WO2022002270A1 - 一种嘧啶类衍生物及其制备方法和应用 - Google Patents
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Classifications
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- 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
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- 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
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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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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
Description
Claims (13)
- 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: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 6为C 1-C 3烷基,C 3-C 7环烷基或R 5。
- 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。
- 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。
- 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。
- 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、前列腺癌、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、精原细胞瘤、睾丸肿瘤、子宫癌(例如子宫颈癌、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、膀胱肿瘤、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。
- 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、地塞米松、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。
- 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。
- 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。
- 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。
- 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、前列腺癌、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、精原细胞瘤、睾丸肿瘤、子宫癌(例如子宫颈癌、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、膀胱肿瘤、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。
- 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、地塞米松、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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CN113880809A (zh) | 2022-01-04 |
EP4154911A1 (en) | 2023-03-29 |
EP4154911A4 (en) | 2024-06-12 |
CN113880809B (zh) | 2022-10-18 |
JP2023531228A (ja) | 2023-07-21 |
KR20230014730A (ko) | 2023-01-30 |
US20230125233A1 (en) | 2023-04-27 |
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