WO2022002270A1 - 一种嘧啶类衍生物及其制备方法和应用 - Google Patents

一种嘧啶类衍生物及其制备方法和应用 Download PDF

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WO2022002270A1
WO2022002270A1 PCT/CN2021/104379 CN2021104379W WO2022002270A1 WO 2022002270 A1 WO2022002270 A1 WO 2022002270A1 CN 2021104379 W CN2021104379 W CN 2021104379W WO 2022002270 A1 WO2022002270 A1 WO 2022002270A1
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cancer
hydrogen
inhibitors
tumor
agents
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PCT/CN2021/104379
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English (en)
French (fr)
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余强
丁炬平
汤木林
郝岩
卢芹
钱申
田旭升
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盛世泰科生物医药技术(苏州)有限公司
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Priority to JP2022579075A priority Critical patent/JP2023531228A/ja
Priority to EP21834581.7A priority patent/EP4154911A1/en
Priority to KR1020227044751A priority patent/KR20230014730A/ko
Publication of WO2022002270A1 publication Critical patent/WO2022002270A1/zh
Priority to US18/145,601 priority patent/US20230125233A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • A—HUMAN NECESSITIES
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present application relates to a compound, in particular to a pyrimidine derivative and a preparation method and application thereof.
  • CDKs cyclin-dependent kinases
  • Cyclin B/CDK1, Cyclin A/CDK2, Cyclin E/CDK2, Cyclin D/CDK4, Cyclin D/CDK6, Cyclin T1/CDK9 and other heterodimers are important for cell cycle progression regulator. Additional functions of Cyclin/CDK heterodimers include regulation of transcription, DNA repair, differentiation and programmed cell death. (Morgan DO. Cyclin-dependent kinases: engines, clocks, and microprocessors. Annu. Rev. Cell. Dev. Biol. (1997) 13:261-291).
  • CDK4 and CDK6 are highly homologous, CDK4 single-gene knockout mice have diabetes symptoms and cell defects, CDK6 single-gene knockout mice lead to mild anemia symptoms due to defective hematopoietic cell proliferation, while CDK4 and CDK6 (CDK4/6) double Gene knockout impaired the proliferation of hematopoietic precursor cells, resulting in late embryonic death in double knockout mice.
  • CDK4/6-Cyclin D/Rb phosphorylated retinoblastoma gene
  • CDK4/6-Cyclin D/Rb phosphorylated retinoblastoma gene
  • Hyperactivation of CDK4 is commonly found in epithelial cell malignancies, whereas hyperactivation of CDK6 is commonly found in mesenchymal cell tumors such as sarcomas and hematological cancers.
  • the establishment of a breast cancer tumor-bearing mouse model found that all wild-type nude mice formed tumors, while CDK4 knockout nude mice were completely unable to form tumors.
  • anti-CDK4 siRNA was used to interfere with the expression of CDK4, it was found that the tumor growth of nude mice was significantly inhibited.
  • Cyclin E2overexpression is associated with endocrine resistance but not in sensitivity to CDK2 inhibition in human breast cancer cells. Mol Cancer Ther. (2012) 11:1488-99; Herrera-Abreu et al., Early Adaptation and Acquired Resistance to CDK4 /6 Inhibition in Estrogen Receptor-Positive Breast Cancer, Cancer Res. (2016) 76:2301-2313). Cyclin E amplification has also been reported to contribute to trastuzumab resistance in HER2+ breast cancer. (Scaltriti et al., Cyclin E amplification/overexpression is a mechanism of trastuzumab resistance in HER2+ breast cancer patients, Proc Natl Acad Sci.
  • Cyclin E overexpression has also been reported to play a role in basal-like and triple-negative breast cancer (TNBC) as well as in inflammatory breast cancer.
  • TNBC basal-like and triple-negative breast cancer
  • Cyclin E overexpression as a biomarker for combination treatment strategies in inflammatory breast cancer, Oncotarget (2017) 8:14897-14911 ).
  • Amplification or overexpression of cyclin E1 (CCNE1) has also been associated with poor prognosis in ovarian, gastric, endometrial and other cancers.
  • Inaciclib MK-7965
  • Seliciclib roscovitine or CYC202
  • CDK7 and CDK9 are also being studied in combination with chemotherapy for the treatment of advanced solid tumors.
  • CDK inhibitors can also be used in the following areas: in the treatment of cardiovascular disorders such as restenosis and atherosclerosis and other vascular disorders caused by abnormal cell proliferation; in the treatment of various infectious agents Caused diseases, including fungi, protozoan parasites (such as Plasmodium falciparum), and DNA and RNA viruses; also used to improve various autoimmune disorders
  • cardiovascular disorders such as restenosis and atherosclerosis and other vascular disorders caused by abnormal cell proliferation
  • infectious agents including fungi, protozoan parasites (such as Plasmodium falciparum), and DNA and RNA viruses
  • CDK inhibitors are effective against other cell proliferation disorders, including psoriasis (characterized by hyperproliferation of keratinocytes), glomerulonephritis, and lupus.
  • the cyclin E/CDK2 complex plays an important role in regulating G1/S transition, histone biosynthesis, and centrosome duplication. Progressive phosphorylation of Rb by cyclin D/CDK4/6 and cyclin E/CDK2 releases the G1 transcription factor E2F and promotes S-phase entry. Activation of cyclin A/CDK2 during early S phase promotes phosphorylation of endogenous substrates, which allows DNA replication and inactivation of E2F to complete S phase. (Asghar et al., The history and future of targeting cyclin-dependent kinasesin cancer therapy, Nat. Rev. Drug. Discov. 2015;14(2):130-146).
  • the purpose of this application is to provide a pyrimidine derivative with a novel structure and its preparation method and application.
  • the pyrimidine derivatives exhibit excellent CDK-inhibiting effects and effects.
  • the present application provides a pyrimidine derivative
  • the pyrimidine derivative is selected from: the compound represented by the general formula (I) or its tautomer, enantiomer, non- Enantiomer, meso, racemate or mixture thereof, or a pharmaceutically acceptable salt or prodrug thereof:
  • R 1 and R 2 are independently selected from fluorine or chlorine
  • R 3 is selected from hydrogen, fluoro or hydroxy
  • A is selected from methylene or covalent bonds
  • Q is selected from carbon or nitrogen atoms, where:
  • X is C 1 -C 3 alkyl, C 3 -C 7 cycloalkyl or R 5 ;
  • R 4 is selected from hydrogen or C 1 -C 3 alkyl
  • R 5 is R, R' and R" are independently selected from hydrogen or C 1 -C 3 alkyl
  • R 6 is C 1 -C 3 alkyl, C 3 -C 7 cycloalkyl or R 5 .
  • the compounds of formula (I) as shown when Q is a nitrogen atom and R 3 is hydrogen, R 5 in R, R 'and R "are independently selected from hydrogen or methyl base.
  • R 4 is hydrogen or methyl
  • R 6 is methyl
  • ethyl or R 5 and among R 5 R, R' and R" are independently selected from hydrogen or methyl.
  • R 1 and R 2 are both fluorine, R 3 is hydrogen, A is selected from methylene or a covalent bond, Q is a nitrogen atom, R , R' and R" in R 5 are independently selected from hydrogen or methyl.
  • R 1 and R 2 are both fluorine, R 3 is fluorine, A is selected from methylene group or covalent bond, Q is a nitrogen atom, X is ethyl.
  • R 1 and R 2 are both fluorine, R 3 is hydrogen or fluorine, A is selected from methylene or a covalent bond, and Q is carbon atom, R 4 is hydrogen or methyl, R 6 is methyl, ethyl or hydroxyethyl.
  • the compound represented by the general formula (I) is selected from compounds having the following structure:
  • the application also provides a preparation method of pyrimidine derivatives, and the preparation method is selected from any one of the following methods:
  • R1, R2, R3, A, Q, X have the same meanings as the corresponding groups in the above-mentioned pyrimidine derivatives; Y is a halogen element.
  • the present application also provides the use of the above-mentioned pyrimidine derivatives as active ingredients in the preparation of pharmaceutical compositions.
  • the pharmaceutical composition is used for the treatment of abnormal cell proliferative diseases, infections (eg viral infections such as herpes, HIV, fungal infections, etc.), inflammatory disorders (eg rheumatoid arthritis, bone arthritis, etc.), autoimmune diseases (such as psoriasis, lupus, type I diabetes, diabetic nephropathy, multiple sclerosis, glomerulonephritis, etc.), cardiovascular diseases (such as myocardial infarction, stroke, atherosclerosis, Post-operative vascular stenosis, restenosis, etc.) or neurodegenerative diseases (such as Alzheimer's disease, Parkinson's disease, etc.), treatment of hematopoietic toxic diseases caused by radiation (such as myelosuppression, neutropenia, leukopenia) disease, anemia) drugs.
  • infections eg viral infections such as herpes, HIV, fungal infections, etc.
  • inflammatory disorders eg rheumatoid arthritis, bone arthritis, etc.
  • the treatment of abnormal cell proliferative disease is the treatment of cancer; optionally, the cancer is selected from breast cancer, ovarian cancer, prostate cancer, melanoma, brain tumor (such as malignant tumor glioma, glioma of oligodendroglioma, etc.), esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer (such as colon cancer, rectal cancer, etc.), lung cancer (such as non-small cell lung cancer, small cell lung cancer, primary or metastatic squamous cancer, etc.), kidney cancer, skin cancer, glioblastoma, neuroblastoma, sarcoma, liposarcoma, osteochondroma, osteoma, osteosarcoma, sperm Primary cell tumor, testicular tumor, uterine cancer (such as cervical cancer, endometrial cancer, etc.), head and neck tumor (such as maxillary bone cancer, laryngeal cancer, pharyngeal
  • reticulum cell sarcoma reticulum cell sarcoma, lymphosarcoma, Hodgkin lymphoma, mantle cell lymphoma, etc.
  • polycythemia vera leukemia (e.g. acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia cell leukemia, etc.), thyroid tumor, ureteral tumor, bladder tumor, gallbladder cancer, cholangiocarcinoma, choriocarcinoma or pediatric tumor (e.g.
  • the cancer is breast cancer or ovarian cancer.
  • the present application also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the above-mentioned pyrimidine derivatives as active ingredients, and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the pharmaceutical composition further comprises another one or more anticancer agents as active ingredients
  • the anticancer agents are selected from alkylating agents (eg cyclophosphamide, ifosfamide, Melphalan, busulfan, nimustine, ramustine, dacarbazine, temozolomide, nitrogen mustard hydrochloride, dibromomannitol, etc.), platinum complexing agents (such as cisplatin, carboplatin, oxali platinum, etc.), metabolic antagonists (such as methotrexate, 5-fluorouracil, tegafur, gemcitabine, capecitabine, fulvestrant, pemetrexed, etc.), plant alkaloids (such as vincristine, Vinblastine, vindesine, etoposide, docetaxel, paclitaxel, irinotecan, vinorelbine, mitoxantrone, vinflunine, topotecan, etc.), antibody drugs (such as
  • the present application also provides a method of treating a disease, the method comprising the steps of: administering an effective dose of the above-mentioned pyrimidine derivatives to a subject in need of treatment of a disease, the disease being an abnormal cell proliferative disease, infection (e.g.
  • Viral infections eg, herpes, HIV, fungal infections, etc.
  • inflammatory conditions eg, rheumatoid arthritis, osteoarthritis, etc.
  • autoimmune diseases eg, psoriasis, lupus, type I diabetes, diabetic nephropathy, multiple sclerosis, glomerulonephritis, etc.
  • cardiovascular disease such as myocardial infarction, stroke, atherosclerosis, postoperative vascular stenosis, restenosis, etc.
  • neurodegenerative disease such as Alzheimer's disease, Parkinson's disease
  • treatment of hematopoietic toxic diseases caused by radiation eg myelosuppression, neutropenia, leukopenia, anemia).
  • the abnormal cell proliferative disease is cancer; optionally, the cancer is selected from breast cancer, ovarian cancer, prostate cancer, melanoma, brain tumor (eg, malignant astrocytic nerves) Glioma of glial and oligodendroglioma components, etc.), esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer (such as colon cancer, rectal cancer, etc.), lung cancer (such as non-small cell lung cancer, Small cell lung cancer, primary or metastatic squamous cell carcinoma, etc.), kidney cancer, skin cancer, glioblastoma, neuroblastoma, sarcoma, liposarcoma, osteochondroma, osteoma, osteosarcoma, spermatogonia tumor, testicular tumor, uterine cancer (such as cervical cancer, endometrial cancer, etc.), head and neck tumor (such as maxillary cancer, laryngeal cancer, phary
  • brain tumor
  • reticulum cell sarcoma reticulum cell sarcoma, lymphosarcoma, Hodgkin lymphoma, mantle cell lymphoma, etc.
  • polycythemia vera leukemia (e.g. acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia etc.), thyroid tumor, ureteral tumor, bladder tumor, gallbladder cancer, cholangiocarcinoma, choriocarcinoma or pediatric tumor (e.g.
  • the cancer is breast cancer or ovarian cancer.
  • the breast cancer is triple negative breast cancer.
  • the method further comprises using in combination another one or more anticancer agents as active ingredients, the anticancer agents are selected from alkylating agents (eg, cyclophosphamide, ifosfamide, Melphalan, busulfan, nimustine, ramustine, dacarbazine, temozolomide, nitrogen mustard hydrochloride, dibromomannitol, etc.), platinum complexing agents (such as cisplatin, carboplatin, oxali platinum, etc.), metabolic antagonists (such as methotrexate, 5-fluorouracil, tegafur, gemcitabine, capecitabine, fulvestrant, pemetrexed, etc.), plant alkaloids (such as vincristine, Vinblastine, vindesine, etoposide, docetaxel, paclitaxel, irinotecan, vinorelbine, mitoxantrone, vinflunine, topotecan, etc.), antibody drugs
  • the present application also provides a CDK inhibitor, including the above-mentioned pyrimidine derivatives.
  • the CDKs include CDK2, CDK4 or CDK6.
  • the present application also provides a preparation method of the above CDK inhibitor, comprising the following steps: using the above preparation method to prepare the pyrimidine derivative described in any one of claims 1-4.
  • the present application also provides an application of the above CDK inhibitor as an active ingredient in preparing a pharmaceutical composition.
  • the pharmaceutical composition is used for the treatment of abnormal cell proliferative diseases, infections (eg viral infections such as herpes, HIV, fungal infections, etc.), inflammatory disorders (eg rheumatoid arthritis, bone arthritis, etc.), autoimmune diseases (such as psoriasis, lupus, type I diabetes, diabetic nephropathy, multiple sclerosis, glomerulonephritis, etc.), cardiovascular diseases (such as myocardial infarction, stroke, atherosclerosis, Post-operative vascular stenosis, restenosis, etc.), neurodegenerative diseases (such as Alzheimer's disease, Parkinson's disease, etc.), hematopoietic toxic diseases caused by radiation (such as myelosuppression, neutropenia, leukopenia) , anemia) drugs.
  • infections eg viral infections such as herpes, HIV, fungal infections, etc.
  • inflammatory disorders eg rheumatoid arthritis, bone arthritis, etc.
  • the treatment of abnormal cell proliferative diseases is the treatment of cancer.
  • the cancer is selected from the group consisting of breast cancer, ovarian cancer, prostate cancer, melanoma, brain tumors (eg glia with malignant astroglial and oligodendroglioma components) stromal tumor, etc.), esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer (such as colon cancer, rectal cancer, etc.), lung cancer (such as non-small cell lung cancer, small cell lung cancer, primary or metastatic squamous cell carcinoma, etc.) , kidney cancer, skin cancer, glioblastoma, neuroblastoma, sarcoma, liposarcoma, osteochondroma, osteoma, osteosarcoma, seminoma, testicular tumor, uterine cancer (eg, cervical cancer, uterine Endometrial cancer, etc.), head and neck tumors (such as maxillary cancer, laryngeal cancer, pharyngeal cancer, tongue cancer, intraoral tumors (such
  • the cancer is breast cancer or ovarian cancer.
  • the breast cancer is triple negative breast cancer.
  • a pharmaceutical composition includes the above CDK inhibitor as an active ingredient, and also includes one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the pharmaceutical composition further comprises another one or more anticancer agents as active ingredients
  • the anticancer agents are selected from alkylating agents (eg cyclophosphamide, ifosfamide, Melphalan, busulfan, nimustine, ramustine, dacarbazine, temozolomide, nitrogen mustard hydrochloride, dibromomannitol, etc.), platinum complexing agents (such as cisplatin, carboplatin, oxali platinum, etc.), metabolic antagonists (such as methotrexate, 5-fluorouracil, tegafur, gemcitabine, capecitabine, fulvestrant, pemetrexed, etc.), plant alkaloids (such as vincristine, Vinblastine, vindesine, etoposide, docetaxel, paclitaxel, irinotecan, vinorelbine, mitoxantrone, vinflunine, topotecan, etc.), antibody drugs (such as
  • the present application also provides a method for inhibiting CDK activity, comprising the steps of: administering an effective dose of the above-mentioned pyrimidine derivatives to a subject in need of inhibiting CDK activity.
  • the pyrimidine derivatives in the present application showed excellent CDK inhibitory effects and effects, especially CDK2, CDK4, and CDK6; compared with Abemacicilib, they showed a lower IC50 value.
  • alkyl refers to saturated aliphatic hydrocarbon groups, including straight and branched chain groups of 1 to 20 carbon atoms. Preferred are alkyl groups containing 1 to 10 carbon atoms, more preferably alkyl groups containing 1 to 6 carbon atoms, most preferably alkyl groups containing 1 to 4 carbon atoms, and most preferably methyl.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2 - methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexy
  • lower alkyl groups containing 1 to 6 carbon atoms include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl , n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3 -Methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl , 2,3-dimethylbutyl, etc.
  • Alkyl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from alkyl groups , alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy group, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, amino, haloalkyl, hydroxyalkyl, carboxyl or carboxylate.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably a cycloalkyl ring comprising 3 to 20 carbon atoms 10 carbon atoms, most preferably the cycloalkyl ring contains 3 to 6 carbon atoms, most preferably cyclopropyl or cyclopentyl.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene cyclooctyl group, cyclooctyl group, etc., preferably cyclopropyl group and cyclopentyl group.
  • Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.
  • Cycloalkyl may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, Heterocycloalkylthio, oxo, amino, haloalkyl, hydroxyalkyl, carboxyl or carboxylate.
  • the substituents are preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloal
  • alkoxy refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl, cycloalkyl are as defined above.
  • Non-limiting examples include methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • Alkoxy can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkoxy Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, amino, haloalkyl, hydroxyalkyl, carboxyl or carboxylate.
  • the substituents are preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkoxy Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl,
  • Haloalkyl means an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
  • Hydroalkyl refers to an alkyl group substituted with hydroxy, wherein alkyl is as defined above.
  • Halogen means fluorine, chlorine, bromine or iodine, preferably fluorine or iodine.
  • Amino means -NH 2.
  • Cyano refers to -CN.
  • Niro refers to -NO 2.
  • Carboxyl refers to -C(O)OH.
  • Carboxylate means -C(O)O(alkyl) or (cycloalkyl), wherein alkyl and cycloalkyl are as defined above.
  • Optional or “optionally” means that the subsequently described event or circumstance can, but need not, occur, and that the description includes instances where the event or circumstance occurs or instances where it does not.
  • a heterocycloalkyl group optionally substituted with an alkyl group means that an alkyl group may, but need not, be present, and the specification includes the case where the heterocycloalkyl group is substituted with an alkyl group and the case where the heterocycloalkyl group is not substituted with an alkyl group replaced situation.
  • Substituted means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of one another, are substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the person skilled in the art can determine (either experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (eg, olefinic) bonds.
  • the crude compound 1 (8.3 g) was dissolved in methanol (150 mL) at room temperature, Pd/C (1.6 g) was added, and the mixture was replaced with hydrogen for 3 times and stirred at room temperature overnight. After filtration, the mother liquor was concentrated to obtain a crude product, which was then slurried with a mixed solvent of ethyl acetate and petroleum ether for half an hour, and then filtered to obtain compound 2 (5.3 g).
  • Substrate peptide 1 ⁇ M FAM-PKTPKKAKKL-OH, FAM is 5-carboxyfluorescein;
  • Substrate peptide 1 ⁇ M FAM-RRFRPASPLRGPPK-NH 2 fragment, FAM is 5-carboxyfluorescein;
  • Substrate peptide Dyrktide
  • MDA-MB-468 (ATCC Item No. HTB-132);
  • Pen Strep (Hyclone item number SV30010)
  • the pyrimidine derivatives of the present application show excellent CDK inhibitory effects and effects, especially CDK2, CDK4, and CDK6; compared with Abemacicilib, it shows a lower IC50 value. And when X includes a methoxy group, a hydroxyl group or an imino group, there is a very excellent effect.
  • the pyrimidine derivatives provided in this application show excellent CDK inhibitory effect and effect, especially CDK2, CDK4, CDK6; compared with Abemacicilib, show lower IC50 value; can be used as an active ingredient for the treatment of various Diseases, eg, abnormal cell proliferative diseases, infections, inflammatory disorders, autoimmune diseases, cardiovascular or neurodegenerative diseases, hematopoietic toxic diseases caused by radiation, and the like.
  • various Diseases eg, abnormal cell proliferative diseases, infections, inflammatory disorders, autoimmune diseases, cardiovascular or neurodegenerative diseases, hematopoietic toxic diseases caused by radiation, and the like.

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Abstract

本申请涉及一种嘧啶类衍生物及其制备方法和应用，所述嘧啶类衍生物选自：通式(I)所示的化合物或其互变异构体、对映异构体、非对映异构体、内消旋体、外消旋体或其混合物形式，或其可药用盐或其前体药物。该嘧啶类衍生物表现出优异的抑制CDK的效果和作用。

Description

一种嘧啶类衍生物及其制备方法和应用
交叉引用
本申请要求于2020年7月3日向中国国家知识产权局提交的、申请号为202010629992.X、发明名称为“一种嘧啶类衍生物及其制备方法和应用”的中国专利申请的优先权，该申请的全部内容通过引用结合在本申请中。
技术领域
本申请涉及一种化合物，具体涉及一种嘧啶类衍生物及其制备方法和应用。
背景技术
大量研究发现肿瘤与细胞周期反常相关，大部分肿瘤细胞都存在有丝***信号蛋白的大量突变/抗有丝***信号蛋白缺陷，也存在肿瘤细胞的基因组不稳定性(GIN)和染色体组不稳定性(CIN)，这三种基本的细胞周期缺陷都直接或间接由细胞周期蛋白依赖性激酶(CDK)的失控引起。CDK通过与其调节性亚单元cyclins(细胞周期蛋白)结合发挥作用，而4大类cyclins(A-，B-，D-，E-型cyclins)在整个细胞周期的不同阶段发挥其不同的作用，至少有16种哺乳动物细胞周期蛋白已被鉴别。细胞周期蛋白Cyclin B/CDK1、Cyclin A/CDK2、Cyclin E/CDK2、Cyclin D/CDK4、Cyclin D/CDK6、Cyclin T1/CDK9和其它杂二聚物(包括CDK3和CDK7)是细胞周期进展的重要调节剂。Cyclin/CDK杂二聚物的另外功能包括对转录、DNA修复、分化和细胞程序性死亡的调节。(Morgan DO.Cyclin-dependent kinases:engines,clocks,and microprocessors.Annu.Rev.Cell.Dev.Biol.(1997)13:261-291)。
研究显示细胞周期蛋白依赖性激酶的活性增加或者活化异常会导致人类肿瘤的形成。事实上，人类肿瘤的形成普遍与CDK蛋白本身或其调节剂的改变有关。研究发现，CDK4和CDK6高度同源，CDK4单基因敲除老鼠存在糖尿病征和细胞缺陷，CDK6单基因敲除老鼠因造血细胞增殖缺陷导致轻微的贫血症状，而CDK4和CDK6(CDK4/6)双基因敲除则会使造血前体细胞增殖能力受损，导致双敲除老鼠胚胎晚期的死亡。在肿瘤细胞中，普遍发现CDK4/6-Cyclin D/Rb(可磷酸化视网膜母细胞瘤基因)信号通路的超活化。在胞内外各种有丝***信号刺激下，Cyclin D高表达，调节CDK4/6蛋白与Cyclin D的相互作用，促进CDK4/6的定位和激酶活性。激活的CDK4/6通过磷酸化Rb，使Rb-E2F复合物解离，释放游离的E2F入核，调节蛋白转录，启动细胞周期的进行。在上皮细胞 恶性肿瘤中常发现CDK4的超活化，而***肿瘤如肉瘤和血液性癌症中常发现CDK6的超活化。构建乳腺癌荷瘤鼠模型发现，野生型裸鼠全部成瘤，而CDK4敲除裸鼠完全无法成瘤；而用anti-CDK4siRNA干扰CDK4的表达，则发现裸鼠的肿瘤生长显著受抑制。
体外实验发现,天然存在的CDK的蛋白质抑制剂例如p16和p27能够抑制肺癌细胞系的生长。研究还发现，细胞周期蛋白E(CDK2的调节细胞周期蛋白)经常在癌症中过表达。长期以来，细胞周期蛋白E扩增或过表达与乳腺癌的预后不良有关。(Keyoma rsi等人，Cyclin E and survival in patients with breast cancer.N Engl J Med.(2002)347:1566-75)。细胞周期蛋白E2(CCNE2)过表达与乳腺癌细胞的内分泌抗性相关，据报道CDK2抑制可在他莫昔芬抗性和CCNE2过表达细胞中恢复对他莫昔芬或CDK4抑制剂的敏感性。(Caldon等人，Cyclin E2overexpression is associated with endocrine resistance but not in sensitivity to CDK2inhibition in human breast cancer cells.Mol Cancer Ther.(2012)11:1488-99；Herrera-Abreu等人,Early Adaptation and Acquired Resistance to CDK4/6 Inhibition in Estrogen Receptor-Positive Breast Cancer,Cancer Res.(2016)76:2301-2313)。据报道，细胞周期蛋白E扩增也有助于HER2+乳腺癌中曲妥珠单抗的抗性。(Scaltriti等人，Cyclin E amplification/overexpression is a mechanism of trastuzumab resistance in HER2+breast cancer patients,Proc Natl Acad Sci.(2011)108:3761-6)。据报道，细胞周期蛋白E过表达还在基底样和三阴性乳腺癌(TNBC)以及炎性乳腺癌中发挥作用。(Elsawaf&Sinn,Triple Negative Breast Cancer:Clinical and Histological Correlations,Breast Care(2011)6:273-278Alexander等人,Cyclin E overexpression as a biomarker for combination treatment strategies in inflammatory breast cancer,Oncotarget(2017)8:14897-14911)。细胞周期蛋白E1(CCNE1)的扩增或过表达也与卵巢癌、胃癌、子宫内膜癌和其他癌症的不良预后相关。(Nakayama等人，Gene amplification CCNE1is related to poor survival and potential therapeutic target in ovarian cancer,Cancer(2010)116:2621-34；Etemadmoghadam等人,Resistance to CDK2Inhibitors Is Associated with Selection of Polyploid Cells in CCNE1-Amplified Ovarian Cancer,Clin Cancer Res(2013)19:5960-71；Au-Yeung等人,Selective Targeting of Cyclin E1-Amplified High-Grade Serous Ovarian Cancer by Cyclin-Dependent Kinase 2and AKT Inhibition,Clin.Cancer Res.(2017)23:1862-1874；Ayhan等人,CCNE1copynumber gain and overexpression identify ovarian clear cell carcinoma with a poor prognosis,Modern Pathology(2017)30:297-303；Ooi等人,Gene amplification of CCNE1,CCND1,and CDK6in gastric cancers detected bymultiplex  ligation-dependent probe amplification and fluorescence in situ hybridization,Hum Pathol.(2017)61:58-67；Noske等人,Detection of CCNE1/URI(19q12)amplification by in situ hybridisation is common in high grade and type II endometrial cancer,Oncotarget(2017)8:14794-14805)。用于抑制CDK1、CDK2、CDK5和CDK9的小分子抑制剂inaciclib(MK-7965)，目前正在进行针对乳腺癌和血液癌的临床开发。通过抑制CDK2、CDK 7和CDK 9的Seliciclib(roscovitine或CYC202)与化疗组合以治疗晚期实体瘤也正在研究中。
除了抑制肿瘤的生长，CDK抑制剂还可以用于以下方面：用于治疗心血管障碍，例如再狭窄和动脉粥样硬化和其它由异常细胞增殖引起的血管障碍；用于治疗由多种感染剂导致的疾病，包括真菌、原生动物寄生虫(例如恶性疟原虫)和DNA与RNA病毒；还可用于改善各种自身免疫障碍，研究发现，在关节炎的大鼠模型中，关节肿胀基本上被p16表达性腺病毒处理所抑制，CDK抑制剂可以有效对抗其它细胞增殖障碍，包括牛皮癖(以角质形成细胞过度增殖为特征)、肾小球性肾炎和狼疮。
研究还发现，在细胞周期中，G1/S转换期和G2/M期细胞对DNA损伤剂如电离辐射(IR)极为敏感，而细胞从G1期向S期转换的过程至少需要通过3种细胞周期蛋白依赖性激酶(CDK2、CDK4和CDK6)及其调节性亚单元cyclins共同磷酸化Rb家族蛋白进行调节。选择性CDK4/6抑制剂可以诱导细胞G1期阻滞，进而提高造血干/祖细胞对DNA损伤剂如IR的耐受性，有效减少由辐射引起的各种造血毒性，包括骨髓抑制、嗜中性白血球减少症、白细胞减少症、贫血等。
研究还发现，CDK2的过表达与细胞周期的异常调节有关。细胞周期蛋白E/CDK2复合物在调节G1/S转换、组蛋白生物合成和中心体复制中起重要作用。细胞周期蛋白D/CDK4/6和细胞周期蛋白E/CDK2对Rb的进行性磷酸化释放G1转录因子E2F，并促进S期进入。在早期S期期间细胞周期蛋白A/CDK2的激活促进内源性底物的磷酸化，其允许DNA复制和E2F的失活，以完成S期。(Asghar等人,The history and future of targeting cyclin-dependent kinasesin cancer therapy,Nat.Rev.Drug.Discov.2015；14(2):130-146)。
公开的选择性抑制CDK4和CDK6的抑制剂专利申请包括WO2003062236、WO2006008874、WO2009126584等。尽管付出了巨大努力，但到目前为止还没有针对CDK2的药剂获批，仍然需要发现具有新活性谱的CDK抑制剂，特别是那些靶向CDK2的CDK抑制剂。
公开于该背景技术部分的信息仅仅旨在增加对本申请的总体背景的理解，而不应当被视为承认或以任何形式暗示该信息构成已为本领域一般技术人员所公知的现有技术。
发明内容
发明目的
本申请的目的在于提供一种新型结构的嘧啶类衍生物及其制备方法和应用。该嘧啶类衍生物表现出优异的抑制CDK的效果和作用。
解决方案
为实现本申请目的，本申请提供了一种嘧啶类衍生物，所述嘧啶类衍生物选自：通式(I)所示的化合物或其互变异构体、对映异构体、非对映异构体、内消旋体、外消旋体或其混合物形式，或其可药用盐或其前体药物：
Figure PCTCN2021104379-appb-000001
其中：
R 1和R 2相互独立地选自氟或氯；
R 3选自氢,氟或羟基；
A选自亚甲基或共价键；
Q选自碳原子或氮原子，其中：
当Q是碳原子时,X是-NR 4R 6；
当Q是氮原子且R 3为氢时，X是-R 5；
当Q是氮原子且R 3为氟或羟基时，X是C 1-C 3烷基,C 3-C 7环烷基或R 5；
R 4选自氢或C 1-C 3烷基；
R 5是
Figure PCTCN2021104379-appb-000002
R、R’和R”相互独立地选自氢或C 1-C 3烷基；
R 6为C 1-C 3烷基、C 3-C 7环烷基或R 5。
在一种可能的实现方式中，通式(I)所示的化合物中，当Q是氮原子且R 3为氢时，R 5中R、R’和R”相互独立地选自氢或甲基。
在一种可能的实现方式中，通式(I)所示的化合物中，当Q是氮原子且R 3为氟或羟基 时，X是乙基或R 5，R 5中R、R’和R”相互独立地选自氢或甲基。
在一种可能的实现方式中，通式(I)所示的化合物中，当Q是碳原子时,R 4为氢或甲基，R 6是甲基、乙基或R 5，R 5中R、R’和R”相互独立地选自氢或甲基。
在一种可能的实现方式中，通式(I)所示的化合物中，R 1和R 2均为氟，R 3是氢，A选自亚甲基或共价键，Q是氮原子，R 5中R、R’和R”相互独立地选自氢或甲基。
在一种可能的实现方式中，通式(I)所示的化合物中，R 1和R 2均为氟，R 3是氟，A选自亚甲基或共价键，Q是氮原子，X是乙基。
在一种可能的实现方式中，通式(I)所示的化合物中，R 1和R 2均为氟，R 3是氢或氟，A选自亚甲基或共价键，Q是碳原子，R 4是氢或甲基，R 6是甲基、乙基或羟乙基。
在一种可能的实现方式中，通式(I)所示的化合物选自具有以下结构的化合物：
Figure PCTCN2021104379-appb-000003
Figure PCTCN2021104379-appb-000004
Figure PCTCN2021104379-appb-000005
Figure PCTCN2021104379-appb-000006
本申请还提供了嘧啶类衍生物的制备方法，所述制备方法选自以下方法中的任意一种：
(1)已知化合物I-A和I-B合环生成苯并咪唑I-C，I-C被转变成频哪醇硼酸酯后，通过Suzuki偶联和I-D反应生成I-E，I-E最后和相应的2－氨基吡啶通过Buchwald偶联反应生成代表性结构I。
Figure PCTCN2021104379-appb-000007
(2)
Figure PCTCN2021104379-appb-000008
(3)
Figure PCTCN2021104379-appb-000009
其中：R1、R2、R3、A、Q、X具有与上述的嘧啶类衍生物中相应基团相同的含义；Y为卤族元素。
本申请还提供了上述嘧啶类衍生物作为活性成分在制备药物组合物中的应用。
在一种可能的实现方式中，所述药物组合物为治疗异常细胞增殖性疾病、感染(例 如病毒感染，如疱疹、HIV，真菌感染等)、炎性病症(例如类风湿性关节炎、骨关节炎等)、自身免疫性疾病(例如牛皮癣、狼疮、I型糖尿病、糖尿病性肾病、多发性硬化、肾小球性肾炎等)、心血管疾病(例如心肌梗塞、中风、动脉粥样硬化、手术后血管狭窄、再狭窄等)或神经变性疾病(例如阿尔茨海默氏病、帕金森病等)、治疗由辐射引起的造血毒性疾病(例如骨髓抑制、嗜中性白血球减少症、白细胞减少症、贫血)的药物。
在一种可能的实现方式中，所述治疗异常细胞增殖性疾病为治疗癌症；可选地，所述癌症选自乳腺癌、卵巢癌、***癌、黑色素瘤、脑瘤(例如具有恶性的星形神经胶质和少突神经胶质细胞瘤成分的神经胶质瘤等)、食管癌、胃癌、肝癌、胰腺癌、结肠直肠癌(例如结肠癌、直肠癌等)、肺癌(例如非小细胞肺癌、小细胞肺癌、原发或转移性鳞状癌等)、肾癌、皮肤癌、成胶质细胞瘤、神经母细胞瘤、肉瘤、脂肪肉瘤、骨软骨瘤、骨瘤、骨肉瘤、***瘤、睾丸肿瘤、子宫癌(例如子***、子宫内膜癌等)、头颈肿瘤(例如上颌骨癌、喉癌、咽癌、舌癌、口内癌等)、多发性骨髓瘤、恶性淋巴瘤(例如网状细胞肉瘤、淋巴肉瘤、霍奇金淋巴瘤、套细胞淋巴瘤等)、真性红细胞增多症、白血病(例如急性粒细胞白血病、慢性粒细胞白血病、急性淋巴细胞白血病、慢性淋巴细胞白血病等)、甲状腺肿瘤、输尿管肿瘤、***、胆囊癌、胆管癌、绒毛膜上皮癌或儿科肿瘤(例如尤因家族性肉瘤、维尔姆斯肉瘤、横纹肌肉瘤、血管肉瘤、胚胎睾丸癌、成神经细胞瘤、视网膜母细胞瘤、肝胚细胞瘤、肾母细胞瘤等)等。
在一种可能的实现方式中，所述癌症是乳腺癌或卵巢癌。
本申请还提供了一种药物组合物，包括上述的嘧啶类衍生物作为活性成分，还包括一种或多种药学上可接受的载体、稀释剂或赋形剂。
在一种可能的实现方式中，所述药物组合物还包括另外一种或多种抗癌剂作为活性成分，所述抗癌剂选自烷化剂(例如环磷酰胺、异环磷酰胺、美法仑、白消安、尼莫司汀、雷莫司汀、达卡巴嗪、替莫唑胺、盐酸氮芥、二溴甘露醇等)、铂络合剂(例如顺铂、卡铂、奥沙利铂等)、代谢拮抗剂(例如甲氨蝶呤、5-氟尿嘧啶、替加氟、吉西他滨、卡培他滨、氟维司群、培美曲塞等)、植物生物碱(例如长春新碱、长春碱、长春地辛、依托泊苷、多西他赛、紫杉醇、伊立替康、长春瑞滨、米托蒽醌、长春氟宁、拓扑替康等)、抗体药物(例如曲妥单抗、帕妥珠单抗、利妥昔单抗、西妥昔单抗、帕尼单抗、贝伐单抗等)、激素抗癌剂(例如亮丙瑞林、戈舍瑞林、度他雄胺、***、他莫昔芬等)、蛋白酶体抑制剂(例如硼替佐米、来那度胺等)、芳香化酶抑制剂(例如依西美坦、来曲唑、阿那曲唑等)、VEGFR或EGFR抑制剂(例如舒尼替尼、索拉非尼、伊马替尼、吉非替尼、埃罗替尼、凡德他尼、帕唑帕尼、拉帕替尼等)、mTOR抑制剂(例如依维莫司、西罗莫 司、佐他莫司等)、PI3K激酶抑制剂(例如BKM-120、XL-147、BEZ-235等)、B-Raf抑制剂(例如威罗菲尼、GSK-2118436等)或AKT抑制剂(例如哌立福新、MK-2206等)等；优选为芳香化酶抑制剂，更优选来曲唑或阿那曲唑。
本申请还提供了一种治疗疾病的方法，所述方法包括以下步骤：向需要治疗疾病的受试者施用有效剂量的上述嘧啶类衍生物，所述疾病为异常细胞增殖性疾病、感染(例如病毒感染，如疱疹、HIV，真菌感染等)、炎性病症(例如类风湿性关节炎、骨关节炎等)、自身免疫性疾病(例如牛皮癣、狼疮、I型糖尿病、糖尿病性肾病、多发性硬化、肾小球性肾炎等)、心血管疾病(例如心肌梗塞、中风、动脉粥样硬化、手术后血管狭窄、再狭窄等)或神经变性疾病(例如阿尔茨海默氏病、帕金森病等)、治疗由辐射引起的造血毒性疾病(例如骨髓抑制、嗜中性白血球减少症、白细胞减少症、贫血)。
在一种可能的实现方式中，所述异常细胞增殖性疾病为癌症；可选地，所述癌症选自乳腺癌、卵巢癌、***癌、黑色素瘤、脑瘤(例如具有恶性的星形神经胶质和少突神经胶质细胞瘤成分的神经胶质瘤等)、食管癌、胃癌、肝癌、胰腺癌、结肠直肠癌(例如结肠癌、直肠癌等)、肺癌(例如非小细胞肺癌、小细胞肺癌、原发或转移性鳞状癌等)、肾癌、皮肤癌、成胶质细胞瘤、神经母细胞瘤、肉瘤、脂肪肉瘤、骨软骨瘤、骨瘤、骨肉瘤、***瘤、睾丸肿瘤、子宫癌(例如子***、子宫内膜癌等)、头颈肿瘤(例如上颌骨癌、喉癌、咽癌、舌癌、口内癌等)、多发性骨髓瘤、恶性淋巴瘤(例如网状细胞肉瘤、淋巴肉瘤、霍奇金淋巴瘤、套细胞淋巴瘤等)、真性红细胞增多症、白血病(例如急性粒细胞白血病、慢性粒细胞白血病、急性淋巴细胞白血病、慢性淋巴细胞白血病等)、甲状腺肿瘤、输尿管肿瘤、***、胆囊癌、胆管癌、绒毛膜上皮癌或儿科肿瘤(例如尤因家族性肉瘤、维尔姆斯肉瘤、横纹肌肉瘤、血管肉瘤、胚胎睾丸癌、成神经细胞瘤、视网膜母细胞瘤、肝胚细胞瘤、肾母细胞瘤等)等。
在一种可能的实现方式中，所述癌症是乳腺癌或卵巢癌。
在一种可能的实现方式中，所述乳腺癌是三阴性乳腺癌。
在一种可能的实现方式中，所述方法还包括联合使用另外一种或多种抗癌剂作为活性成分，所述抗癌剂选自烷化剂(例如环磷酰胺、异环磷酰胺、美法仑、白消安、尼莫司汀、雷莫司汀、达卡巴嗪、替莫唑胺、盐酸氮芥、二溴甘露醇等)、铂络合剂(例如顺铂、卡铂、奥沙利铂等)、代谢拮抗剂(例如甲氨蝶呤、5-氟尿嘧啶、替加氟、吉西他滨、卡培他滨、氟维司群、培美曲塞等)、植物生物碱(例如长春新碱、长春碱、长春地辛、依托泊苷、多西他赛、紫杉醇、伊立替康、长春瑞滨、米托蒽醌、长春氟宁、拓扑替康等)、抗体药物(例如曲妥单抗、帕妥珠单抗、利妥昔单抗、西妥昔单抗、帕尼单抗、贝 伐单抗等)、激素抗癌剂(例如亮丙瑞林、戈舍瑞林、度他雄胺、***、他莫昔芬等)、蛋白酶体抑制剂(例如硼替佐米、来那度胺等)、芳香化酶抑制剂(例如依西美坦、来曲唑、阿那曲唑等)、VEGFR或EGFR抑制剂(例如舒尼替尼、索拉非尼、伊马替尼、吉非替尼、埃罗替尼、凡德他尼、帕唑帕尼、拉帕替尼等)、mTOR抑制剂(例如依维莫司、西罗莫司、佐他莫司等)、PI3K激酶抑制剂(例如BKM-120、XL-147、BEZ-235等)、B-Raf抑制剂(例如威罗菲尼、GSK-2118436等)或AKT抑制剂(例如哌立福新、MK-2206等)等；优选为芳香化酶抑制剂，更优选来曲唑或阿那曲唑。
本申请还提供了一种CDK抑制剂，包括上述嘧啶类衍生物。
在一种可能的实现方式中，CDK包括CDK2、CDK4或CDK6。
本申请还提供了一种上述CDK抑制剂的制备方法，包括以下步骤：使用上述制备方法制备权利要求1-4之一所述的嘧啶类衍生物。
本申请还提供了一种上述CDK抑制剂作为活性成分在制备药物组合物中的应用。
在一种可能的实现方式中，所述药物组合物为治疗异常细胞增殖性疾病、感染(例如病毒感染，如疱疹、HIV，真菌感染等)、炎性病症(例如类风湿性关节炎、骨关节炎等)、自身免疫性疾病(例如牛皮癣、狼疮、I型糖尿病、糖尿病性肾病、多发性硬化、肾小球性肾炎等)、心血管疾病(例如心肌梗塞、中风、动脉粥样硬化、手术后血管狭窄、再狭窄等)、神经变性疾病(例如阿尔茨海默氏病、帕金森病等)、由辐射引起的造血毒性疾病(例如骨髓抑制、嗜中性白血球减少症、白细胞减少症、贫血)的药物。
在一种可能的实现方式中，所述治疗异常细胞增殖性疾病为治疗癌症。
在一种可能的实现方式中，所述癌症选自乳腺癌、卵巢癌、***癌、黑色素瘤、脑瘤(例如具有恶性的星形神经胶质和少突神经胶质细胞瘤成分的神经胶质瘤等)、食管癌、胃癌、肝癌、胰腺癌、结肠直肠癌(例如结肠癌、直肠癌等)、肺癌(例如非小细胞肺癌、小细胞肺癌、原发或转移性鳞状癌等)、肾癌、皮肤癌、成胶质细胞瘤、神经母细胞瘤、肉瘤、脂肪肉瘤、骨软骨瘤、骨瘤、骨肉瘤、***瘤、睾丸肿瘤、子宫癌(例如子***、子宫内膜癌等)、头颈肿瘤(例如上颌骨癌、喉癌、咽癌、舌癌、口内癌等)、多发性骨髓瘤、恶性淋巴瘤(例如网状细胞肉瘤、淋巴肉瘤、霍奇金淋巴瘤、套细胞淋巴瘤等)、真性红细胞增多症、白血病(例如急性粒细胞白血病、慢性粒细胞白血病、急性淋巴细胞白血病、慢性淋巴细胞白血病等)、甲状腺肿瘤、输尿管肿瘤、***、胆囊癌、胆管癌、绒毛膜上皮癌或儿科肿瘤(例如尤因家族性肉瘤、维尔姆斯肉瘤、横纹肌肉瘤、血管肉瘤、胚胎睾丸癌、成神经细胞瘤、视网膜母细胞瘤、肝胚细胞瘤、肾母细胞瘤等)。
在一种可能的实现方式中，所述癌症是乳腺癌或卵巢癌。
在一种可能的实现方式中，所述乳腺癌为三阴性乳腺癌。
一种药物组合物，包括上述CDK抑制剂作为活性成分，还包括一种或多种药学上可接受的载体、稀释剂或赋形剂。
在一种可能的实现方式中，所述药物组合物还包括另外一种或多种抗癌剂作为活性成分，所述抗癌剂选自烷化剂(例如环磷酰胺、异环磷酰胺、美法仑、白消安、尼莫司汀、雷莫司汀、达卡巴嗪、替莫唑胺、盐酸氮芥、二溴甘露醇等)、铂络合剂(例如顺铂、卡铂、奥沙利铂等)、代谢拮抗剂(例如甲氨蝶呤、5-氟尿嘧啶、替加氟、吉西他滨、卡培他滨、氟维司群、培美曲塞等)、植物生物碱(例如长春新碱、长春碱、长春地辛、依托泊苷、多西他赛、紫杉醇、伊立替康、长春瑞滨、米托蒽醌、长春氟宁、拓扑替康等)、抗体药物(例如曲妥单抗、帕妥珠单抗、利妥昔单抗、西妥昔单抗、帕尼单抗、贝伐单抗等)、激素抗癌剂(例如亮丙瑞林、戈舍瑞林、度他雄胺、***、他莫昔芬等)、蛋白酶体抑制剂(例如硼替佐米、来那度胺等)、芳香化酶抑制剂(例如依西美坦、来曲唑、阿那曲唑等)、VEGFR或EGFR抑制剂(例如舒尼替尼、索拉非尼、伊马替尼、吉非替尼、埃罗替尼、凡德他尼、帕唑帕尼、拉帕替尼等)、mTOR抑制剂(例如依维莫司、西罗莫司、佐他莫司等)、PI3K激酶抑制剂(例如BKM-120、XL-147、BEZ-235等)、B-Raf抑制剂(例如威罗菲尼、GSK-2118436等)或AKT抑制剂(例如哌立福新、MK-2206等)等；另外一种或多种抗癌剂优选为芳香化酶抑制剂，更优选来曲唑或阿那曲唑。
本申请还提供了一种抑制CDK活性的方法，包括以下步骤：向需要抑制CDK活性的受试者施用有效剂量的上述嘧啶类衍生物。
有益效果
本申请中嘧啶类衍生物表现出优异的抑制CDK的效果和作用，尤其是抑制CDK2、CDK4、CDK6；相比Abemacicilib，表现出更低的IC50值。
具体实施方式
为使本申请的目的、技术方案和优点更加清楚，下面将结合实施例对本申请中的技术方案进行清楚、完整地描述，显然，所描述的实施例是本申请一部分实施例，而不是全部的实施例。基于本申请中的实施例，本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例，都属于本申请保护的范围。
另外，为了更好的说明本申请，在下文的具体实施方式中给出了众多的具体细节。本领域技术人员应当理解，没有某些具体细节，本申请同样可以实施。在一些实施例中， 对于本领域技术人员熟知的原料、元件、方法、手段等未作详细描述，以便于凸显本申请的主旨。
除非另有其它明确表示，否则在整个说明书和权利要求书中，术语“包括”或其变换如“包含”或“包括有”等等将被理解为包括所陈述的元件或组成部分，而并未排除其它元件或其它组成部分。
术语“烷基”指饱和的脂肪族烃基团，包括1至20个碳原子的直链和支链基团。优选含有1至10个碳原子的烷基，更优选含有1至6个碳原子的烷基，最优选含有1至4个碳原子的烷基，最佳为甲基。非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1，1-二甲基丙基、1，2-二甲基丙基、2，2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1，1，2-三甲基丙基、1，1-二甲基丁基、1，2-二甲基丁基、2，2-二甲基丁基、1，3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2，3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2，3-二甲基戊基、2，4-二甲基戊基、2，2-二甲基戊基、3，3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2，3-二甲基己基、2，4-二甲基己基、2，5-二甲基己基、2，2-二甲基己基、3，3-二甲基己基、4，4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2，2-二乙基戊基、正癸基、3，3-二乙基己基、2，2-二乙基己基，及其各种支链异构体等。更优选的是含有1至6个碳原子的低级烷基，非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1，1-二甲基丙基、1，2-二甲基丙基、2，2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1，1，2-三甲基丙基、1，1-二甲基丁基、1，2-二甲基丁基、2，2-二甲基丁基、1，3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2，3-二甲基丁基等。烷基可以是取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选为一个或多个以下基团，独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、氨基、卤代烷基、羟烷基、羧基或羧酸酯基。
术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，其包括3至20个碳原子，优选包括3至12个碳原子，更优选环烷基环包含3至10个碳原子，最优选环烷基环包含3至6个碳原子，最佳为环丙基或环戊基。单环环烷基的非限制性实例包含环 丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等，优选环丙基、环戊基。多环环烷基包括螺环、稠环和桥环的环烷基。环烷基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、氨基、卤代烷基、羟烷基、羧基或羧酸酯基。
术语“烷氧基”指-O-(烷基)和-O-(未取代的环烷基)，其中烷基、环烷基的定义如上所述。非限制性实例包含甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基等。烷氧基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自为烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氨基、卤代烷基、羟烷基、羧基或羧酸酯基。
“卤代烷基”指烷基被一个或多个卤素取代，其中烷基的定义如上所述。
“羟基”指-OH基团。
“羟烷基”指被羟基取代的烷基，其中烷基的定义如上所述。
“卤素”指氟、氯、溴或碘，优选氟或碘。
“氨基”指-NH 2。
“氰基”指-CN。
“硝基”指-NO 2。
“氧代基”指＝O。
“羧基”指-C(O)OH。
“羧酸酯基”指-C(O)O(烷基)或(环烷基)，其中烷基、环烷基的定义如上所述。
“任选”或“任选地”意味着随后所描述地事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生的场合。例如，“任选被烷基取代的杂环烷基团”意味着烷基可以但不必须存在，该说明包括杂环烷基团被烷基取代的情形和杂环烷基团不被烷基取代的情形。
“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
实施例1合成化合物1979
Figure PCTCN2021104379-appb-000010
化合物2的合成：
将化合物1(3.0g,24.6mmol)和化合物A(5.03g,27.0mmol)室温下溶于THF(80毫升)中，加入3滴乙酸，搅拌半小时后，分批加入醋酸硼氢化钠(15.6g,73.8mmol),加完室温搅拌过夜。加入碳酸钠水溶液50毫升，乙酸乙酯萃取2次，合并有机相，硫酸钠干燥后过滤浓缩得化合物2粗品(7.8g)。
化合物4的合成：
将化合物2粗品(7.8g,26.7mmol)和化合物3(7.17g,22.3mmol)室温下溶于1,4-二氧六环(150毫升)中，加入Pd 2(dba) 3(2.0g,2.23mmol)，Xantphos(2.5g,4.46mmol)，碳酸钾(4.6g,33.45mmol)，氮气置换4次后加热回流5小时。加入水500毫升，二氯甲烷萃取4次后，合并有机相，硫酸钠干燥后过滤浓缩得化合物4粗品，再用乙酸乙酯(150毫升)打浆半小时后过滤，干燥得化合物4(13g)。
化合物5的合成：
将化合物4(13.0g,25mmol)室温下溶于二氯甲烷(50毫升)中，加入15毫升三氟乙酸，室温搅拌过夜。浓缩后用饱和碳酸钠溶液调节pH到8-9，二氯甲烷萃取5次后 合并有机相，干燥浓缩后柱层析，使用甲醇/二氯甲烷梯度洗脱得化合物5(6g)，其中调整甲醇的体积比为0-10％。
1979的合成：
将化合物5(6g,12.5mmol)和溴乙醇(1.9g,15.1mmol)室温下溶于DMF(50毫升)中，加入DIPEA(4.9g,37.7mmol)，碘化钾(催化量)后加热至80℃反应5小时。LC-MS检测反应结束，浓缩除去DMF后直接柱层析，使用甲醇/二氯甲烷梯度洗脱得粗品化合物1979(3.5g)，其中调整甲醇的体积比为0-10％，再用乙酸乙酯100毫升打浆半小时过滤得1979(3.0g)(LCMS,M+1:523)。
实施例2:合成化合物1963
Figure PCTCN2021104379-appb-000011
化合物1的合成：
将化合物A(7.9g,39mmol)和化合物B(10g,47mmol)室温下溶于DMF(50毫升)中，加入碳酸铯(19g,58mmol)，加热到120-125℃反应5小时。冷却到室温后加入水200毫升，搅拌半小时后过滤，干燥后用乙酸乙酯和石油醚混合溶剂打浆半小时后过滤得化合物1粗品(8.3克)。
化合物2的合成：
将化合物1粗品(8.3g)室温下溶于甲醇(150毫升)中，加入Pd/C(1.6g)，氢气置换3次后室温搅拌过夜。过滤，母液浓缩后得粗品，再用乙酸乙酯和石油醚混合溶剂打浆半小时后过滤得化合物2(5.3克)。
化合物4的合成：
将化合物2(5.3g,17.2mmol)和化合物3(5.1g,15.8mmol)室温下溶于1,4-二氧六环(50毫升)中，加入Pd 2(dba) 3(0.72g,0.8mmol)，Xantphos(0.9g,1.7mmol)，碳酸钾(3.2g,72mmol)，氮气置换4次后加热回流5小时。加入水100毫升，过滤，固体再用乙醇(150毫升)打浆半小时后过滤，干燥得化合物4(8.4g)。
化合物5的合成：
将化合物4(8.4g,14.2mmol)室温下溶于二氯甲烷(50毫升)中，加入15毫升三氟乙酸，室温搅拌过夜。浓缩后用饱和碳酸钠溶液调节pH到8-9，二氯甲烷萃取5次后合并有机相，干燥浓缩后柱层析，0-10％甲醇/二氯甲烷洗脱得化合物5(5g)。
1963的合成：
将化合物5(3.2g,6.5mmol)和溴乙醇(0.9g,7.8mmol)室温下溶于DMF(30毫升)中，加入DIPEA(1.72g,13.3mmol)，碘化钾(催化量)后加热至80℃反应5小时。LC-MS检测反应结束，浓缩除去DMF，直接柱层析，0-10％甲醇/二氯甲烷洗脱得粗品化合物1963(1.6g)，再用乙酸乙酯100毫升打浆半小时过滤得1963(1.3g)(LCMS,M+1:537)。
实施例3:合成化合物1984
Figure PCTCN2021104379-appb-000012
化合物2的合成：
将化合物1(18g，76mmol)和碳酸铯(24.6g,76mmol)室温下加入到THF(90g)中，降温至0-5℃，控制温度小于10℃滴加入异丙胺(4.5g，76mmol)，滴完室温反应5h，LC-MS检测反应结束，过滤浓缩得红棕色固体22g。将所得红棕色固体(22g，79mmol)加入到乙醇(80ml)和水(20ml)的混合溶液中，加入氯化铵(7.94g,148mmol)，加入铁粉(25.3g，454mmol)，升温至回流反应1h，LC—MS检测反应结束，加入水和EA搅拌，过滤，水相用EA萃取，干燥浓缩，柱层析，PE洗脱得化合物2(棕色液体12.1g)。
化合物3的合成：
将化合物2(3g，12.14mmol)加入到水(12ml)和浓盐酸(6ml)的溶液中，加入羟基乙酸(4.6g，60.7mmol)，加热回流反应3h，LC-MS检测反应结束，降温用碳酸钠溶液调解PH约为8-9，用EA萃取，干燥浓缩得黄色固体化合物3(3.1g)。
化合物4的化合成：
将化合物3(3g，10.44mmol)加入到DCM(30ml)中，降温至0-5℃，控制小于10℃，滴加入Dast试剂(2.02g，12.54mmol)，室温反应后回流反应，补加入Dast试剂(0.6g)，继续回流反应24h，LC—MS检测大部分原料转化，降温，用碳酸氢钠调解PH＝8，DCM萃取，柱层析，0-5％EA洗脱得黄色固体化合物4(0.9g)。
化合物5和化合物6一锅法合成：
将化合物4(0.92g，3.2mmol)、双(频哪醇合)二硼(0.96g，3.8mmol)、醋酸钾 (0.62g，6.36mmol)、Pd(dppf)Cl 2(0.22g，0.64mmol)依次加入到二氧六环(30ml)中，氮气保护，升温回流反应2h，LC-MS检测反应完成，降温，将碳酸钠(0.67g，6.36mmol)和化合物B(0.53g，3.2mmol)加入到化合物5的反应体系中，加入Pd(dppf)Cl 2(0.11g，0.32mmol)，加入水(7ml)氮气保护升温至80-90℃反应2h，LC-MS检测反应完成，降温加入水，用EA萃取，干燥浓缩，柱层析，0-15％EA洗脱，得黄色固体化合物6(0.62g)。
化合物1984的合成：
将化合物6(0.15g，0.44mmol)和化合物7(0.11g，0.484mmol)加入到二氧六环中，加入Pd 2(dba) 3(44.4mg,0.044mmol)，Xantphos(51mg,0.088mmol)，碳酸钾(91.2mg,0.66mmol)，氮气保护，升温回流反应，LC-MS检测反应结束，降温，加入水，DCM萃取，刮大板，得黄色固体化合物1984(98mg)(LCMS,M+1:525)。
实施例4、其他制备例
其它化合物制备例包括：
Figure PCTCN2021104379-appb-000013
Figure PCTCN2021104379-appb-000014
Figure PCTCN2021104379-appb-000015
实施例5、CDK2激酶活性的测定
体外CDK2激酶活性通过以下的方法进行测试：
最终缓冲液：
100mM 4-羟乙基哌嗪乙磺酸，pH 7.5；
0.1％牛血清白蛋白；
0.01％Triton X-100；
1mM二硫苏糖醇；
5mM氯化镁；
10μM正钒酸钠；
10μMβ-甘油磷酸钠；
10μM ATP；
1％DMSO(来自待测化合物)；
底物肽：1μM FAM-PKTPKKAKKL-OH，FAM是5－羧基荧光素；
0.1nM CDK2/人细胞周期蛋白A(Millipore货号14-448-23984)。
在384孔板加入5μL的缓冲液，加入0.1μL待测化合物(DMSO,100倍最高浓度)，加入5μL底物肽缓冲液。25℃下培养6个小时，用EDTA终结反应。启动电泳读数(Caliper
Figure PCTCN2021104379-appb-000016
3000Drug Discovery System,blue laser(480nm)激发,green CCD(520nm)检测CCD2)。待测化合物对CDK2激酶活性的抑制作用具体见表1。
实施例6、CDK4激酶活性的测定
体外CDK4激酶活性通过以下的方法进行测试：
最终缓冲液：
100mM 4-羟乙基哌嗪乙磺酸,pH 7.5；
0.1％牛血清白蛋白；
0.01％Triton X-100；
1mM二硫苏糖醇；
5mM氯化镁；
10μM正钒酸钠；
10μMβ-甘油磷酸钠；
25μM ATP；
1％DMSO(来自待测化合物)；
底物肽：1μM FAM-RRFRPASPLRGPPK-NH 2片段,FAM是5－羧基荧光素；
5nM CDK4/人细胞周期蛋白D(Life Tech货号PV4400-1754389F)。
在384孔板加入5μL的缓冲液，加入0.1μL待测化合物(DMSO,100倍最高浓度)，加入5μL底物肽缓冲液。25℃下培养6个小时，用EDTA终结反应。启动电泳读数(Caliper
Figure PCTCN2021104379-appb-000017
3000Drug Discovery System,blue laser(480nm)激发,green CCD(520nm)检测CCD2)。待测化合物对CDK4激酶活性的抑制作用具体见表1。
实施例7、CDK6激酶活性的测定
体外CDK6激酶活性通过以下的方法进行测试：
2nM CDK6/人细胞周期蛋白D3(Carna货号04-107)
最终缓冲液：
100mM 4-羟乙基哌嗪乙磺酸,pH 7.5；
0.1％牛血清白蛋白；
0.01％Triton X-100；
1mM二硫苏糖醇；
5mM氯化镁；
10μM正钒酸钠；
10μMβ-甘油磷酸钠；
300μM ATP；
1％DMSO(来自待测化合物)；
底物肽：Dyrktide；
在384孔板加入5μL的缓冲液，加入0.1μL待测化合物(DMSO,100倍最高浓度)，加入5μL底物肽缓冲液。25摄氏度下培养3个小时，用EDTA终结反应。启动电泳读数(Caliper
Figure PCTCN2021104379-appb-000018
3000Drug Discovery System,blue laser(480nm)激发,green CCD(520nm)检测CCD2)。待测化合物对CDK6激酶活性的抑制作用具体见表1。
实施例8、MDA-MB-468细胞活性的测定
MDA-MB-468(ATCC货号HTB-132)；
RPMI 1640(Invitrogen货号22400089)；
FBS(Hyclone货号SV30087.03)；
Pen Strep(Hyclone货号SV30010)；
CellTiter-Glo(Promega货号G7573)；
培养基：89％RPMI 1640,10％FBS and 1％Pen Strep；
300MDA-MB-468细胞和50μL培养基种于板中，加入100μL PBS缓冲液，37℃/5％CO 2条件下培养24h，待测化合物在十个测试点取样，所取样品分别用四倍DMSO稀释，取250nL加入板孔，37℃/5％CO 2条件下培养5天，每个板孔加入25μL CellTiter-Glo，旋转离心(1000rpm)15秒，振动混合(400rpm)10分钟，启动微板读数器Envision读数。待测化合物对MDA-MB-468细胞活性的抑制作用具体结果见表1。
表1、实施例化合物对CDK2激酶活性、CDK4激酶活性、CDK6激酶活性和对
MDA-MB-468细胞活性的IC50数据。
Figure PCTCN2021104379-appb-000019
*Invest New Drugs(2014)32,825-837。
**指Abemacicilib测得是抑制CDK6/CycD1的活性CDK6/CycD1。
由此可见，本申请的嘧啶类衍生物表现出优异的抑制CDK的效果和作用，尤其是抑制CDK2、CDK4、CDK6；相比于Abemacicilib，表现出更低的IC50值。并且当X包括甲氧基、羟基或亚胺基时，具有非常优异的效果。
最后应说明的是：以上实施例仅用以说明本申请的技术方案，而非对其限制；尽管参照前述实施例对本申请进行了详细的说明，本领域的普通技术人员应当理解：其依然可以对前述各实施例所记载的技术方案进行修改，或者对其中部分技术特征进行等同替换；而这些修改或者替换，并不使相应技术方案的本质脱离本申请的精神和范围。
工业实用性
本申请提供的嘧啶类衍生物表现出优异的抑制CDK的效果和作用，尤其是抑制CDK2、CDK4、CDK6；相比于Abemacicilib，表现出更低的IC50值；可作为活性成分 用于治疗多种疾病，例如，异常细胞增殖性疾病、感染、炎性病症、自身免疫性疾病、心血管疾病或神经变性疾病、由辐射引起的造血毒性疾病等。

Claims (13)

  1. 一种嘧啶类衍生物，其特征在于：所述嘧啶类衍生物选自：通式(I)所示的化合物或其互变异构体、对映异构体、非对映异构体、内消旋体、外消旋体或其混合物形式，或其可药用盐或其前体药物：
    Figure PCTCN2021104379-appb-100001
    其中：
    R 1和R 2相互独立地选自氟或氯；
    R 3选自氢，氟或羟基；
    A选自亚甲基或共价键；
    Q选自碳原子或氮原子，其中：
    当Q是碳原子时，X是-NR 4R 6；
    当Q是氮原子且R 3为氢时，X是-R 5；
    当Q是氮原子且R 3为氟或羟基时，X是C 1-C 3烷基，C 3-C 7环烷基或R 5；
    R 4选自氢或C 1-C 3烷基；
    R 5是
    Figure PCTCN2021104379-appb-100002
    R,R’和R”相互独立地选自氢或C 1-C 3烷基；
    R 6为C 1-C 3烷基，C 3-C 7环烷基或R 5。
  2. 根据权利要求1所述的嘧啶类衍生物，其特征在于：
    通式(I)所示的化合物中，
    当Q是氮原子且R 3为氢时，R 5中R、R’和R”相互独立地选自氢或甲基；
    或，当Q是氮原子且R 3为氟或羟基时，X是乙基或R 5，R 5中R、R’和R”相互独立地选自氢或甲基；
    或，当Q是碳原子时，R 4为氢或甲基，R 6是甲基、乙基或R 5，R 5中R、R’和R”相互独立地选自氢或甲基。
  3. 根据权利要求1所述的嘧啶类衍生物，其特征在于：
    通式(I)所示的化合物中，
    R 1和R 2均为氟，R 3是氢，A选自亚甲基或共价键，Q是氮原子，R 5中R、R’和R”相互独立地选自氢或甲基；
    或，R 1和R 2均为氟，R 3是氟，A选自亚甲基或共价键，Q是氮原子，X是乙基；
    或，R 1和R 2均为氟，R 3是氢或氟，A选自亚甲基或共价键，Q是碳原子，R 4是氢或甲基，R 6是甲基、乙基或羟乙基。
  4. 根据权利要求1所述的嘧啶类衍生物，其特征在于：通式(I)所示的化合物选自具有以下结构的化合物：
    Figure PCTCN2021104379-appb-100003
    Figure PCTCN2021104379-appb-100004
    Figure PCTCN2021104379-appb-100005
    Figure PCTCN2021104379-appb-100006
  5. 一种权利要求1-4之一所述的嘧啶类衍生物的制备方法，其特征在于：选自以下方法中的任意一种或几种：
    (1)已知化合物I-A和I-B合环生成苯并咪唑I-C，I-C被转变成频哪醇硼酸酯后，通过Suzuki偶联和I-D反应生成I-E，I-E最后和相应的2-氨基吡啶通过Buchwald偶联反应生成通式结构I；
    Figure PCTCN2021104379-appb-100007
    Figure PCTCN2021104379-appb-100008
    其中：R 1、R 2、R 3、A、Q、X具有与权利要求1-4之一所述的嘧啶类衍生物中相应基团相同的含义；Y为卤族元素。
  6. 权利要求1-4之一所述的嘧啶类衍生物作为活性成分在制备药物组合物中的应用。
  7. 根据权利要求6所述的应用，其特征在于：所述药物组合物为治疗异常细胞增殖性疾病、感染(例如病毒感染，如疱疹、HIV，真菌感染等)、炎性病症(例如类风湿性关节炎、骨关节炎等)、自身免疫性疾病(例如牛皮癣、狼疮、I型糖尿病、糖尿病性肾病、多发性硬化、肾小球性肾炎等)、心血管疾病(例如心肌梗塞、中风、动脉粥样硬化、手术后血管狭窄、再狭窄等)、神经变性疾病(例如阿尔茨海默氏病、帕金森病等)、由辐射引起的造血毒性疾病(例如骨髓抑制、嗜中性白血球减少症、白细胞减少症、贫血)的药物；
    可选地，所述治疗异常细胞增殖性疾病为治疗癌症；进一步可选地，所述癌症选自乳腺癌、卵巢癌、***癌、黑色素瘤、脑瘤(例如具有恶性的星形神经胶质和少突神经胶质细胞瘤成分的神经胶质瘤等)、食管癌、胃癌、肝癌、胰腺癌、结肠直肠癌(例如结肠癌、直肠癌等)、肺癌(例如非小细胞肺癌、小细胞肺癌、原发或转移性鳞状癌等)、肾癌、皮肤癌、成胶质细胞瘤、神经母细胞瘤、肉瘤、脂肪肉瘤、骨软骨瘤、骨瘤、骨肉瘤、***瘤、睾丸肿瘤、子宫癌(例如子***、子宫内膜癌等)、头颈肿瘤(例如上颌骨癌、喉癌、咽癌、舌癌、口内癌等)、多发性骨髓瘤、恶性淋巴瘤(例如网状细胞肉瘤、淋巴肉瘤、霍奇金淋巴瘤、套细胞淋巴瘤等)、真性红细胞增多症、白血病(例如急性粒细胞白血病、慢性粒细胞白血病、急性淋巴细胞白血病、慢性淋巴细胞白血病等)、甲状腺肿瘤、输尿管肿瘤、***、胆囊癌、胆管癌、绒毛膜上皮癌或儿科肿瘤(例 如尤因家族性肉瘤、维尔姆斯肉瘤、横纹肌肉瘤、血管肉瘤、胚胎睾丸癌、成神经细胞瘤、视网膜母细胞瘤、肝胚细胞瘤、肾母细胞瘤等)；更进一步可选地，所述癌症是乳腺癌或卵巢癌；再更进一步可选地，所述乳腺癌为三阴性乳腺癌。
  8. 一种药物组合物，其特征在于：包括权利要求1-4之一所述的嘧啶类衍生物作为活性成分，还包括一种或多种药学上可接受的载体、稀释剂或赋形剂；
    可选地，所述药物组合物还包括另外一种或多种抗癌剂作为活性成分，所述抗癌剂选自烷化剂(例如环磷酰胺、异环磷酰胺、美法仑、白消安、尼莫司汀、雷莫司汀、达卡巴嗪、替莫唑胺、盐酸氮芥、二溴甘露醇等)、铂络合剂(例如顺铂、卡铂、奥沙利铂等)、代谢拮抗剂(例如甲氨蝶呤、5-氟尿嘧啶、替加氟、吉西他滨、卡培他滨、氟维司群、培美曲塞等)、植物生物碱(例如长春新碱、长春碱、长春地辛、依托泊苷、多西他赛、紫杉醇、伊立替康、长春瑞滨、米托蒽醌、长春氟宁、拓扑替康等)、抗体药物(例如曲妥单抗、帕妥珠单抗、利妥昔单抗、西妥昔单抗、帕尼单抗、贝伐单抗等)、激素抗癌剂(例如亮丙瑞林、戈舍瑞林、度他雄胺、***、他莫昔芬等)、蛋白酶体抑制剂(例如硼替佐米、来那度胺等)、芳香化酶抑制剂(例如依西美坦、来曲唑、阿那曲唑等)、VEGFR或EGFR抑制剂(例如舒尼替尼、索拉非尼、伊马替尼、吉非替尼、埃罗替尼、凡德他尼、帕唑帕尼、拉帕替尼等)、mTOR抑制剂(例如依维莫司、西罗莫司、佐他莫司等)、PI3K激酶抑制剂(例如BKM-120、XL-147、BEZ-235等)、B-Raf抑制剂(例如威罗菲尼、GSK-2118436等)或AKT抑制剂(例如哌立福新、MK-2206等)等；另外一种或多种抗癌剂优选为芳香化酶抑制剂，更优选来曲唑或阿那曲唑。
  9. 一种CDK抑制剂，其特征在于：包括权利要求1-4之一所述的嘧啶类衍生物；可选地，CDK包括CDK2、CDK4或CDK6。
  10. 一种权利要求9所述的CDK抑制剂的制备方法，其特征在于：包括以下步骤：使用权利要求5所述的制备方法制备权利要求1-4之一所述的嘧啶类衍生物。
  11. 权利要求9所述的CDK抑制剂作为活性成分在制备药物组合物中的应用。
  12. 根据权利要求11所述的应用，其特征在于：所述药物组合物为治疗异常细胞增殖性疾病、感染(例如病毒感染，如疱疹、HIV，真菌感染等)、炎性病症(例如类风湿性关节炎、骨关节炎等)、自身免疫性疾病(例如牛皮癣、狼疮、I型糖尿病、糖尿病性肾病、多发性硬化、肾小球性肾炎等)、心血管疾病(例如心肌梗塞、中风、动脉粥样硬化、手术后血管狭窄、再狭窄等)、神经变性疾病(例如阿尔茨海默氏病、帕金森病等)、由辐射引起的造血毒性疾病(例如骨髓抑制、嗜中性白血球减少症、白细胞减少症、贫血)的药物；
    可选地，所述治疗异常细胞增殖性疾病为治疗癌症；进一步可选地，所述癌症选自乳腺癌、卵巢癌、***癌、黑色素瘤、脑瘤(例如具有恶性的星形神经胶质和少突神 经胶质细胞瘤成分的神经胶质瘤等)、食管癌、胃癌、肝癌、胰腺癌、结肠直肠癌(例如结肠癌、直肠癌等)、肺癌(例如非小细胞肺癌、小细胞肺癌、原发或转移性鳞状癌等)、肾癌、皮肤癌、成胶质细胞瘤、神经母细胞瘤、肉瘤、脂肪肉瘤、骨软骨瘤、骨瘤、骨肉瘤、***瘤、睾丸肿瘤、子宫癌(例如子***、子宫内膜癌等)、头颈肿瘤(例如上颌骨癌、喉癌、咽癌、舌癌、口内癌等)、多发性骨髓瘤、恶性淋巴瘤(例如网状细胞肉瘤、淋巴肉瘤、霍奇金淋巴瘤、套细胞淋巴瘤等)、真性红细胞增多症、白血病(例如急性粒细胞白血病、慢性粒细胞白血病、急性淋巴细胞白血病、慢性淋巴细胞白血病等)、甲状腺肿瘤、输尿管肿瘤、***、胆囊癌、胆管癌、绒毛膜上皮癌或儿科肿瘤(例如尤因家族性肉瘤、维尔姆斯肉瘤、横纹肌肉瘤、血管肉瘤、胚胎睾丸癌、成神经细胞瘤、视网膜母细胞瘤、肝胚细胞瘤、肾母细胞瘤等)；更进一步可选地，所述癌症是乳腺癌或卵巢癌；再更进一步可选地，所述乳腺癌为三阴性乳腺癌。
  13. 一种药物组合物，其特征在于：包括权利要求9所述的CDK抑制剂作为活性成分，还包括一种或多种药学上可接受的载体、稀释剂或赋形剂；
    可选地，所述药物组合物还包括另外一种或多种抗癌剂作为活性成分，所述抗癌剂选自烷化剂(例如环磷酰胺、异环磷酰胺、美法仑、白消安、尼莫司汀、雷莫司汀、达卡巴嗪、替莫唑胺、盐酸氮芥、二溴甘露醇等)、铂络合剂(例如顺铂、卡铂、奥沙利铂等)、代谢拮抗剂(例如甲氨蝶呤、5-氟尿嘧啶、替加氟、吉西他滨、卡培他滨、氟维司群、培美曲塞等)、植物生物碱(例如长春新碱、长春碱、长春地辛、依托泊苷、多西他赛、紫杉醇、伊立替康、长春瑞滨、米托蒽醌、长春氟宁、拓扑替康等)、抗体药物(例如曲妥单抗、帕妥珠单抗、利妥昔单抗、西妥昔单抗、帕尼单抗、贝伐单抗等)、激素抗癌剂(例如亮丙瑞林、戈舍瑞林、度他雄胺、***、他莫昔芬等)、蛋白酶体抑制剂(例如硼替佐米、来那度胺等)、芳香化酶抑制剂(例如依西美坦、来曲唑、阿那曲唑等)、VEGFR或EGFR抑制剂(例如舒尼替尼、索拉非尼、伊马替尼、吉非替尼、埃罗替尼、凡德他尼、帕唑帕尼、拉帕替尼等)、mTOR抑制剂(例如依维莫司、西罗莫司、佐他莫司等)、PI3K激酶抑制剂(例如BKM-120、XL-147、BEZ-235等)、B-Raf抑制剂(例如威罗菲尼、GSK-2118436等)或AKT抑制剂(例如哌立福新、MK-2206等)等；另外一种或多种抗癌剂优选为芳香化酶抑制剂，更优选来曲唑或阿那曲唑。
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