Novel pyrido[2,3-d]pyrimidin-7(8H)-one derivatives

Abstract

The present invention relates to a compound represented by general formula (1) and a preparation method thereof, and use of the compound represented by general formula (1) and its isomers, crystal forms and pharmaceutically acceptable salts as CDK2 / 4 inhibitors in the preparation of anti-tumor drugs.

Description

[0001] This application claims the priority of Chinese application CN 202010557579.7, filed on June 17, 2020. This application cites the entire text of the above Chinese application. Technical Field

[0002] The present invention relates to the field of pharmaceutical chemistry, and more specifically, to a class of pyrimidine compounds, a preparation method thereof, and the use of the compounds as CDK2 / 4 inhibitors in the preparation of anti-tumor drugs. Background Art

[0003] Cyclin-dependent kinases (CDKs) are a class of enzymes with important functions in cells that can regulate cell division and proliferation of eukaryotic cells. The catalytic unit of CDKs can be activated by cyclins or regulatory subunits. To date, at least 16 mammalian cyclins have been identified. Among them, Cyclin A / CDK2, Cyclin E / CDK2, Cyclin D / CDK4, and Cyclin D / CDK6 are very important regulators of cell cycle progression. Other physiological functions of the cyclin / CDK complex include regulating gene transcription, DNA repair, differentiation, and apoptosis. Abnormal activation or enhanced activity of CDKs has been shown to lead to the occurrence of human tumors, and the growth of human tumors is usually accompanied by changes in the CDK protein itself or its regulatory factors. Amplification, mutation, loss of CDKs regulatory subunits, or transcriptional silencing of endogenous CDK inhibitors have been reported. Currently, CDK inhibitors have been used to treat certain cancers.

[0004] CDK4 / 6 inhibitors Palbociclib and ribociclib have been approved for combination with aromatase inhibitors for the treatment of advanced or metastatic postmenopausal breast cancer patients with estrogen receptor (ER)-positive, human epidermal growth factor (HER-2)-negative disease. In addition, Palbociclib can also be used in combination with fulvestrant for patients whose disease has progressed after endocrine therapy. Although CDK4 / 6 inhibitors have shown strong efficacy in clinical practice, especially in patients with ER-positive metastatic breast cancer, similar to other kinase inhibitors, primary or acquired resistance will weaken the efficacy of CDK4 / 6 inhibitors over time.

[0005] Overexpression of CDK2 is associated with abnormal regulation of the cell cycle. The Cyclin E / CDK2 complex plays a very important role in regulating the G1 / S phase transition of the cell cycle, histone biosynthesis, and centrosome duplication. Rb phosphorylation mediated by cyclin D / CDK4 / 6 and cyclin E / CDK2 releases the G1 transcription factor E2F, thereby promoting entry into the S-phase. In the early S-phase, the activation of Cyclin A / CDK2 promotes the phosphorylation of endogenous substrates, leading to DNA replication and the inactivation of E2F, promoting the completion of the S-phase.

[0006] Cyclin E, the regulatory subunit of CDK2, is often overexpressed in cancer. Amplification or overexpression of Cyclin E has long been associated with poor prognosis in breast cancer. Overexpression of Cyclin E2 (CCNE2) has been associated with resistance to endocrine therapy in breast cancer. Inhibition of CDK2 has been reported to render tamoxifen resistant and CCNE2-overexpressing cells regain sensitivity to tamoxifen or CDK4 inhibitors. Cyclin E amplification has also been reported to contribute to trastuzumab resistance in HER-2-positive breast cancer. Cyclin E overexpression also plays a very important role in triple-negative breast cancer (TNBC) and inflammatory breast cancer.

[0007] Amplification or overexpression of Cyclin E1 (CCNE1) is also associated with poor prognosis in ovarian cancer, gastric cancer, endometrial cancer, and other cancers.

[0008] Although CDK2 and its regulatory subunit Cyclin E play a very important role in the occurrence of cancer, no drug targeting CDK2 has been approved for marketing so far. Therefore, there is an urgent need to study and discover compounds with good CDK2 targeting activity. Summary of the invention

[0009] The present invention aims to provide a compound represented by general formula (1) or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates:

[0010]

[0011] In the general formula (1):

[0012] R 1 is -H, -CN, halogen, (C1-C6) alkyl, (C1-C6) haloalkyl or (C3-C6) cycloalkyl, wherein the alkyl, haloalkyl and cycloalkyl may each independently be optionally substituted by one or more of the following groups: -H, halogen, -OH, -NH2, (C1-C6) alkoxy and -NR 8a R8b ;

[0013] R 2 is (C3-C8)cycloalkyl or (3-8 membered)heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl may each independently be optionally substituted by one or more of the following groups: -H, halogen, -OH, -NH2, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy and -NR 8a R 8b ;

[0014] X is O or NH;

[0015] R 3 -H, -CN, halogen, -OH, -(CH2) m NR 8a R 8b , (C1-C6) alkyl or (C1-C6) alkoxy, wherein the alkyl and alkoxy groups may be optionally substituted with one or more of the following groups: -H and halogen;

[0016] R 4 for or

[0017] Y is -H, -F or -CH3;

[0018] R 5a and R 5b each independently represents -H, (C1-C6)alkyl, (C3-C6)cycloalkyl, (5-6-membered)heterocycloalkyl or (5-9-membered)heteroaryl, wherein said (C1-C6)alkyl, (C3-C6)cycloalkyl, (5-6-membered)heterocycloalkyl and (5-9-membered)heteroaryl may each independently be optionally substituted by one or more of the following groups: -H, halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl and -NR 8a R 8b ; or R 5a and R 5b The carbon atoms connected thereto can together form a (4-8 membered) heterocycloalkyl group, wherein the (4-8 membered) heterocycloalkyl group can be independently substituted by one or more of the following groups: -H, halogen, (C1-C6) alkyl, (C1-C6) alkoxy, (C3-C6) cycloalkyl and -NR 8a R 8b ;

[0019] R 5c and R 5d Each is independently -H, (C1-C6) alkyl or (C3-C6) cycloalkyl, or R 5c and R5d The carbon atoms connected thereto can together form a (4-8 membered) heterocycloalkyl group, wherein the (C1-C6) alkyl group, (C3-C6) cycloalkyl group and (4-8 membered) heterocycloalkyl group can each independently be substituted by one or more of the following groups: -H, halogen, (C1-C6) alkyl group, (C1-C6) alkoxy group, (C3-C6) cycloalkyl group and -NR 8a R 8b ;

[0020] R 5e and R 5f Each is independently -H or (C1-C6) alkyl, or R 5e and R 5f The carbon atoms connected thereto can together form a (4-8 membered) heterocycloalkyl, wherein the (C1-C6) alkyl and (4-8 membered) heterocycloalkyl can each independently be substituted by one or more of the following groups: -H, halogen, (C1-C6) alkyl, (C1-C6) alkoxy, (C3-C6) cycloalkyl and - NR 8a R 8b ;

[0021] R 6a and R 6b Each is independently -H, (C1-C6) alkyl or (C3-C6) cycloalkyl, or R 6a and R 6b The N atoms connected thereto can together form a (4-8 membered) heterocycloalkyl group, which can be independently substituted by one or more of the following groups: -H, halogen, (C1-C6) alkyl, (C1-C6) alkoxy and (C3-C6) cycloalkyl;

[0022] R 7 is -H, (C1-C6)alkyl, (C3-C6)cycloalkyl, (6-10-membered)aryl, (5-10-membered)heteroaryl or (4-8-membered)heterocycloalkyl, wherein the alkyl, cycloalkyl, aryl and heteroaryl groups are each independently optionally substituted with one or more of the following groups: -H, halogen, (C1-C6)alkyl, (C1-C6)alkoxy or (C3-C6)cycloalkyl;

[0023] R 7a and R 7b Each is independently -H, -CN, -OH, halogen, (C1-C6) alkyl, (C1-C6) alkoxy, (C3-C6) cycloalkyl or -(CH2) m NR 8a R 8b, wherein the alkyl and cycloalkyl groups may be independently substituted by one or more of the following groups: -H, halogen, (C1-C6) alkyl, (C1-C6) alkoxy and (C3-C6) cycloalkyl;

[0024] R 8a and R 8b Each is independently -H, (C1-C6) alkyl or (C3-C6) cycloalkyl, or R 8a and R 8b The N atoms connected thereto can together form a (4-8 membered) heterocycloalkyl group, which can be independently substituted by one or more of the following groups: -H, halogen, (C1-C6) alkyl, (C1-C6) alkoxy and (C3-C6) cycloalkyl; and

[0025] m is an integer of 0, 1, 2 or 3.

[0026] In another preferred embodiment, in the general formula (1), R 1 It is -H, -CN, halogen, (C1-C3) alkyl, (C1-C3) haloalkyl or (C3-C4) cycloalkyl, wherein the alkyl, haloalkyl and cycloalkyl may be optionally substituted by one or more of the following groups: -H, -F, -Cl, -Br, -OH, -OCH3, -NH2, -N(CH3)2 and -CH3.

[0027] In another preferred embodiment, in the general formula (1), R 1 For: -H, -CN, -F, -Cl, -Br, -CH3, -CH2CH3, -CH(CH3)2,

[0028] In another preferred embodiment, in the general formula (1), R 2 It is (C5-C6)cycloalkyl or (5-6 membered)heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl may each independently be optionally substituted by one or more of the following groups: -H, -F, -OH, -OCH3, -NH2, -N(CH3)2 and -CH3.

[0029] In another preferred embodiment, in the general formula (1), R 2 for:

[0030]

[0031] In another preferred embodiment, in the general formula (1), R 3 -H, -CN, halogen, -OH, -NR 8a R 8b, (C1-C3) alkyl or (C1-C3) alkoxy, wherein the alkyl and alkoxy may each independently be optionally substituted with one or more of the following groups: -H and -F.

[0032] In another preferred embodiment, in the general formula (1), R 3 It is -H, -CN, -F, -OH, -CH3 or -OCH3.

[0033] In another preferred embodiment, in the general formula (1), when R 4 for When R 5a and R 5b Each is independently -H, (C1-C3) alkyl, (C3-C4) cycloalkyl, (5-6 membered) heterocycloalkyl or (5-6 membered) heteroaryl, wherein the (C1-C3) alkyl and (5-6 membered) heterocycloalkyl may be independently substituted by one or more of the following groups: -H, -F, -CH3, -OCH3, -N(CH3)2, or R 5a and R 5b The carbon atoms connected thereto can together form a (4-6 membered) heterocycloalkyl, wherein the (4-6 membered) heterocycloalkyl is oxetane, azetidine, tetrahydrofuran, pyrrolidine, tetrahydrothiophene, piperidine, tetrahydropyran, morpholine or piperazine, and the (4-6 membered) heterocycloalkyl can be independently substituted by one or more of the following groups: -H, -F, -CH3, -OCH3, and -N(CH3)2.

[0034] In another preferred embodiment, in the general formula (1), R 4 for:

[0035]

[0036] In another preferred embodiment, in the general formula (1), when R 4 for When R 5c and R 5d are each independently -H, (C1-C3)alkyl or (C3-C4)cycloalkyl, or R 5c and R 5d The carbon atoms connected thereto can together form a (4-6 membered) heterocycloalkyl group, wherein the (4-6 membered) heterocycloalkyl group is oxetane, azetidine, tetrahydrofuran, pyrrolidine, tetrahydrothiophene, piperidine, tetrahydropyran, morpholine or piperazine, and the (4-6 membered) heterocycloalkyl group can be independently substituted by one or more of the following groups: -H, -F, -CH3, -OCH3, and -N(CH3)2; R 5e and R 5f Each is independently -H or -CH3.

[0037] In another preferred embodiment, in the general formula (1), R 4 for:

[0038]

[0039] In another preferred embodiment, in the general formula (1), when R 4 for When R 6a and R 6b are each independently -H, (C1-C3)alkyl or (C3-C4)cycloalkyl, or R 6a and R 6b The N atom connected thereto can together form a (4-6 membered) heterocycloalkyl, wherein the (4-6 membered) heterocycloalkyl is azetidine, pyrrolidine, piperidine, morpholine or piperazine, and the (4-6 membered) heterocycloalkyl can be independently substituted by one or more of the following groups: -H, -F, -CH3, -OCH3, and -N(CH3)2.

[0040] In another preferred embodiment, in the general formula (1), R 4 for:

[0041]

[0042] In another preferred embodiment, in the general formula (1), when R 4 for When R 7 is -H, (C1-C3) alkyl, (C3-C4) cycloalkyl, wherein the alkyl and cycloalkyl can be independently substituted by one or more of the following groups: -H, -F, -CH3, -OCH3, and -N(CH3)2.

[0043] In another preferred embodiment, in the general formula (1), R 4 for:

[0044]

[0045] In another preferred embodiment, in the general formula (1), when R 4 for When R 7a and R 7b Each is independently -H, -CN, -OH, -F, (C1-C3) alkyl, (C1-C3) alkoxy, (C3-C6) cycloalkyl, -NR8a R 8b or -(CH2)NR 8a R 8b , wherein the alkyl, alkoxy and cycloalkyl groups may each independently be substituted by one or more of the following groups: -H and -F.

[0046] In another preferred embodiment, in the general formula (1), R 4 for:

[0047]

[0048] In various embodiments, representative compounds of the invention have one of the following structures:

[0049]

[0050]

[0051]

[0052]

[0053]

[0054]

[0055]

[0056]

[0057]

[0058]

[0059]

[0060]

[0061] Another object of the present invention is to provide a pharmaceutical composition comprising a pharmacologically acceptable excipient and / or carrier, and a compound of the general formula (1) of the present invention or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates.

[0062] Another object of the present invention is to provide the use of the above-mentioned compound of the present invention or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates or the above-mentioned pharmaceutical compositions for preparing drugs for treating and / or preventing CDK protein-related diseases.

[0063] Another object of the present invention is to provide a method for treating CDK protein-related diseases, comprising administering to a subject a therapeutically effective amount of the above-mentioned compound or its isomers, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates or the above-mentioned pharmaceutical composition.

[0064] By synthesizing and carefully studying a variety of new compounds having CDK protein inhibitory effects, the inventors found that in the compound of general formula (1), when R 4 for or The compound unexpectedly possessed strong CDK2 and CDK4 inhibitory activity and showed strong anti-cell proliferation activity.

[0065] It is to be understood that both the foregoing general description and the following detailed description of the present invention are exemplary and explanatory and are intended to provide further explanation of the invention as claimed.

[0066] Synthesis of compounds

[0067] The following is a detailed description of the preparation methods of the compounds of the general formula (1) of the present invention, but these specific methods do not constitute any limitation to the present invention.

[0068] The compounds of formula (1) described above can be synthesized using standard synthetic techniques or known techniques in combination with the methods described herein. In addition, the solvents, temperatures and other reaction conditions mentioned herein can be varied. The starting materials used in the synthesis of the compounds can be synthesized or obtained from commercial sources. The compounds described herein and other related compounds having different substituents can be synthesized using known techniques and starting materials, including those found in March, ADVANCED ORGANIC CHEMISTRY 4 th Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4 th Ed., Vols.A and B (Plenum 2000, 2001), Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3 rd Ed., (Wiley 1999). The general methods for the preparation of compounds can be modified by using appropriate reagents and conditions to introduce various groups into the formulae provided herein.

[0069] On the one hand, the compounds described herein are based on methods known in the art. However, the conditions of the method, such as reactants, solvents, bases, the amount of compounds used, reaction temperature, reaction time, etc. are not limited to the following explanation. 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, and such a combination can be easily performed by a technician in the field to which the present invention belongs. On the one hand, the present invention also provides a method for preparing the compound represented by the general formula (1), which is prepared using the following general reaction scheme 1, general reaction scheme 2 or general reaction scheme 3:

[0070] General reaction scheme 1

[0071]

[0072] Embodiments of compounds of formula (1) can be prepared according to general reaction scheme 1, wherein R 2 , R 3 , R 4 , and X are as defined above, and NH2 represents an amine group. As shown in general reaction scheme 1, compound 1-1 and R 2 -NH2 to generate compound 1-2, compound 1-2 is oxidized to generate compound 1-3, compound 1-3 and ethyl acetate are condensed to generate compound 1-4, compound 1-4 is reacted with CF2SO2Na under light conditions to generate compound 1-5, compound 1-5 is oxidized to generate compound 1-6, compound 1-6 and The reaction was carried out under alkaline conditions to generate the target compound 1-7.

[0073] General reaction scheme 2

[0074]

[0075] Embodiments of compounds of formula (1) can be prepared according to general reaction scheme 2, wherein R 2 , R 3 , R 4 , and X are as defined above, and NH2 represents an amine group. As shown in general reaction scheme 2, compound 2-1 and R 2 -NH2 reaction to generate compound 2-2, compound 2-2 through oxidation reaction to generate compound 2-3, compound 2-3 and Compound 2-4 is condensed to form compound 2-4, compound 2-4 is oxidized to form compound 2-5, and compound 2-5 is reacted with The reaction was carried out under alkaline conditions to generate the target compound 2-6.

[0076] General reaction scheme 3

[0077]

[0078] Embodiments of compounds of formula (1) can be prepared according to general reaction scheme 3, wherein R 2 , R 3 , R 4 , and X are as defined above, and NH2 represents an amine group. As shown in general reaction scheme 3, compound 3-1 and R 2 -NH2 reaction to generate compound 3-2, compound 3-2 through oxidation reaction to generate compound 3-3, compound 3-3 and ethyl acetate undergo condensation reaction to generate compound 3-4, compound 3-4 through oxidation reaction to generate compound 3-5, compound 3-5 and The reaction was carried out under alkaline conditions to generate the target compound 3-6.

[0079] Further forms of compounds

[0080] "Pharmaceutically acceptable" as used herein refers to a material, such as a carrier or diluent, that does not abrogate the biological activity or properties of the compound and is relatively non-toxic, i.e., a material that, when administered to a subject, does not cause undesirable biological effects or interact in a deleterious manner with any of its constituent components.

[0081] The term "pharmaceutically acceptable salt" refers to a form of a compound that does not cause significant irritation to the organism to which it is administered and does not cause the biological activity and properties of the compound to disappear. In certain specific aspects, the pharmaceutically acceptable salt is obtained by reacting the compound of formula (1) with an acid, such as an inorganic acid such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, trifluoroacetic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and an acidic amino acid such as aspartic acid and glutamic acid.

[0082] It should be understood that references to pharmaceutically acceptable salts include solvent-added forms or crystal forms, particularly solvates or polymorphs. Solvates contain stoichiometric or non-stoichiometric amounts of solvent and are selectively formed during crystallization with pharmaceutically acceptable solvents such as water, ethanol, etc. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is ethanol. Solvates of compounds of formula (1) are conveniently prepared or formed according to the methods described herein. For example, hydrates of compounds of formula (1) are conveniently prepared by recrystallization from a mixed solvent of water / organic solvent, and the organic solvents used include, but are not limited to, tetrahydrofuran, acetone, ethanol or methanol. In addition, the compounds mentioned herein can exist in unsolvated and solvated forms. In general, for the purposes of the compounds and methods provided herein, the solvated form is considered to be equivalent to the unsolvated form.

[0083] In other specific embodiments, the compound of formula (1) is prepared in different forms, including but not limited to, amorphous, crushed and nano-particle forms. In addition, the compound of formula (1) includes crystalline forms and can also be used as polymorphs. Polymorphs include different lattice arrangements of the same elemental composition of the compound. Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal form, optical and electrical properties, stability and solubility. Different factors such as recrystallization solvents, crystallization rate and storage temperature may cause a single crystal form to dominate.

[0084] In another aspect, the compounds of formula (1) may have chiral centers and / or axial chirality, and therefore appear in the form of racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomers, and cis-trans isomers. Each chiral center or axial chirality will independently produce two optical isomers, and all possible optical isomers and diastereomeric mixtures as well as pure or partially pure compounds are included within the scope of the present invention. The present invention is meant to include all such isomeric forms of these compounds.

[0085] The compounds of the invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125 ( 125 I) and C-14( 14 C). For another example, deuterium can be used to replace hydrogen atoms to form deuterated compounds. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs generally have the advantages of reducing toxic side effects, increasing drug stability, enhancing therapeutic effects, and extending the half-life of drugs in vivo. All isotopic composition changes of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention.

[0086] the term

[0087] Unless otherwise indicated, the terms used in this application, including the specification and claims, are defined as follows. It must be noted that in the specification and the appended claims, the singular forms "a" and "an" include plural meanings unless otherwise clearly indicated in the text. If not otherwise indicated, conventional methods of mass spectrometry, nuclear magnetic resonance, HPLC, protein chemistry, biochemistry, recombinant DNA technology and pharmacology are used. In this application, if not otherwise indicated, the use of "or" or "and" means "and / or".

[0088] Unless otherwise specified, "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight and branched groups of 1 to 14 carbon atoms. Preferred are lower alkyl groups containing 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl. As used herein, "alkyl" includes unsubstituted and substituted alkyl groups, especially alkyl groups substituted by one or more halogens. Preferred alkyl groups are selected from CH3, CH3CH2, CF3, CHF2, CF3CH2, CF3(CH3)CH, i-Pr, n-Pr, i-Bu, n-Bu or t-Bu.

[0089] Unless otherwise specified, "alkenyl" refers to an unsaturated aliphatic hydrocarbon group containing a carbon-carbon double bond, including straight or branched groups of 1 to 14 carbon atoms. Preferably, the lower alkenyl group contains 1 to 4 carbon atoms, such as vinyl, 1-propenyl, 1-butenyl or 2-methylpropenyl.

[0090] Unless otherwise specified, "alkynyl" refers to an unsaturated aliphatic hydrocarbon group containing a carbon-carbon triple bond, including straight and branched chain groups of 1 to 14 carbon atoms. Preferably, it is a lower alkenyl group containing 1 to 4 carbon atoms, such as ethynyl, 1-propynyl or 1-butynyl.

[0091] Unless otherwise specified, "cycloalkyl" refers to a 3- to 14-membered all-carbon monocyclic aliphatic hydrocarbon group, one or more of which may contain one or more double bonds, but none of which has a completely conjugated π electron system. For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexane, cyclohexadiene, etc.

[0092] Unless otherwise specified, "alkoxy" refers to an alkyl group bonded to the rest of the molecule through an ether oxygen atom. Representative alkoxy groups are those having 1-6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy. As used herein, "alkoxy" includes unsubstituted and substituted alkoxy groups, especially alkoxy groups substituted with one or more halogens. Preferred alkoxy groups are selected from OCH3, OCF3, CHF2O, CF3CH2O, i-PrO, n-PrO, i-BuO, n-BuO or t-BuO.

[0093] Unless otherwise specified, "aryl" refers to a hydrocarbon aromatic group, which is monocyclic or polycyclic, for example, a monocyclic aryl ring fused to one or more carbocyclic aromatic groups. Examples of aryl include, but are not limited to, phenyl, naphthyl, and phenanthrenyl.

[0094] Unless otherwise specified, "arylene" refers to a divalent aromatic radical as defined above. Examples of arylene radicals include, but are not limited to, phenylene, naphthylene, and phenanthrenylene.

[0095] Unless otherwise specified, "heteroaryl" refers to an aromatic group containing one or more heteroatoms (O, S or N), and the heteroaryl group is monocyclic or polycyclic, for example, a monocyclic heteroaryl ring is fused with one or more carbocyclic aromatic groups or other monocyclic heterocyclic groups. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolyl, isoquinolyl, furanyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuranyl, benzothiazolyl, benzothienyl, benzoxazolyl, benzopyridinyl and pyrrolopyrimidinyl.

[0096] Unless otherwise specified, "heteroarylene" refers to a divalent heteroaryl group as defined above.

[0097] Unless otherwise specified, "heterocycloalkyl" refers to a saturated or partially unsaturated ring system radical containing one or more heteroatoms (O, S or N), wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom is optionally quaternized as ring atoms. Unless otherwise specified, the ring system of "heterocycloalkyl" can be a monocyclic, bicyclic, spirocyclic or polycyclic ring system. "Heterocycloalkyl" can be attached to the rest of the molecule through more than one ring carbon or heteroatom. Examples of "heterocycloalkyl" include, but are not limited to, pyrrolidine, piperidine, N-methylpiperidine, tetrahydroimidazole, pyrazolidine, butyrolactam, valerolactam, imidazolinone, hydantoin, dioxolane, phthalimide, piperidine, pyrimidine-2,4(1H,3H)-dione, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, 2-azaspiro[3.3]heptane, and the like.

[0098] Unless otherwise specified, "halogen" (or halo) refers to fluorine, chlorine, bromine or iodine. The term "halo" (or "halogen substituted") appearing before the name of a group means that the group is partially or fully halogenated, that is, substituted by F, Cl, Br or I in any combination, preferably substituted by F or Cl.

[0099] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0100] The substituent "-O-CH2-O-" means that two oxygen atoms in the substituent are connected to two adjacent carbon atoms of a heterocycloalkyl, aryl or heteroaryl group, for example:

[0101] When the number of a linking group is 0, such as -(CH2)0-, it means that the linking group is a single bond.

[0102] When one of the variables is selected from a chemical bond, it means that the two groups it connects are directly connected. For example, when L in XLY represents a chemical bond, it means that the structure is actually XY.

[0103] Unless otherwise specified, the key is a solid wedge. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond. and straight dashed key To indicate the relative configuration of a stereocenter, use a wavy line Indicates a wedge-shaped solid key or dotted wedge key Or use a wavy line Represents a straight solid bond or straight dashed key

[0104] Specific pharmaceutical and medical terms

[0105] The term "acceptable," as used herein, means that a formulation component or active ingredient has no undue deleterious effect on health and well-being for the general purpose of treatment.

[0106] The terms "treat", "treatment" or "therapy" as used herein include alleviating, inhibiting or improving symptoms or conditions of a disease; inhibiting the occurrence of complications; improving or preventing potential metabolic syndrome; inhibiting the occurrence of a disease or symptom, such as controlling the development of a disease or condition; alleviating a disease or symptom; reducing a disease or symptom; alleviating complications caused by a disease or symptom, or preventing or treating signs caused by a disease or symptom. As used herein, a compound or pharmaceutical composition, after administration, can improve a disease, symptom or condition, especially improve its severity, delay the onset, slow the progression of the disease, or reduce the duration of the disease. Whether fixed or temporary administration, continuous administration or intermittent administration, can be attributed to or related to the administration.

[0107] "Active ingredient" refers to the compound shown in the general formula (1), and the pharmaceutically acceptable inorganic or organic salt of the compound of the general formula (1). The compounds of the present invention may contain one or more asymmetric centers (chiral centers or axial chirality), and therefore appear in the form of racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomers. The asymmetric center that may exist depends on the properties of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers, and all possible optical isomers and diastereomeric mixtures as well as pure or partially pure compounds are included within the scope of the present invention. The present invention is meant to include all such isomeric forms of these compounds.

[0108] The terms "compound", "composition", "agent" or "medicine or medicament" are used interchangeably herein and refer to a compound or composition that, when administered to a subject (human or animal), is capable of inducing a desired pharmaceutical and / or physiological response through local and / or systemic effects.

[0109] The term "administered," "administering," or "administration" as used herein refers to directly administering the compound or composition, or administering a prodrug, derivative, or analog of the active compound.

[0110] Although the numerical ranges and parameters used to define the broader scope of the present invention are approximate values, the relevant numerical values ​​in the specific embodiments have been presented as accurately as possible. However, any numerical value inherently inevitably contains standard deviations due to individual test methods. Here, "about" generally means that the actual value is within plus or minus 10%, 5%, 1% or 0.5% of a specific value or range. Alternatively, the term "about" means that the actual value falls within the acceptable standard error of the mean value, depending on the consideration of those skilled in the art. Except for the experimental examples, or unless otherwise explicitly stated, it should be understood that all ranges, quantities, values ​​and percentages used herein (for example, to describe the amount of material used, the length of time, temperature, operating conditions, quantitative ratios and the like) are modified by "about". Therefore, unless otherwise stated to the contrary, the numerical parameters disclosed in this specification and the attached claims are all approximate values ​​and can be changed as needed. At least these numerical parameters should be understood as the number of significant digits indicated and the values ​​obtained using the general rounding method.

[0111] Unless otherwise defined in this specification, the meanings of scientific and technical terms used herein are the same as those commonly understood by those skilled in the art. In addition, singular nouns used in this specification include plural forms of the nouns, and plural nouns used also include singular forms of the nouns, unless they conflict with the context.

[0112] Therapeutic Uses

[0113] The present invention provides methods of using the compounds or pharmaceutical compositions of the present invention to treat diseases, including but not limited to conditions involving CDK proteins (eg, cancer).

[0114] In some embodiments, a method for treating cancer is provided, comprising administering to an individual in need thereof an effective amount of any of the aforementioned pharmaceutical compositions of the compounds of formula (1). In some embodiments, the cancer is mediated by a CDK protein. In other embodiments, the cancer is breast cancer, lung cancer, pancreatic cancer, colon cancer, bladder cancer, brain cancer, urothelial cancer, prostate cancer, liver cancer, ovarian cancer, head and neck cancer, gastric cancer, mesothelioma, or all cancer metastases.

[0115] Route of administration

[0116] The compounds of the present invention and their pharmaceutically acceptable salts can be prepared into various preparations, which contain the compounds of the present invention or their pharmaceutically acceptable salts within the safe and effective amount range and pharmacologically acceptable excipients or carriers. The "safe and effective amount" means that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. The safe and effective amount of the compound is determined according to the specific circumstances such as the age, condition, and course of treatment of the subject.

[0117] "Pharmaceutically acceptable excipients or carriers" refers to: one or more compatible solid or liquid fillers or gel substances, which 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 the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmacologically acceptable excipients or 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, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0118] The compounds of the present invention may be administered orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), or topically.

[0119] 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 ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0120] Solid dosage forms such as tablets, pills, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifiers, and the release of the active compound or compounds in such compositions can be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microencapsulated form with one or more of the above-mentioned excipients.

[0121] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, etc.

[0122] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0123] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these substances.

[0124] Compositions for parenteral injection may include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0125] Dosage forms for topical administration of the compounds of the invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0126] The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.

[0127] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage during administration is a pharmaceutically effective dosage, and for a person weighing 60 kg, the daily dosage is usually 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the health status of the patient, which are all within the skill of a skilled physician.

[0128] The above features mentioned in the present invention or the features mentioned in the embodiments can be combined in any way. All the features disclosed in the specification of this case can be used in any combination form, and each feature disclosed in the specification can be replaced by any alternative feature that can provide the same, equal or similar purpose. Therefore, unless otherwise specified, the disclosed features are only general examples of equal or similar features. DETAILED DESCRIPTION

[0129] In the following description, each specific aspect, characteristic and advantage of the above-mentioned compounds, methods and pharmaceutical compositions will be described in detail to make the content of the present invention become very clear. It should be understood that the following detailed description and examples describe specific embodiments and are for reference only. After reading the description of the present invention, those skilled in the art may make various changes or modifications to the present invention, and these equivalent situations also fall within the scope defined by the application.

[0130] In all embodiments, 1 H-NMR was recorded using a Varian Mercury 400 nuclear magnetic resonance instrument, and chemical shifts were expressed in δ (ppm). The silica gel used for separation was 200-300 mesh unless otherwise specified, and the ratios of the eluents were all by volume.

[0131] The present invention adopts the following abbreviations: CDCl3 represents deuterated chloroform; EtOAc represents ethyl acetate; Hexane represents n-hexane; MeCN represents acetonitrile; DCM represents dichloromethane; DIPEA represents diisopropylethylamine; Dioxane represents 1,4-dioxane; DMF represents N,N-dimethylformamide; DMSO represents dimethyl sulfoxide; h represents hour; IPA represents isopropanol; K3PO4 represents potassium phosphate; LiHMDS represents lithium bis(trimethylsilyl)amide; min represents minute; m-CPBA represents meta-chloroperbenzoic acid; min represents minute; MS represents mass spectrometry; NaH represents sodium hydride; NMP represents 1-methylpyrrolidin-2-one; NMR represents nuclear magnetic resonance; Oxone represents potassium peroxydisulfate; Rose bengal represents rose Bengal; TFA (CF3COOH) represents trifluoroacetic acid; TLC represents thin layer chromatography; THF represents tetrahydrofuran.

[0132] Synthesis method A:

[0133] Synthesis of specific compound 1: 8-cyclopentyl-2-(((1-(vinylsulfonyl)piperidin-4-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one using Synthesis Method A:

[0134]

[0135] Step 1: Synthesis of (4-(cyclopentylamino)-2-(methylthio)pyrimidin-5-yl)methanol (compound int_3)

[0136] Add (4-chloro-2-(methylthio)pyrimidin-5-yl)methanol (1.9 g, 10 mmol), cyclopentylamine (935 mg, 11 mmol), DIPEA (3.87 g, 30 mmol) and anhydrous ethanol (40 mL) to a 100 ml single-mouth bottle, and heat to 80 ° C under argon protection to react overnight. After the reaction is completed by LC-MS detection, the reaction solution is concentrated, and the residue is added with EtOAc (50 mL) and water (30 mL), stirred, separated, and the aqueous phase is extracted with EtOAc (30 mL) again, and the combined organic phases are washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to about 10 mL. Then, n-hexane (20 mL) is added dropwise under stirring at room temperature, and the mixed solution is stirred at room temperature for 30 min, filtered, and dried to obtain a white solid product (2.0 g, yield: 83.7%).

[0137] 1H NMR (400MHz, CDCl3) δ: 7.53 (s, 1H), 5.86-5.91 (m, 1H), 4.42 (s, 2H), 4.34-4.37 (m, 1H), 2.45 (s, 3H), 1.99-2.07 (m, 2H), 1.39-1.70 (m, 6H); MS (ESI): 240[M+H] + .

[0138] Step 2: Synthesis of 4-(cyclopentylamino)-2-(methylthio)pyrimidine-5-carbaldehyde (compound int_4)

[0139] 4-(Cyclopentylamino)-2-(methylthio)pyrimidin-5-yl)methanol (2 g, 8.36 mmol), manganese dioxide (5 g) and EtOAc (50 mL) were added to a 100 mL single-necked bottle and reacted overnight at 50° C. After the reaction was completed by LS-MS detection, the reaction solution was filtered and concentrated to obtain a light yellow oily product (1.9 g, yield: 95.8%).

[0140] 1 H NMR (400MHz, CDCl3) δ: 9.64 (s, 1H), 8.56 (br s, 1H), 8.23 ​​(s, 1H), 4.45-4.49 (m, 1H), 2.51 (s, 3H), 2.01-2.07 (m, 2H), 1.47-1.76 (m, 6H); MS (ESI): 238[M+H] + .

[0141] Step 3: Synthesis of 8-cyclopentyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (compound int_5)

[0142] 4-(Cyclopentylamino)-2-(methylthio)pyrimidine-5-carboxaldehyde (1.9 g, 8.0 mmol), redistilled EtOAc (2.12 g, 24 mmol) and anhydrous THF (50 mL) were added to a 100 mL three-necked flask, cooled to -70 ° C under argon protection, and LiHMDS (28 mL, 1 M) was added dropwise. After the dropwise addition, the mixture was stirred at -70 ° C for 30 min, and then slowly warmed to room temperature to react overnight. After the reaction was completed by LS-MS detection, it was quenched with saturated ammonium chloride solution, extracted with EtOAc (30 mL*2), the organic phases were combined, washed with saturated sodium chloride, the organic phases were concentrated, and purified by column chromatography to obtain a light yellow solid product (1.18 g, yield: 56%).

[0143] 1H NMR (DMSO-d6, 400MHz) δ: 8.85 (s, 1H), 7.86 (d, J=9.4Hz, 1H), 6.56 (d, J=9.4Hz, 1H), 5.84-5.78 (m, 1H), 2 .57(s, 3H), 2.24-2.18(m, 2H), 1.99-1.94(m, 2H), 1.80-1.79(m, 2H), 1.64-1.60(m, 2H); LC-MS: 262[M+H] + .

[0144] Step 4: Synthesis of 8-cyclopentyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (compound int_6)

[0145] 8-Cyclopentyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (918 mg, 3.513 mmol), THF / H2O (15 mL / 3 mL) and Oxone (6.48 g, 10.54 mmol) were added to a 100 mL single-mouth bottle, and the mixture was stirred at room temperature for 4 h. After the reaction was completed by LC-MS, EtOAc (30 mL) and H2O (50 mL) were added to the mixture, stirred, separated, and the aqueous phase was extracted with EtOAc (30 mL) again. The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain a yellow-brown solid product (992 mg, yield: 96%).

[0146] MS (ESI): 294 [M+H] + .

[0147] Step 5: Synthesis of 8-cyclopentyl-2-(((1-(vinylsulfonyl)piperidin-4-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (Compound 1)

[0148] To a 50 mL single-necked bottle, 8-cyclopentyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (30 mg, 0.102 mmol), trifluoroacetate of 1-(vinylsulfonyl)piperidin-4-amine (152 mg, 0.49 mmol), DIPEA (66 mg, 0.51 mmol) and DMSO (3 mL) were added. Under argon protection, the mixture was reacted at 60 °C for 1 h. Water (10 mL) was added to the reaction solution, and the mixture was extracted with EtOAc (10 mL*2). The organic phases were combined and washed with saturated sodium chloride. The organic phases were concentrated and purified on a preparative plate to obtain an off-white solid product (19 mg, yield: 46%).

[0149] 1H NMR (400MHz, CDCl3) δ: 8.37 (s, 1H), 7.40 (d, J=9.3Hz, 1H), 6.36 (d, J=9.4H z, 1H), 5.82 (p, J=9.0Hz, 1H), 5.40-5.28 (m, 1H), 4.02 (s, 1H), 3.83 (s, 2H), 2.92(d, J=15.3Hz, 2H), 2.84(s, 3H), 2.31(d, J=20.7Hz, 2H), 2.23-2.17(m, 2H), 2.01(s, 2H), 1.86-1.80(m, 2H), 1.60-1.75(m, 4H); MS(ESI): 404[M+H] + .

[0150] Synthesis method B:

[0151] Synthesis of Specific Compound 2: 6-(difluoromethyl)-8-(((1R,2R)-2-hydroxy-2-methylcyclopentyl)-2-(((1-(vinylsulfonyl)piperidin-4-yl)amino]pyridinyl[2,3-d]pyrimidin-7(8H)-one using Synthesis Method B

[0152]

[0153] Step 1: Synthesis of 1-methyl-6-oxabicyclo[3.1.0]hexane (compound int_2b)

[0154] Add 1-methylcyclopentene (25 mL, 0.24 mol) and DCM (770 mL) to a 2L three-necked flask, and cool to 0-5°C under argon protection; add m-CPBA (73 g, 0.36 mol) in batches, and react at room temperature overnight. Filter the reaction solution, take the filtrate, wash the filter cake with DCM (100 mL*2), combine the filtrate, wash with a mixture of saturated sodium bicarbonate (500 mL) and saturated sodium thiosulfate (100 mL), separate the liquids, dry the organic phase over anhydrous sodium sulfate, filter, and concentrate at 15°C to obtain a light yellow liquid (23.5 g, yield: >100%).

[0155] 1 H NMR (400MHz, CDCl3) δ: 3.42 (s, 1H), 1.81-1.99 (m, 2H), 1.38-1.65 (m, 4H), 1.42 (s, 3H).

[0156] Step 2: Synthesis of 2-(benzylamino)-1-methylcyclopentane-1-ol (compound int_2c)

[0157] Add 1-methyl-6-oxabicyclo[3.1.0]hexane (23.5 g, 0.24 mol), BnNH2 (25.7 g, 0.24 mol) and water (300 mL) to a 500 mL sealed tube and react at 100°C overnight. Adjust the pH of the reaction solution to 2-3 with concentrated hydrochloric acid under ice bath, then wash with EtOAc (300 mL), separate the liquid, take the aqueous phase, adjust the pH of the aqueous phase to 10 with 5N sodium hydroxide solution, extract with EtOAc (200 mL*3), combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate to obtain a crude product. Add n-heptane (250 mL) to the crude product, stir at room temperature, slowly precipitate solids, and filter to obtain a white solid product (15.5 g, yield: 31.5%).

[0158] 1 H NMR (400MHz, DMSO-d6) δ: 7.36-7.25 (m, 4H), 7.24-7.16 (m, 1H), 4.23 (s, 1H), 3 .78-3.65(m, 2H), 2.70(t, J=7.5Hz, 1H), 1.86(dt, J=3.9, 7.8Hz, 1H), 1.73(br s, 1H), 1.62-1.44 (m, 4H), 1.35-1.23 (m, 1H), 1.12 (s, 3H); MS (ESI): 206[M+H] + .

[0159] Step 3: Synthesis of (1R, 2R)-2-(benzylamino)-1-methylcyclopentane-1-ol (compound int_2d)

[0160] Primary separation: Add (S)-2-(3,5-dinitrobenzamido)-2-phenylacetic acid (1.7 g, 4.87 mmol) and ethanol (28 mL) to a 100 mL single-mouth bottle, heat to 80°C until clear, then dropwise add 2-(benzylamino)-1-methylcyclopentane-1-ol (2 g, 9.74 mmol) ethanol (14 mL) solution preheated to 80°C, solid precipitates, stir at 80°C for 4 h after addition, then stir at room temperature overnight. Filter to obtain a white solid product salt (2.3 g, yield: 85%). The above solid was added to water and EtOAc (15 mL) / (20 mL), 4N hydrochloric acid (5 mL) was added, stirred, separated, the aqueous phase was taken, the organic phase was back-extracted with water (10 mL*2), the aqueous phases were combined, the pH was adjusted to 10 with 5N sodium hydroxide solution, and EtOAc (20 mL*3) was extracted. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a white solid product (858 mg, purity: 76.8%, ee: 53.6%).

[0161] Secondary resolution: Add (S)-2-(3,5-dinitrobenzamido)-2-phenylacetic acid (1.11 g, 3.22 mmol) and ethanol (15 mL) to a 100 mL single-mouth bottle, heat to 80°C until clear, then dropwise add 2-(benzylamino)-1-methylcyclopentane-1-ol (858 mg, 4.18 mmol) ethanol (10 mL) solution preheated to 80°C, solid precipitates, stir at 80°C for 4 h after addition, then stir at room temperature overnight. Filter to obtain a white solid product salt (2.3 g, Y: 85%). The solid was added to water and EtOAc (10 mL) / (15 mL), 4N hydrochloric acid (5 mL) was added, stirred, separated, the aqueous phase was taken, the organic phase was back-extracted with water (5 mL*2), the aqueous phases were combined, the pH was adjusted to 10 with 5N sodium hydroxide solution, and EtOAc (20 mL*3) was extracted. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a white solid product (560 mg, purity: 98.68%, ee: 97.36%).

[0162] Step 4: Synthesis of (1R, 2R)-2-amino-1-methylcyclopentane-1-ol (compound int_2)

[0163] Add (1R, 2R)-2-(benzylamino)-1-methylcyclopentane-1-ol (3.9 g, 19 mmol) and isopropanol (100 mL) to a 250 mL single-mouth bottle, add Pd(OH)2 (400 mg), replace with hydrogen, and react at room temperature overnight. Filter the reaction solution, concentrate to about half of the solvent at 30°C, and use it directly in the next step.

[0164] Step 5: Synthesis of (1R, 2R)-2-(((5-(hydroxymethyl)-2-(methylthio)pyrimidin-4-yl)amino)-1-methylcyclopentan-1-ol (Compound int_3)

[0165] To a solution of (1R, 2R)-2-amino-1-methylcyclopentane-1-ol (2.19 g, 19 mmol) in isopropanol (50 mL), (4-chloro-2-(methylthio)pyrimidin-5-yl)methanol (3.62 g, 19 mmol) and DIPEA (7.4 g, 57 mmol) were added, and the mixture was reacted at 80° C. overnight under argon protection. The reaction solution was concentrated and purified by column chromatography to obtain a yellow solid product (4.62 g, yield: 90%).

[0166] 1H NMR (400MHz, CDCl3) δ: 7.76 (s, 1H), 6.01 (d, J=4.6Hz, 1H), 5.31 (br s, 1H), 4.55 (s, 2H), 4.26 (ddd, J=5.7, 8.2, 10.5Hz, 1H), 2.50 (s, 3H), 2.21 (ddd, J=3.5, 8.2, 12.1Hz, 1H), 1.97 ( dt, J=3.5, 7.7Hz, 1H), 1.89-1.76 (m, 2H), 1.75-1.63 (m, 1H), 1.60-1.50 (m, 2H), 1.11 (s, 3H); MS (ESI): 270[M+H] + .

[0167] Step 6: Synthesis of 4-((((1R,2R)-2-hydroxy-2-methylcyclopentyl)amino)-2-(methylthio)pyrimidine-5-carbaldehyde (compound int_4)

[0168] To a 100 mL single-necked bottle, (1R, 2R)-2-(((5-(Hydroxymethyl)-2-(methylthio)pyrimidin-4-yl)amino)-1-methylcyclopentan-1-ol (4.62 g, 17.15 mmol), manganese dioxide (5 g) and EtOAc (60 mL) were added and reacted at 50° C. overnight. The reaction solution was filtered and concentrated to obtain a light yellow solid product (4.24 g, yield: 92%).

[0169] 1 H NMR (400MHz, CDCl3) δ: 9.73 (s, 1H), 8.66 (br s, 1H), 8.35 (s, 1H), 4.39 (ddd, J=6.5, 8.2, 9.6Hz, 1H)., 4.16 (s, 1H), 2.57 (s, 3H), 2.33-2.22 (m , 1H), 2.03-1.92(m, 1H), 1.89-1.68(m, 3H), 1.68-1.56(m, 1H), 1.17(s, 3H); MS(ESI): 268[M+H] + .

[0170] Step 7: Synthesis of 8-((1R, 2R)-2-hydroxy-2-methylcyclopentyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)one (Compound int_5)

[0171] To a 100 mL three-necked flask, 4-((((1R, 2R)-2-hydroxy-2-methylcyclopentyl)amino)-2-(methylthio)pyrimidine-5-carbaldehyde (3.24 g, 12.12 mmol), redistilled EtOAc (3.2 g, 36.36 mmol) and anhydrous THF (60 mL) were added. Under argon protection, the mixture was cooled to -10 to -5 °C, and LiHMDS (42.5 mL, 1 M) was added dropwise. The mixture was reacted at room temperature overnight. The mixture was quenched with saturated ammonium chloride solution, extracted with EtOAc (50 mL*2), the organic phases were combined, washed with saturated sodium chloride, concentrated, and purified by column chromatography to give a light yellow solid product (2.83 g, yield: 80%).

[0172] 1 H NMR (400MHz, CDCl3) δ: 8.61 (s, 1H), 7.56 (d, J = 9.4Hz, 1H), 6.60 (d, J = 9.4Hz, 1H), 5.84 (t, J = 8.6Hz, 1H), 2.92-2 .76(m, 1H), 2.64(s, 3H), 2.34-2.19(m, 2H), 2.13-2.01(m, 2H), 2.00-1.81(m, 2H), 1.16(s, 3H); LC-MS: 292[M+H] + .

[0173] Step 8: Synthesis of 6-(difluoromethyl)-8-(((1R,2R)-2-hydroxy-2-methylcyclopentyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (compound int_6)

[0174] 8-((1R, 2R)-2-hydroxy-2-methylcyclopentyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (1.73 g, 5.94 mmol), Rose bengal (302 mg, 0.297 mmol) and DMSO (50 mL) were added to a 100 mL single-mouth bottle. The mixture was stirred in an open manner under sunlight. Sodium difluoromethanesulfinate (1.64 g, 11.87 mmol) was added in batches and reacted under light for 2 h. Saturated sodium bicarbonate solution was added to the reaction solution under ice bath, and extracted with EtOAc (40 mL*2). The organic phases were combined, washed with saturated sodium chloride, concentrated, and purified by column chromatography to obtain a light yellow solid product (614 mg, yield: 30%).

[0175] 1H NMR (400MHz, CDCl3) δ8.70 (s, 1H), 7.97-7.89 (m, 1H), 6.78 (t, J=54.9Hz, 2H), 5.87 (t, J=8.5Hz, 1H), 2.82-2.71 (m, 1H), 2.64 (s, 3H), 2. 26 (ddd, J=12.6, 10.7, 7.1Hz, 1H), 2.07 (dd, J=16.5, 7.0Hz, 2H), 2.01-1.89 (m, 2H), 1.88-1.80 (m, 1H), 1.14 (s, 3H); MS (ESI): 342[M+H] + .

[0176] Step 9: Synthesis of 6-(difluoromethyl)-8-(((1R,2R)-2-hydroxy-2-methylcyclopentyl)-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (Compound int_7)

[0177] 6-(Difluoromethyl)-8-(((1R, 2R)-2-hydroxy-2-methylcyclopentyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (614 mg, 1.8 mmol), THF / H2O (20 mL / 4 mL) and Oxone (2.8 g, 4.5 mmol) were added to a 100 mL single-necked bottle, and the mixture was stirred at room temperature for 5 h. After the reaction was completed by LC-MS, EtOAc (20 mL) and H2O (40 mL) were added to the mixture, stirred, separated, and the aqueous phase was extracted with EtOAc (20 mL). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain a yellow colloidal solid product (770 mg, yield: >100%).

[0178] 1 H NMR (400MHz, CDCl3) δ: 9.07 (s, 1H), 8.11-8.07 (m, 1H), 6.82 (td, J=54.3, 0.6Hz, 1H), 5.83-5.75 (m, 1H), 3.40 (s, 3 H), 2.80-2.70 (m, 1H), 2.32-2.25 (m, 1H), 2.11 (ttd, J=7.3, 6.1, 5.5, 3.6Hz, 2H), 2.03-1.85 (m, 3H), 1.12 (s, 3H).

[0179] Step 10: Synthesis of 6-(difluoromethyl)-8-(((1R,2R)-2-hydroxy-2-methylcyclopentyl)-2-(((1-(vinylsulfonyl)piperidin-4-yl)amino]pyridinyl[2,3-d]pyrimidine, 7(8H), ketone (Compound 2)

[0180] To a 50 mL single-necked bottle, 6-(difluoromethyl), 8, (((1R, 2R)-2, hydroxy, 2, methylcyclopentyl), 2, (methylsulfonyl) pyrido [2, 3, d] pyrimidine, 7 (8H) ketone (15 mg, 0.04 mmol), 1, (vinylsulfonyl) piperidine-4-amine (25 mg, 0.08 mmol), DIPEA (26 mg, 0.2 mmol) and DMSO (2 mL) were added. Under argon protection, the reaction was carried out at 60 ° C for 1 h. Water (10 mL) was added to the reaction solution, and EtOAc (10 mL * 2) was used for extraction. The organic phases were combined, washed with saturated sodium chloride, and the organic phase was concentrated and purified on a preparative plate to obtain an off-white solid product (12 mg, yield: 63%).

[0181] 1 H NMR (400MHz, CDCl3) δ8.52 (s, 1H), 7.82 (s, 1H), 6.77 (t, J=55.3Hz, 1H), 6.46 (dd, J=16.6, 9.9Hz, 1H), 6.27 (d, J=16.6Hz, 1H), 6.06 (d, J=9.9Hz, 1H), 5.76 (s, 1H), 5.59 (s, 1H), 4.01 ( m, 1H), 3.76 (d, J=13.1Hz, 2H), 2.85 (t, J=11.7Hz, 2H), 2.76 (m, 1H), 2.36-2.11 (m, 4H), 2.0 1(dd, J=11.0, 7.6Hz, 2H), 1.92(s, 1H), 1.85-1.78(m, 1H), 1.72-1.62(m, 2H), 1.16(s, 3H).

[0182] Synthesis method C:

[0183] Synthesis of Specific Compound 3: 8-cyclopentyl-7-oxa-2-((1-(vinylsulfonyl)piperidin-4-yl)amino)-7,8-dihydropyridinyl[2,3-d]pyrimidine-6-carbonitrile (Compound 3) using Synthesis Method C

[0184]

[0185] Step 1: Synthesis of (4, (cyclopentylamino)-2, (methylthio) pyrimidin-5-yl) methanol (compound int_3)

[0186] Add (4-chloro-2-(methylthio)pyrimidin-5-yl)methanol (1.9 g, 10 mmol), cyclopentylamine (935 mg, 11 mmol), DIPEA (3.87 g, 30 mmol) and anhydrous ethanol (40 mL) to a 100 ml single-mouth bottle, and heat to 80 ° C under argon protection to react overnight. After the reaction is completed by LC-MS detection, the reaction solution is concentrated, and the residue is added with EtOAc (50 mL) and water (30 mL), stirred, separated, and the aqueous phase is extracted with EtOAc (30 mL) again, and the combined organic phases are washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to about 10 ml. Then, n-hexane (20 mL) is added dropwise under stirring at room temperature, and the mixed solution is stirred at room temperature for 30 min, filtered, and dried to obtain a white solid product (2.0 g, yield: 83.7%).

[0187] 1 H NMR (400MHz, CDCl3) δ: 7.53 (s, 1H), 5.86-5.91 (m, 1H), 4.42 (s, 2H), 4.34-4.37 (m, 1H), 2.45 (s, 3H), 1.99-2.07 (m, 2H), 1.39-1.70 (m, 6H); MS (ESI): 240[M+H] + .

[0188] Step 2: Synthesis of 4,(cyclopentylamino),2,(methylthio)pyrimidine-5-carboxaldehyde (compound int_4)

[0189] 4, (cyclopentylamino), 2, (methylthio) pyrimidin-5-yl) methanol (2 g, 8.36 mmol), manganese dioxide (5 g) and EtOAc (50 mL) were added to a 100 mL single-necked bottle and reacted overnight at 50° C. After the reaction was completed by LS-MS detection, the reaction solution was filtered and concentrated to obtain a light yellow oily product (1.9 g, yield: 95.8%).

[0190] 1 H NMR (400MHz, CDCl3) δ: 9.64 (s, 1H), 8.56 (br s, 1H), 8.23 ​​(s, 1H), 4.45-4.49 (m, 1H), 2.51 (s, 3H), 2.01-2.07 (m, 2H), 1.47-1.76 (m, 6H); MS (ESI): 238[M+H] + .

[0191] Step 3: Synthesis of 8-cyclopentyl-2-(methylthio)-7-oxa-7,8-dihydropyridinyl[2,3-d]pyrimidine-6-carbonitrile (Compound int_5)

[0192] 4-(Cyclopentylamino)-2-(methylthio)pyrimidine-5-carboxaldehyde (1.9 g, 8.0 mmol), 2-nitroacetic acid (950 mg, 9.6 mmol), catalytic amounts of benzylamine and acetic acid (50 mL) were added to a 100 mL three-necked flask. Under argon protection, the mixture was reacted overnight under mixed flow. After the reaction was completed by LS-MS detection, it was quenched with saturated ammonium chloride solution, extracted with EtOAc (30 mL*2), the organic phases were combined, washed with saturated sodium chloride, the organic phases were concentrated, and purified by column chromatography to obtain a light yellow solid product (1.51 g, yield: 66%).

[0193] 1 H NMR (400MHz, CDCl3) δ8.68 (s, 1H), 8.10 (s, 1H), 5.89-5.98 (m, 1H), 2.64 (s, 3H), 2.23-2 .35(m, 2H), 2.09-2.16(m, 2H), 1.83-1.96(m, 2H), 1.63-1.76(m, 2H); MS(ESI): 287[M+H] + .

[0194] Step 4: Synthesis of 8,cyclopentyl-2-(methylsulfonyl),7-oxa,7,8,dihydropyridinyl[2,3-d]pyrimidine-6-carbonitrile (Compound int_6)

[0195] 8, cyclopentyl, 2-(methylthio)-7, oxa-7, 8, dihydropyridinyl [2, 3-d] pyrimidine, 6-carbonitrile (950 mg, 3.32 mmol), THF / H2O (15 mL / 3 mL) and Oxone (6.48 g, 10.54 mmol) were added to a 100 mL single-mouth bottle, and the mixture was stirred at room temperature for 4 h. After the reaction was completed by LC-MS, EtOAc (30 mL) and H2O (50 mL) were added to the mixture, stirred, separated, and the aqueous phase was extracted with EtOAc (30 mL) again. The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain a yellow-brown solid product (980 mg, yield: 90%).

[0196] MS (ESI): 319 [M+H] + .

[0197] Step 5: Synthesis of 8-cyclopentyl-7-oxa-2-((1-(vinylsulfonyl)piperidin-4-yl)amino)-7,8-dihydropyridinyl[2,3-d]pyrimidine-6-carbonitrile (Compound 3)

[0198] To a 50 mL single-necked bottle, add 8, cyclopentyl-2-(methylsulfonyl)-7, oxa-7, 8-dihydropyridinyl [2, 3, d] pyrimidine, 6, nitrile (30 mg, 0.094 mmol), 1, (vinylsulfonyl) piperidine-4-amine trifluoroacetate (152 mg, 0.49 mmol), DIPEA (66 mg, 0.51 mmol) and DMSO (3 mL). Under argon protection, react at 60 ° C for 1 h. Water (10 mL) was added to the reaction solution, and extracted with EtOAc (10 mL*2). The organic phases were combined, washed with saturated sodium chloride, concentrated, and purified on a preparative plate to obtain an off-white solid product (15 mg, yield: 37%).

[0199] MS (ESI): 429 [M+H] + .

[0200] Example 1 Synthesis of Compound 4-245

[0201] Using synthesis method A, synthesis method B or synthesis method C and adopting different raw materials, the target compound 4-245 in Table 1 can be obtained.

[0202] Table 1

[0203]

[0204]

[0205]

[0206]

[0207]

[0208]

[0209]

[0210]

[0211]

[0212]

[0213]

[0214]

[0215]

[0216]

[0217]

[0218] Table 2. NMR data of some compounds in Table 1

[0219]

[0220]

[0221]

[0222] Example 2 Detection of the inhibitory activity of the compounds of the present invention on CDK2 or CDK4 enzymes

[0223] The ADP-GLO method was used to determine the inhibitory effect of the compounds on the CDK2 and CDK4 enzyme activities. The details are as follows.

[0224] Add the compound diluted with DMSO to a 384-well plate, centrifuge at 1000g for 1 minute, add the enzyme diluted with kinase buffer, centrifuge at 1000g for 30s, incubate at room temperature for 10 minutes, and then add 2X substrate and ATP. Centrifuge at 1000g for 30s and react at room temperature for 60 minutes. Add ADP-Glo ​​and incubate at room temperature for 40 minutes, then add the detection solution. After incubation for another 40 minutes, detect luminescence. Calculate the compound inhibition percentage and IC compared with the DMSO group 50 The results are shown in Table 3 below.

[0225] Table 3. Inhibitory activity of the compounds of the present invention on CDK2 or CDK4

[0226]

[0227] From the data in Table 3, it can be seen that the compounds of the present invention have good inhibitory activity on the enzyme activities of CDK2 and CDK4. Further experiments have proved that other compounds of the present invention also have good inhibitory activity on CDK2 and CDK4.

[0228] Example 3 Antiproliferative activity of the compounds of the present invention on OVCAR-3 cells

[0229] 1000 OVCAR-3 cells were seeded in a 384-well plate. After one day of growth, the compound was added in serial dilutions. Seven days after the addition of the compound, Cell Titer Glow was added to evaluate cell growth, and the percentage of cell growth inhibition and IC of the compound were calculated. 50 The results are shown in Table 4 below.

[0230] Table 4. Antiproliferative activity of the compounds of the present invention on OVCAR-3 cells

[0231]

[0232] As can be seen from the data in Table 4, the antiproliferative activity of most compounds of the present invention on OVCAR-3 cells is less than 200 nM, while the antiproliferative activity of PF-06873600 on OVCAR-3 cells is greater than 2000 nM, which shows that the compounds of the present invention have strong antiproliferative activity on OVCAR-3 cells. Further experiments have shown that other compounds in the present invention also have strong antiproliferative activity on OVCAR-3 cells.

Claims

1. A compound represented by the general formula (1) or an optical isomer or a pharmaceutically acceptable salt thereof: In the general formula (1): R 1 is -H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, wherein the alkyl and haloalkyl may each independently be optionally substituted by one or more of the following groups: -H, halogen, -OH, -NH2 and C1-C6 alkoxy; R 2 is a C3-C8 cycloalkyl group or a 3-8 membered heterocycloalkyl group, wherein the cycloalkyl group and the heterocycloalkyl group may each independently be optionally substituted by one or more of the following groups: -H, halogen, -OH, -NH2, C1-C6 alkyl, C1-C6 haloalkyl and C1-C6 alkoxy; X is O; R 3 is -H or halogen; R 4 for or Y is -H or -CH3; R 5a and R 5b Each is independently -H, C1-C6 alkyl or 5-6 membered heterocycloalkyl, wherein the C1-C6 alkyl and 5-6 membered heterocycloalkyl may be independently optionally substituted by one or more of the following groups: C1-C6 alkyl and -NR 8a R 8b ;or R 5a and R 5b The carbon atoms connected thereto can together form a 4-8 membered heterocycloalkyl group, wherein the 4-8 membered heterocycloalkyl group can be independently optionally substituted by one or more of the following groups: C1-C6 alkyl group; R 6a and R 6b Each is independently -H or C1-C6 alkyl; R 7 is -H or C1-C6 alkyl; R 7a and R 7b Each is independently -H or C1-C6 alkyl; R 8a and R 8b Each independently is a C1-C6 alkyl group, or R 8a and R 8b The N atom connected thereto can together form a 4-8 membered heterocycloalkyl group; and m is an integer of 0, 1, 2 or 3.

2. The compound according to claim 1 or its optical isomer or pharmaceutically acceptable salt, wherein in the general formula (1), R 1 is -H, halogen, C1-C3 alkyl or C1-C3 haloalkyl, wherein the alkyl and haloalkyl may be optionally substituted with one or more of the following groups: -H, -F, -Cl, -Br, -OH, -OCH3 and -NH2.

3. The compound according to claim 2 or its optical isomer or pharmaceutically acceptable salt, wherein in the general formula (1), R 1 for: -H、-F、-Cl、-Br、-CH3、-CH2CH3、-CH(CH3)2、 4. The compound according to any one of claims 1 to 3 or its optical isomer or pharmaceutically acceptable salt, wherein in the general formula (1), R 2 It is a C5-C6 cycloalkyl group or a 5-6-membered heterocycloalkyl group, wherein the cycloalkyl group and the heterocycloalkyl group may each independently be optionally substituted by one or more of the following groups: -H, -F, -OH, -OCH3, -NH2 and -CH3.

5. The compound according to claim 4 or its optical isomer or pharmaceutically acceptable salt, wherein in the general formula (1), R 2 for:

6. The compound according to claim 1 or its optical isomer or pharmaceutically acceptable salt, wherein in the general formula (1), R 3 Either -H or -F.

7. The compound according to claim 1 or its optical isomer or pharmaceutically acceptable salt, wherein in the general formula (1), when R 4 for When R 5a and R 5b Each is independently -H, C1-C3 alkyl or 5-6 membered heterocycloalkyl, wherein the C1-C3 alkyl and 5-6 membered heterocycloalkyl may be independently optionally substituted by one or more of the following groups: -CH3, -N(CH3)2, or R 5a and R 5b The carbon atoms connected thereto can together form a 4-6 membered heterocycloalkyl group, wherein the 4-6 membered heterocycloalkyl group is oxetane, azetidine, tetrahydrofuran, pyrrolidine, tetrahydrothiophene, piperidine, tetrahydropyran, morpholine or piperazine, and the 4-6 membered heterocycloalkyl group can be independently optionally substituted by one or more of the following groups: -CH3.

8. The compound according to claim 7 or its optical isomer or pharmaceutically acceptable salt, wherein in the general formula (1), R 4 for:

9. The compound according to claim 1 or its optical isomer or pharmaceutically acceptable salt, wherein in the general formula (1), when R 4 for When R 6a and R 6b Each is independently -H or C1-C3 alkyl.

10. The compound according to claim 9 or its optical isomer or pharmaceutically acceptable salt, wherein in the general formula (1), R 4 for:

11. The compound according to claim 1 or its optical isomer or pharmaceutically acceptable salt, wherein in the general formula (1), when R 4 for When R 7 It is -H or C1-C3 alkyl.

12. The compound according to claim 11 or its optical isomer or pharmaceutically acceptable salt, wherein in the general formula (1), R 4 for:

13. The compound according to claim 1 or its optical isomer or pharmaceutically acceptable salt, wherein in the general formula (1), when R 4 for When R 7a and R 7b Each is independently -H or C1-C3 alkyl.

14. The compound according to claim 13 or its optical isomer or pharmaceutically acceptable salt, wherein in the general formula (1), R 4 for:

15. The compound according to claim 1 or an optical isomer or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, wherein the compound has one of the following structures:

16. A pharmaceutical composition, characterized in that It contains a pharmaceutically acceptable excipient and / or carrier, and the compound or its optical isomer or pharmaceutically acceptable salt as described in any one of claims 1 to 15.

17. Use of the compound according to any one of claims 1 to 15 or its optical isomer or pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 16, in the preparation of a drug for treating, regulating and / or preventing a disease associated with a CDK protein.

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