WO2020253458A1 - Cdk激酶抑制剂 - Google Patents

Cdk激酶抑制剂 Download PDF

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WO2020253458A1
WO2020253458A1 PCT/CN2020/091324 CN2020091324W WO2020253458A1 WO 2020253458 A1 WO2020253458 A1 WO 2020253458A1 CN 2020091324 W CN2020091324 W CN 2020091324W WO 2020253458 A1 WO2020253458 A1 WO 2020253458A1
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optionally substituted
group
cancer
membered
compound
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PCT/CN2020/091324
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English (en)
French (fr)
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潘峥婴
张睿
戚祖德
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北京睿熙生物科技有限公司
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Priority to US17/620,346 priority Critical patent/US20230002393A1/en
Priority to AU2020295509A priority patent/AU2020295509B2/en
Priority to KR1020227001397A priority patent/KR20220020951A/ko
Priority to CA3143813A priority patent/CA3143813A1/en
Priority to JP2021575915A priority patent/JP7369798B2/ja
Priority to EP20827431.6A priority patent/EP3988551A4/en
Publication of WO2020253458A1 publication Critical patent/WO2020253458A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/113—Spiro-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • the present invention relates to a compound that inhibits the activity of CDK kinase, and the use of the above-mentioned compound in the preparation of a medicine for treating and/or preventing cancer-related diseases mediated by CDK kinase.
  • CDKs Cyclin-Dependent-Kinases
  • CDKs are a group of serine/threonine protein kinases, which are closely related to important cellular processes such as cell cycle or transcriptional regulation. Studies have shown that CDK itself may not exert kinase activity. It exerts protein kinase activity by binding to cyclins to form a specific CDK-Cyclin complex, which can promote cell cycle phase transition, initiate DNA synthesis, and regulate cells Functions such as transcription.
  • CDK1 to CDK13 The CDK family currently has 13 members (CDK1 to CDK13). According to their intracellular functions, they are divided into two categories: CDKs that control the cell cycle (CDK1, CDK2, CDK4, CDK6, etc.) and CDKs that control transcription (CDK7, CDK9) Wait). There are 11 subtypes of cyclin, named after A-I, k, and T. Their expression is regulated by transcription and fluctuates regularly during the cell cycle. Among the CDK subtypes involved in cell cycle regulation, CDK4/6 plays an irreplaceable role. Cancer-related cell cycle mutations mainly exist in the transition process of G1 and G1/S.
  • CDK4/6 binds to CyclinD to form a complex with kinase activity, which releases the bound transcription factors by phosphorylation of tumor suppressor protein Rb E2F, initiates the transcription of genes related to S phase, prompts cells to pass the checkpoint and transfer from G1 phase to S phase.
  • the specific activation of CDK4/6 is closely related to the proliferation of certain tumors. About 80% of human tumors have abnormal cyclin D-CDK4/6-INK4-Rb channels. The change of this channel may accelerate the process of G1 phase, thereby accelerating the proliferation of tumor cells and gaining survival advantages. Therefore, its intervention has become a treatment strategy, and CDK4/6 has therefore become one of the anti-tumor targets.
  • CDK inhibitors At present, more than 50 kinds of CDK inhibitors have been reported, some of which have potential anti-tumor activity, some broad-spectrum CDK inhibitors have been developed as anti-tumor drugs, and some are undergoing preclinical or clinical trials. New CDK inhibitors are constantly being developed.
  • Abemaciclib is an orally effective cyclin-dependent kinase (CDK) inhibitor, which targets the CDK4 (cyclin D1) and CDK6 (cyclin D3) cell cycle pathways, and has potential anti-tumor activity.
  • CDK cyclin-dependent kinase
  • Abemaciclib specifically inhibits CDK4/6, thereby inhibiting retinoblastoma (Rb) protein phosphorylation in the early G1 stage. Inhibit Rb phosphorylation and prevent CDK-mediated transition from G1-S phase, thereby arresting the cell cycle in G1 phase, inhibiting DNA synthesis, and inhibiting cancer cell growth.
  • Eli Lilly announced the success of a Phase III clinical study of Abemaciclib in the treatment of breast cancer.
  • Ribociclib is another orally effective selective inhibitor of CDK4 and CDK6 (IC50 of 10 and 39 nmol/L, respectively) (see literature 3 to 4). As expected, Ribociclib inhibits Rb phosphorylation, causes G0/G1 phase block and induces senescence of tumor cells (including melanoma, breast cancer, liposarcoma, and neuroblastoma with B-Raf or N-Ras mutations). On March 14, 2017, Ribociclib was approved by the US FDA as a combination regimen with aromatase inhibitors for the treatment of hormone receptor-positive and human epidermal growth factor receptor 2 negative postmenopausal women.
  • CDK targeted small molecule inhibitors especially CDK4/6 kinase inhibitors
  • the anti-tumor drugs are of great significance.
  • Patent Document 1 WO2003062236A1;
  • Patent Document 2 WO2005005426A1;
  • Patent Document 3 WO2011101409A1;
  • Patent Document 4 CN103788100A.
  • the subject of the present invention is to provide a kinase inhibitor compound against CDK.
  • the present invention provides a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof:
  • Q is an optionally substituted 6-18 membered arylene group or an optionally substituted 5-18 membered heteroarylene group, wherein the substituent when substituted is selected from halogen, hydroxy, and C 1-6 alkane The group consisting of C 1-6 alkoxy and halogenated C 1-6 alkyl;
  • R 1 is an optionally substituted 3 to 8 membered heterocyclic group, an optionally substituted 6 to 14 membered fused heterocyclic group, an optionally substituted 6 to 12 membered spiro heterocyclic group, wherein When substituted, the substituent is selected from the group consisting of halogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, and halogenated C 1-6 alkyl;
  • R 2 is H, halogen or optionally substituted 3-10 membered cycloalkenyl, optionally substituted 3-10 membered heterocycloalkenyl, optionally substituted 3-10 membered cycloalkyl, Optionally substituted 3 to 10 membered heterocycloalkyl, optionally substituted 6 to 18 membered aryl, optionally substituted 5 to 18 membered heteroaryl, wherein the substituent when substituted It is selected from halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkoxy, oxo group Group
  • R 4 and R 5 are each independently methyl or ethyl
  • R 2 is an optionally substituted 3-10 membered cycloalkenyl group or an optionally substituted 3-10 membered heterocycloalkenyl group
  • Q is an optionally substituted phenylene group or an optionally substituted pyridylene group, wherein the substituent when substituted is selected from halogen, hydroxyl, C 1-6 alkane The group consisting of C 1-6 alkoxy and halogenated C 1-6 alkyl;
  • R 1 is an optionally substituted 3 to 8 membered heterocyclic group, an optionally substituted 6 to 14 membered fused heterocyclic group or an optionally substituted 6 to 12 membered spiro heterocyclic group, wherein When substituted, the substituent is selected from C 1-6 alkyl;
  • R 2 is selected from halogen atoms, or optionally substituted cyclopentenyl, optionally substituted cyclohexenyl, optionally substituted cyclopentyl, optionally substituted cyclohexyl, any Optionally substituted oxacyclohexenyl, optionally substituted azacyclohexenyl, optionally substituted oxolanyl, optionally substituted azacyclopentyl, any Optionally substituted oxacyclohexyl, optionally substituted azacyclohexyl, optionally substituted phenyl, optionally substituted naphthyl, optionally substituted pyridyl, optionally The group consisting of optionally substituted thienyl, optionally substituted pyrazolyl, optionally substituted oxazolyl, optionally substituted isoxazolyl, optionally substituted quinolinyl , Wherein the substituent when substituted is selected from the group consisting of halogen,
  • Both R 4 and R 5 are methyl groups.
  • Q is phenylene
  • R 1 is an optionally substituted group as follows, wherein the substituent when substituted is selected from C 1-6 alkyl:
  • the C 1-6 alkyl group is methyl or ethyl.
  • R 2 is halogen or the following optionally substituted group, wherein the substituent when substituted is selected from C 1-6 alkyl:
  • each example compound in Table 1 or a pharmaceutically acceptable salt thereof is provided.
  • the compound of the present invention is used to inhibit CDK kinase activity, in particular, the compound of the present invention is used to inhibit CDK4/6 kinase activity.
  • a pharmaceutical composition comprising an effective amount of the above-mentioned compound of the present invention and a pharmaceutically acceptable carrier or excipient.
  • a compound of the present invention or a pharmaceutically acceptable salt compound or a pharmaceutically acceptable salt thereof for preparing treatment and/or prevention by CDK kinase (especially CDK4/6 kinase)
  • CDK kinase especially CDK4/6 kinase
  • the cancer-related diseases selected from brain tumor, lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer , Cervical cancer, endometrial cancer, rectal cancer, liver cancer, kidney cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, prostate cancer, female reproductive tract cancer, carcinoma in situ, lymphoma, neurofibromas, thyroid cancer, Bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, gastrointestinal stromal tumor, prostate tumor, mast cell tumor, multiple myeloma, melanoma, glioma or sar
  • the compound of the present invention can inhibit the activity of CDK kinase (especially CDK4/6 kinase) and can be used in the treatment of cancer.
  • C 1-6 alkyl refers to an alkyl group having 1-6 carbon atoms, including methyl, ethyl, propyl, butyl, pentyl and hexyl, including all possible isomeric forms, such as n-propyl And isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl, etc.
  • C 1-6 alkyl includes all sub-ranges contained therein, such as C 1-2 alkyl, C 1-3 alkyl, C 1-4 alkyl, C 1-5 alkyl, C 2-5 Alkyl, C 3-5 alkyl, C 4-5 alkyl, C 3-4 alkyl, C 3-5 alkyl, and C 4-5 alkyl.
  • Aryl and “heteroaryl” include monocyclic or fused-ring polycyclic (ie, rings that share adjacent pairs of ring atoms) groups.
  • Examples of “aryl” include, but are not limited to, phenyl, naphthyl, phenanthryl, anthracenyl, fluorenyl, and indenyl.
  • Examples of “heteroaryl” include:
  • the "6 to 18-membered arylene group” in the present invention refers to a divalent group derived from an aromatic hydrocarbon of 6 to 18 carbon atoms by removing two hydrogen atoms, including, for example, "6 to 14-membered arylene group", “6-10 membered arylene” and the like, examples of which include but are not limited to: phenylene, naphthylene, anthrylene and the like.
  • the "5- to 18-membered heteroarylene” in the present invention refers to a divalent group derived from a 5- to 18-membered heteroarene by removing two hydrogen atoms, including, for example, "5- to 14-membered heteroarylene", " 5- to 10-membered heteroarylene” and the like, examples of which include, but are not limited to: furanylene, thienylene, pyrrolylene, imidazolylidene, thiazolylidene, pyrazolylidene, oxazolylidene, isocyanide Oxazolyl, isothiazolylidene, pyridinylene, pyrazinylene, pyridazinylene, pyrimidinylene and the like, and are preferably pyridinylene, pyrazolylene or thienylene, particularly preferably sub-
  • the pyridyl group is most preferably a pyridylene group in which the nitrogen atom is located
  • the “3 to 8 membered heterocyclic group” in the present invention includes, for example, “3 to 7 membered heterocyclic group”, “3 to 6 membered heterocyclic group”, “4 to 7 membered heterocyclic group”, and "4 to 7 membered heterocyclic group”.
  • 6-membered heterocyclic group “5- to 7-membered heterocyclic group”, “5- to 6-membered heterocyclic group”, “6-membered heterocyclic group” and the like.
  • Specific examples include, but are not limited to: aziridinyl, 2H-aziridinyl, diaziridinyl, 3H-diazepinyl, azetidinyl, 1,4-dioxanyl Heterocyclohexyl, 1,3-dioxanyl, 1,3-dioxolane, 1,4-dioxanyl, tetrahydrofuranyl, dihydropyrrolyl , Pyrrolidinyl, imidazolidinyl, 4,5-dihydroimidazolyl, pyrazolidinyl, 4,5-dihydropyrazolyl, 2,5-dihydrothienyl, tetrahydrothienyl, 4,5 -Dihydrothiazolyl, piperidinyl, piperazinyl, morpholinyl, 4,5-dihydrooxazolyl, 4,5-dihydroisoxazolyl, 2,3
  • the "6 to 14 membered fused heterocyclic group" in the present invention includes, for example, “6 to 11 membered fused heterocyclic group", “6 to 10 membered fused heterocyclic group”, and “7 to 10 membered fused heterocyclic group” , “9-10 membered fused heterocyclic group” and so on. Specific examples include but are not limited to:
  • the "6-12 membered spiroheterocyclic group” in the present invention refers to a ring structure of 6-12 ring atoms with at least one heteroatom formed by at least two rings sharing one atom.
  • the heteroatom Selected from N, S, O, CO, SO and/or SO 2 and so on.
  • the "3- to 10-membered cycloalkenyl group” in the present invention refers to a cyclic alkenyl group derived from a cyclic monoolefin of 3 to 10 carbon atoms by removing one hydrogen atom, including, for example, "3- to 8-membered cycloalkenyl group ", "4--6 membered cycloalkenyl” and so on. Examples thereof include, but are not limited to: cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, cyclodecenyl and the like.
  • the "3- to 10-membered heterocycloalkenyl group” in the present invention refers to a heterocyclic alkenyl group derived from a heteroatom-containing 3- to 10-membered cyclic monoolefin partially removed from one hydrogen atom, including, for example, "3- to 8-membered heterocycle "Cycloalkenyl", "4--6 membered heterocycloalkenyl” and the like. Examples include but are not limited to:
  • the "3- to 10-membered cycloalkyl group” in the present invention refers to a cyclic alkyl group derived from a cycloalkane with 3 to 10 carbon atoms removed by one hydrogen atom, including, for example, "3- to 8-membered cycloalkyl group", "4- to 6-membered cycloalkyl” and so on. Examples thereof include, but are not limited to: cyclopropanyl, cyclobutanyl, cyclopentyl, cyclohexane, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and the like.
  • the “3- to 10-membered heterocycloalkyl group” in the present invention refers to a heterocyclic alkyl group derived from a heteroatom-containing 3- to 10-membered heterocycloalkane by partially removing one hydrogen atom, including, for example, “3- to 8-membered heterocycloalkane "Cycloalkyl", "4- to 6-membered heterocycloalkyl” and the like. Examples include but are not limited to: aziridinyl, azetidinyl, azetidinyl, azetidinyl, azepanyl, azetidinyl, aza Cyclononanyl etc.
  • the "oxo group" in the present invention refers to a substituent in which an oxygen atom is bonded to a carbon atom or a nitrogen atom, and one of the oxygen atoms is bonded to a carbon atom.
  • Examples include carbonyl groups, and specific examples of groups in which one oxygen atom is bonded to one nitrogen atom include N-oxides.
  • Halogen refers to fluorine, chlorine, bromine and iodine.
  • C 1-6 alkoxy refers to a (C 1-6 alkyl)O- group, wherein C 1-6 alkyl is as defined herein.
  • Halo C 1-6 alkyl refers to a halogen-(C 1-6 alkyl)- group, where C 1-6 alkyl is as defined herein.
  • Halogenated C 1-6 alkyl groups include perhalogenated C 1-6 alkyl groups, in which all hydrogen atoms in the C 1-6 alkyl group are replaced by halogens, such as -CF 3 , -CH 2 CF 3 , -CF 2 CF 3. -CH 2 CH 2 CF 3 and so on.
  • Examples of "amide group” include but are not limited to:
  • the compound of the present invention can be prepared or used as a pharmaceutically acceptable salt thereof. This can be done by any salt-forming means known in the art.
  • the pharmaceutically acceptable salt may be an acid addition salt, such as an inorganic acid addition salt or an organic acid addition salt.
  • the pharmaceutically acceptable salt may also be a salt formed by replacing the acidic proton in the compound with a metal ion, or a salt formed by coordination of the compound with an organic base or an inorganic base.
  • the term "pharmaceutically acceptable”, when referring to a formulation, composition or ingredient, means that it does not have a lasting adverse effect on the general health of the subject being treated or does not lose the biological activity or properties of the compound, And relatively non-toxic.
  • an "effective amount” or “therapeutically effective amount” as used herein refers to the amount of a drug or compound that is sufficient to alleviate one or more symptoms of the disease or condition being treated after administration. The result can be to shrink and/or reduce signs, symptoms or causes of disease or any other desired biological system changes.
  • an "effective amount” for therapeutic use is the amount required to provide a significant reduction in the clinical symptoms of the disease without causing excessive side effects.
  • the "effective amount” suitable for any individual situation can be determined using techniques such as escalation studies.
  • the term “therapeutically effective amount” includes, for example, a prophylactically effective amount.
  • the "effective amount” of the compound disclosed herein is an amount effective to achieve the desired pharmacological effect or therapeutic improvement without excessive side effects.
  • the "effective amount” or “therapeutically effective amount” can be different between subjects due to the metabolism of the compound, the age, weight, general condition, the disease being treated, and the severity of the disease being treated. The degree and the judgment of the prescribing doctor are different. Merely by way of example, the therapeutically effective amount can be determined by routine experimental methods, including but not limited to clinical trials of gradually increasing the dose.
  • inhibitor of the kinase as used herein refers to the inhibition of CDK4/6 kinase activity.
  • the starting materials used to synthesize the compounds described herein can be synthesized or can be obtained from commercial sources, such as but not limited to Aldrich Chemical Co. (Milwaukee, Wisconsin), Bachem (Torrance, California), or Sigma Chemical Co. (St. Louis) , Mo.).
  • reaction product can be separated and purified using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography and other methods. These products can be characterized using conventional methods, including physical constants and spectral data.
  • the compounds described herein can be prepared as a single isomer or a mixture of isomers using the synthetic methods described herein.
  • the compounds described herein may have one or more stereocenters, and each center may exist in the R or S configuration.
  • the compounds provided herein include all diastereomeric, enantiomeric and epimeric forms and suitable mixtures thereof. If desired, stereoisomers can be obtained by methods known in the art, such as separation of stereoisomers by chiral chromatography columns.
  • Known methods can be used to separate the mixture of diastereomers into their individual diastereomers based on differences in physicochemical properties.
  • the enantiomers can be separated by chiral column chromatography.
  • the enantiomers can be separated by reacting with a suitable optically active compound (such as alcohol) to convert a mixture of enantiomers into a mixture of diastereomers, and separate diastereomers.
  • a suitable optically active compound such as alcohol
  • the methods and formulations described herein include the use of N-oxides, crystalline forms (also known as polymorphs), or pharmaceutically acceptable salts of the compounds described herein, as well as active metabolites of these compounds having the same type of activity .
  • compounds may exist as tautomers. All tautomers are included within the scope of the compounds provided herein.
  • the compounds described herein can exist in an unsolvated form, or in a solvated form in a pharmaceutically acceptable solvent such as water, ethanol, and the like.
  • the solvated forms of the compounds proposed herein are also believed to be disclosed herein.
  • a reducing agent such as but not limited to sulfur, sulfur dioxide, triphenylphosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, etc.
  • a suitable inert organic solvent for example, but not limited to, acetonitrile, ethanol, dioxane aqueous solution, etc.
  • the compounds described herein are made into prodrugs.
  • Prodrug refers to a substance that will be converted into an active drug in the body. Prodrugs are often useful because, in some cases, they may be easier to administer than the parent drug. For example, in some cases, the active compound itself is difficult to be bioavailable by oral administration, and prodrugs can be used to achieve this goal. The prodrug may also have improved solubility in the pharmaceutical composition than the parent drug. Prodrugs can be designed as reversible drug derivatives to enhance drug delivery to specific sites. In some embodiments, the design of the prodrug increases effective water solubility. See, for example, Fedorak et al., Am. J.
  • prodrugs are (not limited to): the compound described herein is administered as an ester (the "prodrug") to facilitate its transport across the cell membrane (water solubility is not conducive to this transfer), and then metabolized and hydrolyzed It is a carboxylic acid, active entity (once it enters the cell, water solubility is beneficial).
  • prodrugs may be short peptides (polyamino acids) linked to acid groups, where the peptide will be metabolized to show the active part.
  • the prodrug when administered in vivo, is chemically converted into the biological, drug, or therapeutically active form of the compound.
  • the prodrug is enzymatically metabolized into the biological, drug, or therapeutically active form of the compound through one or more steps or methods.
  • the pharmaceutically active compound can be modified to produce a prodrug that can regenerate the active compound after administration in the body.
  • the prodrug can be designed to change the metabolic stability or transport characteristics of the drug to mask side effects or toxicity, thereby improving the effect of the drug or changing other characteristics or properties of the drug.
  • prodrug form of the compound described herein wherein the prodrug is metabolized in the body to produce a derivative as previously described and included in the scope of the claims.
  • some of the compounds described herein may be prodrugs or other derivatives of the active compound.
  • the compounds described herein encompass compounds that include isotopes.
  • the compounds including isotopes are the same in molecular and structural formula as the compounds described herein, but have one or more atoms belonging to the same element but having the same elements as those most commonly found in nature. Replacement of nuclides with different atomic weights or mass numbers. For example, when hydrogen is shown at any position in the compound described herein, it also includes the case where hydrogen is an isotope (such as protium, deuterium, and tritium) at that position.
  • isotopes that can be introduced into the compounds described herein include, but are not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 35 S, 18 F, 36 Cl.
  • the compounds described herein that include certain isotopes e.g., radioisotopes, such as 3 H and 14 C
  • the compounds described herein will be metabolized to produce metabolites in the body of an organism in need after being administered, and the produced metabolites are then used to produce the desired effect, including the desired therapeutic effect .
  • the compounds described herein can be formulated and/or used as pharmaceutically acceptable salts.
  • the types of pharmaceutically acceptable salts include, but are not limited to: (1) acid addition salts, formed by reacting the free base form of a compound with a pharmaceutically acceptable inorganic acid, such as hydrochloric acid, hydrobromic acid, Sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, etc.; or formed by reaction with organic acids, such as acetic acid, propionic acid, caproic acid, cyclopentane propionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, and adipic acid Acid, sebacic acid, succinic acid, malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, Mandelic acid, methanesulfonic acid, ethanesul
  • Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, trimethylamine, N-methylglucamine, etc.; acceptable inorganic bases include aluminum hydroxide, calcium hydroxide , Potassium hydroxide, sodium carbonate, sodium hydroxide, etc.
  • the corresponding counterions of pharmaceutically acceptable salts can be analyzed and identified using various methods, including but not limited to ion exchange chromatography, ion chromatography, capillary electrophoresis, inductively coupled plasma, atomic absorption spectroscopy, mass spectrometry, or their Any combination.
  • the salt can be recovered using at least one of the following techniques: filtration, precipitation with a non-solvent followed by filtration, solvent evaporation, or lyophilization in the case of an aqueous solution.
  • the mentioned pharmaceutically acceptable salts include solvent added forms or crystal forms thereof, especially solvates or polymorphs.
  • Solvates contain stoichiometric or non-stoichiometric amounts of solvent and can be formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. A hydrate is formed when the solvent is water, or an alcoholate is formed when the solvent is an alcohol.
  • solvents such as water, ethanol, and the like.
  • a hydrate is formed when the solvent is water
  • an alcoholate is formed when the solvent is an alcohol.
  • solvates of the compounds described herein can be conveniently prepared or formed.
  • the compounds provided herein can exist in unsolvated and solvated forms.
  • the solvated form is considered to be active equivalent to the unsolvated form.
  • the compounds described herein can be in various forms, including but not limited to amorphous, spherical, and nanoparticle forms.
  • the compounds described herein include crystalline forms, also known as polymorphs.
  • Polymorphs include different crystal packing arrangements of the same elemental composition of the compound. Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability and solubility. Various factors such as recrystallization solvent, crystallization rate and storage temperature can lead to a single crystalline form.
  • Thermal analysis methods focus on thermochemical degradation or thermophysical processes, which include but are not limited to polymorphic transformation. Thermal analysis methods can be used to analyze the relationship between polymorphs and measure weight loss to find the glass transition temperature, or use To study the compatibility of excipients. These methods include, but are not limited to, differential scanning calorimetry (DSC), modulated differential scanning calorimetry (MDCS), thermogravimetric analysis (TGA), and thermogravimetric and infrared analysis (TG/IR).
  • DSC differential scanning calorimetry
  • MDCS modulated differential scanning calorimetry
  • TGA thermogravimetric analysis
  • TG/IR thermogravimetric and infrared analysis
  • X-ray diffraction methods include but are not limited to single crystal and powder diffractometers and synchrotron sources.
  • the various spectroscopy techniques used include but are not limited to Raman, FTIR, UVIS and NMR (liquid and solid state).
  • Various microscopy techniques include, but are not limited to, polarized light microscopy, scanning electron microscopy (SEM) and energy dispersive X-ray analysis (EDX), environmental scanning electron microscopy and EDX (in a gas or water vapor atmosphere), IR microscopy technology And Raman microscope technology.
  • the carrier herein includes conventional diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption promoters, surfactants, adsorption carriers, lubricants, and flavoring agents in the pharmaceutical field. , Sweeteners, etc.
  • the medicament of the present invention can be made into various forms such as tablets, powders, granules, capsules, oral liquids and injections, and the above-mentioned medicaments in various dosage forms can be prepared according to conventional methods in the pharmaceutical field.
  • IC 50 refers to an amount of a particular test compound the following, concentration or dosage, which is a measure CDK kinases (e.g., CDK4 / 6-kinase) inhibiting the reaction of such tests, 50% of the maximal effect of suppression The amount, concentration, or dose.
  • CDK kinases e.g., CDK4 / 6-kinase
  • Boc tert-butoxycarbonyl
  • DIPEA N,N-diisopropylethylamine
  • NMP N-methylpyrrolidone
  • TEA triethylamine
  • TFA trifluoroacetic acid
  • THF Tetrahydrofuran
  • HATU 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate
  • NBS N-bromosuccinimide
  • step 1
  • step 6 Add the crude compound 1-11 obtained in step 6 to a 250 mL flask, then add 100 mL of ethanol as a solvent, add 1.7 g of potassium hydroxide and heat to reflux overnight. After the reaction is completed, add acetic acid to adjust the pH to 5-6, solids precipitate out, and filter The filter cake was washed with water, then washed with a small amount of ether, and dried under infrared light to obtain 2.5 g of product.
  • step 1
  • step 1
  • step 1
  • step 1
  • step 1
  • step 1
  • the obtained salt-forming compounds can be obtained in non-salt form by methods known in the art, for example, the following desalting scheme I or II is used.
  • Test Example 1 In vitro inhibitory activity analysis of CDK kinase
  • CDK6/CyclinD1 kinase activity was measured using time-resolved fluorescence resonance energy transfer (TR-FRET) method.
  • TR-FRET time-resolved fluorescence resonance energy transfer
  • a 384-well assay plate was used for the measurement with a reaction volume of 20 ⁇ L.
  • the reaction was terminated by adding a mixture of peptide antibody (brand Cisbio, article number 64CUSKAY) and Sa-XL665 (brand Cisbio, article number 610SAXLB) diluted with HTRF KinEASE detection buffer (brand Cisbio, article number 62SDBRDF, containing EDTA).
  • the mixture was incubated at room temperature for 1 hour and then the plate was read.
  • a multi-mode plate reader EnVision TM , multi-function microplate detector, PerkinElmer
  • the TR-FRET signal was measured at an excitation wavelength ( ⁇ Ex ) of 330 nm and detection wavelengths ( ⁇ Em ) of 615 nm and 665 nm.
  • the activity is determined by the ratio of fluorescence at 665nm and 615nm. For each compound, enzyme activity for different concentrations of compound were measured to determine the IC 50. The negative control is the case where no inhibitor is added, and two no enzyme controls are used to determine the baseline fluorescence level.
  • GraphPad6.02 use software to get fit IC 50.
  • each example compound and reference example compound were prepared according to the scheme described above, as shown in Table 1 for details.
  • 8-10 concentrations are prepared, and they are prepared by DMSO, and the preparation concentration is 200 ⁇ of the working concentration.
  • the working concentration is 100nM, which corresponds to the prepared stock solution concentration of 20 ⁇ M.
  • the IC 50 value of each example compound and the reference example compound was determined.
  • the IC 50 value is given according to the interval of the IC 50 value, where "+++” means IC 50 ⁇ 100nM;"++” means 100nM ⁇ IC 50 ⁇ 1000nM;"+” means 1000nM ⁇ IC 50 ⁇ 3000nM. "-" stands for "3000nM and above”.
  • MCF-7 cells obtained from the Shanghai Cell Bank of Chinese Academy of Sciences
  • they are cultured at 37°C, 5% CO 2 and 95% humidity.
  • Luminescent Cell Viability Assay Promega, Cat#G7572
  • a microplate reader EnVision TM , multi-function microplate detector, PerkinElmer
  • IC 50 value of each example compound is listed in Table 2 below, where "+++” represents IC 50 ⁇ 500nM;"++” represents 500nM ⁇ IC 50 ⁇ 2500nM;"+” represents 2500nM ⁇ IC 50 ⁇ 10000nM , "-" means more than 10000nM.
  • the compound of the present invention can achieve an excellent inhibitory effect on MCF-7 cells.

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Abstract

本申请公开了一种可作为CDK激酶(尤其是CDK4/6激酶)抑制剂的通式(I)化合物及其盐，其中所有变量如本文所定义。该化合物可用于治疗或预防癌症等疾病。本申请还涉及包含式(I)化合物的药用组合物。

Description

CDK激酶抑制剂 技术领域
本发明涉及抑制CDK激酶活性的化合物，以及上述化合物在制备治疗和/或预防由CDK激酶介导的癌症相关疾病的药物中的应用。
背景技术
细胞周期依赖性蛋白激酶(Cyclin-Dependent-Kinases，CDKs)，是一组丝氨酸/苏氨酸蛋白激酶，其与重要的细胞过程如细胞周期或转录调节密切相关。研究表明，CDK自身可能不发挥激酶活性，其通过与细胞周期蛋白(cyclins)结合形成特异的CDK-Cyclin复合物而发挥蛋白激酶活性，从而具有促进细胞周期时相转变、启动DNA合成以及调控细胞转录等功能。
CDK家族目前有13个成员(CDK1至CDK13)，根据其细胞内功能不同，分为两大类：控制细胞周期的CDK(CDK1、CDK2、CDK4、CDK6等)和控制转录的CDK(CDK7、CDK9等)。周期蛋白有11种亚型，分别以A-I、k和T命名，它们的表达均受转录调控，在细胞周期中呈规律性波动。在参与细胞周期调控的CDK亚型中，CDK4/6发挥着不可替代的作用。与癌症有关的细胞周期突变主要存在于G1期和G1/S期转化过程中，CDK4/6与CyclinD结合形成有激酶活性的复合物，通过使抑癌蛋白Rb磷酸化，释放出结合的转录因子E2F，启动与S期有关的基因转录，促使细胞通过检验点，并从G1期向S期转移。CDK4/6特异性的激活与某些肿瘤的增殖密切相关，大约80％的人类肿瘤中存在cyclin D-CDK4/6-INK4-Rb通道异常。这条通道的改变可能使得G1期进程加速，从而使得肿瘤细胞增殖加快并获得生存优势。因此，对其干预成为一种治疗策略，CDK4/6因此成为抗肿瘤的靶点之一。
目前已有50种以上的CDK抑制剂被报道过，其中一些具有潜在的抗肿瘤活性，某些广谱CDK抑制剂已经被开发为抗肿瘤药物，另 有一些正在进行临床前或临床实验，而新的CDK抑制剂也在不断被研发。目前针对CDK的抑制剂，Flavopiridol(夫拉平度)，又称为L86-8275或HMR1275，它是第一代CDK抑制剂的代表，因为药效不明显而且显示较高毒性而一直未能进入Ⅲ期临床。
目前，包括辉瑞、礼来和诺华等在内的一些医药公司陆续报道了一系列选择性较好的CDK抑制剂，正在临床试验阶段。其中，特别值得关注的是辉瑞公司开发的Palbociclib(PD-0332991)、礼来公司的Abemaciclib(LY2835219)和诺华公司的Ribociclib(LEE011)。
Palbociclib是Pfizer研发的一种高特异性的CDK4(IC 50＝0.011μmol/L)和CDK6(IC 50＝0.016μmol/L)选择性抑制剂(参见文献1～2)，对包括其他CDKs酪氨酸/丝氨酸和苏氨酸激酶在内的36种蛋白激酶无活性。2015年2月，Palbociclib获美国FDA批准与雌激素受体阳性乳腺癌患者的治疗，该化合物的成功上市再次掀起了关于CDK抑制剂的研发热潮。
Abemaciclib是一种口服有效的细胞周期蛋白依赖性激酶(CDK)抑制剂，靶向作用于CDK4(cyclin D1)和CDK6(cyclin D3)细胞周期通路，具有潜在的抗肿瘤活性。Abemaciclib特异性抑制CDK4/6，从而在早G1期抑制视网膜母细胞瘤(Rb)蛋白磷酸化。抑制Rb磷酸化，防止CDK介导的G1-S期转换，从而使细胞周期停滞在G1期，抑制DNA合成，且抑制癌细胞生长。2017年3月，礼来宣布Abemaciclib治疗乳腺癌的一项III期临床研究成功。
Ribociclib为又一口服有效的CDK4、CDK6选择性抑制剂(IC50分别为10和39nmol/L)(参见文献3～4)。与预期一样，Ribociclib抑制Rb磷酸化，引起G0/G1期阻滞并诱导肿瘤细胞(包括有B-Raf或N-Ras突变的黑色素瘤、乳腺癌、脂肪肉瘤和神经母细胞瘤)衰老。2017年3月14日，Ribociclib获美国FDA批准作为与芳香酶抑制剂的联用方案，用于治疗激素受体阳性和人表皮生长因子受体2阴性的绝经后妇女患者。
目前，对该靶点的研究为世界前沿热点，CDK靶向小分子抑制剂(特别是CDK4/6激酶抑制剂)类药物具有很高的开发价值，发展 空间大，对于在该领域内探索新的抗肿瘤药物具有重大的意义。
现有技术文献
专利文献1：WO2003062236A1；
专利文献2：WO2005005426A1；
专利文献3：WO2011101409A1；
专利文献4：CN103788100A。
发明内容
发明要解决的课题
本发明的课题在于提供一种针对CDK的激酶抑制剂化合物。
用于解决课题的手段
本发明提供通式(I)所示的化合物或其药学上可接受的盐：
Figure PCTCN2020091324-appb-000001
其中，
Q为任选地被取代的6～18元亚芳基或任选地被取代的5～18元杂亚芳基，其中，被取代时的取代基选自卤素、羟基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基构成的组；
R 1为任选地被取代的3～8元杂环基、任选地被取代的6～14元稠杂环基、任选地被取代的6～12元螺杂环基，其中，被取代时的取代基选自卤素、羟基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基构成的组；
R 2为H、卤素或者任选地被取代的3～10元环烯基、任选地被取代的3～10元杂环烯基、任选地被取代的3～10元环烷基、任选地被取代的3～10元杂环烷基、任选地被取代的6～18元芳基、任选地被取代的5～18元杂芳基，其中，被取代时的取代基选自卤素、羟基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、C 1-6烷氧基-C 1-6烷氧基、氧代基构成的组；
R 3为H、CN、-C(＝O)-NR 4R 5或者任选地被取代的6～18元芳基、任选地被取代的5～18元杂芳基、任选地被取代的5～8元内酰胺基，其 中，被取代时的取代基选自卤素、羟基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基构成的组；
R 4和R 5各自独立地为甲基或乙基；
并且，当R 3为-C(＝O)-NR 4R 5时，R 2为任选地被取代的3～10元环烯基、任选地被取代的3～10元杂环烯基、任选地被取代的以N原子与通式(I)中的非R 2结构相连接的3～10元杂环烷基、任选地被取代的6～18元芳基，其中，被取代时的取代基选自卤素、羟基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、C 1-6烷氧基-C 1-6烷氧基、氧代基构成的组。
在一种优选的实施方案中，Q为任选地被取代的亚苯基或任选地被取代的亚吡啶基，其中，被取代时的取代基选自卤素、羟基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基构成的组；
R 1为任选地被取代的3～8元杂环基、任选地被取代的6～14元稠杂环基或任选地被取代的6～12元螺杂环基，其中，被取代时的取代基选自C 1-6烷基；
R 2选自卤原子、或者任选地被取代的环戊烯基、任选地被取代的环己烯基、任选地被取代的环戊基、任选地被取代的环己基、任选地被取代的氧杂环己烯基、任选地被取代的氮杂环己烯基、任选地被取代的氧杂环戊基、任选地被取代的氮杂环戊基、任选地被取代的氧杂环己基、任选地被取代的氮杂环己基、任选地被取代的苯基、任选地被取代的萘基、任选地被取代的吡啶基、任选地被取代的噻吩基、任选地被取代的吡唑基、任选地被取代的噁唑基、任选地被取代的异噁唑基、任选地被取代的喹啉基构成的组，其中，被取代时的取代基选自卤素、羟基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、氧代基构成的组；
R 3为H、-CN、-C(＝O)-NR 4R 5或者任选地被取代的苯基、萘基、吡唑基、吡啶基、噻吩基、噁唑基、异噁唑基、嘧啶基、咪唑基、吡咯基、
Figure PCTCN2020091324-appb-000002
其中，被取代时的取代基选自卤素、羟基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基构成的组；
R 4和R 5均为甲基。
在另一种优选的实施方案中，Q为亚苯基或
Figure PCTCN2020091324-appb-000003
在另一种优选的实施方案中，R 1为任选地被取代的下述基团，其中，被取代时的取代基选自C 1-6烷基：
Figure PCTCN2020091324-appb-000004
在另一种优选的实施方案中，所述C 1-6烷基为甲基或乙基。
在另一种优选的实施方案中，R 2为卤素或者任选地被取代的下述基团，其中，被取代时的取代基选自C 1-6烷基：
Figure PCTCN2020091324-appb-000005
在本发明的另一个方面中，提供了表1中各实例化合物或其药学上可接受的盐。
在本发明的另一个方面中，本发明化合物用于抑制CDK激酶活性，特别地，本发明化合物用于抑制CDK4/6激酶活性。
在本发明的另一个方面中，提供了一种药用组合物，其包含有效量的上述本发明化合物和药学上可接受的载体或赋形剂。
在本发明的另一个方面中，提供了本发明的化合物或其药学上可接受的盐化合物或其药学上可接受的盐在制备治疗和/或预防由CDK激酶(特别是CDK4/6激酶)介导的癌症相关疾病的药物中的应用，所述癌症相关的疾病选自脑瘤、肺癌、鳞状上皮细胞癌、膀胱癌、胃癌、卵巢癌、腹膜癌、胰腺癌、乳腺癌、头颈癌、子宫颈癌、子宫内膜癌、直肠癌、肝癌、肾癌、食管腺癌、食管鳞状细胞癌、前列腺癌、雌性生殖道癌、原位癌、淋巴瘤、神经纤维瘤、甲状腺癌、骨癌、皮肤癌、脑癌、结肠癌、睾丸癌、胃肠道间质瘤、前列腺肿瘤、肥大细胞肿瘤、多发性骨髓瘤、黑色素瘤、胶质瘤或肉瘤。
发明的效果
本发明的化合物可抑制CDK激酶(特别是CDK4/6激酶)活性，可用于癌症的治疗中。
具体实施方式
除非另外定义，本文中使用的所有科技术语都具有与要求保护的 主题所属领域的技术人员一般理解相同的含义。
“C 1-6烷基”是指碳原子为1-6的烷基，包括甲基、乙基、丙基、丁基、戊基和己基，包括所有可能的异构形式，例如正丙基和异丙基，正丁基、异丁基、仲丁基和叔丁基，等等。“C 1-6烷基”包括其中所含的全部子范围，例如C 1-2烷基、C 1-3烷基、C 1-4烷基、C 1-5烷基、C 2-5烷基、C 3-5烷基、C 4-5烷基、C 3-4烷基、C 3-5烷基和C 4-5烷基。
“芳基”和“杂芳基”包括单环或稠环多环(即共用相邻的环原子对的环)基团。“芳基”的实例包括但不限于苯基、萘基、菲基、蒽基、芴基和茚基。“杂芳基”的实例包括：
Figure PCTCN2020091324-appb-000006
Figure PCTCN2020091324-appb-000007
等。
本发明所述的“6～18元亚芳基”，是指6～18个碳原子的芳香烃除去2个氢原子衍生的二价基团，包括例如“6～14元亚芳基”、“6～10元亚芳基”等，其实例包括但不限于：亚苯基、亚萘基、亚蒽基等。
本发明所述的“5～18元杂亚芳基”，是指5～18元杂芳烃除去2个氢原子衍生的二价基团，包括例如“5～14元杂亚芳基”、“5～10元杂亚芳基”等，其实例包括但不限于：亚呋喃基、亚噻吩基、亚吡咯基、亚咪唑基、亚噻唑基、亚吡唑基、亚噁唑基、亚异噁唑基、亚异噻唑基、亚吡啶基、亚吡嗪基、亚哒嗪基、亚嘧啶基以及类似物，并且优选地是亚吡啶基、亚吡唑基或亚噻吩基，尤其优选亚吡啶基，最优选氮原子位于位于R1键结位置的3位上的亚吡啶基。
本发明所述的“3～8元杂环基”，包括例如“3～7元杂环基”、“3～6元杂环基”、“4～7元杂环基”、“4～6元杂环基”、“5～7 元杂环基”、“5～6元杂环基”、“6元杂环基”等。具体实例包括但不限于：氮杂环丙烷基、2H-氮杂环丙烷基、二氮杂环丙烷基、3H-二氮杂环丙烯基、氮杂环丁烷基、1,4-二氧杂环己烷基、1,3-二氧杂环己烷基、1,3-二氧杂环戊烷基、1,4-二氧杂环己二烯基、四氢呋喃基、二氢吡咯基、吡咯烷基、咪唑烷基、4,5-二氢咪唑基、吡唑烷基、4,5-二氢吡唑基、2,5-二氢噻吩基、四氢噻吩基、4,5-二氢噻唑基、哌啶基、哌嗪基、吗啉基基、4,5-二氢噁唑基、4,5-二氢异噁唑基、2,3-二氢异噁唑基、2H-1,2-噁嗪基、6H-1,3-噁嗪基、4H-1,3-噻嗪基、6H-1,3-噻嗪基、2H-吡喃基、2H-吡喃-2-酮基、3,4-二氢-2H-吡喃基等，优选为“5～6元杂环基”。
本发明所述的“6～14元稠杂环基”，包括例如“6～11元稠杂环基”、“6～10元稠杂环基”、“7～10元稠杂环基”、“9～10元稠杂环基”等。具体实例包括但不仅限于：
Figure PCTCN2020091324-appb-000008
本发明所述的“6～12元螺杂环基”，是指至少有两个环共享一个原子形成的至少含有一个杂原子的6～12个环原子的环状结构，所述的杂原子选自N、S、O、CO、SO和/或SO 2等。其中包括例如“6～11元螺杂环基”、“7～11元螺杂环基”、“7～10元螺杂环基”、“7～9元螺杂环基”、“7～8元螺杂环基”等。其实例包括但不仅限于例如：
Figure PCTCN2020091324-appb-000009
本发明所述的“3～10元环烯基”，是指3～10个碳原子的环状单烯烃部分去除一个氢原子衍生的环状烯基，包括例如“3～8元环烯基”、“4～6元环烯基”等。其实例包括但不限于：环丙烯基、环丁烯基、环戊烯基、环己烯基、环庚烯基、环辛烯基、环壬烯基、环癸烯基等。
本发明所述的“3～10元杂环烯基”，是指含杂原子的3～10元环状单烯烃部分去除一个氢原子衍生的杂环烯基，包括例如“3～8元杂环烯基”、“4～6元杂环烯基”等。其实例包括但不限于：
Figure PCTCN2020091324-appb-000010
本发明所述的“3～10元环烷基”，是指3～10个碳原子的环烷烃部分去除一个氢原子衍生的环状烷基，包括例如“3～8元环烷基”、“4～6元环烷基”等。其实例包括但不限于：环丙烷基、环丁烷基、 环戊烷基、环己烷基、环庚烷基、环辛烷基、环壬烷基、环癸烷基等。
本发明所述的“3～10元杂环烷基”，是指含杂原子的3～10元杂环烷烃部分去除一个氢原子衍生的杂环状烷基，包括例如“3～8元杂环烷基”、“4～6元杂环烷基”等。其实例包括但不限于：氮杂环丙烷基、氮杂环丁烷基、氮杂环戊烷基、氮杂环己烷基、氮杂环庚烷基、氮杂环辛烷基、氮杂环壬烷基等。
本发明所述的“氧代基”是指一种取代基，其中一个氧原子被键合在一个碳原子或氮原子上，并且其中一个氧原子被键合在一个碳原子上的结构的具体实例包括羰基，并且其中一个氧原子被键合在一个氮原子上的基团的具体实例包括N-氧化物。
“卤素”是指氟、氯、溴和碘。“C 1-6烷氧基”是指(C 1-6烷基)O-基团，其中C 1-6烷基如本文中定义。“卤代C 1-6烷基”是指卤素-(C 1-6烷基)-基团，其中C 1-6烷基如本文中定义。卤代C 1-6烷基包括全卤代C 1-6烷基，其中C 1-6烷基中的全部氢原子被卤素代替，如-CF 3、-CH 2CF 3、-CF 2CF 3、-CH 2CH 2CF 3等。
本发明所述的“5～8元内酰胺基”，是指环内含有-C(＝O)-N基团的内酰胺去除1个氢原子衍生的基团，包括例如“5～7元内酰胺基”，其实例包括但不限于：
Figure PCTCN2020091324-appb-000011
本发明的化合物可以被制备为其药学上可接受的盐或作为其药学上可接受的盐来使用。这可通过本领域中已知的任何成盐手段来进行。例如，所述药学上可接受的盐可以为酸加成盐，例如无机酸加成盐或有机酸加成盐。例如，所述药学上可接受的盐还可以是所述化合物中的酸性质子被金属离子置换而形成的盐、或所述化合物与有机碱或无机碱配位形成的盐。
本文使用的术语“药学上可接受的”，当涉及制剂、组合物或成分时，是指对被治疗的受治疗者的一般健康状况没有持久的不利影响或不损失化合物的生物活性或性质，并且相对无毒性。
本文使用的术语“有效量”或“治疗有效量”，是指给予后足以在一定程度上减轻被治疗的疾病或病症的一种或多种症状的药物或化合物的量。结果可以是缩小和/或减轻征兆、症状或疾病原因或任意其它期望的生物系统的改变。例如，用于治疗用途的“有效量”是提供以使疾病的临床症状显著减轻、而不产生过度的毒副作用所需的量。对任意个体情况适合的“有效量”可以使用例如逐步增大剂量研究等技术来确定。术语“治疗有效量”包括例如预防有效量。本文公开的化合物的“有效量”是有效达到所期望的药理效果或治疗改善而没有过度的毒副作用的量。可以理解的是，“有效量”或“治疗有效量”在受治疗者之间可以不同，原因在于化合物的新陈代谢、受治疗者年龄、体重、一般状况、被治疗的疾病、被治疗疾病的严重程度以及开处方医生的判断的不同。仅举例来说，治疗有效量可以是通过常规实验方法来确定，包括但不限于逐步增大剂量临床试验。
本文使用的术语激酶的“抑制”、“抑制的”或“抑制剂”，是指CDK4/6激酶活性被抑制。
关于制备本文公开的化合物的一般方法，可参考本领域中已知的反应，并且本领域技术人员可合理选择适当的试剂和条件对本领域中已知的反应加以调整或改良，以引入本文公开的化合物结构中的各部分。
用于合成本文描述的化合物的起始原料可以被合成或可以从商业来源获得，例如但不限于Aldrich Chemical Co.(Milwaukee，Wisconsin)、Bachem(Torrance，California)或Sigma Chemical Co.(St.Louis，Mo.)。本文描述的化合物和具有不同取代基的其它相关化合物可以使用本领域技术人员已知的技术和原料合成，例如在March的《ADVANCED ORGANIC CHEMISTRY》第四版，(Wiley 1992)；Carey和Sundberg的《ADVANCED ORGANIC CHEMISTRY》第四版，A卷和B卷(Plenum 2000，2001)；Green和Wuts的《PROTECTIVE GROUPS IN ORGANIC SYNTHESIS》第三版，(Wiley 1999)；Fieser的《Reagents for Organic Synthesis》第1-17卷(John Wiley and Sons，1991)；《Rodd′s Chemistry of Carbon  Compounds》第1-5卷和补充本(Elsevier Science Publishers，1989)；《Organic Reactions》第1-40卷(John Wiley and Sons，1991)；以及Larock的《Comprehensive Organic Transformations》(VCH Publishers Inc.，1989)(通过引用将其全部并入本文中)中所述的。
如果需要，反应产物可以使用常规技术分离和纯化，包括但不限于过滤、蒸馏、结晶、色谱等方法。这些产物可以使用常规方法来表征，包括物理常数和图谱数据。
本文描述的化合物可以使用本文描述的合成方法制备为单一异构体或异构体混合物。
本文描述的化合物可以具有一个或多个立构中心，并且每一个中心可以存在R或S构型。本文提供的化合物包括所有非对映异构体、对映异构体和差向异构体的形式及其合适的混合物。如果需要，立体异构体可以通过本领域已知的方法获得，例如通过手性色谱柱分离立体异构体。
可以利用已知的方法，例如通过色谱法和/或分级结晶，基于物理化学性质差异，将非对映异构体的混合物分离为它们的单独的非对映异构体。在一个实施方式中，对映异构体可以通过手性柱色谱分离。在其它一些实施方式中，可以通过与适当的光学活性化合物(例如醇)反应，将对映异构体的混合物转化为非对映异构体的混合物而分离对映异构体，分离出非对映异构体并转化(例如水解)单独的非对映异构体为相应的纯的对映异构体。所有这些异构体，包括非对映异构体、对映异构体及其混合物被认为是本文描述的组合物的组成部分。
本文描述的方法和制剂包括使用N-氧化物、结晶形式(也可以认为是多晶型)、或本文描述的化合物的药用可接受的盐，以及这些具有相同类型活性的化合物的活性代谢物。在一些情况下，化合物可以作为互变异构体存在。所有互变异构体都包括在本文提供的化合物的范围内。另外，本文描述的化合物能以非溶剂化物的形式存在，也可以以溶剂化物的形式存在于药用可接受的溶剂如水、乙醇等中。本文提出的化合物的溶剂化形式也被认为在此公开。
可以通过用还原剂(例如但不限于硫、二氧化硫、三苯基膦、硼 氢化锂、硼氢化钠、三氯化磷、三溴化物等)在0℃至80℃下和合适的惰性有机溶剂(例如但不限于乙腈、乙醇、二烷水溶液等)中处理，从N-氧化物制备非氧化形式。
在一些实施方式中，将本文描述的化合物制成前体药物。“前体药物”是指将在体内转化为活性药物的物质。前体药物经常是有用的，因为，在一些情况下，它们可能比母体药物更容易给药。例如，某些情况下，活性化合物本身难以通过口服给药而被生物利用，而可利用前体药物来实现此目的。前体药物也可能具有比母体药物改善的、在药用组合物中的溶解度。前体药物可以被设计为可逆的药物衍生物，以增强药物转运至特定位点组织。在一些实施方式中，对前体药物的设计增加了有效的水溶解性。参见例如Fedorak等，Am.J.Physiol，269：G210-218(1995)；McLoed等，Gastroenterol，106：405-413(1994)；Hochhaus等，Biomed.Chrom.，6：283-286(1992)；J.Larsen and H.Bundgaard，Int.J.Pharmaceutics，37，87(1987)；J.Larsen等，Int.J.Pharmaceutics，47，103(1988)；Sinkula等，J.Pharm.Sd.，64：181-210(1975)；T.Higuchi和V.Stella的《Pro-drugs as Novel Delivery Systems》the A.C.S.Symposium Series的第14卷；和Edward B.Roche的《Carriers in Drug Design》American Pharmaceutical Association and Pergamon Press，1987，在此通过引用将其全部并入本文中。前体药物的实例是(不限于)：将本文描述的化合物作为酯给予(所述“前体药物”)以促进其被传送穿过细胞膜(水溶解性不利于此转移)，然后再代谢水解为羧酸、活性实体(一旦进入到细胞内，水溶解性是有益的)。前体药物的其它实例可以是连接于酸基的短肽(多聚氨基酸)，其中肽将被代谢以显示活性部分。在某些实施方式中，在体内给药时，前体药物被化学转化为化合物的生物、药物或治疗活性形式。在某些实施方式中，前体药物通过一个或多个步骤或方法被酶代谢为化合物的生物、药物或治疗活性形式。可对药物活性化合物进行修饰以产生出下述这样的前体药物，所述前体药物在体内给药后能够再产生该活性化合物。所述前体药物可以被设计为改变药物的代谢稳定性或转运特性，以掩盖副作用或毒性，从而改善药物的作用或改变药物 的其它特性或性质。基于对药效方法和药物体内代谢的知识，一旦药物活性化合物是已知的，本领域技术人员就能设计出化合物的前体药物(参见例如《Nogrady(1985)Medicinal Chemistry A Biochemical Approach》Oxford University Press，New York，第388-392页；Silverman(1992)《The Organic Chemistry of Drug Design and Drug Action》Academic Press，Inc.，San Diego，第352-401页，Saulnier等(1994)，《Bioorganic and Medicinal Chemistry Letters》第4卷，第1985页)。
本文描述的化合物的前体药物形式，其中所述前体药物在体内代谢，产生如前所述的、包括在权利要求的范围内的衍生物。在一些情况下，本文所述的一些化合物可以是活性化合物的前体药物或其它衍生物。
本文描述的化合物涵盖其中包括同位素的化合物，所述包括同位素的化合物与本文所述的化合物在分子式和结构式上相同，但有一个或多个原子被属于同一元素但具有与自然界中最通常发现的原子量或质量数不同的核素代替。例如，本文描述的化合物中的任何位置上显示为氢时，也包括该位置上为氢的同位素(例如氕、氘和氚等)的情况。可以被引入至本文描述的化合物中的同位素的实例包括但不限于，氢、碳、氮、氧、氟和氯的同位素，例如分别为 2H、 3H、 13C、 14C、 15N、 18O、 17O、 35S、 18F、 36Cl。包括某些同位素(例如放射性同位素，如 3H和 14C)的本文描述的化合物可以用于测定药物和/或底物组织分布。
在另外的或进一步的实施方式中，本文描述的化合物将在被给予有需要的生物体后在其体内代谢产生代谢物，所产生的代谢物然后用于产生期望的效果，包括期望的治疗效果。
本文描述的化合物可以被制成和/或被用作药学上可接受的盐。药学上可接受的盐的类型包括但不限于：(1)酸加成盐、通过将化合物的游离碱形式与药用可接受的无机酸反应形成，所述无机酸如盐酸、氢溴酸、硫酸、硝酸、磷酸、偏磷酸等；或与有机酸反应形成，所述有机酸如乙酸、丙酸、己酸、环戊烷丙酸、羟基乙酸、丙酮酸、乳酸、丙二酸、己二酸、癸二酸、琥珀酸、苹果酸、马来酸、反丁烯 二酸、三氟乙酸、酒石酸、柠檬酸、苯甲酸、3-(4-羟基苯甲酰基)苯甲酸、肉桂酸、扁桃酸、甲烷磺酸、乙烷磺酸、1，2-乙二磺酸、2-羟基乙磺酸、苯磺酸、甲苯磺酸、2-萘磺酸、4-甲基双环-[2.2.2]辛-2-烯-1-甲酸、葡庚糖酸、马尿酸、龙胆酸、4，4′-亚甲基双-(3-羟基-2-烯-1-甲酸)、烟酸、3-苯基丙酸、三甲基乙酸、叔丁基乙酸、十二烷基硫酸、葡糖酸、谷氨酸、羟基萘酸、水杨酸、硬脂酸、粘康酸等；(2)母体化合物中的酸性质子被金属离子置换时形成的盐，例如碱金属离子(例如锂、钠、钾)、碱土金属离子(例如镁或钙)或铝离子；或(3)与有机碱或无机碱配位形成的盐，可接受的有机碱包括乙醇胺、二乙醇胺、三乙醇胺、三甲胺、N-甲基葡萄糖胺，等等；可接受的无机碱包括氢氧化铝、氢氧化钙、氢氧化钾、碳酸钠、氢氧化钠，等等。
药学上可接受的盐的相应的平衡离子可以使用各种方法分析和鉴定，所述方法包括但不限于离子交换色谱、离子色谱、毛细管电泳、电感耦合等离子体、原子吸收光谱、质谱或它们的任何组合。
可以使用以下技术的至少一种回收所述盐：过滤、用非溶剂沉淀接着过滤、溶剂蒸发，或水溶液的情况下使用冻干法。
应该理解，提及的药学上可接受的盐包括溶剂加入形式或其晶体形式，尤其是溶剂化物或多晶型。溶剂化物包含化学计量的或非化学计量的溶剂量，并且可以在与药用可接受的溶剂如水、乙醇等结晶的过程期间形成。当溶剂是水时形成水合物，或当溶剂是醇时形成醇化物。本文描述的方法中，本文描述的化合物的溶剂化物可以被方便地制备或形成。另外，本文提供的化合物能以非溶剂化物及溶剂化物形式存在。对于本文提供的化合物和方法而言，通常，溶剂化物形式认为与非溶剂化物形式在活性上等价。
本文描述的化合物可以是各种形式，包括但不限于无定形、球形和纳米颗粒形式。另外，本文描述的化合物包括结晶形式，也称为多晶型。多晶型包括化合物的相同元素组成的不同晶体堆积排列。多晶型通常具有不同的X射线衍射图、红外光谱、熔点、密度、硬度、晶体形状、光学和电学性质、稳定性和溶解性。各种因素如再结晶溶剂、 结晶速率和储存温度可以导致单一的结晶形式为主。
对药用可接受的盐、多晶型和/或溶剂化物的筛选和表征可以使用多种技术完成，所述技术包括但不限于热分析、X射线衍射、光谱、蒸汽吸着和显微镜方法。热分析方法着重于热化学降解或热物理过程，其包括但不限于多晶型变换，可通过热分析方法来分析多晶型之间的关系，测定失重，以发现玻璃化转变温度，或者用于赋形剂相容性研究。这些方法包括但不限于差示扫描量热法(DSC)、调制差示扫描量热法(MDCS)、热重量分析法(TGA)、以及热重量和红外分析(TG/IR)。X射线衍射方法包括但不限于单晶体和粉末衍射计和同步加速器源。使用的各种光谱技术包括但不限于Raman、FTIR、UVIS和NMR(液体和固体状态)。各种显微镜技术包括但不限于偏振光显微镜技术、扫描电子显微镜技术(SEM)与能量分散X射线分析(EDX)、环境扫描电子显微镜技术与EDX(在气体或水蒸汽气氛下)、IR显微镜技术和拉曼(Raman)显微镜技术。
本文中的载体包括药学领域的常规稀释剂、赋形剂、填充剂、粘合剂、湿润剂、崩解剂、吸收促进剂、表面活性剂、吸附载体、润滑剂，必要时可以加入香味剂、甜味剂等。本发明药物可以制成片剂、粉剂、粒剂、胶囊、口服液及注射用药等多种形式，上述各剂型的药物均可以按照药学领域的常规方法制备。
本文使用的IC 50是指，特定测试化合物的下述量、浓度或剂量，其是在测量CDK激酶(例如CDK4/6激酶)的抑制这样的反应的试验中，达到最大效应的50％抑制时的量、浓度或剂量。
实施例
以下具体的非限制性实施例将被解释为仅仅是说明性的，并不以任何方式限制本发明。虽然无需进一步详细描述，但是可以相信本领域技术人员能基于本文的描述，完全利用本发明。
化合物的合成
在以下的合成方案中，使用如下缩写：
Boc：叔丁氧基羰基；
Et：乙基；
H：小时；
rt/RT：室温；
Me：甲基；
MeOH：甲醇
DIPEA：N,N-二异丙基乙胺；
DCM：二氯甲烷；
NMP：N-甲基吡咯烷酮；
TEA：三乙胺；
TFA：三氟乙酸；
THF：四氢呋喃；
HATU：2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯；
DMF：二甲基甲酰胺。
NBS：N-溴代丁二酰亚胺
NIS：N-碘代丁二酰亚胺
DPPF PdCl 2：[1,1'-双(二苯基膦基)二茂铁]二氯化钯
XantPhos：4,5-双二苯基膦-9,9-二甲基氧杂蒽
Pd 2(dba) 3：三(二亚苄基丙酮)二钯
合成方案I
步骤1：
Figure PCTCN2020091324-appb-000012
在1L二颈烧瓶中加入100g化合物1-1，91g化合物1-2，再加入500mL二氧六环作为溶剂，连接分水器、冷凝管，加入9mL盐酸溶液(2mol/L)，升温至115℃反应1h，再加入2mL HCl溶液(2mol/L)，控制反应温度为95℃，反应过夜；反应完毕，冷却至室温，再加入饱和碳酸氢钠溶液，条pH至碱性，浓缩除去二氧六环，乙酸乙酯萃取，取 有机层，无水硫酸钠干燥，过滤，浓缩，柱层析(梯度洗脱，丙酮：正己烷＝1:8到1:5)，得到40g产物。
步骤2：
Figure PCTCN2020091324-appb-000013
在二颈烧瓶中加入40g化合物1-3，再加入250mL乙腈(超声)溶解，氩气保护下，冰盐浴中缓慢滴加20mL化合物1-4，反应1h，反应完全后，继续在冰盐浴中加入40mL DMF搅拌反应1h，反应完毕后，将其倒入冰水中，乙酸乙酯萃取，得有机层，无水硫酸钠干燥，过滤，浓缩，柱层析(梯度洗脱，乙酸乙酯：正己烷＝1:10到1:5)，得到38g产物。
步骤3：
Figure PCTCN2020091324-appb-000014
在1L烧瓶中加入38g化合物1-5，加入665mL乙腈作为溶剂，氩气保护下降温至-30℃，再缓慢加入27.5g化合物1-6，继续搅拌反应5min，升至室温反应2h，反应完毕后，加入乙酸乙酯，饱和食盐水萃取，得有机层，无水硫酸钠干燥，过滤，浓缩，柱层析(梯度洗脱，乙酸乙酯：正己烷＝1:10到1:5)，得到47g产物。
步骤4：
Figure PCTCN2020091324-appb-000015
在2L烧瓶中加入47g化合物1-7，加入940mL乙醇作为溶剂，再加入470mL氨水，室温下缓慢滴加83.5mL双氧水(30％)，滴加完毕搅拌过夜，反应完毕，浓缩除去乙醇，过滤得到浅黄固体，纯水洗涤，再用甲基叔丁基醚与正己烷(1:1)洗至白色，真空干燥得到37g产物。
步骤5：
Figure PCTCN2020091324-appb-000016
在100mL烧瓶中加入6g化合物1-8，加入10mL二氯甲烷溶解，再滴加20mL三氟乙酸，室温下搅拌反应2h，反应完全后浓缩除去溶剂及过量三氟乙酸，使用饱和碳酸氢钠调pH至7-8，乙酸乙酯萃取，取有机层，无水硫酸钠干燥，过滤，浓缩得到3.6g产物。
步骤6：
Figure PCTCN2020091324-appb-000017
在250mL烧瓶中加入3g化合物1-9，加入100mL二氯甲烷，再加入2.4g化合物1-10，室温下搅拌，再缓慢滴加三乙胺(4.5g)，TLC监控反应，反应完全后，浓缩，直接待用。
步骤7：
Figure PCTCN2020091324-appb-000018
在250mL的烧瓶中加入步骤6得到的粗品化合物1-11，再加入100mL的乙醇作为溶剂，加入1.7g氢氧化钾加热回流过夜，反应完毕后加入醋酸调pH至5-6，固体析出，过滤，滤饼水洗，再用少量乙醚洗涤，红外灯下干燥，得到2.5g产物。
步骤8：
Figure PCTCN2020091324-appb-000019
在100mL耐压管中加入2.5g化合物1-13，然后再加入20mL化合物1-14，DIPEA 10mL，加热至125℃反应48h；反应完毕后浓缩除去过量三氯氧磷以及DIPEA，加入100mL乙酸乙酯溶解稀释，在冰水浴下加入少量冰块，然后缓慢滴加饱和碳酸氢钠溶液，调pH至7-8，加入饱和氯化钠溶液，乙酸乙酯萃取，得有机层，干燥，过滤，浓缩，柱层析得到1.5g产物。
步骤9：
Figure PCTCN2020091324-appb-000020
在100mL的烧瓶中加入3.9g化合物1-15、0.9g硼氢化钠，加入40mL THF作为溶剂，再加入2mL异丙醇，室温下搅拌反应1h；反应完全后，过滤除去固体，DCM洗涤，浓缩滤液，除去过量THF，异丙醇及DCM；再加入DCM作为溶剂，5g DDQ，室温下搅拌反应30分钟，反应完毕后过滤除去固体，滤液加入饱和碳酸氢钠溶液，DCM萃取，干燥，过滤，浓缩，柱层析得到3g产物。
步骤10：
Figure PCTCN2020091324-appb-000021
在50mL烧瓶中加入1g化合物1-16、0.9g化合物1-17、0.3gDPPF PdCl 2、0.9g碳酸钾，再加入10mL甲苯以及1mL水作为溶剂，氩气保护下，100℃反应过夜，反应完毕，加入乙酸乙酯，饱和氯化钠溶液萃取，得有机层，干燥，过滤，浓缩，柱层析得到430mg产物。
步骤11：
Figure PCTCN2020091324-appb-000022
在100mL烧瓶中加430mg化合物1-18、565mg化合物1-19、106mg XantPhos、84mg Pd 2(dba) 3、900mg叔丁醇钠，加入20mL甲苯作为溶剂，氩气保护下，加热至105℃反应过夜，反应完毕，加入饱和氯化钠溶液，乙酸乙酯萃取，取有机层，干燥，过滤，浓缩，柱层析得到200mg产物。
步骤12：
Figure PCTCN2020091324-appb-000023
在50mL烧瓶中加入150mg化合物1-20，加入15mL四氢呋喃作为溶剂，0℃下搅拌10min，然后再缓慢加入56mg NBS，继续在0℃下搅拌反应，反应15min监控反应，待反应完毕后，使用饱和氯化钠溶液，乙酸乙酯萃取，得有机层，干燥，过滤，浓缩，柱层析得到160mg产物。
步骤13：
Figure PCTCN2020091324-appb-000024
在50mL烧瓶中加入100mg化合物1-22、42mg化合物1-23、13mg DPPF PdCl 2、38mg碳酸钾，加入15mL二氧六环作为溶剂，再加入1.5mL 水，氩气保护下升温至110℃反应过夜，反应完毕，加入饱和氯化钠溶液，乙酸乙酯萃取，取有机层，干燥，过滤，浓缩，厚制备板薄层层析，得到10mg产物。
步骤14：
Figure PCTCN2020091324-appb-000025
在25mL烧瓶中，加入10mg化合物1-24，加入5mL二氯甲烷溶解，再加入0.5mL HCl/MeOH溶液(3N)，室温下搅拌反应2h，反应完毕浓缩除去溶剂及过量HCl/MeOH，真空干燥，得到9mg产物。
合成方案II
步骤1：
Figure PCTCN2020091324-appb-000026
在50mL耐压管中加入2.2g化合物1-16，加入10mL四氢呋喃作为溶剂，再加入5mL氨水(质量分数28％)，加热至100℃，反应过夜，反应完全后直接浓缩除去溶剂及过量氨水，得到2.3g产物。
步骤2：
Figure PCTCN2020091324-appb-000027
在50mL烧瓶中加入2.3g化合物2-2，加入15mL化合物2-3，升温至100℃反应4h，反应完毕，加入饱和氯化钠溶液，乙酸乙酯萃取，取有机层，干燥，过滤，浓缩，得到粗品；使用甲基叔丁基醚与正己烷(1:1)洗涤，真空干燥，得到2.2g产物。
步骤3：
Figure PCTCN2020091324-appb-000028
在10mL烧瓶中加入200mg化合物2-4，211mg化合物2-5，加入40mg催化剂(CAS:1447963-75-8)，加入2.5mL醋酸钾溶液(0.5N)，氩气保护下升温至100℃反应2h，反应完毕，加入饱和氯化钠溶液，乙酸乙酯萃取，取有机层，无水硫酸钠干燥，过滤，浓缩，柱层析得到110mg产物。
步骤4：
Figure PCTCN2020091324-appb-000029
在50mL烧瓶中加入110mg化合物2-6，加入20mL四氢呋喃，冰水浴下搅拌10min，再缓慢加入86mg化合物21，监控反应，反应完毕，加入饱和氯化钠溶液，乙酸乙酯萃取，取有机层，无水硫酸钠干燥，过滤，浓缩，柱层析得到150mg产物。
步骤5：
Figure PCTCN2020091324-appb-000030
在50mL烧瓶中加入150mg化合物2-7、149mg化合物2-8、37.4mg DPPF PdCl 2、106mg碳酸钾，加入15mL二氧六环作为溶剂，再加入1.5mL水，氩气保护下升温至110℃反应过夜，反应完毕，加入饱和氯化钠溶液，乙酸乙酯萃取，取有机层，干燥，过滤，浓缩，柱层析，得到80mg产物。
步骤6：
Figure PCTCN2020091324-appb-000031
在50mL烧瓶中加入80mg化合物2-9，加入10mL四氢呋喃作为溶剂，再加入5mL氢氧化钠溶液(2N)，加热回流反应4h，反应完毕，加入饱和氯化钠溶液，乙酸乙酯萃取，取有机层，无水硫酸钠干燥，过滤，浓缩，真空干燥得到50mg产物。
步骤7：
Figure PCTCN2020091324-appb-000032
在50mL烧瓶中加入50mg化合物2-11、129mg化合物2-12、XantPhos 12.8mg、Pd 2(dba) 3 10mg、叔丁醇钠32mg，再加入15mL甲苯作为溶剂，氩气保护下升温至110℃反应过夜，反应完毕，加入饱和氯化钠溶液，乙酸乙酯萃取，得有机层，无水硫酸钠干燥，过滤，浓缩，厚制备板薄层层析得到10mg产物。
步骤8：
Figure PCTCN2020091324-appb-000033
在25mL烧瓶中，加入10mg化合物2-13，加入5mL二氯甲烷溶解，再加入0.5mL HCl/MeOH溶液(3N)，室温下搅拌反应2h，反应完毕浓缩除去溶剂及过量HCl/MeOH，真空干燥，得到9mg产物。
合成方案III
步骤1：
Figure PCTCN2020091324-appb-000034
在100mL烧瓶中加入500mg化合物2-2、964mg化合物3-1、XantPhos 135.8mg、Pd 2(dba) 3 107.5mg、叔丁醇钠338mg，再加入40mL甲苯作为溶剂，氩气保护下升温至105℃反应过夜，反应完毕，加入饱和氯化钠溶液，乙酸乙酯萃取，得有机层，无水硫酸钠干燥，过滤，浓缩，柱层析得到480mg产物。
步骤2：
Figure PCTCN2020091324-appb-000035
在50mL烧瓶中加入230mg化合物3-2、121mg化合物1-17、35mg DPPF PdCl 2、101mg碳酸钾，加入15mL二氧六环作为溶剂，再加入1.5mL水，氩气保护下升温至110℃反应过夜，反应完毕，加入饱和氯化钠溶液，乙酸乙酯萃取，得有机层，无水硫酸钠干燥，过滤，浓缩，柱层析得到150mg产物。
其他步骤参见合成方案I中步骤12、13、14
合成方案IV
步骤1：
Figure PCTCN2020091324-appb-000036
在100mL烧瓶中加入1g化合物2-2，再加入50mL DMF溶解，冰水浴下搅拌10min，再加入1.06g化合物4-1(分三批，间隔15分钟)，反应0.5h后，监控反应，反应完毕后，加入饱和氯化钠溶液，乙酸乙酯萃取，得有机层，无水硫酸钠干燥，过滤，浓缩，柱层析得到0.9g产物。
步骤2：
Figure PCTCN2020091324-appb-000037
在100mL烧瓶中加入0.9g化合物4-2、610mg化合物2-8、194mg DPPF PdCl 2、732mg碳酸钾，加入50mL二氧六环作为溶剂，再加入5mL水，氩气保护下升温至72℃反应过夜，反应完毕，加入饱和氯化钠溶液，乙酸乙酯萃取，取有机层，干燥，过滤，浓缩，柱层析，得到380mg产物。
步骤3：
Figure PCTCN2020091324-appb-000038
在100mL烧瓶中加入380mg化合物4-3、559mg化合物3-1、XantPhos 78mg、Pd 2(dba) 3 62mg、叔丁醇钠131mg，再加入30mL甲苯作为溶剂，氩气保护下升温至105℃反应过夜，反应完毕，加入饱和氯化钠溶液，乙酸乙酯萃取，得有机层，无水硫酸钠干燥，过滤，浓缩， 柱层析得到390mg产物。
步骤4：
Figure PCTCN2020091324-appb-000039
在100mL烧瓶中加入43mg化合物4-4、52mg化合物4-5、DMAP1mg，乙腈作为溶剂，室温反应过夜，反应完毕，加入饱和氯化钠溶液，乙酸乙酯萃取，得有机层，无水硫酸钠干燥，过滤，浓缩，柱层析得到35mg产物。
步骤5：
Figure PCTCN2020091324-appb-000040
在100mL烧瓶中加入35mg化合物4-6、21mg化合物4-7、DPPF PdCl 2 4mg、氟化钾9.5mg，再加入5mL DMSO作为溶剂，氩气保护下微波升温至130℃反应1h，反应完毕，加入饱和氯化钠溶液，乙酸乙酯萃取，得有机层，无水硫酸钠干燥，过滤，浓缩，薄层层析得到7mg产物。
步骤：6
Figure PCTCN2020091324-appb-000041
在25mL烧瓶中，加入7mg化合物4-8，加入5mL二氯甲烷溶解，再加入0.5mL TFA，室温下搅拌反应2h，反应完毕浓缩除去溶剂及过量的TFA，真空干燥，得到7mg产物。
合成方案V
步骤1：
Figure PCTCN2020091324-appb-000042
向微波管中加入化合物4-4(1.0g)、双联频哪醇硼酸酯(1.19g)、PdCl 2(dppf)(57.11mg)、醋酸钾(459.63mg)和DMF(15mL)，氩气保护，135℃，微波反应1.5h，反应完毕后，加入EA、H 2O，萃取、分液，有机相干燥除水后，旋干，过柱纯化(梯度洗脱，洗脱剂EA:Hex＝1:5～1:1)，得到化合物5-2(787.6mg)。
步骤2：
Figure PCTCN2020091324-appb-000043
向微波管中加入化合物5-2(50mg)、化合物5-3(34.18mg)、PdCl 2(dppf)(5.32mg)、氟化钾(21.12mg)、DMSO(5mL)和水(0.5mL)，在氩气保护下，于130℃微波反应1.5h，反应完全后，加入EA、H 2O，萃取、分液，有机相旋干后，薄层层析纯化，得到化合物5-4(7mg)；
步骤3：
Figure PCTCN2020091324-appb-000044
在25mL烧瓶中，加入7mg化合物5-4，加入5mL二氯甲烷溶解，再加入0.5mL TFA，室温下搅拌反应2h，反应完毕浓缩除去溶剂及过量TFA，真空干燥，得到6.3mg产物。
合成方案VI
步骤1：
Figure PCTCN2020091324-appb-000045
向100mL反应瓶中加入化合物1-16(500mg)、二甲基胺盐酸盐(210.47mg)、Pd 2(dba) 3(147.72mg)、Xantphos(186.68mg)、K 3PO 4(1.0g)和甲苯15mL，通入CO气体，升温至105℃，搅拌过夜；垫硅藻土抽滤，DCM淋洗，滤液旋干后，过柱纯化(梯度洗脱，洗脱剂EA:Hex＝1:3～3:1)，得到产物6-2(250mg)。
步骤2：
Figure PCTCN2020091324-appb-000046
向反应瓶中加入化合物6-2(250mg)、THF(9mL)、MeOH(3mL)，冰水浴，分批加入NBS(200mg)，继续搅拌1h，撤去冰浴升至室温再搅拌1h，反应完全后，加入EA、H 2O，静置、分液，有机相干燥后，旋干，过柱纯化(梯度洗脱，洗脱剂EA:Hex＝1:1～3:1)，得到化合物6-3(125mg)。
步骤3：
Figure PCTCN2020091324-appb-000047
向微波管中加入化合物6-3(150mg)、1-环戊烯硼酸频哪醇(143.86mg)、催化剂PdCl 2(dppf)(36.16mg)、碳酸钾(170.74mg)、溶剂二氧六环4mL和水0.4mL。氩气保护下，于110℃微波反应1h，反应完全。加入EA、H 2O，静置、分液，有机相用无水硫酸钠干燥后，旋干，过柱纯化(梯度洗脱，洗脱剂EA:Hex＝1:1～3:1)，得到化合物6-4(100mg)。
步骤4：
Figure PCTCN2020091324-appb-000048
向20mL耐压管中，加入450mg化合物6-4，四氢呋喃(4mL)作为溶剂，再加入8mL氨水(质量分数28％)，加热至100℃，反应过夜，反应完全后直接浓缩除去溶剂及过量氨水，得到300mg产物。
步骤5：
Figure PCTCN2020091324-appb-000049
向反应瓶中加入化合物6-5(40mg)、化合物6-6(67.63mg)、Pd 2(dba) 3(6.75mg)，Xantphos(9.38mg)、叔丁醇钠(35.42mg)和 甲苯(10mL)，氩气保护下，升温至105℃，搅拌过夜，反应完全后，滤除固体，滤液旋干后薄层层析纯化，得到化合物6-7(43mg)。
步骤6：
Figure PCTCN2020091324-appb-000050
在25mL烧瓶中，加入43mg化合物6-7，加入5mL二氯甲烷溶解，再加入1mL TFA，室温下搅拌反应2h，反应完毕浓缩除去溶剂及过量TFA，真空干燥，得到60mg产物。
合成方案VII
步骤1：
Figure PCTCN2020091324-appb-000051
在50mL烧瓶中加入150mg化合物4-3、168mg化合物1-17、39mgDPPF PdCl 2、148mg碳酸钾，再加入10mL甲苯以及1mL水作为溶剂，氩气保护下，110℃反应过夜，反应完毕，加入乙酸乙酯，饱和氯化钠溶液萃取，得有机层，干燥，过滤，浓缩，柱层析得到90mg产物。
步骤2：
Figure PCTCN2020091324-appb-000052
向100mL反应瓶中加入90mg化合物7-1、Pd/C催化剂适量，再加 入8mL四氢呋喃以及甲醇15mL，置换氢气，在氢气氛围下室温反应2h，反应完毕，过滤，浓缩滤液，真空干燥得到中间体产物。
将得到的中间体产物加入15mL二氯甲烷中溶解，再加入100mg DDQ，室温下搅拌反应1h，反应完毕，过滤，滤液加入饱和碳酸氢钠溶液，乙酸乙酯萃取，得有机层，干燥，浓缩，柱层析，得到50mg产物(7-2)。
步骤3：
Figure PCTCN2020091324-appb-000053
向反应瓶中加入20mg化合物7-2、37mg化合物3-1、4mg Pd 2(dba) 3、5mg Xantphos、14mg叔丁醇钠和10mL甲苯，氩气保护下，升温至105℃，搅拌过夜，反应完全后，滤除固体，滤液旋干后薄层层析纯化，得到7mg化合物7-3。
步骤4：
Figure PCTCN2020091324-appb-000054
在25mL烧瓶中，加入7mg化合物7-3，加入5mL二氯甲烷溶解，再加入1mL TFA，室温下搅拌反应2h，反应完毕浓缩除去溶剂及过量TFA，真空干燥，得到8.2mg产物7-4。
上述合成方案I至VII中，得到的成盐化合物均可通过本领域已知 的方法得到非成盐形式，例如采用下述脱盐方案I或II来进行。
脱盐方案I
Figure PCTCN2020091324-appb-000055
在烧瓶中，加入化合物I的盐形式，加入甲醇作溶剂，再加入过量饱和碳酸氢钠溶液，室温下搅拌反应4小时，反应完毕，浓缩除去部分甲醇，加入二氯甲烷萃取，得有机层，无水硫酸钠干燥，过滤，浓缩除去溶剂，真空干燥，得到目标化合物I。
更具体的实例(下文所述的实例111化合物)为：
Figure PCTCN2020091324-appb-000056
在25mL烧瓶中，加入13mg化合物8-1，加入3mL甲醇作溶剂，再加入2mL饱和碳酸氢钠溶液，室温下搅拌反应4h，反应完毕，浓缩除去部分甲醇，加入二氯甲烷萃取，得有机层，无水硫酸钠干燥，过滤，浓缩除去溶剂，真空干燥，得到9.4mg目标化合物8-2。
脱盐方案II
Figure PCTCN2020091324-appb-000057
在烧瓶中，加入化合物II的盐形式，加入甲醇作溶剂，再加入过量 饱和碳酸氢钠溶液，室温下搅拌反应4小时，反应完毕，浓缩除去部分甲醇，加入二氯甲烷萃取，得有机层，无水硫酸钠干燥，过滤，浓缩除去溶剂，真空干燥，得到目标化合物II。
更具体的实例(下文所述的实例112化合物)为：
Figure PCTCN2020091324-appb-000058
在25mL烧瓶中，加入27mg化合物9-1，加入3mL甲醇作溶剂，再加入3mL饱和碳酸氢钠溶液，室温下搅拌反应4h，反应完毕，浓缩除去部分甲醇，加入二氯甲烷萃取，得有机层，无水硫酸钠干燥，过滤，浓缩除去溶剂，真空干燥，得到20.5mg目标化合物9-2。
试验例1：对CDK激酶的体外抑制活性分析
在体外无细胞激酶活性测定中，采用如下方法来检测本发明化合物对CDK6/CyclinD1(品牌Carna，货号04-114)的半抑制浓度(IC 50)。需要说明，也可以采用类似的方法来进行测定。本试验例中的测定步骤如下：
使用时间分辨荧光共振能量转移(time-resolved fluorescence resonance energy transfer)(TR-FRET)方法测定CDK6/CyclinD1激酶活性。使用384孔测定板，以20μL反应体积进行测定。将激酶、抑制剂、ATP(浓度为CDK6/CyclinD1激酶的K m，品牌Sigma，货号A7699)和多肽底物(浓度为CDK6/CyclinD1激酶的K m，品牌Cisbio，货号64CUS000C01B)在反应缓冲液(pH7.5)中孵育1.5小时，所述反应缓冲液由20mM HEPES(pH7.5)、1mM EGTA、10mM MgCl 2、0.02％Briji35、0.02mg/ml BSA、0.1mM Na 3VO 4、2mM DTT、1％DMSO组成。通过加入用HTRF KinEASE检测缓冲液(品牌Cisbio，货号62SDBRDF，含有EDTA)稀释的多肽抗体(品牌Cisbio，货号 64CUSKAY)和Sa-XL665(品牌Cisbio，货号610SAXLB)混合物终止反应。将该混合物室温孵育1小时后读板。使用多模式读板仪(EnVision TM，多功能微孔板检测仪，PerkinElmer)，在330nm的激发波长(λ Ex)及615nm和665nm的检测波长(λ Em)下测量TR-FRET信号。通过665nm与615nm下的荧光比确定活性。对每一种化合物，对不同浓度化合物的酶活性进行测定以确定IC 50。阴性对照为不添加抑制剂的情况，使用两个无酶对照来确定基线荧光水平。使用GraphPad6.02软件拟合获得IC 50。
各实例化合物和参考例化合物按照上文所述的方案来制备，详见表1。针对各化合物分别准备为8-10种浓度，通过DMSO进行配制，配制浓度为工作浓度的200×。例如工作浓度为100nM，对应配制的储液浓度20μM。
在CDK激酶的体外抑制活性分析中，测定了各实例化合物和参考例化合物的IC 50值。按照IC 50值所处区间给出IC 50值，其中“+++”代表IC 50<100nM；“++”代表100nM≤IC 50<1000nM；“+”代表1000nM≤IC 50<3000nM。“-”代表“3000nM以上”。
表1各实例化合物及其针对CDK6/CyclinD1激酶的IC 50值
Figure PCTCN2020091324-appb-000059
Figure PCTCN2020091324-appb-000060
Figure PCTCN2020091324-appb-000061
Figure PCTCN2020091324-appb-000062
Figure PCTCN2020091324-appb-000063
Figure PCTCN2020091324-appb-000064
Figure PCTCN2020091324-appb-000065
Figure PCTCN2020091324-appb-000066
Figure PCTCN2020091324-appb-000067
Figure PCTCN2020091324-appb-000068
Figure PCTCN2020091324-appb-000069
Figure PCTCN2020091324-appb-000070
Figure PCTCN2020091324-appb-000071
Figure PCTCN2020091324-appb-000072
Figure PCTCN2020091324-appb-000073
Figure PCTCN2020091324-appb-000074
Figure PCTCN2020091324-appb-000075
Figure PCTCN2020091324-appb-000076
Figure PCTCN2020091324-appb-000077
Figure PCTCN2020091324-appb-000078
Figure PCTCN2020091324-appb-000079
从表1中可看出，处于本发明保护范围内的实施例化合物能够良好地抑制CDK6激酶活性。
试验例2：细胞活性试验
使用一些实例化合物，遵循以下步骤进行体外细胞活性试验：
1、将MCF-7细胞(获得自中国科学院上海细胞库)复苏后，置于37℃、5％CO 2、95％湿度条件下培养。
2、针对各实例化合物，分别配制8个不同浓度的化合物溶液，针对每个浓度的化合物溶液，取50μL加入到96孔黑板中。
3、调整细胞浓度至约30,000个/mL，分别添加100μL细胞悬液至96孔板中，混合均匀，至细胞终密度约为3,000个/孔。
4、将96孔板置于37℃、5％CO 2、95％湿度条件下培养168小时(即7天)。
5、遵循
Figure PCTCN2020091324-appb-000080
Luminescent Cell Viability Assay(Promega,Cat#G7572)的使用方法针对细胞存活率进行测量，使用酶标仪(EnVision TM，多功能微孔板检测仪，PerkinElmer)读取荧光数据。
6、使用GraphPad Prism软件对得到的荧光数据进行分析，计算出使用各浓度的各实施例化合物时的细胞存活率，求得各实施例化合物的IC 50所处区间。
将各实施例化合物的IC 50值列于下表2中，其中“+++”代表IC 50<500nM；“++”代表500nM≤IC 50<2500nM；“+”代表2500nM≤IC 50<10000nM，“-”代表10000nM以上。
表2各实例化合物体外对MCF-7细胞的抑制
Figure PCTCN2020091324-appb-000081
Figure PCTCN2020091324-appb-000082
Figure PCTCN2020091324-appb-000083
Figure PCTCN2020091324-appb-000084
从上表可见，本发明的化合物能够实现优异的对MCF-7细胞的抑制作用。
可以理解的是，本文描述的实施例和实施方式仅用于举例说明的目的，并且据此所作出的各种修改或改变可以给本领域技术人员做出启示，并且包括在本文申请的精神和范围和随附的权利要求书的范围内。本文引用的所有出版物、专利和专利申请都通过引用全文并入本文中以用于所有的目的。

Claims (10)

  1. 通式(I)所示的化合物或其药学上可接受的盐：
    Figure PCTCN2020091324-appb-100001
    其中，
    Q为任选地被取代的6～18元亚芳基或任选地被取代的5～18元杂亚芳基，其中，被取代时的取代基选自卤素、羟基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基构成的组，
    R 1为任选地被取代的3～8元杂环基、任选地被取代的6～14元稠杂环基、任选地被取代的6～12元螺杂环基，其中，被取代时的取代基选自卤素、羟基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基构成的组，
    R 2为H、卤素或者任选地被取代的3～10元环烯基、任选地被取代的3～10元杂环烯基、任选地被取代的3～10元环烷基、任选地被取代的3～10元杂环烷基、任选地被取代的6～18元芳基、任选地被取代的5～18元杂芳基，其中，被取代时的取代基选自卤素、羟基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、C 1-6烷氧基-C 1-6烷氧基、氧代基构成的组，
    R 3为H、CN、-C(＝O)-NR 4R 5或者任选地被取代的6～18元芳基、任选地被取代的5～18元杂芳基、任选地被取代的5～8元内酰胺基，其中，被取代时的取代基选自卤素、羟基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基构成的组，
    R 4和R 5各自独立地为甲基或乙基，
    并且，当R 3为-C(＝O)-NR 4R 5时，R 2为任选地被取代的3～10元环烯基、任选地被取代的3～10元杂环烯基、任选地被取代的以N原子与通式(I)中的非R 2结构相连接的3～10元杂环烷基、任选地被取代的6～18元芳基，其中，被取代时的取代基选自卤素、羟基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、C 1-6烷氧基-C 1-6烷氧基、氧代基构成的组。
  2. 如权利要求1所述的化合物或其药学上可接受的盐，其中，
    Q为任选地被取代的亚苯基或任选地被取代的亚吡啶基，其中，被取代时的取代基选自卤素、羟基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基构成的组，
    R 1为任选地被取代的3～8元杂环基、任选地被取代的6～14元稠杂环基或任选地被取代的6～12元螺杂环基，其中，被取代时的取代基选自C 1-6烷基，
    R 2选自卤原子、或者任选地被取代的环戊烯基、任选地被取代的环己烯基、任选地被取代的环戊基、任选地被取代的环己基、任选地被取代的氧杂环己烯基、任选地被取代的氮杂环己烯基、任选地被取代的氧杂环戊基、任选地被取代的氮杂环戊基、任选地被取代的氧杂环己基、任选地被取代的氮杂环己基、任选地被取代的苯基、任选地被取代的萘基、任选地被取代的吡啶基、任选地被取代的噻吩基、任选地被取代的吡唑基、任选地被取代的噁唑基、任选地被取代的异噁唑基、任选地被取代的喹啉基构成的组，其中，被取代时的取代基选自卤素、羟基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、氧代基构成的组，
    R 3为H、-CN、-C(＝O)-NR 4R 5或者任选地被取代的苯基、萘基、吡唑基、吡啶基、噻吩基、噁唑基、异噁唑基、嘧啶基、咪唑基、吡咯基、
    Figure PCTCN2020091324-appb-100002
    其中，被取代时的取代基选自卤素、羟基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基构成的组，
    R 4和R 5均为甲基。
  3. 如权利要求1或2所述的化合物或其药学上可接受的盐，其中，Q为亚苯基或
    Figure PCTCN2020091324-appb-100003
  4. 如权利要求1～3中任一项所述的化合物或其药学上可接受的盐，其中，R 1为任选地被取代的下述基团，其中，被取代时的取代基选自C 1-6烷基：
    Figure PCTCN2020091324-appb-100004
  5. 如权利要求4中任一项所述的化合物或其药学上可接受的盐，其中，所述C 1-6烷基为甲基或乙基。
  6. 如权利要求1～5中任一项所述的化合物或其药学上可接受的盐，其中，R 2为卤素或者任选地被取代的下述基团，其中，被取代时的取代基选自C 1-6烷基：
    Figure PCTCN2020091324-appb-100005
  7. 如权利要求1所述的化合物或其药学上可接受的盐，所述化合物选自：
    Figure PCTCN2020091324-appb-100006
    Figure PCTCN2020091324-appb-100007
    Figure PCTCN2020091324-appb-100008
    Figure PCTCN2020091324-appb-100009
    Figure PCTCN2020091324-appb-100010
    Figure PCTCN2020091324-appb-100011
    Figure PCTCN2020091324-appb-100012
    Figure PCTCN2020091324-appb-100013
    Figure PCTCN2020091324-appb-100014
    Figure PCTCN2020091324-appb-100015
  8. 如权利要求1～7中任一项所述的化合物，用于抑制CDK4/6激酶活性。
  9. 一种药用组合物，其包含治疗有效量的权利要求1～8中任一项所述的化合物和药学上可接受的载体或赋形剂。
  10. 权利要求1～8中任一项所述的化合物或其药学上可接受的盐在制备治疗和/或预防由CDK4/6激酶介导的癌症相关疾病的药物中的应用，所述癌症相关疾病选自脑瘤、肺癌、鳞状上皮细胞癌、膀胱癌、胃癌、卵巢癌、腹膜癌、胰腺癌、乳腺癌、头颈癌、子宫颈癌、子宫内膜癌、直肠癌、肝癌、肾癌、食管腺癌、食管鳞状细胞癌、前列腺癌、雌性生殖道癌、原位癌、淋巴瘤、神经纤维瘤、甲状腺癌、骨癌、皮肤癌、脑癌、结肠癌、睾丸癌、胃肠道间质瘤、前列腺肿瘤、肥大细胞肿瘤、 多发性骨髓瘤、黑色素瘤、胶质瘤或肉瘤。
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KR1020227001397A KR20220020951A (ko) 2019-06-18 2020-05-20 Cdk 키나제 억제제
CA3143813A CA3143813A1 (en) 2019-06-18 2020-05-20 Cdk kinase inhibitor
JP2021575915A JP7369798B2 (ja) 2019-06-18 2020-05-20 Ｃｄｋキナーゼ阻害剤
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