Heteroaromatic ring compound as CDK7 kinase inhibitor and preparation and application thereof

Abstract

The invention provides a heteroaromatic ring compound serving as a CDK7 kinase inhibitor as well as preparation and application of the heteroaromatic ring compound. The heteroaromatic ring compound is a compound with a structure shown in a formula (I) or pharmaceutically acceptable salt, ester, stereoisomer, solvent compound or prodrug of the compound, and the invention also provides a pharmaceutical composition, and the pharmaceutical composition comprises the compound with the structure shown in the formula (I) or pharmaceutically acceptable salt, ester, stereoisomer, solvent compound or prodrug of the compound. The invention also provides application of the compound with the structure shown in the formula (I) or the pharmaceutical composition in preparation of a CDK kinase inhibitor and preparation of a medicine for treating and / or inhibiting CDK related diseases. The CDK7 kinase inhibitor compound provided by the invention has enzyme and cellular level biological activity superior to that of the disclosed similar target compounds, and has lower cardiotoxicity. The compound provided by the invention provides more choices for novel antitumor drugs, and has a good drug application prospect.

Description

Heteroaromatic compounds as CDK7 kinase inhibitors and their preparation and use Technical Field

[0001] The present invention relates to a series of derivative compounds of heteroaromatic ring structures and their use as CDK7 kinase inhibitors, particularly compounds represented by formula (I) or pharmaceutically acceptable salts thereof. Background Art

[0002] Cyclin-dependent kinases (CDKs) belong to the serine / threonine kinase family. Cyclin-dependent kinases are inactive on their own and must bind to corresponding cyclins (cyclins) to form active heterodimeric complexes to exert their regulatory functions. They catalyze the phosphorylation of their substrates, directly or indirectly regulating cell cycle progression and promoting cell growth and proliferation. Currently, the human genome has been found to encode 21 CDKs and over 15 cyclins. Based on their functions, CDKs can be divided into two major categories: those that control the cell cycle and those that control cellular transcription. CDK1 / 2 / 4 / 6 are primarily involved in the cell cycle, while CDK7 / 8 / 9 / 10 are primarily involved in the transcriptional machinery of genetic information within the cell.

[0003] CDK7 is an important member of the CDKs family and regulates the cell cycle mainly through two indirect ways: CDK7, together with cyclin H and Matl, forms CAK (CDKs activating kinase), which further phosphorylates CDKl / 2, thereby activating their functions in the cell cycle.

[0004] Another way is that CDK7, as a subunit of the general transcription factor TFIIH, phosphorylates the carboxyl-terminal domain (CTD) of the large subunit of RNA polymerase II (RNAP II), regulating gene transcription in cells. Because CDK7 has the dual functions of CAK and CTD phosphorylation, it plays an important role in cell proliferation, cell cycle, and transcription.

[0005] In recent years, inhibiting CDK7 has gradually become a potential therapeutic strategy for various cancers. Inhibiting CDK7 can suppress the expression of key oncogenes such as c-Myc. Preclinical research data show that small molecule inhibitors that inhibit CDK7 have good anti-cancer effects in hormone receptor-positive and triple-negative breast cancers, as well as cancers driven by transcription factors such as small cell lung cancer (SCLC), such as the small molecule drug CT-7001 developed by Emory University. These cancers currently lack effective treatments and have significant unmet medical needs. Moreover, due to their different mechanisms of action, CDK7 inhibitors may also be effective for cancers that have become resistant to current treatments. Therefore, the development of CDK7 inhibitors is likely to become an effective means of treating these malignancies.

[0006] Summary of the Invention

[0007] The purpose of the present invention is to provide a class of heteroaromatic compounds that are CDK7 kinase inhibitors.

[0008] The purpose of the present invention can be achieved by the following measures:

[0009] The first object of the present invention is to provide a compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, solvate or prodrug thereof,

[0010] wherein R1 is a substituted or unsubstituted deuterated C1-C3 alkyl group, a C1-C3 alkyl group, a C2-C6 alkene group, a C2-C6 alkyne group, or a substituted or unsubstituted C6-10 aryl C1-6 alkyl group;

[0011] The substituents are independently selected from H, D, halogen, hydroxy, -CN, carbonyl, C1-C3 alkyl, C2-C3 alkene, C2-C3 alkyne, deuterated C1-C3 alkyl, C1-C3 alkoxy, hydroxy C1-C3 alkyl, fluorinated C1-C3 alkyl, cyano C1-C3 alkyl, C3-8 cycloalkyl, C3-10 heterocyclyl, C6-10 aryl;

[0012] R2 is selected from halogen, hydroxy, -CN, carbonyl, C1-C3 alkyl, C1-C3 alkene or alkyne, deuterated C1-C3 alkyl, C1-C3 alkoxy, hydroxy C1-C3 alkyl, fluorinated C1-C3 alkyl, cyano C1-C3 alkyl;

[0013] When R1 is benzyl, R2 is -CN

[0014] Further, R1 is a substituted or unsubstituted C1-C3 alkyl, C2-C6 alkene, C2-C6 alkyne, or a substituted or unsubstituted C6-10 aryl C1-6 alkyl.

[0015] Furthermore, R2 is selected from -CN and C1-C3 alkyl.

[0016] Furthermore, R1 is substituted or unsubstituted

[0017] Furthermore, the compound is selected from:

[0018] The salts that may be formed by the compounds of the present invention also fall within the scope of the present invention. Unless otherwise indicated, the compounds of the present invention are understood to include their salts. For example, the compound of formula (I) reacts with a certain amount of acid or base, such as an equivalent amount, and is salted out in a medium, or freeze-dried in an aqueous solution. The basic fragments contained in the compounds of the present invention, including but not limited to amines or pyridine or imidazole rings, may form salts with organic or inorganic acids. Non-limiting examples of pharmaceutically acceptable salts of the compound of formula I include monohydrochloride, dihydrochloride, methanesulfonate, trifluoroacetate and ditrifluoroacetate.

[0019] The compounds of the present invention, obtained by sequential preparation, isolation, and purification, are described in the text to a concentration of 90% or greater by weight, for example, 95% or greater, or 99% or greater ("very pure" compounds). Such "very pure" compounds of the present invention are also considered part of the present invention.

[0020] The third object of the present invention is to provide a pharmaceutical composition comprising a compound having the structure of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, solvate or prodrug thereof.

[0021] Furthermore, the pharmaceutical composition also includes other therapeutic agents and / or pharmaceutically acceptable carriers.

[0022] The fourth object of the present invention is to provide the use of a compound having a structure of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, solvate, prodrug or the aforementioned pharmaceutical composition in the preparation of a CDK kinase inhibitor.

[0023] A fifth object of the present invention is to provide a compound having a structure of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, solvate, prodrug or the aforementioned pharmaceutical composition for preparing a drug for treating and / or inhibiting CDK-related diseases.

[0024] Furthermore, the CDK-related disease is cancer.

[0025] Also provided herein is a method of inhibiting cell proliferation in vitro or in vivo, comprising contacting the cell with an effective amount of a compound of formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof.

[0026] Also provided herein is a method of treating a CDK-related disease or condition in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound of formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof.

[0027] Also provided herein is a method of treating cancer in a patient in need of such treatment and / or inhibiting metastasis associated with a particular cancer, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof.

[0028] Also provided herein is a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, for use in therapy.

[0029] Also provided herein is a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, for use in treating cancer and / or inhibiting cancer metastasis associated with a specific cancer.

[0030] Also provided herein is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in inhibiting CDK kinase activity.

[0031] Also provided herein is a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, for use in treating a CDK-related disease or disorder.

[0032] Also provided herein is the use of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for treating cancer and / or inhibiting metastasis associated with a particular cancer.

[0033] Also provided herein is the use of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for inhibiting CDK kinase activity.

[0034] Also provided herein is the use of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for treating a CDK-related disease or disorder.

[0035] Also provided herein is a method for treating cancer in a patient in need thereof, comprising: (a) determining whether the cancer is associated with dysregulation of the expression, activity, or level of a CDK gene, a CDK kinase, or any thereof (e.g., a CDK-associated cancer); and (b) if it is determined that the cancer is associated with dysregulation of the expression, activity, or level of a CDK gene, a CDK kinase, or any thereof (e.g., a CDK-associated cancer), administering to the patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof.

[0036] Also provided herein is a pharmaceutical combination for treating cancer in a patient in need thereof (e.g., a CDK-related cancer, such as a CDK-related cancer with a mutation that confers resistance to one or more CDK inhibitors), comprising: (a) a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, (b) an additional therapeutic agent, and (c) optionally at least one pharmaceutically acceptable carrier, wherein the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof and the additional treatment are formulated into a separate composition or dosage for simultaneous, separate or sequential use in treating cancer, wherein the amount of the compound of formula I or a pharmaceutically acceptable salt or solvate thereof and the amount of the additional therapeutic agent are effective together to treat cancer. Also provided herein is a pharmaceutical composition comprising such a combination. Also provided herein is a use of such a combination for the preparation of a medicament for treating cancer. Also provided herein is a commercial package or product comprising such a combination, in the form of a combined preparation for simultaneous, separate or sequential use; and a method for treating cancer in a patient in need thereof.

[0037] Also provided herein is a method for reversing or preventing acquired resistance to an anticancer drug, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof to a patient at risk of developing or having acquired resistance to an anticancer drug. In some embodiments, a dose of an anticancer drug is administered to the patient (e.g., substantially simultaneously with administering a dose of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof to the patient).

[0038] Also provided herein is a method of delaying and / or preventing the development of cancer resistance to an anticancer drug in an individual, comprising administering to the individual an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof before, during or after administering an effective amount of the anticancer drug.

[0039] Also provided herein is a method of treating an individual having cancer with an increased likelihood of developing resistance to an anticancer drug, comprising administering to the individual (a) an effective amount of a compound of formula (I) before, during, or after administering (b) an effective amount of an anticancer drug.

[0040] Also provided are methods of treating an individual with a CDK-related cancer who has one or more CDK inhibitor resistance mutations that increase the cancer's resistance to a first CDK inhibitor, the method comprising administering a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof before, during, or after administration of another anti-cancer drug.

[0041] Also provided are methods of treating an individual having a CDK-related cancer comprising administering a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof before, during, or after administration of another anticancer drug (eg, a first CDK kinase inhibitor).

[0042] The present invention also provides a method for preventing and / or treating tumors, comprising administering to a subject in need of such treatment a therapeutically effective amount of the compound as shown in Formula I or its tautomers, stereoisomers or isotopic derivatives, or a pharmaceutically acceptable salt of any of the foregoing, or a crystalline form or solvate of any of the foregoing.

[0043] In some embodiments, the cancer or tumor can be breast cancer, ovarian cancer, small cell lung cancer, acute myeloid leukemia, acute lymphoblastic leukemia, bladder cancer, colon cancer, prostate cancer, epithelial sarcoma, or soft tissue sarcoma.

[0044] In some embodiments, the patient is a human.

[0045] The compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof are also suitable for treating CDK-related cancers.

[0046] Also provided herein is a method for treating a patient diagnosed with or identified as having a CDK-related cancer (e.g., any exemplary CDK-related cancer disclosed herein), comprising administering to the patient a therapeutically effective amount of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof.

[0047] Unless otherwise specified, the terms in this invention are defined as follows:

[0048] The term "halogen" refers to -F (sometimes referred to herein as "fluorine"), -Cl, -Br, and -I.

[0049] The term "deuterated C1-C3 alkyl" refers to a saturated, linear or branched, monovalent hydrocarbon radical having one to three carbon atoms, wherein one to three carbon atoms are substituted with deuterium. Examples include, but are not limited to, deuterated methyl, deuterated ethyl, deuterated 1-propyl, and deuterated isopropyl.

[0050] The terms "C1-C3 alkyl," "C1-C6 alkyl," "C2-C6 alkyl," and "C3-C6 alkyl" refer to saturated, straight-chain or branched, monovalent hydrocarbon radicals having one to three, one to six, two to six, or three to six carbon atoms, respectively. Examples include, but are not limited to, methyl, ethyl, 1-propyl, isopropyl, 1-butyl, isobutyl, sec-butyl, tert-butyl, 2-methyl-2-propyl, pentyl, neopentyl, and hexyl.

[0051] The term "C1-C6 alkoxy" refers to a saturated linear or branched monovalent alkoxy group having one to six carbon atoms, wherein the bond is through the oxygen atom. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, and tert-butoxy.

[0052] The terms "hydroxy C1-C6 alkyl-" and "hydroxy C2-C6 alkyl-" refer to a saturated straight or branched chain monovalent alkyl group having one to six or two to six carbon atoms, respectively, wherein one carbon atom is substituted with a hydroxy group.

[0053] The terms "deuterated C1-C6 alkyl-", "halogenated C1-C6 alkyl" and "cyano C1-C6 alkyl" refer to saturated straight-chain or branched monovalent alkyl groups of one to six carbon atoms, respectively, wherein one carbon atom is substituted by deuterium, halogen or cyano.

[0054] The term "heterocycle" refers to a monocyclic or bicyclic non-aromatic heterocycle containing, in addition to carbon atoms, 2 to 4 heteroatoms selected from the group consisting of O, S, P or N atoms.

[0055] The term "aryl" refers to an aromatic monocyclic or polycyclic group containing 6 to 19 carbon atoms. Aryl groups include, but are not limited to, groups such as unsubstituted or substituted phenyl, and unsubstituted or substituted naphthyl.

[0056]

[0014] The terms "treating" or "treatment" are used throughout this document in a conventional sense, eg, to manage or care for an individual for the purpose of combating, alleviating, reducing, relieving, ameliorating the condition of a disease or disorder, such as cancer.

[0057] The term "subject" or "patient" includes organisms that can develop a cell proliferative disorder or that can benefit from the administration of the compounds of the present invention, such as humans and non-human animals. Preferred humans include human patients suffering from or susceptible to a cell proliferative disorder or related condition as described herein. The term "non-human animal" includes vertebrates, such as mammals, such as non-human primates, sheep, cows, dogs, cats, and rodents (e.g., mice), as well as non-mammals, such as chickens, amphibians, reptiles, and the like.

[0058] The term "cell proliferation" includes unwanted or uncontrolled proliferation of cells. The compounds of the present invention can be used to prevent, inhibit, block, reduce, decrease, control, etc. cell proliferation and / or cell division, and / or produce apoptosis. The method comprises administering to an individual (including mammals, including humans) in need thereof a compound of the present invention or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate or solvate thereof in an amount effective to treat or prevent the condition.

[0059] Compared with the prior art, the present invention has the following beneficial effects:

[0060] The CDK7 kinase inhibitor compounds of the present invention have superior bioactivity at the enzyme and cellular levels compared to previously disclosed compounds of the same target species and exhibit improved bioavailability. The compounds of the present invention provide more options for novel anti-tumor drugs and have promising pharmaceutical application prospects. DETAILED DESCRIPTION

[0061] The present invention is further explained below with reference to the following examples, but the examples do not limit the present invention in any form.

[0062] The following representative examples are intended to help illustrate the present invention and are not intended to, and should not be construed as, limiting the scope of the present invention. In fact, except for those appearing and described herein, the entire contents of the documents herein, including examples based on the scientific literature and patents cited herein, as well as various modifications and numerous further variations thereof, will be clear to those skilled in the art. It should also be understood that the citation of these references helps to present the present invention. The following examples contain important supplementary information, examples, and guidance that can be adapted to various variations and similar situations in the present invention.

[0063] Example 1

[0064] The synthetic route of the compound represented by formula 8 of the present invention is as follows:

[0065] The preparation method of the above compound 2 is:

[0066] In a 100 mL round-bottom flask, compound 1 (2.0 g, 15.98 mmol) was dissolved in ethanol at room temperature. Sodium ethoxide (3.26 g, 47.9 mmol) and diethyl malonate (3.33 g, 20.8 mmol) were added. The mixture was heated to 80°C (internal temperature) and stirred for 15 hours. After the reaction, the mixture was cooled to room temperature and 1 M HCl solution was added to adjust the pH to 2.0. A solid precipitated, which was filtered and washed with water to obtain compound 2 as a white solid (2.8 g, 14.5 mmol) with a yield of 91%. The above-mentioned compound 3 was prepared as follows:

[0067] To a 100mL round-bottom flask, add 8mL of phosphorus oxychloride and 7mL of acetonitrile at room temperature. Subsequently, slowly add 2 (500mg, 2.6mmol) to the reaction solution. Then, add triethylamine (521.13mg, 5.2mmol) dropwise at 0°C. After the addition is complete, the reaction mixture is heated to 90°C and stirred overnight until the reaction is complete. After the reaction is complete, the reaction mixture is concentrated and slowly added dropwise to ice water to quench. The pH is adjusted to alkaline with solid sodium bicarbonate. Extraction is performed with methyl tert-ether, and the organic phase is concentrated to obtain the crude product 3 as a brownish-red solid.

[0068] The preparation method of the above compound 4 is:

[0069] In a 100 mL round-bottom flask, compound 3 (500 mg, 2.17 mmol), deuterated benzylamine (521.02 mg, 4.78 mmol), and triethylamine (439.2 mg, 4.34 mmol) were added at room temperature in ethanol and refluxed overnight until the starting materials reacted completely. After the reaction, the reaction mixture was dried and isolated by column chromatography (PE:EA = 10:1) to obtain compound 4 (491.5 mg, 1.64 mmol) in a 78% yield.

[0070] The preparation method of the above compound 5 is:

[0071] To a 100 mL round-bottom flask, add 4 (491.5 mg, 1.64 mmol), BoC2O (465.3 mg, 2.13 mmol), and THF. Stir at room temperature for 2 h until the starting materials react completely. After completion of the reaction, the reaction solution was spin-dried and isolated by column chromatography (PE:EA = 10:1) to obtain compound 5 (616.2 mg, 1.54 mmol) in a 94.3% yield.

[0072] The preparation method of the above compound 7 is:

[0073] In a 100 mL round-bottom flask, 5 (500 mg, 1.25 mmol), Pd2dba3 (114.4 mg, 0.125 mmol), BINAP (233.5 mg, 0.38 mmol), and sodium tert-butoxide (180.2 mg, 1.88 mmol) were dissolved in toluene (20 mL). The mixture was stirred at room temperature for 5 minutes. 6 (345 mg, 1.5 mmol) was then slowly added to the reaction mixture. The mixture was then heated to 95°C and refluxed overnight. TLC analysis indicated that no starting material remained. The reaction mixture was extracted with water and ethyl acetate. The organic phases were combined and separated by column chromatography (PE:EA = 1:1) to afford the final product 7 (370 mg, 0.62 mmol) in a 50% yield.

[0074] The preparation method of the above compound 8 is:

[0075] In a 100 mL round-bottom flask, 7 (370 mg, 0.62 mmol) was slowly added dropwise into 30 mL of hydrochloric acid and ethyl acetate. The mixture was stirred at room temperature for 2 h until the reaction was complete. The final product 8 (98 mg, 0.24 mmol) was separated by thin-layer chromatography (TLC) with a yield of 40%.

[0076] 1 H NMR(400MHz,Chloroform-d)δ7.65(s,1H),7.39–7.30(m,5H),6.46(s,1H),4.98(s, 1H),4.80–4.71(m,1H),4.30(ddd,J=14.8,8.1,2.9Hz,1H),3.22(ddd,J=20.9,10.5, 4.9Hz,2H),3.13–2.98(m,2H),2.92(ddd,J=14.6,5.6,1.8Hz,1H),2.58(td,J=12.0 ,2.8Hz,1H),2.48(t,J=10.7Hz,1H),1.60–1.41(m,3H),1.29(dd,J=9.3,6.9Hz,6H).

[0077] LC-MS [M+H + ]397.37.

[0078] Example 2

[0079] The synthetic route of the compound represented by formula 22 of the present invention is as follows:

[0080] The preparation method of the above compound 17 is:

[0081] In a 100 mL round-bottom flask, 16 (2.0 g, 18.5 mmol) was dissolved in ethanol at room temperature. Sodium ethoxide (3.78 g, 55.5 mmol) and diethyl malonate (3.85 g, 1.3 mmol) were added. The mixture was heated to 80°C (internal temperature) and stirred for 15 h. After the reaction, the mixture was cooled to room temperature and the pH was adjusted to 2.0 by adding 1 M HCl solution. A solid precipitated, which was filtered and washed with water to obtain compound 17 as a white solid (1.7 g, 9.6 mmol) in a 52% yield.

[0082] The preparation method of the above compound 18 is:

[0083] To a 100mL round-bottom flask, 25mL of phosphorus oxychloride and 24mL of acetonitrile were added at room temperature. 17 (1.7g, 9.66mmol) was then slowly added to the reaction mixture. Triethylamine (1.96g, 19.32mmol) was then added dropwise at 0°C. After the addition was complete, the temperature was raised to 90°C and stirred overnight until the reaction was complete. After the reaction, the reaction mixture was concentrated and slowly added dropwise to ice water to quench the reaction. The pH was adjusted to alkaline with solid sodium bicarbonate. Extraction was performed with methyl tert-ether, and the organic phase was concentrated to afford the crude product 18 (1.2g, 5.69mmol) as a brownish-red solid in a 59% yield.

[0084] The preparation method of the above compound 19 is:

[0085] To a 100 mL round-bottom flask, 18 (1.2 g, 5.69 mmol), benzylamine (1.34 g, 12.5 mmol), and triethylamine (2.02 g, 11.38 mmol) were added at room temperature in ethanol and refluxed overnight until the starting materials reacted completely. After the reaction, the reaction mixture was dried and isolated by column chromatography (PE:EA = 10:1) to obtain compound 19 (1.3 g, 4.5 mmol) in a 79% yield.

[0086] The preparation method of the above compound 20 is:

[0087] To a 100 mL round-bottom flask, 19 (1.3 g, 4.5 mmol), BoC2O (5.1 g, 23.4 mmol), and DMAP (114.5 mg, 0.9 mmol) were added to THF at room temperature and stirred at room temperature for 12 h until the starting materials reacted completely. After the reaction, the reaction solution was dried and separated by column chromatography (PE:EA = 10:1) to obtain compound 20 (1.6 g, 4.23 mmol) with a yield of 94%. The above-mentioned compound 21 was prepared as follows:

[0088] In a 100 mL round-bottom flask, 20 (400 mg, 1.04 mmol), Pd2dba3 (95.16 mg, 0.11 mmol), BINAP (194.28 mg, 0.312 mmol), and sodium tert-butoxide (151.36 mg, 1.58 mmol) were dissolved in toluene (20 mL). The mixture was stirred at room temperature for 5 minutes. 6 (288.3 mg, 1.25 mmol) was then slowly added to the reaction mixture. The mixture was then heated to 95°C and refluxed overnight. TLC analysis indicated that no starting material remained. The reaction mixture was extracted with water and ethyl acetate. The organic phases were combined and separated by column chromatography (PE:EA = 1:1) to afford the final product 21 (277.8 mg, 0.58 mmol) in a 56% yield.

[0089] The preparation method of the above compound 22 is:

[0090] In a 100 mL round-bottom flask, 21 (277.8 mg, 0.58 mmol) was added portionwise to a hydrochloric acid and ethyl acetate solution and stirred at room temperature for 2 h until the reaction of the raw materials was complete and ammonia was liberated. The mixture was extracted with ethyl acetate, and the organic phases were combined and separated by column chromatography to obtain 45 mg of the product 22.

[0091] 1H NMR(400MHz, DMSO-d6)δ9.11(s,1H),8.28(s,1H),7.47(s,1H),7.39–7.32(m,4H),7.27(dd,J=8.0,5.0Hz,1H),5.57(s,1H),5.41(s,1H),4 .46(s,2H),3.68–3.47(m,2H),3.16(td,J=16.1,14.1,8.1Hz,3H),2.65(dt,J=53.2,11.6Hz,2H),1.63(d,J=9.9Hz,2H),1.52–1.15(m,3H).

[0092] LC-MS [M+H + ]378.34.

[0093] Example 3

[0094] The synthetic route of the compound represented by formula 33 of the present invention is as follows:

[0095] The preparation method of the above compound 30 is:

[0096] To a 100 mL round-bottom flask, 3 (500 mg, 2.17 mmol), propargylamine (119.5 mg, 2.17 mmol), and DIPEA (336.7 mg, 2.6 mmol) were added and dissolved in isopropanol at room temperature. The mixture was allowed to react overnight at room temperature until the starting materials reacted completely. After the reaction, the reaction solution was dried and isolated by column chromatography (PE:EA = 10:1) to obtain compound 30 (468.2 mg, 1.89 mmol) in an 87% yield. The above-mentioned compound 31 was prepared as follows:

[0097] To a 100 mL round-bottom flask, 30 (468.2 mg, 1.89 mmol), BoC2O (536.2 mg, 2.46 mmol), and DMAP (22 mg, 0.18 mmol) were dissolved in THF and stirred at room temperature for 2 h until the starting materials reacted completely. After the reaction, the reaction mixture was dried and isolated by column chromatography (PE:EA = 10:1) to obtain compound 31 (618.3 mg, 1.78 mmol) in a 94% yield.

[0098] The preparation method of the above compound 32 is:

[0099] In a 100 mL round-bottom flask, 31 (618.3 mg, 1.78 mmol), 6 (409.4 mg, 1.78 mmol), and DIPEA (460.3 mg, 3.56 mmol) were dissolved in DMAC and then heated to 130°C and refluxed overnight. TLC analysis indicated no residual starting material. The reaction mixture was extracted with water and ethyl acetate. The combined organic phases were separated by column chromatography (PE:EA = 3:1) to afford the final product 32 (646.38 mg, 1.19 mmol) in a 67% yield.

[0100] The preparation method of the above compound 33 is:

[0101] A 100 mL round-bottom flask was prepared with a 3 mol / L methanesulfonic acid / dry dichloromethane solution. 32 (646.38 mg, 1.19 mmol) was added portionwise to the reaction solution and stirred at room temperature for 2 h until the reaction of the starting material was complete and saturated potassium carbonate solution was liberated. The product 33 was extracted with dichloromethane, and the organic phases were combined and purified by high pressure to obtain 48 mg of the product 33.

[0102] 1H NMR(400MHz,Chloroform-d)δ7.72–7.57(m,1H),6.34(s,1H),5.52(s,1H),5.27(s,1H),4.25(s,1H),3.99(d,J=30.0Hz,2H),3.39–3.33(m,1 H),3.28–3.16(m,2H),3.08–2.96(m,2H),2.74–2.57(m,2H),2.34(dd,J=22.7,2.5Hz,1H),1.55(dd,J=26.2,11.9Hz,3H),1.28–1.23(m,6H).

[0103] LC-MS [M+H + ]343.30.

[0104] Example 4

[0105] The synthetic route of the compound represented by formula 38 of the present invention is as follows:

[0106] The preparation method of the above compound 34 is:

[0107] Accurately weigh compound 3 (1.05 g, 4.56 mmol) and ammonia water (25%) (10.86 g, 77.5 mmol) and add them sequentially into a 75 mL sealed tube. Seal the air duct, control the temperature to 80°C, and react for 6 h.

[0108] LC-MS analysis indicated complete reaction of the starting material. The reaction mixture was cooled to room temperature and stirred at 0°C for 15 minutes to precipitate more solid. The mixture was filtered, the filter cake rinsed with water, and then dried. The filter cake was dissolved in methyl tert-butyl ether, the aqueous phase was separated, and the organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was vacuum-desolvated to yield an off-white solid 34 (0.8 g, 3.80 mmol), with a yield of 83.3%.

[0109] The preparation method of the above compound 35 is:

[0110] Compound 34 (610 mg, 2.9 mmol), THF (6.0 g), Boc2O (664 mg, 3.05 mmol), triethylamine (293 mg, 2.9 mmol) and 4-dimethylaminopyridine (DMAP) (35 mg, 0.29 mmol) were accurately weighed and added sequentially into a 100 mL single-necked bottle and reacted at room temperature for 4 h.

[0111] TLC analysis showed that the reaction of the starting material was complete, and the reaction solution was vacuum-desolvated. The residue was dissolved in a small amount of dichloromethane and purified by column chromatography (PE:EA=20:1) to obtain compound 35 (800 mg, 2.58 mmol) as a white solid in a yield of 88.9%.

[0112] The preparation method of the above compound 36 is:

[0113] Compound 35 (400 mg, 1.29 mmol), ACN (4.0 g), 1-bromo-2-butyne (189 mg, 1.42 mmol) and cesium carbonate (463 mg, 1.42 mmol) were accurately weighed and added sequentially into a 15 mL sealed tube. The temperature was controlled at 80°C and the reaction was carried out for 2 h.

[0114] TLC confirmed complete reaction of the starting material. The mixture was cooled to room temperature and filtered. The filter cake was rinsed with DCM and dried, and the filtrate was vacuum-desolvated. The residue was dissolved in a small amount of dichloromethane and purified by column chromatography (PE:EA = 20:1) to afford 36 (450 mg, 1.24 mmol) as a white solid in a 96.3% yield.

[0115] The preparation method of the above compound 37 is:

[0116] Accurately weigh compound 36 (400 mg, 1.1 mmol), dimethylacetamide (4.0 g), compound 6 (330 mg, 1.43 mmol) and DIPEA (427 mg, 3.3 mmol) and add them sequentially into a 15 mL sealed tube. Under argon protection, seal the tube tightly, control the temperature at 130°C, and react for 20 h.

[0117] TLC confirmed complete reaction of the starting material. The reaction mixture was cooled to room temperature and poured into water. The mixture was extracted three times with EA. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was vacuum-desolvated. The residue was dissolved in a small amount of DCM and purified by column chromatography using a gradient elution (PE:EA = 5:1 → 3:1 → 2:1) to afford 37 (510 mg, 1.07 mmol) as a pale yellow liquid in a 97.8% yield.

[0118] The preparation method of the above compound 38 is:

[0119] Compound 37 (510 mg, 0.917 mmol), dry DCM (5 mL) and methanesulfonic acid (528 mg, 5.5 mmol) were accurately weighed and added sequentially into a 25 mL single-necked bottle under argon protection and reacted at room temperature for 3 h.

[0120] LC-MS analysis showed complete reaction of the starting material and the intermediate (one Boc removed). The reaction system was poured into saturated sodium bicarbonate solution, and the aqueous phase pH was measured to be 8-9. Extraction was performed three times with EA. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was vacuum-desolvated. A small amount of diethyl ether was added to the residue to precipitate a solid. The mixture was stirred at room temperature for 15 minutes, filtered, and the filter cake was collected and vacuum-dried.

[0121] A light yellow solid 38 (75 mg) was obtained with a yield of 23%.

[0122] 1 H NMR(400MHz,Chloroform-d)δ7.67(s,1H),6.20(s,1H),5.17(s,1H),4.91(t,J=6.9Hz,1H),4.36(ddd,J =14.8,7.9,3.3Hz,1H),4.01(s,2H),3.55(td,J=10.4,3.8Hz,1H),3.49(t,J=7.0Hz,1H),3.41(dd,J=11 .9,4.5Hz,1H),3.33(d,J=12.4Hz,1H),3.16–2.98(m,2H),2.74(td,J=12.4,3.3Hz,1H),2.65(t,J=11.4 Hz,1H),1.83(t,J=2.4Hz,3H),1.79–1.65(m,2H),1.59(d,J=11.3Hz,1H),1.30(dd,J=11.4,6.9Hz,6H).

[0123] Example 5

[0124] The synthetic route of the compound represented by formula 41 of the present invention is as follows:

[0125] The preparation method of the above compound 39 is:

[0126] Compound 35 (300 mg, 0.97 mmol), ACN (4.0 g), allyl bromide (130 mg, 1.07 mmol) and cesium carbonate (350 mg, 1.07 mmol) were accurately weighed and added sequentially into a 15 mL sealed tube. The temperature was controlled at 80° C. and the reaction was carried out for 2 h.

[0127] TLC confirmed complete reaction of the starting material. The mixture was cooled to room temperature and filtered. The filter cake was rinsed with DCM and dried, and the filtrate was vacuum-desorbed. The residue was dissolved in a small amount of DCM and purified by column chromatography (PE:EA = 20:1) to afford 39 (303 mg, 0.869 mmol) as a white solid in an 89.6% yield.

[0128] The preparation method of the above compound 40 is:

[0129] Compound 39 (300 mg, 0.86 mmol), DMAc (5.0 g), compound 6 (256 mg, 1.12 mmol) and DIPEA (333 mg, 2.58 mmol) were accurately weighed and added sequentially into a 15 mL sealed tube. Under argon protection, the tube was sealed tightly, the temperature was controlled at 130°C, and the reaction was carried out for 7 h.

[0130] TLC indicated complete reaction of the starting material. The reaction mixture was cooled to room temperature and poured into water. The mixture was extracted three times with EA. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was vacuum-desolvated. The residue was dissolved in a small amount of DCM and purified by column chromatography using a gradient elution (PE:EA = 4:1 → 2.5:1) to afford 40 (350 mg), a pale yellow liquid, in a yield of 75.1%.

[0131] The preparation method of the above compound 41 is:

[0132] Compound 40 (300 mg, 0.643 mmol), dry ethyl acetate (4 mL) and 4M HCl-EA (1 ml, 4 mmol) were accurately weighed and added sequentially into a 25 mL single-necked bottle under argon protection and reacted at room temperature for 3 h.

[0133] LC-MS analysis showed that the reaction of the starting material and the intermediate (one Boc was removed) was complete. The reaction system was poured into a saturated sodium bicarbonate solution, and the aqueous phase pH was measured to be 8-9. The product was extracted three times with EA, and the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was vacuum-desolvated. A small amount of diethyl ether was added to the residue to precipitate a solid. The product was stirred at room temperature for 15 minutes, filtered, and the filter cake was collected and vacuum-dried to obtain a light yellow solid 41 (68 mg) in a 30% yield.

[0134] 1H NMR(400MHz,Chloroform-d)δ7.67(s,1H),6.19(d,J=6.4Hz,1H),5.91(tt,J=10.6, 5.3Hz,1H),5.30(dd,J=30.8,13.8Hz,2H),5.02(s,1H),4.71(s,1H),4.38(dd,J=14. 3,8.4Hz,1H),3.92(s,2H),3.53–3.18(m,2H),3.16–3.02(m,2H),2.97(dd,J=14.7, 5.3Hz, 1H), 2.57 (dt, J = 43.4, 11.3Hz, 2H), 1.71–1.41 (m, 3H), 1.31 (d, J = 7.6Hz, 6H).

[0135] Example 6

[0136] The synthetic route of the compound represented by formula 45 of the present invention is as follows:

[0137] The preparation method of the above compound 42 is:

[0138] Accurately weigh compound 3 (500 mg, 2.17 mmol), ethanol (6 g), cyclopropylmethylamine (300 mg, 4.34 mmol) and triethylamine (438 mg, 4.34 mmol) and add them sequentially into a 15 mL sealed tube. Seal the tube tightly, control the temperature to 80°C, and react for 3 h.

[0139] LC-MS analysis showed that the starting material was completely reacted, and the reaction solution was removed by vacuum desolvation. The residue was dissolved in a small amount of DCM and purified by column chromatography (PE:EA = 20:1) to give an off-white solid 42 (490 mg, 1.86 mmol) in a yield of 85.5%.

[0140] The preparation method of the above compound 43 is:

[0141] Compound 42 (490 mg, 1.85 mmol), THF (4.0 g), Boc2O (484 mg, 2.22 mmol), TEA (280 mg, 2.78 mmol) and DMAP (23 mg, 0.19 mmol) were accurately weighed and added sequentially into a 100 mL single-necked bottle and reacted at room temperature for 20 h.

[0142] TLC analysis showed that the starting material had reacted completely, and the reaction solution was removed by vacuum desolvation. The residue was dissolved in a small amount of DCM and purified by column chromatography (PE:EA=30:1) to obtain a light yellow oil 43 (600 mg, 1.64 mmol) in a yield of 88.9%.

[0143] The preparation method of the above compound 44 is:

[0144] Compound 43 (600 mg, 1.66 mmol), DMAc (6.0 g), compound 6 (492 mg, 2.14 mmol) and DIPEA (638 mg, 4.93 mmol) were accurately weighed and added sequentially into a 75 mL sealed tube. Under argon protection, the tube was sealed tightly, the temperature was controlled at 130°C, and the reaction was carried out for 4 h.

[0145] TLC indicated complete reaction of the starting material. The reaction mixture was cooled to room temperature and poured into water. The mixture was extracted three times with EA. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was vacuum-desolvated. The residue was dissolved in a small amount of DCM and purified by column chromatography using a gradient elution (PE:EA = 4:1 → 2:1) to afford 44 (680 mg, 1.23 mmol) as a pale yellow liquid in a yield of 73.9%.

[0146] The preparation method of the above compound 45 is:

[0147] Compound 44 (100 mg, 0.18 mmol), ethyl acetate (1 mL) and hydrochloric acid / ethyl acetate (3 M) (3 mL, 9 mmol) were accurately weighed and added sequentially into a 25 mL single-necked bottle under argon protection and reacted at room temperature for 6 h.

[0148] LC-MS analysis indicated complete reaction of the starting material and the intermediate (one Boc removed). The reaction system was poured into saturated sodium bicarbonate solution, and the aqueous phase measured pH = 8-9. Extraction was performed three times with EA. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was vacuum-desolvated. The residue was dissolved in a small amount of DCM and purified by column chromatography using a gradient elution (DCM:MeOH = 10:1 → 5:1 → 4:1) to afford 45 as an off-white solid (33 mg, 0.09 mmol) in a 51.6% yield.

[0149] 1H NMR(400MHz,Chloroform-d)δ7.67(s,1H),6.10(s,1H),5.02(s,1H),4.72(dd,J=8.2,5.5Hz,1H),4. 38(ddd,J=14.9,8.2,2.6Hz,1H),3.31(td,J=11.0,9.5,4.4Hz,1H),3.25(dd,J=11.4,4.5Hz,1H),3. 15–3.05(m,4H),2.97(dd,J=14.6,5.4Hz,1H),2.70–2.60(m,1H),2.54(t,J=10.8Hz,1H),1.68–1.59 (m,1H),1.57–1.51(m,2H),1.39(s,1H),1.35–1.23(m,6H),0.70–0.56(m,2H),0.32(q,J=5.2Hz,2H).

[0150] LC-MS: [M+H] + =359.43, [M+2H] 2+ / 2=180.30.

[0151] Biological activity test

[0152] The following assay method uses a known CDK inhibitor (CT7001, developed by Emory University, homemade) and the compound prepared by the present invention for biological assay, demonstrating that the compound prepared by the present invention has the effect of inhibiting CDK7 kinase activity and has better enzyme and cellular biological activity than similar target compounds disclosed previously.

[0153] Experiment 1: ICR mouse PK experiment

[0154] ICR male mice (weighing 18-20 g) were administered 10 mg / kg via gavage and tail vein injection with the known CDK inhibitor CT7001 and compounds 33 and 41 of this invention, respectively, with 12 animals per group. The dosing solvent consisted of 10% DMSO + 10% polyoxyethylene castor oil + 80% saline solution. The gavage group fasted for approximately 12 hours before dosing and then received a regular meal 4 hours after dosing. Water was not withheld throughout the experiment. Approximately 0.2 mL of blood was collected from the orbital cavity before dosing and at 5, 15, 30 minutes, and 1, 2, 4, 6, 8, and 24 hours after dosing. Blood was collected in EDTA-K2-anticoagulated EP tubes on ice and centrifuged at 3500 rpm for 5 minutes at 4°C to separate plasma. Plasma separation was completed within 1 hour of blood collection and stored at -20°C until analysis. Plasma concentrations of CT7001, 33, and 41 were quantified using liquid chromatography-tandem mass spectrometry (LC-MS / MS). The pharmacokinetic parameters of the sample analysis results were calculated using WinNonlin software.

[0155] As can be seen from the data in Table 1, compound 41 prepared in the present invention has better bioavailability after oral administration compared with CT7001.

[0156] Table 1. Pharmacokinetic parameters of oral administration group

[0157] Table 2. Pharmacokinetic parameters of the intravenous administration group

[0158] As can be seen from the data in Table 2, compound 33 prepared in the present invention has a longer half-life after intravenous administration compared with CT7001, which can reduce the frequency of administration. After intravenous administration of compounds 33 and 41, the steady-state apparent distribution volume (Vss) in mice is higher, and the drug is more widely distributed in tissues.

[0159] Experiment 2: Detection of the inhibitory effect of the prepared compounds on CDK7 / CycH / MAT1 enzyme activity

[0160] Thaw CDK7 / CycH / MAT1 protein on ice and equilibrate all other reagents to room temperature. Prepare CDK7 / CycH / MAT1 protein and ATP / substrate to the appropriate concentrations in enzyme reaction buffer (50 mM Hepes, 10 mM MgCl2, 0.01% Brij35, 1 mM EGTA, 2 mM DTT). Add 20 nL of test compound to each well of a 384-well, white-walled, low-volume microtiter plate, followed by the prepared CDK7 / CycH / MAT1 protein (2 μL / well), mix thoroughly, and incubate at 25°C for 10 minutes. Then, initiate the reaction by adding ATP / substrate and incubate at 25°C for 60 minutes. The concentrations of the reaction components in the enzyme reaction working system were as follows: 3.5 ng / μl CDK7 / CycH / MAT1 protein, 30 μM ATP, and 0.1 μM substrate. The test compound concentrations, from high to low, were 5000, 1667, 556, 185, 62, 21, 7, 2, 1, and 0.3 nM. After the enzyme reaction, 4 μl ADP-Glo ​​Reagent was added to each well and incubated at 25°C for 40 min. Then, 8 μl Kinase Detection Reagent was added to each well and incubated at 25°C for 40 min. Chemiluminescent signals were recorded using a microplate reader, and curves were plotted to calculate the IC. 50 value.

[0161] As shown in the data of Table 3, the IC50 values ​​of compounds 8, 22, 33, and 41 are all less than 10 nM, indicating that the compounds prepared in the present invention have the effect of inhibiting the activity of CDK7 / CycH / MAT1 kinases.

[0162] Table 3. Enzyme activity inhibition data

[0163] Experiment 3: Testing of the compound's inhibition on tumor cell proliferation

[0164] Cells were cultured in the corresponding growth medium. HCT-116, MDA-MB-468, Jurkat, HCC70, and MDA-MB-436 tumor cell lines were seeded into 384-well plates at 600, 300, 800, 800, and 1000 cells / well (18 μL / well) and incubated overnight at 37°C in 5% CO2 (MDA-MB-468 was incubated overnight at 37°C in 100% air). A 10X intermediate dilution plate was prepared by preparing a 10 mM working solution of the test sample in DMSO and performing 10 1:3 dilutions in 1% DMSO. Cell plates were treated by adding 2 μL / well of the 10X intermediate dilution plate to the cell plates to achieve the final experimental concentrations (10,000, 3,333, 1,111, 370, 123, 41, 14, 4.6, and 1.5 nM). HCT-116, Jurkat, and HCC70 cell plates were incubated at 37°C, 5% CO2 for 3, 7, and 7 days, respectively (MDA-MB-468 cell plates were incubated at 37°C, 100% air for 7 days). After treatment, the Cell Titer-Glo reagent was removed from -20°C and allowed to equilibrate to room temperature. Cell Titer-Glo reagent (20 μL / well) was added to the cell plate and incubated for 10 minutes. After 10 minutes, luminescence was read using a microplate reader. Data were analyzed using Excel and related calculations were performed using Graph Pad Prism 7.0 software. The table shows the IC values ​​of the compounds for inhibition of tumor cell proliferation. 50 Numeric value.

[0165] As shown in the data in Table 4, among all the tumor cells tested, 41 had a stronger inhibitory effect on tumor cell proliferation than CT7001.

[0166] Table 4. Inhibition of tumor cell proliferation by compounds

[0167] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be considered as the scope of protection of the present invention.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, solvate or prodrug thereof, in, R1 is a substituted or unsubstituted deuterated C1-C3 alkyl, C1-C3 alkyl, C2-C6 alkene, C2-C6 alkyne, or a substituted or unsubstituted C6-10 arylC1-6 alkyl; The substituents are independently selected from H, D, halogen, hydroxy, -CN, carbonyl, C1-C3 alkyl, C2-C3 alkene, C2-C3 alkyne, deuterated C1-C3 alkyl, C1-C3 alkoxy, hydroxy C1-C3 alkyl, fluorinated C1-C3 alkyl, cyano C1-C3 alkyl, C3-8 cycloalkyl, C3-10 heterocyclyl, C6-10 aryl; R2 is selected from halogen, hydroxy, -CN, carbonyl, C1-C3 alkyl, C2-C3 alkene or alkyne, deuterated C1-C3 alkyl, C1-C3 alkoxy, hydroxy C1-C3 alkyl, fluorinated C1-C3 alkyl, cyano C1-C3 alkyl; When R1 is benzyl, R2 is -CN.

2. The compound according to claim 1 or a pharmaceutically acceptable salt, ester, stereoisomer, solvate or prodrug thereof, characterized in that: R1 is a substituted or unsubstituted C1-C3 alkyl group, a C2-C6 alkene or an alkyne, or a substituted or unsubstituted C6-10 aryl C1-6 alkyl group.

3. The compound according to claim 1 or a pharmaceutically acceptable salt, ester, stereoisomer, solvate or prodrug thereof, characterized in that: R2 is selected from -CN, C1-C3 alkyl.

4. The compound according to claim 1 or a pharmaceutically acceptable salt, ester, stereoisomer, solvate or prodrug thereof, characterized in that: R1 is substituted or unsubstituted 5. The compound according to claim 1 or a pharmaceutically acceptable salt, ester, stereoisomer, solvate or prodrug thereof, characterized in that: The compound is selected from:

6. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises the compound of claim 1 or a pharmaceutically acceptable salt, ester, stereoisomer, solvate or prodrug thereof.

7. The pharmaceutical composition according to claim 6, characterized in that: The pharmaceutical composition further comprises other therapeutic agents and / or pharmaceutically acceptable carriers.

8. Use of the compound according to claim 1 or its pharmaceutically acceptable salt, ester, stereoisomer, solvate, prodrug or the pharmaceutical composition according to claim 6 in the preparation of a CDK kinase inhibitor.

9. Use of the compound according to claim 1 or its pharmaceutically acceptable salt, ester, stereoisomer, solvate, prodrug or the pharmaceutical composition according to claim 6 in the preparation of a drug for treating and / or inhibiting CDK-related diseases.

10. The use according to claim 9, characterized in that: The CDK-related disease is cancer.

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