enzyme solution containing enzyme, substrate and cofactor.

[0197] ② Add 15 μL of 1.3x enzyme solution to each well and incubate at room temperature for 30 minutes.

[0198] ③ Add 5 μL of 4x ATP solution to start the reaction. Each test well contains the components listed in the table, and the final volume is 20 μL.

[0199] ④Incubate for 150 minutes, then add 75 μL of buffer (containing 0.5 M EDTA) to stop the reaction.

[0200] ⑤ Use EZ to read and analyze the data from each test well.

[0201] (3) Data Analysis:

[0202] The suppression percentage is calculated using the following formula, based on the concern ratio (CR):

[0203] The wells treated with DMSO were used as positive control, and the wells without enzyme were used as negative control.

[0204] % (inhibition percentage) = 100-100*((CRPC-CRSample) / (CRPC-CRNC)).

[0205] Through the above detection, the inhibition activity IC50 of the test sample on CDK4, CDK6 kinase was obtained 50 The (nM) value is shown in Table 1.

[0206] Table 1

[0207] From the above table, through in vitro biological activity screening, the compound synthesized in the application has good inhibitory capacity 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. It is expected to be further developed as a drug for regulating CDK4 kinase activity or treating CDK4 related diseases.

[0208] Test Example 2 Cell Anti-proliferation Experiment

[0209] I. Experimental materials and equipment:

[0210] 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), 1xPBS (phosphate buffer, PH7.2), 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).

[0211] II. Experimental preparation:

[0212] 1. Cell plating

[0213] 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.

[0214] B) Remove the culture medium in the 10 cm culture dish;

[0215] C) rinse the cells with 10 ml 1xPBS once;

[0216] D) add 4 ml 0.25% EDTA-Tripsin into 37°C, 5% CO2 incubator for 5 minutes, transfer to 15 ml centrifuge tube, 200g centrifuge for 5 minutes, discard the supernatant to get the cell pellet;

[0217] E) resuspend with 4 ml DMEM medium, count and adjust to 50,000 cells / ml.

[0218] F) add the cell suspension into 96-well plate with 100 μL per well, incubate in 37°C, 5% CO2 incubator overnight.

[0219] 2、Compound treatment

[0220] Compound dilution

[0221] A) prepare the gradient dilution solution of the tested compound: prepare 1 mM stock solution of the tested compound. Then dissolve 1.5 μl of the stock solution in 1.5 ml of DMSO-free medium, and dilute it with 0.1% DMSO medium by 3-fold serial dilution, totally 9 concentrations, the compound concentrations after dilution are as follows:

[0222] 333.33 nM, 111.11 nM, 37.03 nM, 12.35 nM, 4.15 nM, 1.37 nM, 0.46 nM, 0.15 nM

[0223] B) after mixing well, take 100 μL of the compound solution to replace the medium in the cell culture plate, 4 replicates for each concentration;

[0224] C) transfer the cells to the incubator for incubation for 5 days.

[0225] 3、MTT detection

[0226] A) take out the cell culture plate and add 10 μL of 5 mg / ml MTT in a biological safety cabinet;

[0227] B) put the cell culture plate back into the incubator for further incubation for 3 hours;

[0228] C) take out the cell culture plate, remove the medium, add 100 μL of isopropanol (containing 0.4 mM HCl, 0.1% NP-40), and shake on a shaker at room temperature for 30 minutes;

[0229] D) select 570 nm wavelength on a TECAN enzyme-linked immunoassay instrument to measure the absorbance value.

[0230] 4、Data analysis

[0231] Cell Viability was calculated using the following formula:

[0232] Cell Viability = 100% x (Lum_Sample - Lum_LC) / (Lum_HC - Lum_LC)

[0233] Lum_HC: 0.1% DMSO control cell reading

[0234] Lum_Sample: cell reading with compound added

[0235] Lum_LC: blank media reading

[0236] IC was obtained by curve fitting through GraphPad Prism 8 software 50 in numerical value (unit nM).

[0237] As shown in Table 2.

[0238] Table 2

[0239] 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.

[0240] Experimental Example 3 Preclinical rat pharmacokinetic test

[0241] I. Experimental materials and equipment:

[0242] 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.

[0243] II. Experimental process:

[0244] 1. Drug preparation

[0245] 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.

[0246] Take 0.2 mL of sample in a 1.5 mL centrifuge tube and store at -80℃ for concentration analysis of the administration solution.

[0247] 2. Animal preparation

[0248] Animals were housed in rat cages, fasted (no less than 10h) but not water deprived one day before the test, and weighed and marked on the tail on the test day. The blank blood was collected before dosing. The blood was collected from the tail vein.

[0249] 3. Dosing

[0250] Dosing route: p.o.

[0251] Dosing dose: 10 mg / kg

[0252] Dosing volume: 10 mL / kg

[0253] Operation procedure: The rat was caught with the left hand wearing a bite-proof glove, and made to stand upright. A 16-gauge gavage needle was inserted into the throat from the mouth, and the needle was inserted until no resistance was felt. Then the drug was injected into the stomach.

[0254] 4. Sample collection

[0255] The test animals were collected 0.5h, 1h, 2h, 4h, 6h, 8h, 12h, 24h before and after dosing 0.1ml of whole blood in EDTA-Na2 anticoagulant tubes, mixed well by turning upside down 3-4 times, centrifuged at 10000g for 5min at 4°C to separate the plasma, and stored at -80°C for testing. The blood was collected from the tail vein.

[0256] Specific operation, the rat was fixed on the fixator, so that the tail was completely exposed, the rat tail was wiped with alcohol, so that the surface skin absorbed alcohol, to achieve the effect of obvious venous dilation, the appropriate veins were selected from both sides, and the needle was inserted at about one-third of the tail tip. The syringe was an insulin syringe, the needle was inserted with the bevel facing up, and immediately parallel after feeling the skin piercing, the needle sliding resistance in the vein was small, and the syringe had backflow. It had entered the vein, and about 0.1-0.2ml of whole blood was drawn. After the needle was pulled out, it was pressed to stop bleeding.

[0257] III. Sample analysis:

[0258] Preparation of standard curve: 25μL of rat blank plasma was taken into a centrifuge tube, 25μL of prepared standard series solution (prepared with methanol) was added, 200μL of internal standard solution (prepared with methanol) was added, vortex mixed for 2min, centrifuged at 10000g for 10min at 4°C.

[0259] Unknown plasma sample treatment: 25μL of rat drug-containing plasma was taken, 25μL of methanol and 200μL of internal standard solution were added in turn, vortex mixed for 2min, centrifuged at 10000g for 10min at 4°C. The supernatant was taken for LC / MS / MS detection.

[0260] Four, data processing

[0261] The quantitative 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 non-compartment model in winnonlin Phoenix software. The detailed data are shown in Table 3.

[0262] Table 3

[0263] All the documents mentioned in the present application are cited as references in the present application, as if 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 of the present application.

Claims

1. A compound, characterized in that, The compounds have a structure according to Formula I or Formula II, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotopically enriched compound, or prodrug thereof, wherein: -X Y is selected from the group consisting of -N=C(R6)-, -N=N-, and -C(R6)=C(R6)-; -X Y is selected from the group consisting of -N=C(R6)-, -N=N-, -C(R6)=C(R6)-, -CO-NH-, -COO-, -S-C(R6)(R7)-, -0-C(R6)(R7)-, and -N(R8)-C(R6)(R7)-; Z is each independently selected from the group consisting of N, CR9; m is selected from 0, 1, 2, 3, 4, 5, and 6; R is each independently selected from the group consisting of H, halogen (such as F, Cl, Br, I), cyano, hydroxyl, amino, C 1-6 alkyl (such as methyl, ethyl, isopropyl), C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, halogenated C 1-6 alkyl (such as CF3), halogenated C 3-8 cycloalkyl, -CO-C 1-6 alkyl, C 1-6 alkoxy (such as -O-methyl), C 1-6 halogenated alkoxy (such as -O-CF3), -COOH, -CONH2, -COO-C 1-6 alkoxy (such as -COO-C(CH3)3), hydroxyl substituted C 1-6 alkyl, methylsulfonyl, C 6-10 aryl, 5-8 membered heterocycloalkyl containing 1, 2, or 3 heteroatoms selected from N, O, or S, or 5-10 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, or S; and one or more hydrogens on the group are independently optionally substituted with a group selected from halogen, cyano, hydroxyl, C 1-4 alkyl, halogenated C 1-4 alkyl, C 1-4 hydroxyalkyl, and C 1-4 alkoxy substituted; R1and R2are each independently selected from the group consisting of H, halogen (such as F, Cl, Br, I), hydroxyl, C 1-6 alkyl (such as methyl, ethyl, isopropyl), C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, halogenated C 1-6 alkyl (such as CF3), amino, keto carbonyl, C 1-6 alkoxy (such as -O-methyl), C 1-6 halogenated alkoxy (such as -O-CF3), -COO-C 1-6 alkoxy (such as -COO-C(CH3)3), -CO-C 1-6 alkyl, C 1-6 halogenated alkoxy, hydroxyl substituted C 1-6 alkyl, C 6-10 aryl, 5-8 membered heterocycloalkyl containing 1, 2, or 3 heteroatoms selected from N, O, or S, or 5-10 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, or S; and one or more hydrogens on the group are independently optionally substituted with a group selected from halogen, cyano, hydroxyl, C 1-4 alkyl, halogenated C 1-4 alkyl, C 1-4 hydroxyalkyl and C 1-4 alkoxy substituted; R3are each independently selected from the group consisting of H, C 1-6 alkyl (such as methyl, ethyl, isopropyl), halo-C 1-6 alkyl, C 3-8 cycloalkyl (such as cyclopropyl), halo-C 3-8 cycloalkyl, -C 1-3 alkyl-C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl; R4is each independently selected from the group consisting of H, halogen (such as F, CI, Br), C 2-6 alkynyl (such as ethynyl, propynyl), cyano, C 1-6 alkyl (such as methyl, ethyl), C 1-6 haloalkyl (such as CF3), C 1-6 alkoxy (such as methoxy), C 1-6 haloalkoxy (such as -O-CF3), C 3-6 cycloalkyl (such as cyclopropyl); R5is each independently selected from the group consisting of: wherein: R6and R7are each independently selected from the group consisting of H, halogen, cyano, C 1-6 alkyl (e.g. methyl, ethyl, isopropyl), C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl (e.g. cyclopropyl), hydroxy, amino, C 1-6 alkoxy (e.g. methoxy), -COO-C 1-6 alkoxy (e.g. ), -CO-C 1-6 alkyl (such as haloalkyl (e.g., CF3), C 1-6 haloalkyl (e.g., CF3), C 1-6 haloalkyl (e.g., CF3), C 6-10 aryl, hydroxy-substituted C 1-6 alkyl, 5-10 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, or S, 5-10 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, or S, 5-10 membered heteroaryl; R8is each independently selected from the group consisting of H, C 1-6 alkyl (e.g., methyl, ethyl, isopropyl), C 2-6 alkenyl, C 2-6 alkynyl, -COO-C 1-6 alkoxy (e.g., ), -CO-C 1-6 alkyl or haloalkyl (such as haloalkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, -C 1-3 alkyl-C 3-8 cycloalkyl, hydroxy-substituted C 1-6 alkyl, -CONH-C 1-6 alkyl, C 3-6 cycloalkyl, 5-8 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O or S, C 6-10 aryl, 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S; wherein each of said alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, heterocyclyl, heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, -C(=O)-C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, -N(C 1-6 alkyl)2; R9is each independently selected from the group consisting of H, halogen (such as F, CI, Br), cyano, C 1-6 alkyl (such as methyl, ethyl), C 1-6 haloalkyl (such as CF3), C 1-6 alkoxy (such as methoxy), C 1-6 haloalkoxy, C 3-6 cycloalkyl (such as cyclopropyl); R 10 each independently is selected from the group consisting of C 1-6 alkyl (such as methyl, ethyl, isopropyl), -C 1-3 alkyl-C 3-8 cycloalkyl, C 3-8 cycloalkyl (such as cyclopropyl), -NH2.

2. The compound of claim 1, wherein: -X Y is selected from the group consisting of -N=C(R6)- and -N=N-; -X Y is selected from the group consisting of -N=C(R6)-, -CO-NH-, -S-C(R6)(R7)-, -0-C(R6)(R7)-, and -N(R8)-C(R6)(R7)-; Z is selected from the group consisting of N, CR9(preferably, Z is N); R is selected from the group consisting of H, halogen (e.g., F, Cl, Br, I), cyano, hydroxyl, amino, C 1-6 alkyl (e.g., methyl, ethyl, isopropyl), C 3-8 cycloalkyl, halo C 1-6 alkyl (e.g., CF3), hydroxyl substituted C 1-4 alkyl, halo C 3-8 cycloalkyl, -CO-C 1-6 alkyl, C 1-6 alkoxy (e.g., -O-methyl), -COOH, -CONH2, -COO-C 1-6 alkoxy (e.g., -COO-C(CH3)3), methylsulfonyl, C 6-10 aryl, 5-8 membered heterocycloalkyl containing 1, 2, or 3 heteroatoms selected from N, O, or S; R1and R2are selected from the group consisting of H, halogen (e.g. F, Cl, Br, I), hydroxyl, C 1-6 alkyl (e.g. methyl, ethyl, isopropyl), C 3-8 cycloalkyl, halogenated C 1-6 alkyl (e.g. CF3), amino, keto carbonyl, C 1-6 alkoxy (e.g. -O-methyl), -COO-C 1-6 alkoxy (e.g. -COO-C(CH3)3), -CO-C 1-6 alkyl, C 1-6 halogenated alkoxy, hydroxyl substituted C 1-6 alkyl, 5-8 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S, 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S; R3is selected from the group consisting of H, C 1-6 alkyl (such as methyl, ethyl, isopropyl), C 3-8 cycloalkyl (such as cyclopropyl); R4is selected from the group consisting of H, halogen (such as F, CI, Br), C 2-6 alkynyl; R5is selected from the group consisting of: m, R6, R7, R8, and R9 are as defined in claim 1.

3. The compound of claim 1, wherein In formula I, X is N and Y is CR6, or X is CR6and Y is N; R6is selected from the group consisting of H, F, Cl, Br, cyano, hydroxy, methyl, ethyl, isopropyl, cyclopropyl, methoxy, CF3, -O-CF3; m is 0 or 1 ; R is selected from the group consisting of H, F, Cl, Br, cyano, hydroxy, methyl, ethyl, isopropyl, hydroxy substituted isopropyl, hydroxy substituted isobutyl, cyclopropyl, methoxy, CF3, -0-CF3.

4. The compound of claim 1, wherein In formula II, -X Y is selected from the group consisting of -N=C(R6)-, -CO-NH-, -S-C(R6)(R7)- and O-C(R6)(R7)-; R6and R7are each independently selected from the group consisting of H, halogen, cyano, hydroxy, methyl, ethyl, isopropyl, cyclopropyl, methoxy, - CF3, -O-CF3; preferably, R6and R7are H; R1and R2are each independently selected from the group consisting of H, F, Cl, Br, hydroxyl, methyl, ethyl, isopropyl, CF3.

5. The compound of claim 1, wherein R3are each independently selected from the group of H, C 1-6 alkyl (such as methyl, ethyl, isopropyl), haloC 1-6 alkyl, C 3-6 cycloalkyl, haloC 3-6 cycloalkyl, -C 1-2 alkyl-C 3-6 cycloalkyl; R4is each independently selected from the group consisting of H, halogen (such as F, CI, Br), cyano, C 1-6 alkyl (such as methyl, ethyl), C 1-3 haloalkyl (such as CF3), C 1-3 haloalkoxy (such as -O-CF3); R 10 selected from the group consisting of C 1-3 alkyl (such as methyl, ethyl, isopropyl), -C 1-3 alkyl-C 3-6 cycloalkyl, C 3-6 cycloalkyl (such as cyclopropyl); R5is selected from the group consisting of:

6. The compound of claim 1, wherein The compound is selected from the group consisting of:

7. A pharmaceutical composition, characterized by, a prophylactically and / or therapeutically effective amount of a compound of any one of claims 1-6, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotopically enriched compound, or prodrug thereof, and a pharmaceutically acceptable carrier.

8. Use of a compound of any one of claims 1-6, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotopically enriched compound, or prodrug thereof, or a pharmaceutical composition of claim 7, for the manufacture of a CDK4 protein kinase inhibitor.

9. Use of a compound of any one of claims 1-6, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotopically enriched compound, or prodrug thereof, or a pharmaceutical composition of claim 7, for the manufacture of a medicament for the prevention or treatment of a CDK4 associated disease.

10. The compound of claim 9, wherein the CDK4 associated disease is selected from the group consisting of inflammation, cancer, cardiovascular disease, infection, immune disease, metabolic disease; more preferably, the disease or condition is cancer.

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