Compound used as CDK2 / 4 protein kinase inhibitor and use thereof

Abstract

Disclosed in the present application are a compound used as a CDK2 / 4 protein kinase inhibitor and use thereof. The compound can be used for treating diseases such as inflammations, cancers, cardiovascular diseases, infections, immune diseases, and metabolic diseases.

Description

Compounds used as CDK2 / 4 protein kinase inhibitors and their applications Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to a class of novel compounds used as CDK2 / 4 protein kinase inhibitors, and their applications in regulating CDK2 / 4 protein kinase activity or treating CDK2 / 4-related proliferative diseases and symptoms, especially cancer. Background Technology

[0002] Protein kinases regulate a wide range 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 remains a need for novel compounds that can selectively inhibit protein kinase activity and are effective as therapeutic antiproliferative agents.

[0003] Cyclin-dependent kinases (CDKs) belong to the serine / threonine kinase family. They exert their physiological functions by binding to their corresponding cyclins to form active dimer complexes, thereby inducing cell growth and proliferation. Currently, more than 20 CDKs have been identified, which can be divided into two main categories based on their primary functions: CDKs that regulate the cell cycle and CDKs that regulate cell transcription. CDK1-CDK6 and CDK14-CDK18, along with their cyclin chaperones (e.g., Cyclins A, B, D1, D2, D3, E, F, etc.), participate in the regulation of cell cycle progression and are considered cell cycle regulators. CDK7-CDK13 and CDK19-CDK20, along with their cyclin chaperones (e.g., Cyclins C, H, K, L1, L2, T1, T2, etc.), participate in the regulation of cell transcription and are considered transcription regulators. Therefore, CDKs are involved in the regulation of cell cycle control, apoptosis, differentiation and transcription, and CDK inhibitors have now been shown to be used to treat a variety of diseases, including cancer.

[0004] CDK4 / 6, after binding to Cyclin D, participates in regulating the cell cycle from G1 to S phase. Abnormalities in the Cyclin D-CDK4 / 6-Rb pathway have been reported to be associated with the progression of resistance to endocrine therapy. Currently, several CDK4 / 6 inhibitors are approved for clinical treatment, such as palbociclib, ribociclib, and abemaciclib, and are used in combination with endocrine therapy to treat hormone receptor (HR)-positive, human epidermal growth factor 2 (HER2)-negative advanced or metastatic breast cancer. However, hematological toxicities such as neutropenia and / or gastrointestinal toxicities frequently occur during CDK4 / 6 inhibitor treatment, leading to discontinuation or intermittent dosing, severely impacting efficacy and patient adherence. Current research data suggests that the activity of cyclin Cyclin D3-CDK6 may be related to these side effects. Meanwhile, resistance to the CDK4 / 6 inhibitor palbociclib, when used in combination with endocrine therapy, has been observed in clinical practice. Analysis of transcriptional profiling data from patient samples revealed that this resistance mechanism is highly correlated with the activation of the MYC oncogene and Cyclin E-CDK2 activity. Currently, CDK2 has been proposed as a therapeutic target for various cancers, such as KRAS-driven lung cancer, MYC-amplified neuroblastoma, melanoma, acute myeloid leukemia, glioblastoma, prostate cancer, and breast cancer. The cyclin-binding mates of CDK2 (i.e., Cyclin E1 and Cyclin E2) are amplified in a significant proportion of human cancers, a phenotype that predicts poor overall survival. Inhibiting Cyclin E-CDK2 activity holds promise for overcoming the resistance problem currently present with clinical CDK4 / 6 inhibitors.

[0005] In conclusion, given the toxic side effects of current CDK4 / 6 dual-target inhibitors and the development of drug resistance when used in combination with endocrine therapy, the development of selective CDK2 / 4 kinase inhibitors may offer better safety and efficacy, as well as broader clinical application prospects. Summary of the Invention

[0006] One or more embodiments of this application provide compounds having CDK2 / 4 protein kinase inhibitory activity.

[0007] In one or more embodiments, the compounds of this application have good pharmacodynamic and pharmacokinetic properties.

[0008] In one or more embodiments, the compounds of this application can be used as inhibitors of cyclin-dependent kinases (CDKs), particularly for regulating and / or treating diseases caused by overexpression and / or abnormal activity of cyclin-dependent kinases CDK2 / 4.

[0009] In one or more embodiments, the compounds of this application may be used to prevent and / or treat cell proliferative diseases and conditions, including various types of cancer.

[0010] One or more embodiments of this application provide compounds of formula (I), or pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates, solvates, crystals, deuterated derivatives, isotopic compounds, or prodrugs thereof.

[0011] in

[0012] X1 is selected from N and CH;

[0013] R1 is selected from H, halogens (such as F, Cl, Br, I), hydroxyl groups, C. 1-6 Alkyl (such as methyl), C 3-8 cycloalkyl, halogenated C 1-6 Alkyl (e.g., CF3), amino, cyano, C 1-6 Alkylamino, hydroxy C 1-6 Alkyl, -NH-C 1-6 Alkyl, -N(C) 1-6 Alkyl)2、-NH-C 3- 8-cycloalkyl, -NH-5-8-membered heterocycloalkyl, -NH-C 6-10 Aryl, -NH-5-8 heteroaryl, -C(O)C 1-6 Alkyl, -C(O)C 3- 8-cycloalkyl, C 1-6 Alkoxy groups (such as -O-methyl), -COO-C 1-6 Alkyl groups (such as -COO-C(CH3)3), C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, 5-8 membered heterocyclic alkyl, C 6-10 Aryl and 5-8-membered heteroaryl; optionally, the 5-8-membered heterocyclic alkyl group is substituted with one, two or three substituents selected from halogens, hydroxyl groups and carbonyl groups;

[0014] R2 is selected from H and C. 1-6 Alkyl (such as methyl), halogenated C 1-6 Alkyl, C 3-8 cycloalkyl, halogenated C 3-8 Cycloalkyl, 5-8 membered heterocycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl and 5-8 quinone heteroaryl groups;

[0015] R3, R4, R5, and R6 are each independently selected from H, halogens (such as F, Cl, Br, I), cyano, hydroxyl, amino, and C.1-6 Alkyl (such as methyl), C 3-8 cycloalkyl, halogenated C 1-6 Alkyl groups (such as CF3), halogenated C 3-8 cycloalkyl, -NH-C 1-6 Alkyl, -N(C) 1- 6-alkyl)2、-NH-C 3-8 Cycloalkyl, -NH-5-8 membered heterocycloalkyl, -NH-C 6-10 Aryl, -NH-5-8 heteroaryl, -C(O)C 1- 6-alkyl, -C(O)C 3-8 cycloalkyl, C 1-6 Alkoxy (e.g., -O-methyl), C 1-6 Halogenated alkoxy groups, -COOH, -CONH2, -CONH-C 1-6 Alkyl, -CONH-C 6-10 Aryl, -CONH-5-8 heteroaryl, -COO-C 1-6 Alkyl groups (such as -COO-C(CH3)3), C 1-6 Hydroxyalkyl, -SO3H, -SO2-C 1-6 Alkyl groups (such as methanesulfonyl groups), -SO2-C 6-10 Aryl, -SO2-5-8 heteroaryl, 5-8 heterocyclic alkyl, C 6-10 Aryl and 5-8 quinone heteroaryl groups;

[0016] R7 is selected from H and C. 1-6 Halogenated alkyl groups (e.g., CF3), halogens (e.g., F, Cl, Br), cyano groups, alkynyl groups, and C 1-6 Alkyl groups (such as methyl groups);

[0017] R8 is selected from H, halogens (such as F, Cl, Br), and C. 1-6 Alkyl groups (such as methyl groups);

[0018] Ring A is selected from 5-9 membered heterocyclic alkyl groups, C 3-8 cycloalkyl, 5-8 membered heteroaryl and C 6-10 Aryl; optionally, the 5-9 membered heterocyclic alkyl group, C 3-8 cycloalkyl, 5-8 membered heteroaryl, C 6-10 Each aryl group is independently selected by one, two, or three groups chosen from R, -SO2R, -N(SO2R)R, -COR, cyano, amino, hydroxyl, halogen, C 1-6 alkyl, Halogenated C 1-6 Alkyl substituents; wherein each R is independently selected from H, halogen, hydroxyl, amino, C with or without substitution 1-6Alkyl, substituted or unsubstituted C 1-3 Alkyl-C 3-8 Cycloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5-8-membered heteroaryl; wherein R' and R" are each independently selected from H and C. 1-6 alkyl;

[0019] The heterocyclic alkyl or heteroaryl group contains one, two, or three heteroatoms selected from N, O, and S.

[0020] In one or more embodiments, X1 is N.

[0021] In one or more embodiments, R1 is selected from H, F, Cl, hydroxyl, C. 1-6 Alkyl (such as methyl), C 3-8 Cycloalkyl (e.g., cyclopropyl), halogenated C 1-6 Alkyl (e.g., CF3), amino, cyano, C 1-6 Alkylamino, hydroxy C 1-6 Alkyl, -NH-C 1-6 Alkyl, -N(C) 1-6 Alkyl)2、-NH-C 3-8 cycloalkyl, C 1-6 Alkoxy (e.g., -O-methyl), C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl and 5-8 membered heterocyclic alkyl groups.

[0022] In one or more embodiments, R1 is selected from H, C 1-6 Alkyl, C 1-6 Alkylamino, hydroxy C 1-6 Alkyl groups and 5-8 membered heterocyclic alkyl groups; optionally, the 5-8 membered heterocyclic alkyl groups are substituted with substituents selected from halogens, hydroxyl groups and carbonyl groups.

[0023] In one or more embodiments, R1 is selected from H, C 1-3 Alkyl, -NH-C 1-3 Alkyl, -N(C) 1-3 Alkyl)2, hydroxyl-substituted C 1-6 Alkyl group, nitrogen-containing five-membered heterocyclic alkyl group; wherein the nitrogen-containing five-membered heterocyclic alkyl group may optionally be further substituted with halogen, hydroxyl and oxo groups.

[0024] In one or more embodiments, R1 is selected from H, C 1-3 Alkyl, -NH-C 1-3 Alkyl, -N(C) 1-3 Alkyl)2, hydroxyl-substituted C 1-6 alkyl,

[0025] In one or more embodiments, R1 is selected from H, methyl,

[0026] In one or more embodiments, R2 is selected from H and C. 1-6 Alkyl (such as methyl), halogenated C 1-6 Alkyl, C 3-8 cycloalkyl, halogenated C 3-8 Cycloalkyl and 5-8 membered heterocyclic alkyl groups.

[0027] In one or more embodiments, R2 is selected from H and C. 1-6 Alkyl and C 3-8 Cycloalkyl.

[0028] In one or more embodiments, R2 is selected from H and C. 1-3 Alkyl or C 3-6 Cycloalkyl.

[0029] In one or more embodiments, R2 is selected from H, methyl, isopropyl, and cyclopropyl.

[0030] In one or more embodiments, R3, R4, R5, and R6 are each independently selected from H, F, Cl, cyano, hydroxyl, amino, and C. 1-6 Alkyl (such as methyl), C 3-8 Cycloalkyl (e.g., cyclopropyl), halogenated C 1-6 Alkyl groups (such as CF3), halogenated C 3-8 cycloalkyl, -NH-C 1-6 Alkyl, -NH-C 3-8 cycloalkyl, NH-C 6-10 Aryl, -NH-5-8 heteroaryl, -C(O)C 1-6 Alkyl, -C(O)C 3- 8-cycloalkyl, C 1-6 Alkoxy (e.g., -O-methyl), C 1-6 Halogenated alkoxy groups, -COOH, -CONH2, -CONH-C 1-6 Alkyl, -CONH-C 6-10 Aryl, -CONH-5-8 heteroaryl, -COO-C 1-6 Alkyl groups (such as -COO-C(CH3)3), C 1-6 Hydroxyalkyl, -SO2-C 1-6 Alkyl groups (such as methanesulfonyl), 5-8 membered heterocyclic alkyl groups, C 6-10 Aryl and 5-8 quinone heteroaryl groups.

[0031] In one or more embodiments, R3, R4, R5, and R6 are each independently selected from H, halogens, and C. 1-3 Alkyl, Halogenated C1-3 Alkyl, -N(C) 1-3 alkyl)2 and -C(O)C 1-3 alkyl.

[0032] In one or more embodiments, R3, R4, R5, and R6 are each independently selected from H, F, Cl, methyl, -CF3, -N(CH3)2, -C(O)CH3, and -CHF2.

[0033] In one or more embodiments, R5 is H.

[0034] In one or more embodiments, R6 is H.

[0035] In one or more embodiments, R7 is selected from H, CF3, F, Cl, and Br.

[0036] In one or more embodiments, R7 is selected from CF3, F, Cl, and Br.

[0037] In one or more embodiments, R8 is selected from H, F, Cl, Br, and methyl.

[0038] In one or more embodiments, R8 is H.

[0039] In one or more embodiments, ring A is selected from...

[0040] in

[0041] R is selected from H, halogen, hydroxyl, amino, C with or without substitution 1-6 Alkyl, substituted or unsubstituted C 1-3 Alkyl-C 3-8 Cycloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5-8-membered heteroaryl; wherein R' and R" are each independently selected from H and C. 1-6 alkyl.

[0042] In one or more embodiments, ring A is selected from...

[0043] in

[0044] R is selected from H, halogen, hydroxyl, amino, C with or without substitution 1-6 Alkyl, substituted or unsubstituted C 1-3 Alkyl-C 3-8Cycloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5-8-membered heteroaryl; wherein R' and R" are each independently selected from H and C. 1-6 alkyl.

[0045] In one or more embodiments, ring A is selected from... R is defined above.

[0046] In one or more embodiments, ring A is selected from... R is defined above.

[0047] In one or more embodiments, ring A is selected from... In one or more embodiments, ring A is selected from... In one or more embodiments, ring A is selected from... R is defined above.

[0048] In one or more embodiments, ring A is selected from...

[0049] In one or more embodiments, ring A is selected from...

[0050] In one or more embodiments, ring A is selected from... R is defined above.

[0051] In one or more embodiments, ring A is selected from... R is defined above.

[0052] In one or more embodiments, ring A contains at least a substituent selected from NH2, NHSO2R and -SO2R, where R is as described above.

[0053] In one or more embodiments, the compound is selected from structures represented by any of the following general formulas:

[0054] Y represents O, CR 10 R 11 or NR 12 ;

[0055] Z represents C-SO2R or C-NR. 12 R 13 ;

[0056] R 10 H, deuterium, halogen, OH, CN or C1-3 alkyl;

[0057] R 11 It can be H, NHSO2R, or -SO2R;

[0058] R 12 R 13 Each is independently H or -SO2R, or R 12 R 13 Together with the N linked to it, a 5-6 membered heterocyclic group is formed, and the 5-6 membered heterocyclic group may optionally be further replaced by NH2, NHSO2R or -SO2R;

[0059] R9 is independently selected from halogen, OH, C. 1-3 Alkyl or halogen-substituted C 1-3 alkyl;

[0060] n is 0, 1, or 2.

[0061] In one or more embodiments, R 10 For H.

[0062] In one or more embodiments, R 11 It is either NHSO2R or -SO2R.

[0063] In one or more embodiments, R 12 R 13 Together with the N linked to it, a 6-membered heterocyclic group is formed, which is further replaced by -SO2R.

[0064] In one or more embodiments, R is C 1-3 Alkyl or C 3-6 Cycloalkyl.

[0065] In one or more embodiments, R9 is each independently selected from F, OH, methyl, or an F-substituted methyl group.

[0066] In one or more embodiments, the structure is selected from any of the following general formulas:

[0067] in

[0068] R1, R2, R3, R4, and R7 are as described above;

[0069] R 901 R 902 Each is independently H or R9;

[0070] R9 is independently selected from halogen, OH, C. 1-3 Alkyl or halogen-substituted C 1-3 alkyl.

[0071] In one or more embodiments, R 901 R 902 Each is independently selected from F, OH, methyl, or F-substituted methyl groups. In one or more embodiments, the compound has the structure shown in the following general formula:

[0072] R1, R2, R3, R4, R5, R6, R7, and R8 are as described above.

[0073] In one or more embodiments, the compound is selected from:

[0074] One or more embodiments of this application provide pharmaceutical compositions comprising a preventive and / or therapeutically effective amount of the compound of this application or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, crystal, deuterated, isotopic compound or prodrug, as well as a pharmaceutically acceptable carrier, excipient or excipient.

[0075] One or more embodiments of this application provide the use of the compound of this application or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, crystal, deuterated product, isotopic compound or prodrug or composition thereof in the preparation of CDK2 and / or CDK4 protein kinase inhibitors.

[0076] One or more embodiments of this application provide the use of the compound of this application or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, crystal, deuterated product, isotopic compound or prodrug or composition thereof in the preparation of a medicament for regulating the activity of CDK2 and / or CDK4 protein kinases.

[0077] One or more embodiments of this application provide the use of the compound of this application or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, crystal, deuterated product, isotopic compound or prodrug or composition of this application in the preparation of a preventive and / or therapeutic agent for diseases associated with CDK2 and / or CDK4 protein kinases.

[0078] One or more embodiments of this application provide the compound of this application or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, crystal, deuterated product, isotopic compound or prodrug or composition of this application, which are used as pharmaceuticals.

[0079] One or more embodiments of this application provide the compounds of this application or their pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates, solvates, crystals, deuterated derivatives, isotopic compounds or prodrugs, or compositions of this application, for the prevention and / or treatment of diseases associated with CDK2 and / or CDK4 protein kinases.

[0080] One or more embodiments of this application provide the compounds of this application or their pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates, solvates, crystals, deuterated derivatives, isotopic compounds or prodrugs or compositions of this application, which are used as CDK2 and / or CDK4 protein kinase inhibitors.

[0081] One or more embodiments of this application provide the compound of this application or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, crystal, deuterated product, isotopic compound or prodrug or composition of this application for regulating CDK2 and / or CDK4 protein kinase activity.

[0082] One or more embodiments of this application provide a method for preventing and / or treating diseases associated with CDK2 and / or CDK4 protein kinases, comprising administering a compound of this application or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, crystal, deuterated product, isotopic compound, or prodrug, or a composition of this application, to a subject in need.

[0083] One or more embodiments of this application provide a method for inhibiting CDK2 and / or CDK4 protein kinases, comprising giving a desired object a compound of this application or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, crystal, deuterated product, isotopic compound, or prodrug or composition thereof.

[0084] One or more embodiments of this application provide a method for modulating the activity of CDK2 and / or CDK4 protein kinases, comprising giving a desired object a compound of this application or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, crystal, deuterated product, isotopic compound, or prodrug or a composition thereof.

[0085] In one or more embodiments, the disease associated with CDK2 and / or CDK4 protein kinases is inflammation, cancer, cardiovascular disease, infection, immune disease, or metabolic disease.

[0086] In one or more embodiments, the cancer is selected from lung cancer, breast cancer, prostate cancer, colorectal cancer, liver cancer, pancreatic cancer, ovarian cancer, leukemia, neuroblastoma, gastric cancer, kidney cancer, esophageal cancer, uterine cancer, and liposarcoma. Detailed Implementation

[0087] In one or more embodiments, the CDK2 / 4-related diseases are selected from the group consisting of: inflammation, cancer, cardiovascular disease, infection, immune disease, and metabolic disease.

[0088] In one or more embodiments, the cancer is selected from the group consisting of: lung cancer, breast cancer, prostate cancer, colorectal cancer, liver cancer, pancreatic cancer, ovarian cancer, leukemia, neuroblastoma, gastric cancer, kidney cancer, esophageal cancer, uterine cancer, and liposarcoma.

[0089] In one or more embodiments, a method for preventing or treating CDK2 / 4-related diseases is provided, comprising administering to a subject in need a compound as described in the first aspect, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotopic compound, or prodrug thereof, or a pharmaceutical composition containing said compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotopic compound, or prodrug thereof.

[0090] In one or more embodiments, the CDK2 / 4-related diseases are as previously defined.

[0091] In one or more embodiments, a method for inhibiting CDK2 / 4 protein kinase is provided, comprising: contacting the CDK2 / 4 protein kinase with a compound as described in the first aspect, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotopic compound, or prodrug thereof, thereby inhibiting the CDK2 / 4 protein kinase.

[0092] In one or more embodiments, the method is non-therapeutic in vitro.

[0093] In one or more embodiments, a method for modulating CDK2 / 4 protein kinase activity is provided, comprising: contacting the CDK2 / 4 protein kinase with a compound as described in the first aspect, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotopic compound, or prodrug thereof, thereby modulating the CDK2 / 4 protein kinase activity.

[0094] In one or more embodiments, the method is non-therapeutic in vitro.

[0095] In one or more embodiments, a method for inhibiting cell proliferation is provided, comprising: contacting cells with the compound of the present application, thereby inhibiting cell proliferation.

[0096] In one or more embodiments, the cells are cancer cells or tumor cells.

[0097] In one or more embodiments, the cells are selected from breast cancer cells (such as MCF-7), ovarian cancer cells (such as A2780), or combinations thereof.

[0098] In one or more embodiments, the method is non-therapeutic in vitro.

[0099] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here.

[0100] the term

[0101] Unless otherwise specified, the following terms used in this application (including the specification and claims) have the definitions given below.

[0102] When a substituent is described using a conventional chemical formula written from left to right, it also includes chemically equivalent substituents obtained when the structural formula is written from right to left. For example, -CH2O- is equivalent to -OCH2-.

[0103] As used in this article, the group is in the form of The "---" indicates the position where the group is attached to other parts of the compound or molecule.

[0104] "alkyl", alone or as part of other groups, refers to a monovalent straight-chain or branched saturated hydrocarbon group (i.e., C12) consisting only of carbon and hydrogen atoms and containing 1 to 12 carbon atoms. 1-12 Alkyl groups are preferably C16. 1-6 Alkyl (i.e., alkyl containing 1, 2, 3, 4, 5 or 6 carbon atoms), more preferably C4. 1-4 Alkyl (i.e., an alkyl group containing 1, 2, 3, or 4 carbon atoms). Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, etc. Unless otherwise stated, in this application, alkyl is also intended to include substituted alkyl, i.e., one or more positions of an alkyl group are substituted, particularly 1-4 substituents, which may be substituted at any position. Unless otherwise stated, in this application, "substituted alkyl" includes, for example, haloalkyl, hydroxyalkyl, etc. As used herein, "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are substituted by the same or different halogens as defined herein. Haloalkyl is preferably C10. 1-6 Halogenated alkyl groups, more preferably C40, are also present. 1-4Haloalkyl groups. Examples of haloalkyl groups include -CH2Cl, -CH2CF3, -CH2CCl3, perfluoroalkyl groups (e.g., -CF3), etc. As used herein, "hydroxyalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by hydroxyl groups. Hydroxyalkyl groups are preferably C10-30 ... 1-6 Hydroxyalkyl, more preferably C 1-4 Hydroxyalkyl groups. Examples of hydroxyalkyl groups include -CH2OH, -C(CH3)2OH, etc.

[0105] "alkylene" refers to a divalent alkyl group as defined herein, preferably having 1-4 carbon atoms, i.e., C1-4 alkylene. Examples of alkylene include, for example, -CH2-, -CH2CH2- and -CH2CH2CH2-.

[0106] "Alkoxy group," alone or as part of other groups, refers to an alkyl group having an oxygen-containing group attached thereto, possessing an alkyl O- structure, wherein the alkyl group has the definition described above. Preferably, the alkoxy group is C10. 1-6 Alkoxy (i.e. -OC) 1- 6-alkyl), more preferably, C6-alkyl 1-4 Alkoxy (i.e. -OC) 1-4 Alkyl groups. Alkyl groups include, but are not limited to, methoxy, ethoxy, propoxy, tert-butoxy, etc. "Haloalkoxy" refers to a group of formula -OR, where R is a haloalkyl group as defined herein. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, 2,2,2-trifluoroethoxy, etc.

[0107] "Thioalkyl" refers to an alkyl group in which the carbon atom is replaced by S, S(O) or S(O)2, for example -SC. 1-6 Alkyl, -S(O)C 1-6 Alkyl or -S(O)2C 1-6 alkyl.

[0108] "Alkenyl," alone or as part of other groups, refers to an aliphatic group containing at least one double bond, typically having 2 to 20 carbon atoms (i.e., C64-C ... 2-20 Alkenyl group). Preferably, the alkenyl group is C. 2-6 Alkenyl (i.e., alkenyl groups containing 2, 3, 4, 5, or 6 carbon atoms). Alkenyl groups include, but are not limited to, for example, vinyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, etc. Unless otherwise defined, in this invention, alkenyl groups also include substituted alkenyl groups.

[0109] "Alkenyl" refers to an alkenyl group as defined above that has two connection points; for example, "vinylene" represents the group -CH=CH-. The alkenyl group is preferably C-. 2-6An alkenyl group (i.e., an alkenyl group containing 2, 3, 4, 5, or 6 carbon atoms). Unless otherwise defined, an alkenyl group can be in an unsubstituted form or in a substituted form with one or more substituents.

[0110] "Alkyne group," alone or as part of other groups, refers to a straight-chain or branched hydrocarbon chain containing two or more carbon atoms and characterized by having one or more triple bonds, typically having 2 to 20 carbon atoms (i.e., C64-C ... 2-20 (Alkyne group). The alkynyl group is preferably C. 2-6 The alkynyl group (i.e., an alkynyl group having 2, 3, 4, 5, or 6 carbon atoms). The alkynyl group includes, but is not limited to, ethynyl, propynyl, and 3-hexynyl. One of the carbon atoms in the triple bond may optionally be the linking point for the alkynyl substituent. In this invention, unless otherwise defined, the alkynyl group also includes substituted alkynyl groups.

[0111] "Idemynyl" refers to an alkynyl group as defined above, having two connection points. For example, "ethynyl" indicates a group with the following structure: -C≡C-. The alkynyl group is preferably C. 2-6 Alynyl group (i.e., an alynyl group containing 2, 3, 4, 5, or 6 carbon atoms). Unless otherwise defined, an alynyl group can be in its unsubstituted form or in its substituted form with one or more substituents.

[0112] "Aliphatic groups" refer to straight-chain, branched, or cyclic hydrocarbon groups, including saturated and unsaturated groups such as alkyl, alkenyl, and alkynyl groups.

[0113] "Aromatic ring system" or "aromatic ring" refers to a monocyclic, bicyclic, or polycyclic hydrocarbon ring system, wherein at least one ring is aromatic. Preferably, the "aromatic ring system" or "aromatic ring" has 6-12 ring atoms, i.e., carbon atoms. 6-12 Aromatic rings, examples of which include benzene rings, naphthalene rings, anthracene rings, etc.

[0114] "Aryl," alone or as part of other groups, refers to a monovalent group in an aromatic ring system (aromatic ring). Representative aryl groups include phalloaromatic systems such as phenyl, naphthyl, and anthracene; and ring systems in which an aromatic carbon ring is fused with one or more non-aromatic carbon rings, such as indanyl, phthalimide, naphthylimide, or tetrahydronaphthyl. For example, an aryl group is C 5-10 Aryl groups (e.g., 5, 6, 7, 8, 9, or 10 carbon atoms).

[0115] "Arylalkyl" or "arylalkyl group" refers to an alkyl moiety in which one or more hydrogen atoms of the alkyl group are replaced by aryl groups. Arylalkyl groups include groups in which one or more hydrogen atoms of the alkyl group are replaced by aryl groups, as defined above. Examples of "arylalkyl" or "arylalkyl group" include benzyl, 2-phenylethyl, 3-phenylpropyl, 9-fluorenyl, diphenylmethyl, and triphenylmethyl.

[0116] "Aryloxy group" refers to -O-(aryl), where the aryl part is defined as above.

[0117] "Heteroalkyl" refers to an alkyl group in which the carbon atom has been replaced, having one or more skeletal chain atoms selected from atoms other than carbon, such as oxygen, nitrogen, sulfur, phosphorus, or combinations thereof. Numerical ranges can be given, for example, C... 1-6 Heteroalkyl refers to a chain containing 1 to 6 carbon atoms (i.e., alkyl groups containing 1, 2, 3, 4, 5, or 6 carbon atoms). For example, the -CH2OCH2CH3 group is called a "C3" heteroalkyl. Connection to the rest of the molecule can be via heteroatoms or carbon atoms in the heteroalkyl chain. "Heteroalkylene" refers to a divalent alkyl group in which carbon atoms are replaced, having one or more skeletal chain atoms selected from atoms other than carbon, such as oxygen, nitrogen, sulfur, phosphorus, or combinations thereof. Unless otherwise defined, "heteroalkyl" and "heteroalkylene" include substituted or unsubstituted forms.

[0118] A "carbocyclic system" or "carbocyclic ring" refers to a monocyclic, bicyclic, or polycyclic hydrocarbon ring system, wherein each ring is fully saturated or contains one or more unsaturated units, but none of the rings are aromatic. Preferably, the "carbocyclic system" or "carbocyclic ring" has 6-12 ring atoms, i.e., carbon atoms. 6-12 Carbocyclic group. "Carbocyclic group" refers to a carbocyclic system or a monovalent group of a carbocyclic ring as defined above. Preferably, the carbocyclic group has 6-12 ring atoms, i.e., C atoms. 6-12 Carbocyclic groups. Examples of carbocyclic groups include cycloalkyl groups (such as cyclopentyl, cyclobutyl, cyclopropyl, cyclohexyl, etc.) and cycloalkenyl groups (such as cyclopentenyl, cyclohexenyl, cyclopentadienyl, etc.).

[0119] "Cycloalkyl" refers to a monovalent saturated carbocyclic group composed of a single or bicyclic ring, having 3-12 carbon atoms (i.e., C12, C23, C32, C42, C53, C62, C7 ... 3-12 cycloalkyl groups), preferably 3-10 (i.e., C10, C20, C30, C4 3-10 cycloalkyl), more preferably 3-8 cyclic atoms (i.e., C 3-8 The cycloalkyl group has, for example, 3, 4, 5, 6, 7, or 8 ring atoms. Unless otherwise defined, the cycloalkyl group may optionally be substituted by one or more substituents. Preferably, the substituents of the cycloalkyl group may be independently hydroxyl, alkyl, alkoxy, halogen, haloalkyl, amino, monoalkylamino, or dialkylamino. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0120] “Cycloalkoxy” refers to a group of the formula -OR, where R is a cycloalkyl group as defined herein. Exemplary cycloalkyloxy groups include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, etc. “Cycloalkylalkyl” or “cycloalkylalkylene” refers to an alkylene (cycloalkyl) group, where cycloalkyl and alkylene are as previously defined. “Cycloalkylalkyl” or “cycloalkylalkylene” is bonded to the parent molecule structure via an alkyl group (alkylene).

[0121] A "heterocyclic system" or "heterocycle" refers to a monocyclic, bicyclic, or polycyclic system in which at least one ring is saturated or partially unsaturated (but not aromatic) and contains at least one heteroatom as a ring atom. Heterocyclic systems or heterocycles can be attached to side groups at any heteroatom or carbon atom, resulting in a stable structure, and any ring atom can optionally be substituted.

[0122] A "heteroaromatic ring system" or "heteroaromatic ring" refers to a monocyclic (e.g., 5- or 6-membered), bicyclic (6-12-membered, e.g., 6, 7, 8, 9, 10-membered), or polycyclic system in which at least one ring is an aromatic ring containing at least one heteroatom (e.g., N, O, or S) as a ring atom and the remaining ring atoms are all carbon. In some cases, the aromatic ring containing at least one heteroatom may contain 1, 2, 3, or 4 heterocyclic atoms. Apart from aromatic rings containing at least one heteroatom as a ring atom, the remaining rings in a "heteroaromatic ring system" or "heteroaromatic ring" may be saturated, partially unsaturated, or fully unsaturated rings.

[0123] "Heteroaryl," alone or as part of other groups, refers to a monovalent group of a "heteroary ring system" or "heteroary ring" as defined above. The junction of the heteroaryl group should be located on the aromatic ring. Examples of heteroaryl groups include, but are not limited to: imidazole, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiazolyl, pyrazinyl, thiophene, furanyl, pyranyl, pyridinyl, pyrroleyl, pyrazolyl, pyrimidinyl, quinolinyl, isoquinolinyl, benzofuranyl, benzofuranyl, benzothiophene, benzothiaranyl, benzoimidazolyl, benzooxazolyl, benzooxadiazolyl, benzothiazolyl, benzothiazolyl, benzopyranyl, indole, isindole, triazolyl, triazinyl, quinoxolinyl, purine, quinazolinyl, quinazinyl, naphthidyl, pteridinyl, carbazole, and azazolyl. basalt, diazoxide Acridine, acridine, etc. A heteroaryl group is a heteroaryl group as defined above that has two linking sites. Unless otherwise defined, heteroaryl groups include substituted or unsubstituted forms.

[0124] "Heterocyclic group" refers to a heterocyclic system or a monovalent group of a heterocycle as defined above, typically referring to a stable monocyclic (e.g., 3-8 quinary, 4-5-6-7-8 quinary, 6-7-8 quinary, 4-5-6-7-8 quinary, 6-7-8-9-10-11-12 quinary, 6-7-8-9-10-11-12-13-14 quinary, 7-8-9-10-11-12-13-14 quinary, including fused rings, spirorings, and / or bridged ring structures, which are saturated or partially unsaturated, and contain a carbon atom and one, two, three, or four heteroatoms independently selected from N, O, and S as ring atoms. Heterocyclic groups are preferably 3- to 14-quinary heterocyclic groups, more preferably 3- to 8-quinary heterocyclic groups, and most preferably 4- to 6-quinary heterocyclic groups. Representative heterocyclic groups include the following ring systems, wherein (1) each ring is non-aromatic and at least one ring contains a heteroatom, for example, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, pyrrolylalkyl, pyrrolidoneyl, piperidinyl, pyrrololinyl, decahydroquinolinyl, oxazolylalkyl, piperazineyl, dioxalyl, dioxopentyl, diachexenyl, oxachexenyl, thiaachexenyl, morpholinyl, and quininecycloyl; and (2) at least one ring is non-aromatic. The ring comprises 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 comprises a heteroatom and at least one other ring is aromatic and comprises a heteroatom, for example, 3,4-dihydro-1H-pyrano[4,3-c]pyridine and 1,2,3,4-tetrahydro-2,6-diazanaphthalene. A heterocyclic group refers to a heterocyclic group as defined above having two linking sites. In this invention, the heterocyclic group is preferably a bicyclic ring, one ring being a heteroaryl group and linked to the other parts of the general formula via the heteroaryl group. In this invention, the heterocyclic group is preferably a 5-6 member monocyclic heterocyclic group or an 8-10 member bicyclic heterocyclic group. Unless otherwise defined, "heterocyclic group" and "heterocyclic group" include substituted or unsubstituted forms. When the heterocyclic group is saturated, the heterocyclic group can also be called a heterocyclic alkyl group.

[0125] "Heterocyclic alkyl" refers to an alkyl group that has been replaced by a heterocyclic group, where the heterocyclic group and alkyl group are defined as above.

[0126] "Alkylamine group" refers to a group having an alkyl-NR- structure, where R is H, or an alkyl, cycloalkyl, aryl, heteroaryl, etc. as described above.

[0127] "Cycloalkylamine" refers to the formula -N(Ra)Rb group, wherein Ra is H, an alkyl group as defined herein, or a cycloalkyl group as defined herein, Rb is a cycloalkyl group as defined herein, or Ra and Rb together with the N atom attached to them form a 3-10 member N-containing monocyclic or bicyclic heterocyclic group, such as tetrahydropyrrole. As used in this invention, C3-C8 cycloalkylamine refers to an amine group containing 3-8 carbon atoms.

[0128] In this invention, "ester group" refers to having a -C(O)-OR or RC(O)-O- structure, wherein R independently represents hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, as defined above.

[0129] In this invention, the term "amide group" refers to a group with the structure -CONRR', wherein R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, aryl or substituted aryl, heterocyclic or substituted heterocyclic, as defined above. R and R' can be the same or different in dialkylamine segments.

[0130] In this invention, the term "sulfonamide group" refers to a group having the structure -SO2NRR', wherein R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, aryl or substituted aryl, heterocyclic or substituted heterocyclic, as defined above. R and R' can be the same or different in the dialkylamine segment.

[0131] "Ketocarbonyl" refers to RC (=O)-, where R is an alkyl, cycloalkyl, etc., as mentioned above.

[0132] When the substituent is a non-terminal substituent, it is a subunit of the corresponding group. For example, alkyl corresponds to alkylene, cycloalkyl corresponds to cycloalkylene, heterocyclic corresponds to heterocyclic, alkoxy corresponds to alkoxy, etc.

[0133] In this invention, each of the above-mentioned groups such as alkyl, alkoxy, cycloalkyl, heteroalkyl, aryl, heteroaryl, cyclohexaalkyl, alkenyl, alkyne, heterocycle, and heterocyclic can be substituted or unsubstituted.

[0134] In this invention, the term "substitution" refers to the substitution of one or more hydrogen atoms on a specific group by a specific substituent. The specific substituent is the substituent described accordingly above, or the substituent appearing in the various embodiments. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substituted site of that group, and the substituents may be the same or different at each position. Those skilled in the art will understand that the combinations of substituents contemplated in this invention are those that are stable or chemically feasible. Typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (e.g., monohalogen substituents or polyhalogen substituents, the latter such as trifluoromethyl or alkyl containing Cl3), cyano, nitro, oxo (e.g., =O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, alkynyl, heterocyclic, aromatic, OR a SR a S(=O)R e S(=O)2R eP(=O)2R e S(=O)2OR e P(=O)2OR e NR b R c NR b S(=O)2R e NR b P(=O)2R e S(=O)2NR b R c P(=O)2NR b R c C(=O)OR d C(=O)R a C(=O)NR b R c OC(=O)R a OC (=O)NR b R c NR b C(=O)OR e NR d C(=O)NR b R c NR d S(=O)2NR b R c NR d P(=O)2NR b R c NR b C(=O)R a , or NR b P(=O)2R e , where R a R can independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, ynyl, heterocyclic, or aromatic rings. b R c and R d It can independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocyclic or aromatic ring, or R b and R c Together with N atoms, it can form heterocycles; 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-C10 acyl, C2-C10 ester, amino, C1-C6 alkoxy, C1-C10 sulfonyl, and C1-C6 urea, etc.

[0135] "Cyano" refers to -CN.

[0136] "Nitro" refers to -NO2.

[0137] "Hydroxy group" refers to -OH.

[0138] "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.

[0139] "Halogen (halogenated)" refers to any halogen group, such as -F, -Cl, -Br or -I.

[0140] "Deuterated compounds" refer to compounds in which one or more hydrogen atoms (H) are replaced by deuterium atoms (D).

[0141] In this invention, the term "multiple" independently refers to 2, 3, 4, or 5.

[0142] The structural formula of the carbamate group is -NH-C(=O)-OR, where R is an alkyl, aryl, heteroaryl, etc.

[0143] Active ingredients

[0144] As used herein, the terms “compound of the invention” or “active ingredient of the invention” are used interchangeably to refer to a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, isotopic compound (such as a deuterated compound), or prodrug thereof. The term also includes racemic mixtures and optical isomers.

[0145] Salts that may form from the compounds of this invention are also within the scope of this invention. Unless otherwise stated, compounds of this invention are understood to include their salts. The term "salt" as used herein refers to a salt formed from an inorganic or organic acid and a base in an acidic or basic form. Furthermore, when a compound of this invention contains a basic segment, it includes, but is not limited to, pyridine or imidazole; when it contains an acidic segment, it includes, but is not limited to, carboxylic acids; and any zwitterions ("internal salts") that may form are included within the scope of the term "salt." Pharmaceutically acceptable (i.e., non-toxic and physiologically acceptable) salts are preferred, although other salts are also useful, for example, for separation or purification steps in the preparation process. The compounds of this invention may form salts, for example, by reacting compound I with a certain amount, such as an equimolar amount, of an acid or base, precipitating it in a medium, or by freeze-drying it in an aqueous solution.

[0146] The prodrugs and solvates (or solvents) of the compounds in this invention are also within the scope of this invention.

[0147] The term "prodrug" here refers to a compound that, in the course of treating a related disease, undergoes a metabolic or chemical transformation to produce the compounds, salts, or solvates of this invention. The compounds of this invention include solvates, such as hydrates.

[0148] The compounds, salts, or solvates of this invention may exist in tautomer forms (e.g., amides and imine ethers). All such tautomers are part of this invention.

[0149] All stereoisomers of the compounds (e.g., those with asymmetric carbon atoms due to various substitutions), including their enantiomers and diastereomeric forms, are within the scope of this invention. The compounds of this invention may independently exist in stereoisomers that do not coexist with other isomers (e.g., possessing special activity as a pure or substantially pure optical isomer), or may be mixtures, such as racemates, or mixtures formed with all other stereoisomers or a portion thereof. The chiral center of this invention has two configurations, S or R, as defined by the International Union of Theoretical and Applied Chemistry (IUPAC) in 1974. Racemic forms can be resolved by physical methods, such as stepwise crystallization, or by derivatization into diastereomers followed by crystallization, or by chiral column chromatography. Individual optical isomers can be obtained from racemates by suitable methods, including but not limited to conventional methods, such as recrystallization after salting with an optically active acid.

[0150] The compounds of this invention, obtained sequentially through preparation, separation, and purification, have a weight content equal to or greater than 90%, for example, equal to or greater than 95%, or equal to or greater than 99% (“very pure” compounds), as listed in the text description. Such “very pure” compounds of this invention are also included as part of this invention.

[0151] All configurational isomers of the compounds of this invention are included within the scope of this invention, whether in mixtures, pure or very pure forms. The definition of compounds in this invention includes both cis (Z) and trans (E) olefin isomers, as well as cis and trans isomers of carbocyclic and heterocyclic compounds.

[0152] Throughout the specification, groups and substituents can be selected to provide stable fragments and compounds.

[0153] Specific functional groups and chemical terminology definitions are detailed below. For the purposes of this invention, chemical elements are defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75. th The definitions in Ed. are consistent. The definitions of specific functional groups are also described there. In addition, the basic principles of organic chemistry, as well as specific functional groups and reactivity, are explained in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, the full contents of which are included in the references.

[0154] Some compounds of this invention may exist in specific geometric or stereoisomeric forms. This invention covers all compounds, including their cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, racemic mixtures, and other mixtures. Additionally, the asymmetric carbon atom may represent a substituent, such as an alkyl group. All isomers and mixtures thereof are included in this invention.

[0155] According to the present invention, the ratio of isomers in a mixture of isomers can be varied. For example, a mixture containing only two isomers can have the following combinations: 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0. All ratios of isomers are within the scope of the present invention. Similar ratios readily understood by those skilled in the art, as well as ratios for mixtures of more complex isomers, are also within the scope of the present invention.

[0156] 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.

[0157] 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.

[0158] As described herein, the compounds of this invention can be expanded with any number of substituents or functional groups. Generally, whether the term "substitution" appears before or after the term "optional," the general formula for substituents in the formulations of this invention refers to replacing a hydrogen radical with a substituent of a specified structure. When multiple positions in a particular structure are replaced by multiple specific substituents, each position of the substituent can be the same or different. The term "substitution" as used herein includes all permissible substitutions in organic compounds. In a broad sense, permissible substituents include acyclic, cyclic, branched-unbranched, carbocyclic, and heterocyclic, aromatic and non-aromatic organic compounds. In this invention, heteroatomic nitrogen may be supplemented with hydrogen substituents or any permissible organic compound described above to complete its valence state. Furthermore, this invention is not intended to limit permissible substituted organic compounds in any way. This invention considers the combination of substituents and variable groups to be beneficial in the treatment of diseases in the form of stable compounds. The term "stable" here refers to a compound that is stable enough to maintain the integrity of its structure when tested over a sufficiently long period of time, preferably remaining effective over a sufficiently long period of time, and is used here for the purposes described above.

[0159] The compounds involved in this application and their pharmaceutically acceptable salt metabolites, as well as prodrugs that can be converted in vivo into structures of the compounds involved in this application and their pharmaceutically acceptable salts, are also included in the claims of this application.

[0160] Preparation method

[0161] The following schemes and examples describe methods for preparing compounds of formula (I). Starting materials and intermediates are purchased from commercial sources, prepared by known procedures, or otherwise described. In some cases, the order of steps in performing the reaction scheme may be altered to promote the reaction or avoid unwanted byproducts.

[0162] The preparation method of the compound of formula (I) of the present invention is described in more detail below, but these specific methods do not constitute any limitation on the present invention. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, such combinations can be easily performed by those skilled in the art.

[0163] Typically, in the preparation process, each reaction is carried out under inert gas protection, in a suitable solvent, at 0 to 150°C, and the reaction time is usually 2 to 24 hours.

[0164] The preferred preparation method is as follows:

[0165] method:

[0166] Step 1: In a solvent (e.g., hexafluoroisopropanol, tetrahydrofuran, 1,2-dichloroethane, dichloromethane), SM1 and S1 are reacted at 0-50°C via Friedel-Crafts alkylation to obtain SM2;

[0167] Step 2: In a solvent (e.g., acetonitrile, tetrahydrofuran, N-methylpyrrolidone, N,N-dimethylformamide), SM2 and S2 are reacted under alkaline conditions via palladium-catalyzed coupling or nucleophilic substitution to obtain product T.

[0168] In the above formulas, R1, R2, R3, R4, R5, R6, R7, R8, X1 and ring A are as described above.

[0169] Unless otherwise specified, all of the above starting materials can be purchased commercially or synthesized according to the reported literature.

[0170] Pharmaceutical Compositions and Administration

[0171] Because the compounds of the present invention possess excellent CDK2 / 4 protein kinase inhibitory activity, the compounds of the present invention and their various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compounds of the present invention as the main active ingredient can be used for the prevention and / or treatment of CDK2 / 4-related diseases. According to the prior art, the compounds of the present invention or pharmaceutical compositions containing the compounds of the present invention can be used for the prevention and / or treatment of the following diseases: inflammation, cancer, cardiovascular disease, infection, immune diseases, and metabolic diseases.

[0172] The compounds of the present invention can be used in combination with other known drugs for treating or improving similar symptoms. When administered in combination, the original drug's administration method and dosage can remain unchanged, while the compound of the present invention is taken simultaneously or subsequently. When the compounds of the present invention are taken concurrently with one or more other drugs, a pharmaceutical composition containing one or more known drugs and the compound of the present invention is preferred. Drug combination also includes taking the compound of the present invention with one or more other known drugs during overlapping time periods. When the compounds of the present invention are used in combination with one or more other drugs, the dosage of the compound of the present invention or the known drugs may be lower than the dosage of either drug alone.

[0173] Drugs or active ingredients that can be used in combination with compounds of general formula (I) 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), PD-L1 inhibitors (such as durvalumab, atezolizumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F...520, GR1405, MSB2311 or biosimilars of the above drugs, etc., CD20 antibodies (such as rituximab, olibutuzumab, oflamumab, tosimomumab, teimomab, 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, oxcalinib), PI3K inhibitors (such as ederaris, dactolisib, taselisib, bupa BTK inhibitors (such as ibrutinib, tirabrutinib, acalabrutinib, etc.), EGFR inhibitors (such as afatinib, gefitinib, erlotinib, lapatinib, dacomitinib, icotinib, canatinib, etc.), VEGFR inhibitors (such as sorafenib, pazopanib, rivatinib, cabozantinib, sunitinib, donafenib, etc.), HDAC inhibitors (such as givinostat, droxinostat, entinostat, dacistar, tebufenozide, etc.), CDK inhibitors (such as palbocicib, ribocicib, abemaciclib, lerociclib, etc.), MEK inhibitors (such as selumetinib, ribocicib, terbinafine ... 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, oxanotetinib, linsitinib, BMS-754807, etc.). 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, totopotecan, etc.), PARP inhibitors (such as olaparib, veliparib, rucaparib, etc.), ATR / ATM inhibitors (such as ceralasertib, berzosertib, etc.), or combinations thereof.

[0174] The dosage forms of the pharmaceutical compositions of the present invention include (but are not limited to): injections, tablets, capsules, aerosols, suppositories, films, pellets, topical liniments, controlled-release or sustained-release or nano-formulations.

[0175] The pharmaceutical compositions of the present invention comprise, within a safe and effective range, the compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective range" refers to an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably, 10-1000 mg of the compound of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0176] "Pharmaceutically acceptable carriers" refers to one or more compatible solid or liquid fillers or gelling substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with and with the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as... Wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0177] There are no particular limitations on the administration of the compounds or pharmaceutical compositions of the present invention. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and local administration.

[0178] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following components: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain complex silicates, and sodium carbonate; (e) slowing agents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. Buffers may also be included in capsules, tablets, and pills.

[0179] Solid dosage forms such as tablets, sugar pills, capsules, pellets, and granules can be prepared using coatings and shells, such as casings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compound from such compositions can be delayed in a portion of the digestive tract. Examples of encapsulating components that can be used are polymeric substances and waxes. If necessary, the active compound may also be formed into microcapsules with one or more of the excipients described above.

[0180] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0181] In addition to these inert diluents, the composition may also contain auxiliaries such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.

[0182] In addition to the active compound, the suspension may contain suspending agents such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0183] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0184] Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays, and inhalers. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be necessary.

[0185] The treatment method of the present invention can be used alone or in combination with other treatment methods or drugs.

[0186] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to the mammal (such as a human) requiring treatment. The dosage administered is the pharmaceutically considered effective dose. For a person weighing 60 kg, the daily dose is typically 1–2000 mg, preferably 50–1000 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the scope of the skills of a skilled physician.

[0187] The present invention also provides a method for preparing a pharmaceutical composition, comprising the steps of: mixing a pharmaceutically acceptable carrier with the compound or its crystal form described in the present invention, a pharmaceutically acceptable salt, hydrate or solvate, thereby forming a pharmaceutical composition.

[0188] The present invention also provides a treatment method comprising the steps of: administering to a subject requiring treatment a compound described in the present invention, or a crystal form thereof, a pharmaceutically acceptable salt, hydrate or solvate thereof, or administering a pharmaceutical composition described in the present invention for inhibiting CDK2 / 4 protein kinase.

[0189] The main advantages of this invention include

[0190] (1) The compounds of the present invention have excellent inhibitory ability against CDK2 / 4 protein kinase;

[0191] (2) The compounds of this invention have lower toxicity and side effects;

[0192] (3) The compounds of the present invention have better pharmacodynamic and pharmacokinetic properties.

[0193] Example

[0194] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions, such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are weight percentages and parts by weight.

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

[0196] Example 1: Synthesis of compound T-1

[0197] The synthetic route for compound T-1 is as follows:

[0198] The experimental procedure is as follows:

[0199] first step

[0200] Indole (500 mg, 1.0 eq) was dissolved in hexafluoroisopropanol (5.0 mL) at room temperature under nitrogen protection. Then, 2,4-dichloro-5-trifluoromethylpyrimidine (1.02 g, 1.1 eq) was added sequentially to the solution. The reaction mixture was stirred at room temperature for 4 hours. After the reaction was complete, the reaction mixture was extracted with ethyl acetate and water, and the organic phase was dried over anhydrous sodium sulfate, filtered, and finally distilled under reduced pressure. The residue was purified by silica gel column chromatography to give compound 2 (800 mg, 63.5%).

[0201] Step 2

[0202] Compound 2 (100 mg, 1.0 eq) was dissolved in DMSO (3 mL) at room temperature. Then, DIPEA (130 mg, 3.0 eq) and (3r, 4r)-4-amino-1-(methylsulfonyl)piperidin-3-ol (98 mg, 1.5 eq) were added sequentially to the solution. The reaction mixture was heated in a microwave at 130 °C for 40 minutes. After the reaction was complete, the reaction mixture was extracted with ethyl acetate and water, and the organic phase was dried over anhydrous sodium sulfate, filtered, and finally distilled under reduced pressure. The residue was purified by silica gel column chromatography to give compound T-1 (80 mg, 52.3%). LCMS: [M+H] +=456.9.

[0203] Examples 2-45: Synthesis of compounds T-2 to T-45

[0204] Following the synthesis method of Example 1, and using the corresponding starting materials, the compounds shown in the table below were synthesized:

[0205] Experimental Example 1: Enzyme Activity Test

[0206] The following describes bioactivity testing experiments on the compounds from the above embodiments and comparative compounds. The bioactivity testing procedure is as follows:

[0207] 1. Kinase activity test:

[0208] The test compound was subjected to CDK2 and CDK4 kinase IC50 assay. 50 Value detection.

[0209] (I) Reagent Information

[0210] (II) Equipment Information

[0211] (III) Research Design

[0212] (1) Compound preparation:

[0213] ① Prepare a 0.5 mM DMSO solution of the test compound and a 0.5 mM DMSO solution of the positive control drug palbociclin.

[0214] ② The compound was diluted three times to obtain 10 different concentrations of the compound solution.

[0215] (2) Perform enzyme assay:

[0216] ① As shown below, prepare a 1.3× enzyme solution containing enzyme, substrate and cofactor.

[0217] ② Add 15 μL of 1.3× enzyme solution to each well and incubate at room temperature for 30 minutes.

[0218] ③ Add 5 μL of 4×ATP solution to start the reaction. Each test well contains the components listed in the list, and the final volume is 20 μL.

[0219] ④Incubate for 150 minutes, then add 75 μL of buffer (containing 0.5 M EDTA) to stop the reaction.

[0220] ⑤ Use EZ to read and analyze the data from each test well.

[0221] (3) Data Analysis:

[0222] The suppression percentage is calculated using the following formula, based on the concern ratio (CR):

[0223] Wells treated with DMSO served as positive controls, while wells without enzymes served as negative controls.

[0224] % (inhibition percentage) = 100 - 100 * ((CRPC - CR)) Sample ) / (CRPC-CRNC)).

[0225] The above tests were used to determine the IC50 inhibitory activity of the test samples against CDK2 and CDK4 kinases. 50 The nM values ​​are shown in Table 1.

[0226] Table 1

[0227] As shown in the table above, through in vitro bioactivity screening with palbociclib as a reference, the compounds in this application all have good inhibitory ability against CDK2 / 4 kinases, and are expected to be further developed into drugs for regulating CDK2 / 4 protein kinase activity or treating CDK2 / 4 related diseases.

[0228] Experiment Example 2: Cell Anti-proliferation Experiment

[0229] I. Experimental Materials and Equipment:

[0230] Human breast cancer cells MCF-7, ovarian cancer cells A2780, DMEM medium (Bio-Channel), DMSO (dimethyl sulfoxide), MTT (thiazolyl blue), 0.25% EDTA-Tripsin (trypsin digestion solution), 1×PBS (phosphate buffer, pH 7.2), 96-well plates (Corning), fetal bovine serum (FBS), 10,000 U / mL penicillin-G / streptomycin, high-speed refrigerated centrifuge (EPPENDORF 5810R), enzyme-linked immunosorbent assay (ELISA) system (TecanSpark).

[0231] II. Experimental Preparation:

[0232] 1. Cell plating

[0233] A) Tumor cells were cultured at 37°C, 5% CO2 and saturated humidity in DMEM (high glucose, containing 10% FBS and 100 U / mL penicillin-G / streptomycin) to a density of 80-90%.

[0234] B) Remove the culture medium from the 10cm petri dish;

[0235] C) Rinse the cells once with 10 ml of 1×PBS;

[0236] D) Add 4 ml of 0.25% EDTA-Tripsin and incubate at 37°C in a 5% CO2 incubator for trypsin digestion for 5 minutes. Transfer to a 15 ml centrifuge tube, centrifuge at 200 g for 5 minutes, and discard the supernatant to obtain cell pellet.

[0237] E) Resuspend in 4 ml of DMEM medium, count and adjust to 50,000 cells / ml.

[0238] F) Add 100 μL of cell suspension to each well of a 96-well plate and incubate overnight at 37°C in a 5% CO2 incubator.

[0239] 2. Compound treatment

[0240] compound dilution

[0241] A) Preparation of serially diluted solutions of the test compounds: Prepare a 1 mM stock solution of the test compound. Then, dissolve 1.5 μl of the stock solution in 1.5 ml of DMSO-free culture medium, and then perform a 3-fold serial dilution with 0.1% DMSO culture medium, resulting in a total of 9 concentrations. The concentrations of the compounds after dilution are as follows:

[0242] 333.33nM, 111.11nM, 37.03nM, 12.35nM, 4.15nM, 1.37nM, 0.46nM, 0.15nM

[0243] B) After thorough mixing, take 100 μL of the culture compound solution to replace the culture medium in the cell culture plate, with 4 replicates for each concentration;

[0244] C) Transfer the cells to an incubator and incubate for 5 days.

[0245] 3. MTT test

[0246] A) Remove the cell culture plate and add 10 μL of 5 mg / ml MTT in the biosafety cabinet;

[0247] B) Place the cell culture plate back into the incubator and continue incubation for 3 hours;

[0248] C) Remove the cell culture plate and the culture medium, add 100 μL of isopropanol (containing 0.4 mM HCl and 0.1% NP-40), and shake in a shaker at room temperature for 30 minutes.

[0249] D) Measure the absorbance value at a wavelength of 570 nm on the TECAN enzyme-linked immunosorbent assay (ELISA) instrument.

[0250] 4. Data Analysis

[0251] Calculate the retention rate (%CellViability) using the following formula:

[0252] %Cell Viability=100%×(Lum_Sample-Lum_LC) / (Lum_HC-Lum_LC)

[0253] Lum_HC:0.1% DMSO control group cell readings

[0254] Lum_Sample: Cell readings with added compounds

[0255] Lum_LC: Blank culture medium reading

[0256] IC was obtained by curve fitting using GraphPadPrism8 software. 50 Numerical values ​​(unit: nM). As shown in Table 2.

[0257] Table 2

[0258] Experimental Example 3: Preclinical Rat Pharmacokinetic Study

[0259] I. Experimental Materials and Equipment:

[0260] Healthy adult male SD rats, 6-8 weeks old, weighing 200-300 grams. EDTA-Na2 anticoagulant. Analytical balance, animal weighing scale, magnetic stirrer, refrigerated centrifuge, single-channel manual pipette, etc.

[0261] II. Experimental Procedure:

[0262] 1. Drug preparation

[0263] Accurately weigh approximately 10 mg of the sample to be tested, dissolve it in 5% DMSO (converted), then add 10% Solutol HS-15 and 85% physiological saline, sonicate, and vortex to mix, obtaining a solution with a concentration of 1 mg / mL; prepare fresh before use.

[0264] Pipe 0.2 mL of the sample into a 1.5 mL centrifuge tube and store at -80 °C for analysis of the concentration of the drug solution.

[0265] 2. Animal preparation

[0266] Animals were housed in rat cages and fasted for at least 10 hours starting the day before the experiment, but water was allowed. On the day of the experiment, each animal was weighed and marked on its tail. Blank blood samples were collected before drug administration. Blood was collected via tail vein.

[0267] 3. Administration

[0268] Route of administration: Oral administration (po)

[0269] Dosage: 10 mg / kg

[0270] Dosage volume: 10 mL / kg

[0271] Procedure: Hold the rat upright with your left hand wearing a bite-proof glove. Insert a 16-gauge gavage needle into the throat through the mouth. Once you feel no obvious resistance, insert the needle and then inject the medication into the stomach.

[0272] 4. Sample Collection

[0273] Whole blood (0.1 ml) was collected from the test animals before administration and at 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, and 24 h after administration into EDTA-Na2 anticoagulant tubes. The tubes were inverted 3-4 times to mix thoroughly, and the plasma was separated by centrifugation at 10000g for 5 min at 4°C and stored at -80°C for later analysis. Blood was collected via tail vein.

[0274] The procedure involves securing the rat to a restraint device, ensuring its tail is fully exposed. The tail is then wiped with alcohol to allow the skin to absorb the alcohol, resulting in significant venous dilation. Suitable veins are selected from both sides, and the needle is inserted approximately one-third of the way from the tail tip. An insulin syringe is used, with the needle bevel facing upwards. Once the skin is pierced, the needle is immediately moved horizontally. A feeling of minimal resistance while the needle slides through the vein, along with blood return in the syringe, indicates that the needle has entered the vein. Approximately 0.1-0.2 ml of whole blood is drawn. After removing the needle, pressure is applied to stop the bleeding.

[0275] III. Sample Analysis:

[0276] Preparation of standard curve: Take 25 μL of rat blank plasma into centrifuge tubes, add 25 μL of prepared standard series solution (prepared with methanol), then add 200 μL of internal standard solution (prepared with methanol), vortex to mix for 2 min, and centrifuge at 10000g for 10 min at 4℃.

[0277] Unknown plasma sample processing: Take 25 μL of drug-containing rat plasma, add 25 μL of methanol and 200 μL of internal standard solution sequentially, vortex to mix for 2 min, and centrifuge at 10000g for 10 min at 4℃. Take the supernatant for LC / MS / MS detection.

[0278] IV. Data Processing

[0279] A quantitative detection method for the analyte was established using Shimadzu liquid chromatography and TripleQuad™ 6500+AB mass spectrometry. The concentration of the parent drug in plasma was determined. Blood drug concentration-time curves were plotted, and the main pharmacokinetic parameters were calculated using a non-compartmental model in WinNonLin Phoenix software.

[0280] Detailed data is shown in Table 3.

[0281] Table 3

[0282] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, crystal, deuterated compound, isotopic compound, or prodrug thereof, in X1 is selected from N and CH; R1 is selected from H, halogens (such as F, Cl, Br, I), hydroxyl groups, C. 1-6 Alkyl (such as methyl), C 3-8 cycloalkyl, halogenated C 1-6 Alkyl (e.g., CF3), amino, cyano, C 1-6 Alkylamino, hydroxy C 1-6 Alkyl, -NH-C 1-6 Alkyl, -N(C) 1-6 Alkyl)2, NH-C 3- 8-cycloalkyl, -NH-5-8-membered heterocycloalkyl, -NH-C 6-10 Aryl, -NH-5-8 heteroaryl, -C(O)C 1-6 Alkyl, -C(O)C 3- 8-cycloalkyl, C 1-6 Alkoxy groups (such as -O-methyl), -COO-C 1-6 Alkyl groups (such as -COO-C(CH3)3), C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, 5-8 membered heterocyclic alkyl, C 6-10 Aryl and 5-8-membered heteroaryl; optionally, the 5-8-membered heterocyclic alkyl group is substituted with one, two or three substituents selected from halogens, hydroxyl groups and carbonyl groups; R2 is selected from H and C. 1-6 Alkyl (such as methyl), halogenated C 1-6 Alkyl, C 3-8 cycloalkyl, halogenated C 3-8 Cycloalkyl, 5-8 membered heterocycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl and 5-8 quinone heteroaryl groups; R3, R4, R5, and R6 are each independently selected from H, halogens (such as F, Cl, Br, I), cyano, hydroxyl, amino, and C. 1-6 Alkyl (such as methyl), C 3-8 cycloalkyl, halogenated C 1-6 Alkyl groups (such as CF3), halogenated C 3-8 cycloalkyl, -NH-C 1-6 Alkyl, -N(C) 1- 6-alkyl)2、-NH-C 3-8 Cycloalkyl, -NH-5-8 membered heterocycloalkyl, -NH-C 6-10 Aryl, -NH-5-8 heteroaryl, -C(O)C 1- 6-alkyl, -C(O)C 3-8 cycloalkyl, C 1-6 Alkoxy (e.g., -O-methyl), C 1-6 Halogenated alkoxy groups, -COOH, -CONH2, -CONH-C 1-6 Alkyl, -CONH-C 6-10 Aryl, -CONH-5-8 heteroaryl, -COO-C 1-6 Alkyl groups (such as -COO-C(CH3)3), C 1-6 Hydroxyalkyl, -SO3H, -SO2-C 1-6 Alkyl groups (such as methanesulfonyl groups), -SO2-C 6-10 Aryl, -SO2-5-8 heteroaryl, 5-8 heterocyclic alkyl, C 6-10 Aryl and 5-8 quinone heteroaryl groups; R7 is selected from H and C. 1-6 Halogenated alkyl groups (e.g., CF3), halogens (e.g., F, Cl, Br), cyano groups, alkynyl groups, and C 1-6 Alkyl groups (such as methyl groups); R8 is selected from H, halogens (such as F, Cl, Br), and C. 1-6 Alkyl groups (such as methyl groups); Ring A is selected from 5-9 membered heterocyclic alkyl groups, C 3-8 cycloalkyl, 5-8 membered heteroaryl and C 6-10 Aryl; optionally, the 5-9 membered heterocyclic alkyl group, C 3-8 cycloalkyl, 5-8 membered heteroaryl, C 6-10 Each aryl group is independently selected by one, two, or three groups chosen from R, -SO2R, -N(SO2R)R, -COR, cyano, amino, hydroxyl, halogen, C 1-6 alkyl, and halogenated C 1-6 Alkyl substituents; wherein each R is independently selected from H, halogen, hydroxyl, amino, C with or without substitution 1-6 Alkyl, substituted or unsubstituted C 1-3 Alkyl-C 3-8 Cycloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5-8-membered heteroaryl; wherein R' and R" are each independently selected from H and C. 1-6 alkyl; The heterocyclic alkyl or heteroaryl group contains one, two, or three heteroatoms selected from N, O, and S.

2. The compound of claim 1 or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, crystal, deuterated product, isotopic compound or prodrug, wherein X1 is N.

3. The compound of claim 1 or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, crystal, deuterated derivative, isotopic compound, or prodrug, wherein R1 is selected from H, F, Cl, hydroxyl, C. 1-6 Alkyl (such as methyl), C 3-8 Cycloalkyl (e.g., cyclopropyl), halogenated C 1-6 Alkyl (e.g., CF3), amino, cyano, C 1-6 Alkylamino, hydroxy C 1-6 Alkyl, -NH-C 1-6 Alkyl, -N(C) 1-6 Alkyl)2、-NH-C 3-8 cycloalkyl, C 1-6 Alkoxy (e.g., -O-methyl), C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl and 5-8 membered heterocyclic alkyl groups.

4. The compound of claim 1 or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, crystal, deuterated derivative, isotopic compound, or prodrug, wherein R1 is selected from H, C 1-6 Alkyl, C 1- 6-alkylamino, hydroxy C 1-6 Alkyl groups and 5-8 membered heterocyclic alkyl groups; optionally, the 5-8 membered heterocyclic alkyl groups are substituted with substituents selected from halogens, hydroxyl groups and carbonyl groups.

5. The compound of claim 1 or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, crystal, deuterated derivative, isotopic compound, or prodrug, wherein R1 is selected from H, methyl, 6. The compound of claim 1 or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, crystal, deuterated derivative, isotopic compound, or prodrug, wherein R2 is selected from H, C 1-6 Alkyl (such as methyl), halogenated C 1-6 Alkyl, C 3-8 cycloalkyl, halogenated C 3-8 Cycloalkyl and 5-8 membered heterocyclic alkyl groups.

7. The compound of claim 1 or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, crystal, deuterated derivative, isotopic compound, or prodrug, wherein R2 is selected from H, C 1-6 Alkyl and C 3- 8-Cycloalkyl.

8. The compound of claim 1 or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, crystal, deuterated derivative, isotopic compound or prodrug, wherein R2 is selected from H, methyl, isopropyl, and cyclopropyl.

9. The compound of claim 1 or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, crystal, deuterated derivative, isotopic compound, or prodrug, wherein R3, R4, R5, and R6 are each independently selected from H, F, Cl, cyano, hydroxyl, amino, C 1-6 Alkyl (such as methyl), C 3-8 Cycloalkyl (e.g., cyclopropyl), halogenated C 1-6 Alkyl groups (such as CF3), halogenated C 3-8 cycloalkyl, -NH-C 1-6 Alkyl, -N(C) 1-6 Alkyl)2、-NH-C 3-8 cycloalkyl, NH-C 6-10 Aryl, -NH-5-8 heteroaryl, -C(O)C 1-6 Alkyl, -C(O)C 3-8 cycloalkyl, C 1-6 Alkoxy (e.g., -O-methyl), C 1-6 Halogenated alkoxy groups, -COOH, -CONH2, -CONH-C 1-6 Alkyl, -CONH-C 6-10 Aryl, -CONH-5-8 heteroaryl, -COO-C 1-6 Alkyl groups (such as -COO-C(CH3)3), C 1-6 Hydroxyalkyl, -SO2-C 1-6 Alkyl groups (such as methanesulfonyl), 5-8 membered heterocyclic alkyl groups, C 6-10 Aryl and 5-8 quinone heteroaryl groups.

10. The compound of claim 1 or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, crystal, deuterated product, isotopic compound or prodrug, wherein R3, R4, R5, and R6 are each independently selected from H, F, Cl, methyl, -CF3, -N(CH3)2, -C(O)CH3 and -CHF2.

11. The compound of claim 1 or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, crystal, deuterated product, isotopic compound or prodrug, wherein R7 is selected from H, CF3, F, Cl, Br.

12. The compound of claim 1 or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, crystal, deuterated product, isotopic compound or prodrug, wherein R7 is selected from CF3, F, Cl, Br.

13. The compound of claim 1 or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, crystal, deuterated product, isotopic compound or prodrug, wherein R8 is selected from H, F, Cl, Br, methyl.

14. The compound of claim 1 or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, crystal, deuterated product, isotopic compound or prodrug, wherein R8 is H.

15. The compound of claim 1 or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, crystal, deuterated derivative, isotopic compound, or prodrug, wherein ring A is selected from... in R is selected from H, halogen, hydroxyl, amino, C substituted or unsubstituted 1-6 Alkyl, substituted or unsubstituted C 1-3 Alkyl-C 3-8 Cycloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5-8-membered heteroaryl; wherein R' and R" are each independently selected from H and C. 1-6 alkyl.

16. The compound of claim 1 or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, crystal, deuterated derivative, isotopic compound, or prodrug, wherein ring A is selected from... in, R is as defined in claim 1.

17. The compound of claim 1 or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, crystal, deuterated derivative, isotopic compound, or prodrug, wherein ring A is selected from...

18. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, crystal, deuterated compound, isotopic compound, or prodrug thereof, selected from any one of the following general structures: Y represents O, CR 10 R 11 or NR 12 ; Z is C-SO2R or C-NR 12 R 13 ; R 10 is H; R 11 It is -NHSO2R or -SO2R; R 12 , R 13 each independently H or -SO2R, or R 12 , R 13 and the N to which it is attached form a 6-membered heterocyclyl group, and said 6- membered heterocyclyl group is optionally further substituted with NH2, NHSO2R or -SO2R; R is C 1-3 alkyl or C 3-6 cycloalkyl; R1is selected from H, C 1-3 alkyl, -NH-C 1-3 alkyl, -N(C 1-3 alkyl)2, hydroxy C 1-6 alkyl, R2is selected from H, C 1-3 alkyl or C 3-6 cycloalkyl; R3, R4are each independently selected from H, halogen, C 1-3 alkyl, haloC 1-3 alkyl, -N(C 1-3 alkyl)2, -C(O)C 1-3 alkyl; R7 is selected from CF3, F, Cl, and Br; R9is each independently selected from halogen, OH, C 1-3 alkyl or haloC 1-3 alkyl; n is 0, 1, or 2.

19. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, crystal, deuterated compound, isotopic compound, or prodrug thereof, selected from any one of the following general structures: in R1, R2, R3, R4, and R7 are as described in claim 1; R 901 , R 902 each independently H or R9; R9is each independently selected from halogen, OH, C 1-3 alkyl or haloC 1-3 alkyl.

20. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, crystal, deuterated compound, isotopic compound, or prodrug thereof, having the structure of the following general formula: in R1, R2, R3, R4, R5, R6, R7, and R8 are as described in claim 1.

21. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, crystal, deuterated compound, isotopic compound, or prodrug thereof, selected from:

22. A pharmaceutical composition comprising a preventive and / or therapeutically effective amount of the compound of any one of claims 1-21 or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, crystal, deuterated, isotopic compound or prodrug, as well as a pharmaceutically acceptable carrier, excipient or adjuvant.

23. Use of the compound of any one of claims 1-21, or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, crystal, deuterated product, isotopic compound, or prodrug, or the composition of claim 22, in the preparation of CDK2 and / or CDK4 protein kinase inhibitors.

24. Use of the compound of any one of claims 1-21, or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, crystal, deuterated product, isotopic compound, or prodrug, or the composition of claim 22, in the preparation of a medicament for modulating the activity of CDK2 and / or CDK4 protein kinases.

25. Use of the compound of any one of claims 1-21, or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, crystal, deuterated product, isotopic compound, or prodrug, or the composition of claim 22, in the preparation of a drug for the prevention and / or treatment of diseases associated with CDK2 and / or CDK4 protein kinases.

26. The use as described in claim 25, wherein the disease associated with CDK2 and / or CDK4 protein kinases is inflammation, cancer, cardiovascular disease, infection, immune disease, or metabolic disease.

27. The use as described in claim 26, wherein the cancer is selected from lung cancer, breast cancer, prostate cancer, colorectal cancer, liver cancer, pancreatic cancer, ovarian cancer, leukemia, neuroblastoma, gastric cancer, kidney cancer, esophageal cancer, uterine cancer, and liposarcoma.

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