Classifications

• • 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
  • 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
  • A61K31/495—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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/14—Antivirals for RNA viruses
  • A61P31/18—Antivirals for RNA viruses for HIV
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • 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
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
  • Y02P20/00—Technologies relating to chemical industry
  • Y02P20/50—Improvements relating to the production of bulk chemicals
  • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

• the invention belongs to the field of medicine, and specifically relates to a series of substituted 2-(pyridin-2-yl)aminopyrimidine compounds having protein kinase inhibition, a preparation method thereof and a medical use.
• CDK Cyclin Dependent Kinase
• CDI Cyclin and Cyclin-dependent Protein Kinase Inhibitor
• cyclins are periodically expressed and degraded continuously and bind to CDKs that are transiently activated by them, catalyzing the phosphorylation of different substrates through CDK activity, and promoting the promotion of different phases of the cell cycle. Transformation.
• CDK1-CDK13 13 members have been found in the CDK family, namely CDK1-CDK13; CDK1, CDK2, CDK3, CDK4 and CDK6 are involved in the regulation of cell proliferation, and CDK7, CDK8, CDK9, CDK11, CDK12 and CDK13 are involved in the regulation of transcription.
• Cyclin is divided into A-L, and different CDKs are linked to different subtypes of Cyclin.
• the Cyclin D family (Cyclin D1, D2, D3), expressed in the G1 phase, binds to and activates CDK4 and CDK6, forming a CDK4/6-Cyclin D complex, including retinoblastoma protein (Rb).
• Rb retinoblastoma protein
• Rb phosphorylates and releases proteins that bind to and are inhibited by it, mainly transcription factor E2F, etc.
• E2F activates and transcribes some genes necessary for S phase (Maer, CDK4/6 inhibitor anti-tumor effect research, "foreign Medicine and Antibiotics, 2013, 34(5): 197-202).
• CDK4/6 as an anti-tumor target are: (1) Most proliferating cells rely on CDK2 or CDK4/6 proliferation, but inhibitors of CDK4/6 do not exhibit cytotoxicity of "pan-CDK inhibitors", such as Myelosuppression and intestinal reactions. (2) Preclinical experiments show that if the cell Cyclin D level is elevated or p16INK4a is inactivated, it can increase the sensitivity of the cells to the drug. Since the tumor cells have the above phenomenon relative to normal cells, the drug targeting is increased to some extent. .
• CDks inhibitors are also used for the treatment of other conditions; for example, for the treatment of cardiovascular disorders, including atherosclerosis, restenosis after stent implantation, and other cardiovascular disorders caused by abnormal cell proliferation; Such as for the treatment of fungi, protozoan parasites (such as Plasmodium falciparum) and diseases caused by DNA and RNA virus infection, including malaria, AIDS and so on.
• CDKs inhibitors can also be used in autoimmune diseases (such as psoriasis, rheumatoid arthritis, glomerulonephritis and lupus erythematosus) to inhibit the proliferation of inflammatory cells.
• PD0332991 inhibits the IC50 of CDK4 and CDK6 by 11 nmol/L and 15 nmol/L, respectively; while the IC50 of inhibiting CDK2, CDK1 and CDK5 is greater than 10 ⁇ mol/L (Fry DW, Harvey PJ, Keller PR, et al. Specifi c inhibition of cyclin- Dependent kinase 4/6by PD 0332991 and associated antitumor activity in human tumor xenografts [J]. Molecular Cancer Therapeutics, 2004, 3(11): 1427).
• Compound LEE011 (disclosed by WO2011101409), which is under research by Novartis, has the structural formula shown in 2.
• Compound LY2835219 (published by WO2010075074), also known as Bemaciclib, has the structural formula shown as 3; it has been reported to have an inhibitory IC50 of 2 nmol/L and 9.9 nmol/L for CDK4 and CDK6, respectively (Lawrence MG, SFCai, X. Lin et Al. Preclinical characterization of the CDK4/6 inhibitor LY2835219: in-vivo cell cycle-dependent/independent anti-tumor activities alone/in combination with gemcitabine [J]. Invest New Drugs, (2014), 32: 825). At present, LY2835219 is undergoing Phase III clinical trials by Eli Lilly and Company.
• CDK4/6 Due to the emergence of these compounds, CDK4/6 has become a clear anti-tumor target.
• the applicant also filed a patent application for a new series of substituted 2-(pyridin-2-yl)aminopyrimidines (application no. 201510708487.3, application date October 27, 2015), and these compounds show selective inhibition of CDK4/ 6 activity.
• CDK4/6 inhibitors with active, selective and bioavailability to provide more clinical options for treating diseases such as cancer and abnormal cell proliferation.
• the compound provided by the present invention is capable of selectively inhibiting the cyclin kinase CDK4/6 and stopping the cells in the G1 phase, thereby being useful for treating a cell proliferative disorder.
• the invention provides a compound of formula I or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, a deuterated compound, a prodrug Or a mixture thereof, or a compound of formula I, a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, a deuterated compound, a prodrug or a mixture thereof Pharmaceutically acceptable salt or solvate,
• R 1 , R 2 , R 3 are each independently selected from a hydrogen atom, an unsubstituted C 1 -C 6 hydrocarbon group or one or more hydrocarbon groups selected from C 1 -C 6 , C 3 -C 6 Cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, hydroxy, halogen, cyano, -NR 8 R 9 , Substituted substituted C 1 -C 6 hydrocarbyl group;
• R 4 and R 5 are each independently selected from hydrogen, halogen, and at least one of R 4 and R 5 is halogen;
• R 6 is selected from a hydrogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, a hydroxyl group or a halogen;
• R 10 cannot be NH 2 , -NHR 8 , -NR 8 R 9 ,
• R 6 and R 7 together with the C atom to which they are attached form a 5-7 membered heterocyclic ring containing one or more selected from N, O or S, and the 5-7 membered heterocyclic ring is selected from one or more C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 hydroxyalkyl, hydroxy, Halogen, cyano, -NH 2 , -NHR 8 , -NR 8 R 9 , Substituted by a substituent;
• R 8 and R 9 are each independently selected from a hydrogen atom, a C 1 -C 6 alkyl group, and a C 1 -C 6 hydroxyalkyl group.
• R 1 , R 2 , R 3 are each independently selected from a hydrogen atom, an unsubstituted C 1 -C 6 hydrocarbon group or one or more hydrocarbon groups selected from C 1 -C 6 , C 3 -C a C 1 -C 6 hydrocarbon group substituted with a cycloalkyl group of 6 , a C 1 -C 6 haloalkyl group, a C 1 -C 6 alkoxy group, a hydroxyl group or a halogen substituent.
• R 1 , R 2 , R 3 are each independently selected from a hydrogen atom, an unsubstituted C 1 -C 6 hydrocarbon group or one or more hydrocarbon groups selected from C 1 -C 6 , a hydroxyl group or a halogen. Substituent substituted C 1 -C 6 hydrocarbyl group.
• R 1 , R 2 , and R 3 are each independently selected from a hydrogen atom, an unsubstituted C 1 -C 6 linear or branched alkyl group, and an unsubstituted C 2 -C 4 linear chain. Or a branched alkenyl group.
• R 1 , R 2 , R 3 are each independently selected from a hydrogen atom, an unsubstituted C 1 -C 4 linear or branched alkyl group.
• R 2 and R 3 together with the co-bonded C atoms form a saturated or unsaturated 3-7 membered ring.
• R 2 and R 3 together with the co-bonded C atoms form a saturated 3-7 membered ring.
• R 4 and R 5 are each independently hydrogen, fluorine or chlorine, and at least one of R 4 and R 5 is fluorine or chlorine.
• R 4 and R 5 are each independently hydrogen or fluorine, and at least one of R 4 and R 5 is fluorine.
• R 4 is hydrogen or fluorine and R 5 is fluorine.
• R 6 is selected from a hydrogen atom or a C 1 -C 6 alkyl group.
• W and Y are each independently selected from C or N, but W and Y cannot be C at the same time.
• R 10 , R 11 , R 12 and R 13 are each independently selected from a hydrogen atom, a C 1 -C 6 alkyl group, a C 3 -C 6 cycloalkyl group, a C 1 -C 6 hydroxyalkyl group.
• R 10 , R 11 , R 12 and R 13 are each independently selected from a hydrogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 hydroxyalkyl group, a C 1 -C 6 haloalkyl group.
• a C 1 -C 6 alkoxy group or -NR 8 R 9 , R 8 and R 9 are each independently selected from a hydrogen atom and a C 1 -C 4 alkyl group.
• R 7 is selected from the group consisting of the following substituents:
• R 14 and R 15 are each independently selected from a hydrogen atom, a C 1 -C 6 alkyl group, a C 3 -C 6 cycloalkyl group, a C 1 -C 6 haloalkyl group, a C 1 -C 6 hydroxyalkyl group.
• R 16 is selected from a hydrogen atom, a C 3 -C 6 cycloalkyl group, a C 1 -C 6 haloalkyl group, a C 1 -C 6 hydroxyalkyl group, C A- C 6 alkoxy group, hydroxyl group or -NR 8 R 9 , R 8 and R 9 are each independently selected from a hydrogen atom and a C 1 -C 4 alkyl group.
• R 14 and R 15 are each independently selected from a hydrogen atom, a C 1 -C 6 alkyl group, a C 3 -C 6 cycloalkyl group, a C 1 -C 6 hydroxyalkyl group
• R 16 is selected from the group consisting of a hydrogen atom, a C 1 -C 6 alkyl group, a C 3 -C 6 cycloalkyl group, a C 1 -C 6 hydroxyalkyl group or -NR 8 R 9
• R 8 and R 9 are each independently selected from a hydrogen atom.
• an alkyl group of C 1 -C 4 is an alkyl group of C 1 -C 4 .
• R 6 and R 7 together with the C atom to which they are attached form a 6-membered heterocyclic ring containing one or more selected from N, O or S.
• R 6 and R 7 together with the C atom to which they are attached form a 6-membered heterocyclic ring containing one N.
• R 6 and R 7 together with the C atom to which they are attached form the following chemical structure:
• R 17 is selected from a hydroxyl group or a C 1 -C 3 alkoxy group; further preferably a hydroxyl group.
• the present invention also provides compounds of the formula II, III, IV or V or the respective tautomers, meso, racemates, enantiomers, diastereomers a compound of a deuterated compound, a prodrug or a mixture thereof, or a compound of the formula II, III, IV or V, a respective tautomer, a mesomer, a racemate, an enantiomer, a pharmaceutically acceptable salt or solvate of a diastereomer, a deuterated compound, a prodrug or a mixture thereof,
• Z, W, Y, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 10 , R 11 and R 17 are as defined above, and the ring A is a saturated 3-7 membered ring.
• the A ring is a saturated 3-6 membered ring.
• the present invention provides a compound of the formula VIII or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, a deuterated compound, a prodrug or In the form of a mixture, or a compound of the formula VIII or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, a deuterated compound, a prodrug or a mixture thereof Pharmaceutically acceptable salt or solvate,
• R 20 , R 21 , R 22 are each independently selected from a C 1 -C 4 alkyl group, or R 20 is a C 1 -C 4 alkyl group, and R 21 and R 22 form a 5 with the C atom to which they are attached a -6 membered saturated ring;
• R 23 is selected from hydrogen or fluorine;
• n 0 or 1;
• R 24 is selected from hydrogen, C 1 -C 4 alkyl or C 1 -C 4 hydroxyalkyl;
• Q is C or N .
• the present invention provides a compound having the structure or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, a deuterated compound, and the like Or a mixture thereof, or the compound, its tautomer, meso, racemate, enantiomer, diastereomer, deuterated compound, prodrug or mixture thereof
• Pharmaceutically acceptable salt or solvate :
• the compounds described herein also include all of the above compounds isotopically labeled.
• the invention provides a compound of formula VI, or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a compound of the formula VI, a tautomer, a mesophile, a racemate, an enantiomer, a pharmaceutically acceptable salt or solvate of a diastereomer,
• R 1 , R 2 , R 3 , R 4 and R 5 are as defined above, and X is a leaving group or an amino group.
• X is a halogen or an amino group, more preferably a fluorine, bromine, chlorine or amino group.
• the present invention provides a process for the preparation of a compound of formula I, which comprises a compound of formula VI and a compound of formula VII, in a solvent, by palladium catalyzed coupling reaction to give a compound of formula I,
• R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined above, and X and M are each independently a leaving group or an amino group, and only one of X and M may be Must have one for the amino group;
• the leaving group is a halogen
• the leaving group is fluorine, bromine or chlorine.
• the above preparation method may further include a deprotection group.
• the above preparation method may further comprise product separation and purification, and the separation and/or purification may be carried out by a method generally employed in organic synthesis, such as filtration, extraction, washing, concentration, chromatography, and the like.
• the invention provides compounds of structural formula IV and VIII or their respective tautomers, meso, racemates, enantiomers, diastereomers, deuterated compounds, a prodrug or a mixture thereof, or a compound of the formula IV and VIII or a respective tautomer, mesogen, racemate, enantiomer, diastereomer thereof, hydrazine
• a pharmaceutically acceptable salt or solvate of a compound, prodrug or mixture thereof for the preparation of a pharmaceutical preparation for the treatment of a cell proliferative disorder.
• the pharmaceutical preparation comprises a pharmaceutically acceptable excipient.
• the cell proliferative disorder refers to a cancer of a mammal or a human, more preferably a cancer of a human, including a malignant solid tumor and a malignant non-solid tumor, including but not limited to breast cancer, lung cancer, prostate cancer. , leukemia, brain cancer, stomach cancer, glioma, etc.
• the cell proliferative disorder may also refer to AIDS, atherosclerosis, and restenosis after stent implantation.
• the above use refers to the compounds of the formulae IV and VIII or their respective tautomers, meso, racemates, enantiomers, diastereomers, deuterated a compound, a prodrug or a mixture thereof, or a compound of the formula IV and VIII or a respective tautomer, mesogen, racemate, enantiomer or diastereomer thereof
• a pharmaceutically acceptable salt or solvate of a deuterated compound, prodrug or mixture thereof as the sole active ingredient or in combination with other biologically active substances for the preparation of a pharmaceutical preparation for the treatment of a cell proliferative disorder.
• Such other biologically active substances include, but are not limited to, anticancer agents, immunosuppressive agents, antiviral agents, and the like.
• the anticancer agent is selected from the group consisting of alkylating agents (such as cyclophosphamide, ifosfamide, thiotepa, semustine, nitrogen mustard, busulfan, chlorambucil, phenylalanine mustard) , nicardine mustard, nitrogen, carmustine, lomustine, hexamethylene melamine, dibromomannitol, temozolomide, etc.), antimetabolite antineoplastic agents (cytarabine, fluorouracil, methotrexate, Hydroxyurea, tegafur, formazan, guanidine, etc.), platinum complexing agents (such as cisplatin, carboplatin, oxaliplatin, etc.), antibiotic antineoplastic agents (actinomycin D, mitogen , doxorubicin, ping
• the present invention provides a combination for treating a cell proliferative disorder, the combination comprising a compound selected from Structural Formula IV, VIII or a respective tautomer, mesogen, and external Racemates, enantiomers, diastereomers, deuterated compounds, prodrugs or mixtures thereof, compounds of structural formula IV, VIII or their respective tautomers, meso, external One or more of a pharmaceutically acceptable salt or solvate in the form of a racemate, enantiomer, diastereomer, deuterated compound, prodrug or mixture thereof.
• the pharmaceutical product further comprises a pharmaceutically acceptable excipient. and / or
• the combination product is a kit.
• the present invention provides a method of treating a cell proliferative disorder, comprising administering an effective dose of a compound of the present invention or a combination thereof to a patient having the cell proliferative disorder by oral or parenteral route. product.
• the above method for treating a cell proliferative disorder comprises administering to the patient an effective amount of a compound of the present invention and the other biologically active substance by an oral or parenteral route.
• Such other biologically active substances include, but are not limited to, anticancer agents, immunosuppressive agents, antiviral agents, and the like.
• the anticancer agent is selected from the group consisting of alkylating agents (such as cyclophosphamide, ifosfamide, thiotepa, semustine, nitrogen mustard, busulfan, chlorambucil, phenylalanine) Nitrogen mustard, nicardine, nitrogen, carmustine, lomustine, hexamethylene melamine, dibromomannitol, temozolomide, etc., antimetabolite antineoplastic agents (cytarabine, fluorouracil, methotrexate) Antimony, hydroxyurea, tegafur, formazan, guanidine, etc.), platinum complexing agents (such as cisplatin, carboplatin, oxaliplatin, etc.), antibiotic antineoplastic agents (actinomycin D, silk Mitomycin, doxorubicin, pingyangmycin, epirubicin, pirarubicin, daunorubicin, bleomycin, etc.,
• the oral or parenteral route can be delivered to the patient by oral, injection, patch, spray, and other known one or more.
• the effective amount can include an amount effective to treat, reduce, alleviate, alleviate, eliminate, or condition one or more symptoms, the condition seeking to be treated, or alternatively, the condition seeking to be avoided, or In addition A clinically identifiable favorable change occurs in the condition or its effect.
• the present invention provides a compound for treating a cell proliferative disorder or a respective tautomer, meso, racemate, enantiomer, diastereomer thereof , deuterated compounds, prodrugs or mixtures thereof, or the compounds or their respective tautomers, meso, racemates, enantiomers, diastereomers, a pharmaceutically acceptable salt or solvate in the form of a deuterated compound, prodrug or mixture thereof, the structural formula of said compound being selected from one or more of Structural Formulas IV and VIII;
• the cell proliferative disorder refers to a cancer of a mammal or a human, more preferably a cancer of a human, including a malignant solid tumor and a malignant non-solid tumor, including but not limited to breast cancer, lung cancer, prostate cancer. , leukemia, brain cancer, glioma and stomach cancer. and / or
• the cell proliferative disorder is selected from one or more of AIDS, atherosclerosis, and restenosis after vascular stent implantation.
• C 1 -C 6 alkyl group means a C 1 -C 6 linear or branched alkyl group unless otherwise specified;
• C 1 -C 4 alkyl group means It is a linear or branched alkyl group of C 1 -C 4 , preferably a methyl group, an ethyl group, a propyl group or an isopropyl group.
• C 1 -C 6 alkoxy group means a C 1 -C 6 linear or branched alkoxy group, preferably a C 1 -C 4 linear or branched alkoxy group, further preferably It is a methoxy group, an ethoxy group, a propoxy group or a 2-methylethoxy group.
• C 3 -C 6 cycloalkyl group means an unsubstituted or C 1 -C 4 alkyl group, a C 1 -C 4 alkoxy-substituted C 3 -C 6 cycloalkyl group, preferably not Substituted or C 1 -C 4 alkyl, C 1 -C 4 alkoxy-substituted C 3 -C 6 cycloalkyl, further preferably cyclopropane, cyclobutane, methylcyclopropane, cyclopentane or ring Hexane.
• halogen refers to bromine, chlorine or fluorine.
• C 1 -C 6 haloalkyl refers to a bromine-substituted, chloro- or fluoro-substituted C 1 -C 6 straight or branched alkyl group, preferably a chloro- or fluoro-substituted C 1 -C 4 straight a chain or branched alkyl group, further preferably a monofluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a monochloromethyl group, a dichloromethyl group, a trichloromethyl group, a 1-fluoroethyl group Base, 1-chloropropyl, 1-chloroethyl, 1-chloropropyl.
• CDKs inhibitors are primarily related to inhibition of CDK1 and other protein kinases, such as the threonine/serine kinase Pim-1 encoded by the same-named proto-oncogene. Therefore, as a CDKs inhibitor-like compound, it is expected that the difference in the effects on CDK4/CDK6 and CDK1 and other kinases is more remarkable, that is, selective inhibition of CDK4/CDK6.
• the compounds provided by the present invention are superior in activity or comparable to the candidate drug LY2835219 currently in Phase III clinical trials, and some compounds exhibit better kinase selectivity.
• the preferred compound (prepared in Example 17) has good oral absorption and good blood brain distribution. The above results indicate that the compounds of the present invention are promising to be developed into new drugs for treating cell proliferation-related diseases, particularly malignant tumors, particularly brain cancer.
• the compound of the formula VI of the present invention is a key intermediate for the synthesis of a compound of the formula I, which is reacted with a compound of the formula VII in a solvent by palladium catalyzed coupling to give a compound of the formula I.
• R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined above, and X is a leaving group or an amino group.
• R 1 , R 2 , R 3 are each independently selected from a hydrogen atom, an unsubstituted C 1 -C 6 hydrocarbon group or one or more hydrocarbon groups selected from C 1 -C 6 , a hydroxyl group or a halogen. Substituent substituted C 1 -C 6 hydrocarbyl group.
• R 1 , R 2 , R 3 are each independently selected from a hydrogen atom, an unsubstituted C 1 -C 6 straight or branched alkyl group, an unsubstituted C 2 -C 4 linear chain Or a branched alkenyl group.
• R 1 , R 2 and R 3 are each independently selected from a hydrogen atom, an unsubstituted C 1 -C 4 linear or branched alkyl group.
• R 1 is as defined above, and R 2 and R 3 together with the co-bonded C atoms form a saturated or unsaturated 3-7 membered ring; more preferably, R 2 and R 3 Together with the commonly attached C atoms, a saturated 3-7 membered ring is formed.
• R 4 and R 5 are each independently hydrogen or fluorine, and at least one of R 4 and R 5 is fluorine.
• X is preferably a halogen or an amino group, more preferably fluorine, bromine, chlorine or an amino group.
• R 6 is preferably a hydrogen atom or a C 1 -C 4 alkyl group.
• R 7 is preferably a substituent of the following structure:
• R 14 and R 15 are each independently selected from a hydrogen atom, a C 1 -C 4 alkyl group, and a C 1 -C 4 hydroxyalkyl group.
• R 6 and R 7 together with the C atom to which they are attached form the following chemical structure:
• R 17 is selected from a hydroxyl group or a C 1 -C 3 alkoxy group; further preferably a hydroxyl group.
• PE petroleum ether
• Step 1 4-(6-Nitropyridin-3-yl)piperazine-1-carboxy tert-butyl ester
• Step 2 4-(6-Aminopyridin-3-yl)piperazine-1-carboxy tert-butyl ester
• Step 6 4-(6-((5-Fluoro-4-(7-fluoro-2,3,3-trimethyl-3H-indol-5-yl)pyrimidin-2-yl)amino)pyridine-3 Synthesis of 1-piperazine-l-carboxy-tert-butyl ester
• Step 2 4-(6-Aminopyridin-3-yl)piperidin-1-carboxy tert-butyl ester
• the 5-fluoro-4-(7'-fluoro-2'-methylspiro[cyclopentane-1,3'- ⁇ ]-5'-yl)-nitrogen-prepared from the above step was added to the reaction flask.
• Step 4 4-(6-((4-(3,3-Diethyl-7-fluoro-2-methyl-3H-indol-5-yl)-5-fluoropyrimidin-2-yl)amino) Pyridin-3-yl)piperazine-1-carboxytert-butyl ester
• Step 5 4-(3,3-Diethyl-7-fluoro-2-methyl-3H-indol-5-yl)-5-fluoro-N-(5-(piperazin-1-yl)pyridine -2-yl)pyrimidine-2-amino
• Step 6 4-(3,3-Diethyl-7-fluoro-2-methyl-3H-indol-5-yl)-5-fluoro-nitro-(5-(4-methylpiperazine-1 -yl)pyridin-2-yl)pyrimidine-2-amino
• Step 1 1'-Methyl-6-nitro-1',2',3',6'-tetrahydro-3,4'-dipyridine
• Step 4 4-(3-Ethyl-7-fluoro-2,3-dimethyl-3H-indol-5-yl)-nitro-(5-(4-ethylpiperazin-1-yl)pyridine Synthesis of 2-yl)-5-fluoropyrimidine-2-amino
• Example 39 1-(2-((4-(3-ethyl-7-fluoro-2,3-dimethyl-3H-indol-5-yl)-5-fluoropyrimidin-2-yl)amino) )-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)-2-hydroxyacetamide
• Step 2 1-(2-((4-(ethyl-7-fluoro-2,3-dimethyl-3H-indol-5-yl)-5-fluoropyrimidin-2-yl)amino) -7,8-Dihydro-16-naphthyridine-6(5H)-yl)-2-hydroxyacetamide
• Example 40 1-(2-((5-Fluoro-4-(7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indole]-5'-yl)pyrimidine-2) -yl)amino)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-2-hydroxyacetamide
• Step 2 2 -Bromo-5-((1-methylpiperidin-4-yl)oxy)pyridine
• Step 4 Completion of the nitrogen-(5-((1-methylpiperidin-4-yl)oxy)-pyridin-2-yl)-5-fluoro-4-(7' Synthesis of -fluoro-2'-methylspiro[cyclopentane-1,3'-indole]-5'-yl)pyrimidine-2-amino group.
• CDK1, CDK4, CDK6 The inhibitory effect of the compounds of the present invention on CDK (CDK1, CDK4, CDK6) kinase activity in vitro was tested by the following method.
• test compound solution diluted with kinase reaction buffer I to a final concentration of 50 ⁇ M compound solution;
• the inhibition rate of each compound at each concentration point was calculated according to the following formula, and curve fitting was performed by software GraphPad Prism 5 to obtain an IC 50 value.
• CDK1/CDK6, CDK9/CKD6 and Pim-1/CDK6 can reflect the selectivity of the compound for protein kinase. The higher the value, the better the selectivity of the compound for CDK6, indicating the toxicity of the ubiquitin kinase inhibition of the compound. The smaller.
• Human breast cancer cells MDA-MB-231 were purchased from Beijing Xiehe Cell Resource Center, DAPI (5mg/mL, Biyuntian, c1002), 4% paraformaldehyde (Dingguo Bio, AR-0211), black transparent Bottom 96-well plate (PE, 6005182), In Cell Analyzer 2200 (GE Healthcare)
• MDA-MB-231 cells were inoculated into 96-well black clear bottom cell plates at 4000 cells/100 ul/well, respectively, and cultured overnight at 37 °C;
• the inhibition rate of each compound at each concentration point was calculated according to the following formula, and curve fitting was performed by software GraphPad Prism 5 to obtain an IC 50 value.
• the compounds of Examples 12 and 17 had significant proliferation inhibitory activity against the MDA-MB-231 cell line, and the representative compounds of the present invention had higher proliferation inhibitory activity relative to the control compound LY2835219.
• SD rats were used as test animals, and the concentration of the drug in plasma at different times after intravenous administration and intragastric administration of the representative compound was determined by LC/MS/MS method to study the drug of the compound of the present invention in rats. Generational dynamics behavior was evaluated for its pharmacokinetic characteristics.
• Control drug LY2835219 homemade.
• Administration by intragastric administration weigh an appropriate amount of sample, add 0.1% hydroxyethyl cellulose / 0.5% Tween 80 to the final volume, and prepare a 1mg / ml solution;
• Intravenous injection weigh the appropriate amount of sample, add 10% N-methyl-2-pyrrolidone and 90% 18% sulfobutyl- ⁇ -cyclodextrin to the final volume, and prepare a 0.4mg/ml solution for intravenous injection. Dosing.
• Intravenous administration 3 male Sprague-Dawley rats of each test compound were intravenously administered after fasting overnight, at a dose of 2 mg/kg, and the administration volume was 1 ml/kg.
• Blood was taken through the carotid cannula before and after administration at 0.0833, 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours after administration.
• Whole blood EDTA-K2 was anticoagulated, centrifuged to the supernatant, and stored frozen at -20 ° C until sample analysis.
• Plasma sample analysis was performed by LC-MS/MS, and sample pretreatment was performed by protein precipitation method.
• the linear range of sample analysis was 1-2000 ng/ml.
• the minimum limit of quantification was 1 ng/ml.
• ICR mice were used as test animals, and the concentration of the drug in plasma at different times after intragastric administration and intravenous administration of the representative compound of the present invention was measured by LC/MS/MS method to study the pharmacokinetics of the compound of the present invention in mice. Dynamic behavior was evaluated for its pharmacokinetic characteristics.
• Control drug LY2835219 homemade.
• the gavage administration group took blood through the carotid cannula before, and after administration, at 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours.
• Whole blood EDTA-K2 was anticoagulated, centrifuged to the supernatant, and stored frozen at -20 ° C until sample analysis.
• the intravenous administration group took blood through the carotid cannula before and after administration at 0.083 h, 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours.
• Plasma sample treatment was administered intragastrically. Plasma sample analysis was performed by LC-MS/MS, and sample pretreatment was performed by protein precipitation method. The linear range of sample analysis was 1-2000 ng/ml. The minimum limit of quantification was 1 ng/ml.
• CD-1 mice were used as test animals, and the concentration of the drug in plasma and brain tissue at different times after the single administration of the representative compound of the present invention was measured by LC/MS/MS method to study the compound of the present invention. Plasma and brain leakage levels in mice.
• Control drug LY2835219 homemade.
• LY2835219 At 0.25, 1.5, and 6 hours before and after administration, blood was taken through the carotid cannula, and 3 mice were sacrificed. The whole brain was collected and minced and frozen in liquid nitrogen. After 10 hours, the remaining animals were sacrificed, and whole blood was collected by cardiac puncture, the whole brain was collected and minced and frozen in liquid nitrogen.
• Example 17 At 2, 4, and 24 hours before and after administration, blood was taken through the carotid cannula, and 3 mice were sacrificed, and the whole brain was collected and chopped and frozen in liquid nitrogen; Forty-eight hours after the drug, the remaining animals were sacrificed, and whole blood was collected by cardiac puncture, the whole brain was collected and minced and frozen in liquid nitrogen.
• Whole blood sample treatment The collected whole blood EDTA-K2 was anticoagulated, centrifuged to remove the supernatant, and stored frozen at -20 ° C until the sample was analyzed by LC-MS/MS.
• the sample analysis has a linear range of 1-2000 ng/ml.
• the minimum limit of quantitation is 1 ng/ml.
• the representative compound of the present invention (prepared in Example 17) has a better blood brain distribution, a higher AUC 0-last ratio (brain/plasma), and a higher C max ratio than the compound LY2835219. (brain / plasma), T max and T max brain and plasma are equal, indicating that the drug has a similar PK behavior in the brain and plasma. It is suggested that the compound of the present invention can cross the blood-brain barrier to inhibit the growth of brain tumors (brain cancer) and treat brain cancer.
• Human glioma cell line U87MG was purchased from Shanghai University of Chinese Academy of Sciences cell bank, DAPI (5mg/mL, Biyuntian, c1002), 4% paraformaldehyde (Dingguo Bio, AR-0211), black transparent bottom 96 holes Plate (PE, 6005182), In Cell Analyzer 2200 (GE Healthcare).
• the inhibition rate of each compound at each concentration point was calculated according to the following formula, and curve fitting was performed by software GraphPad Prism 5 to obtain an IC 50 value.
• cytological activity measurement results of LY2835219 and the compound of Example 17 disclosed in WO2010075074 are shown by IC 50 , and the specific results are shown in Table 11.
• the compound of Example 17 had significant proliferation inhibitory activity against the U87MG cell line, and the representative compound of the present invention had higher proliferation inhibitory activity than the control compound LY2835219.
• Control drug LY2835219 homemade.
• Temozolomide was purchased from selleck.
• Compound 17 was weighed and a solvent of 0.1% hydroxyethylcellulose/0.5% Tween 80 was added to 0.3125 mg/ml.
• temozolomide sample was weighed and a solvent of 1% CMC-Na + 0.25% Tween 80 was added to 0.3 mg/ml.
• mice Male BALB/c nude mice were anesthetized by intraperitoneal injection of sodium pentobarbital at a dose of 80 mg/kg. To reduce the pain, buprenorphine was administered subcutaneously to the animals 30 minutes before surgery and 6 hours after surgery at a dose of 0.1 mg/kg. Animals were observed after anesthesia until all animals were awakened.
• the anesthetized animals were properly fixed, the animal's head skin was sterilized with 70% ethanol, and a 10 mm long incision was made between the midline to the right and the forehead to interaural line.
• 3 ⁇ 10 5 U87-luc cells (3 ⁇ l, 4:1 mixed with PBS and Matrigel) were inoculated at 2 mm on the right side of the front of each animal and 1 mm on the anterior side of the coronal suture.
• the incision was sutured with No. 6 thread and sterilized with polyvinylpyrrolidone. Animals are kept warm until they recover.
• tumor-bearing animals Six days after tumor cell transplantation, tumor-bearing animals were grouped by stratified randomization according to the fluorescence signal intensity values, and the average bioluminescence reached 2.812E+07 photosns/sec when administered in groups. Different groups of animals were started at different doses for a total of 35 days.
• Representative Compound 17 of the present invention was able to significantly prolong the median survival of animals in a U87-luc orthotopic brain xenograft model and was dose dependent. In a combination study with temozolomide, combined administration further extended the median survival of the animals compared to temozolomide alone.
• the present invention provides a series of novel compounds having selective CDK4/6 kinase inhibitory activity which is superior to or comparable to the candidate drug LY2835219 currently in Phase III clinical trials, with some compounds exhibiting better selectivity.
• the preferred compounds have good oral absorption and good blood-brain distribution, and have significant pharmacological effects on the U87-luc in situ brain xenograft model, indicating that the compounds of the present invention are promising to be developed into new therapeutic cells for cell proliferation, especially Medications for malignant tumors (especially brain cancer) provide new options for clinicians and patients.
• the invention also provides a kit comprising a compound of the formula IV, VIII or its respective tautomer, meso, racemate, enantiomer, diastereomer Isomers, deuterated compounds, prodrugs or mixtures thereof, or compounds of structural formula IV and VIII or their respective tautomers, meso, racemates, enantiomers, non-pairs
• kit may also include instructions for use.
• the present invention also relates to a combination product for treating a cell proliferative disorder comprising a pharmaceutically acceptable carrier, and a compound of the formula IV, VIII or their respective tautomers, meso, Racemates, enantiomers, diastereomers, deuterated compounds, prodrugs or mixtures thereof, or compounds of structural formula IV, VIII or their respective tautomers, meso forms A pharmaceutically acceptable salt or solvate in the form of a racemate, enantiomer, diastereomer, deuterated compound, prodrug or mixture thereof.
• Acceptable salts or solvates may be in an effective amount or in a therapeutically effective amount in the pharmaceutical composition.
• an effective amount refers to an amount that is functional or active to a human and/or animal and that is acceptable to humans and/or animals.
• a "pharmaceutically acceptable” ingredient is suitable for use in humans and/or animals (such as mammals or birds) without Poor side effects (such as toxicity, irritation, and allergies), that is, substances with a reasonable benefit/risk ratio.
• “Pharmaceutically acceptable carrier” means a carrier for administration, and may include various excipients, diluents and the like. Such carriers may include, but are not limited to, water, physiological saline, liposomes, lipids, proteins, protein-antibody conjugates, peptides, cellulose, nanogels, buffers, dextrose, glycerol, ethanol, and Its combination. The choice of carrier should generally be matched to the mode of administration, as is well known to those of ordinary skill in the art.
• the effective amount of the present invention may vary depending on the mode of administration and the severity of the disease to be treated and the like.
• the preferred effective amount can be determined by one of ordinary skill in the art based on various factors (e.g., by clinical trials).
• the factors include, but are not limited to, the pharmacokinetic parameters of the active ingredient, such as bioavailability, metabolism, half-life, etc.; the severity of the disease to be treated by the patient, the weight of the patient, the immune status of the patient, The route of medicine, etc.
• the invention also provides a method of treating a cell proliferative disorder, the method comprising administering to the patient an effective amount of a compound of structural formula IV, VIII or a respective tautomer thereof, by oral or parenteral route, Racemates, racemates, enantiomers, diastereomers, deuterated compounds, prodrugs or mixtures thereof, or compounds of structural formula IV and VIII or their respective tautomers, A pharmaceutically acceptable salt or solvate in the form of a meso form, a racemate, an enantiomer, a diastereomer, a deuterated compound, a prodrug or a mixture thereof, or a pharmaceutical composition as described above.
• the oral or parenteral route may be through the gastrointestinal tract, nasal cavity, trachea, lung, non-lesional vein or epidermis, intradermal, subcutaneous, intracardiac, intramuscular, bone marrow, abdominal cavity, epidural, oral, sublingual. , eye, rectum, vagina, urethra, ear canal and other routes of administration.
• Preferred modes of administration or modes of administration include oral, respiratory, injection, transdermal, mucosal or intraluminal administration.
• the oral administration includes swallowing, incorporation, and the like.
• the method of administration of the respiratory tract includes an inhalation method such as ultrasonic atomization inhalation, oxygen atomization inhalation, hand pressure atomization inhalation, and the like.
• the administration mode of injection includes arterial injection, intravenous injection, intramuscular injection, intracardiac injection, intradermal injection, and the like.
• the transdermal or transdermal administration methods include iontophoresis, electroporation, and the like.
• the mucosal administration forms include nasal mucosa administration, oral mucosal administration, ocular mucosal administration, rectal mucosal administration, uterine administration, and vaginal mucosal administration.
• the method of administration of the lumen includes rectal administration, vaginal administration, urethral administration, nasal administration, ear canal administration, and the like.

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