WO2018045956A1 - Composé de benzimidazole inhibiteur de kinase, son procédé de préparation et son application - Google Patents

Composé de benzimidazole inhibiteur de kinase, son procédé de préparation et son application Download PDF

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WO2018045956A1
WO2018045956A1 PCT/CN2017/100678 CN2017100678W WO2018045956A1 WO 2018045956 A1 WO2018045956 A1 WO 2018045956A1 CN 2017100678 W CN2017100678 W CN 2017100678W WO 2018045956 A1 WO2018045956 A1 WO 2018045956A1
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group
cancer
amino
cycloalkyl
fluoro
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PCT/CN2017/100678
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English (en)
Chinese (zh)
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刘世强
周远峰
吴雪松
包如迪
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江苏豪森药业集团有限公司
上海翰森生物医药科技有限公司
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Priority claimed from CN201710157847.4A external-priority patent/CN107793399A/zh
Application filed by 江苏豪森药业集团有限公司, 上海翰森生物医药科技有限公司 filed Critical 江苏豪森药业集团有限公司
Priority to CN201780050147.3A priority Critical patent/CN109963842B/zh
Priority to CN202011082470.9A priority patent/CN112225724B/zh
Publication of WO2018045956A1 publication Critical patent/WO2018045956A1/fr

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    • 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
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • 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
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

  • the invention belongs to the field of drug development, and particularly relates to a benzimidazole compound kinase inhibitor and a preparation method and application thereof.
  • Cyclin-dependent kinase is a type of serine (Ser)/threonine (Thr) kinase. This family contains 13 members, which are divided into A-L by cyclin. Different CDKs and cyclins form CDK-cyclin complexes, which catalyze the phosphorylation of different substrates through CDK kinase activity, initiate DNA synthesis, promote the promotion and transformation of different phases of the cell cycle, regulate gene transcription, and participate in Cell growth, proliferation, dormancy or entry into apoptosis. Therefore, CDKs have important functions in the regulation of proliferation and death of all cells, including tumor cells and normal cells.
  • CDK4/6-Cyclin D complex plays an important role in the transformation of cells from G1 to S phase.
  • CDK4/6 binds to cyclin D and phosphorylates a range of substrates including Retinoblastoma protein (Rb).
  • Rb phosphorylates and releases the protein bound to and inhibited by it, mainly the transcription factor E2F, etc.
  • E2F activates and transcribes some genes necessary for S phase, and promotes the transformation of G1/S cells.
  • CDK4/6-specific activation is closely related to the proliferation of some tumors, and the abnormalities of the cyclinD–CDK4/6–INK4–Rb pathway are ubiquitous.
  • the performance is as follows: (1) p16INK4a gene deletion, point mutation, or DNA methylation results in inactivation of p16INK4a; (2) CDK4 gene amplification or point mutation (R24C), loss of binding ability to p16INK4a; (3) cyclinD1 due to gene weight Excretion or gene amplification is overexpressed.
  • the change of this pathway accelerates the G1 phase process, which accelerates the proliferation of tumor cells and gains a survival advantage. Therefore, its intervention has become a therapeutic strategy, and CDK4/6 has thus become one of the targets for anti-tumor.
  • Pfizer's Palbociclib (PD0332991) is the first FDA-approved CDK4/6 small molecule inhibitor for breast cancer treatment.
  • Novartis ribociclib (LEE011) was approved in March 2017 for treatment with aromatase inhibitors.
  • Some compounds, such as Lilly Abemaciclib (LY2835219), are in clinical research and both perform well.
  • selective CDK4/6 inhibitors have multiple tumors in ovarian cancer, non-small cell lung cancer, B-cell lymphoma, liver cancer, glioma, colon cancer, multiple myeloma, and the like. Very good anti-tumor activity. Therefore, the development of new CDK4/6 small molecule inhibitors has become a new and effective method for treating these tumors, inspiring generations of scientists to make continuous efforts.
  • Inhibitors of the disclosed selective inhibition of CDK4/6 include WO2004065378, WO2012101013, WO2016192630, WO2016015604 and WO2016015604, and the like.
  • CDK4/6 inhibitor has good application prospect in cancer or tumor treatment as a medicine, the invention A novel structure of highly selective CDK4/6 inhibitor will be provided, and compounds having such a structure are found to exhibit excellent effects and effects.
  • An object of the present invention is to provide a compound represented by the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound represented by the formula (I) has the following structure:
  • L is a bond, -C(O)- or -C(O)NH-;
  • Ring A is a heterocyclic group wherein the heterocyclic group is selected from the group consisting of a monocyclic heterocyclic group, a spirocyclic heterocyclic group, a fused ring heterocyclic group, and a bridged heterocyclic group;
  • R is selected from a hydrogen atom, a halogen atom or a halogen
  • R 1 is selected from the group consisting of a halogen atom, an alkyl group, a halogenated alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, a cycloalkyl group, a heterocyclic group, an aryl group, and a hetero group.
  • aryl - (CH 2) n OR 3, - (CH 2) n SR 3, - (CH 2) n C (O) R 3, - (CH 2) n C (O) OR 3, - (CH 2 ) n S(O) m R 3 , -(CH 2 ) n NR 4 R 5 , -(CH 2 ) n C(O)NR 4 R 5 , -(CH 2 ) n C(O)NHR 4 , -(CH 2 ) n NR 4 C(O)R 5 and -(CH 2 ) n NR 4 S(O) m R 5 , wherein the alkyl group, haloalkyl group, cycloalkyl group, heterocyclic group, aryl group
  • the base and heteroaryl are optionally further selected from the group consisting of a halogen atom, an alkyl group, a halogenated alkyl group, a halogen, an amino group, a nitro group,
  • Base aryl, heteroaryl, -(CH 2 ) n OR 6 , -SR 6 , -(CH 2 ) n C(O)R 6 , -(CH 2 ) n C(O)OR 6 , -( CH 2 ) n S(O) m R 6 , -(CH 2 ) n NR 7 R 8 , -(CH 2 ) n C(O)NR 7 R 8 , -(CH 2 ) n C(O)NHR 7 Substituting one or more substituents of -(CH 2 ) n NR 7 C(O)R 8 and -(CH 2 ) n NR 7 S(O) m R 8 ;
  • R 2 is the same or different and is each independently selected from the group consisting of a hydrogen atom, a halogen atom, an alkyl group, a halogenated alkyl group, a halogenated alkyl group, an alkoxy group, an aminoalkoxy group, a halogenated alkoxy group, a halogen, an amino group, an oxo group, Nitro, hydroxy, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) n OR 3 , -(CH 2 ) n SR 3 , -(CH 2 ) n C(O R 3 , —(CH 2 ) n C(O)OR 3 , —(CH 2 ) n S(O) m R 3 , —(CH 2 ) n NR 4 R 5 , —(CH 2 ) n C( O) NR 4 R 5 , -(CH 2 ) n
  • R 3 is selected from the group consisting of a hydrogen atom, a halogen atom, an alkyl group, a halogenated alkyl group, a halogenated alkyl group, a hydroxyl group, an amino group, an alkoxy group, a halogenated alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;
  • the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected from the group consisting of a halogen atom, an alkyl group, a halogen, an amino group, a nitro group, a cyano group, a hydroxyl group, a hydroxyalkyl group, Alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, -(CH 2 ) n OR 6 , -(CH 2 ) n
  • R 4 and R 5 are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen atom, an alkyl group, a halogenated alkyl group, a halogenated alkyl group, a hydroxyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group.
  • R 6 is selected from the group consisting of a hydrogen atom, a halogen atom, an alkyl group, a halogenated alkyl group, a halogenated alkyl group, a hydroxyl group, an amino group, an alkoxy group, a halogenated alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;
  • the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected from the group consisting of a halogen atom, an alkyl group, a halogen, an amino group, a nitro group, a cyano group, a hydroxyl group, a hydroxyalkyl group, Substituted by one or more substituents of alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R 7 and R 8 are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen atom, an alkyl group, a halogenated alkyl group, a halogenated alkyl group, a hydroxyl group, an amino group, an ester group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, wherein said alkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are further optionally selected from the group consisting of a halogen atom, an alkyl group, a halogen group, a hydroxyl group, an amino group, a nitro group, a cyano group, and an ester group. Substituted by one or more substituents of a group, an alkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an ary
  • x is an integer of 0, 1, 2, 3, 4 or 5;
  • n is an integer of 0, 1, or 2;
  • n is an integer of 0, 1, 2, 3, 4 or 5.
  • the compound of the formula (I) is a compound represented by the formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
  • B is selected from a 3-8 membered monocyclic heterocyclic group, a 6-12 membered spirocyclic heterocyclic group, a 6-12 membered fused ring heterocyclic group or a 6-12 membered bridged heterocyclic group; preferably a 3-8 membered monocyclic ring. Heterocyclic group;
  • L is a bond or -C(O)-
  • R, R 1 , R 2 and x are as defined in claim (II).
  • the compound of the formula (II) is a compound represented by the formula (III), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
  • Rings B, R, R 1 , R 2 and x are as defined in the formula (II).
  • the compound of the formula (II) is a compound represented by the formula (IV), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
  • Rings B, R, R 1 , R 2 and x are as defined in the formula (II).
  • M is CR 2 R 2 , NR 2 or O;
  • R is a hydrogen atom or a halogen, wherein the halogen is preferably a fluorine atom;
  • R 1 is alkyl or halogen, wherein the alkyl group is a C 1-6 alkyl group, preferably a C 1-3 alkyl group;
  • R 2 is the same or different and is each independently selected from a hydrogen atom, a C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 1-6 alkoxy group, a C 1-6 amino alkoxy group, a C 1-6 Haloalkoxy, halogen, amino, oxo, nitro, hydroxy, cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, -(CH 2 ) n OR 3 and -(CH 2 ) n NR 4 R 5 , wherein the C 1-6 alkyl group, the C 1-6 haloalkyl group, the C 1-6 amino alkoxy group, the C 3-8 cycloalkyl group and the 3-8 membered heterocyclic group are optional Further selected from C 1-6 alkyl, C 1-6 haloalkyl, halogen, amino, cyano, hydroxy, alkenyl, alkynyl, C 1-6 alkoxy, C 1-6
  • the two R 2 are bonded to each other to form a 3-10 membered cycloalkyl or heterocyclic group, wherein the 3-8 membered cycloalkyl or heterocyclic group is optionally further substituted by one or more C 1 - 6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 amino alkoxy, C 1-6 haloalkoxy, halogen, amino, oxo, hydroxy, cyano and C a substituent of a 3-8 cycloalkyl group; preferably a 5-8 membered cycloalkyl group or a heterocyclic group;
  • Y is an integer of 0, 1, 2 or 3;
  • R 3 to R 8 , n and x are as defined in the formula (I).
  • M is selected from CHR 2 or NR 2 ;
  • R 2 is selected from the group consisting of a hydrogen atom, a C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 1-6 alkoxy group, a C 1-6 amino alkoxy group, a C 1-6 haloalkoxy group, a halogen, an amino group, Oxo, hydroxy, cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, -(CH 2 ) n OR 3 and -(CH 2 ) n NR 4 R 5 , wherein said C The 1-6 alkyl group, the C 1-6 haloalkyl group, the C 1-6 amino alkoxy group, the C 3-8 cycloalkyl group and the 3-8 membered heterocyclic group are optionally further selected from a C 1-6 alkyl group, C 1-6 haloalkyl, halogen, amino, cyano, hydroxy, C 2-6 alkenyl, C 2-6 alkynyl, C
  • R, R 1 , R 3 to R 8 , x, n and y are as defined in the formula (V).
  • R 4 and R 5 are each independently selected from a hydrogen atom, a C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 3-8 cycloalkyl group, —(CH 2 ) n OR 6 , —(CH 2 ) n C(O)R 6 wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl is optionally further selected from C 1-6 alkyl, halo, hydroxy, amino Substituted with one or more substituents of cyano, C 1-6 alkoxy, C 1-6 hydroxyalkyl and C 1-6 cycloalkyl;
  • R 4 and R 5 form a 3-8 membered heterocyclic group, wherein said 3-8 membered heterocyclic group is further selected from C 1-6 alkyl, -(CH 2 )n-, Substituting one or more substituents of halogen, hydroxy, amino, cyano, C 1-6 alkoxy, C 1-6 hydroxyalkyl and C 1-6 cycloalkyl; preferably R 4 and R 5 are formed
  • the heterocyclic group is 4-6 yuan;
  • R, R 1 and n are as defined in the formula (V).
  • R 1 is selected from the group consisting of C 1-8 alkyl and halogen, wherein The C 1-8 alkyl group, preferably a C 1-6 alkyl group, more preferably a C 1-3 alkyl group; most preferably a methyl group, wherein the halogen is preferably fluorine.
  • R 2 is selected from the group consisting of a hydrogen atom, a C 1-8 alkyl group, C 1-8 haloalkyl, C 1-8 alkoxy, C 3-8 cycloalkyl, C 2-6 alkenyl, halogen, oxo, -(CH 2 ) n NR 4 R 5 and 3-10 a cyclic group wherein the C 1-8 alkyl group, C 1-8 haloalkyl group, C 1-8 alkoxy group, C 3-8 cycloalkyl group and 3-10 membered heterocyclic group are optionally further selected from the group consisting of Substituted by one or more substituents of halogen, hydroxy, cyano, C 1-8 alkyl, -(CH 2 ) n OR 6 and C 1-8 alkoxy; preferably C 1-6 alkyl, C a 1-6 haloalkyl
  • R 4 and R 5 are the same or different and are each independently selected from a hydrogen atom, a C 1-8 alkyl group, a C 1-8 haloalkyl group, a C 3-8 cycloalkyl group, a —(CH 2 ) n C(O)R 6 and a C 1-8 alkoxy group, wherein said C 1-8 alkyl, C 1-8 haloalkyl, C 3-8 cycloalkyl and C 1-8 alkoxy are optionally further selected from the group consisting of halogen, hydroxy, cyano, C 1-8 alkyl, C Substituted with one or more substituents of 3-8 cycloalkyl, -(CH 2 ) n OR 6 and C 1-8 alkoxy; preferably C 1-6 alkyl and C 3-6 cycloalkyl, Wherein the C 1-6 alkyl group and the
  • the compound of the formula (I) is obtained by coupling the compound of the formula (VA) with the compound of the formula (VB), and the compound of the formula (I) is optionally further reacted or further deprotected to give a different compound of the formula (I)
  • the catalytic reagent in the coupling reaction is preferably Pd 2 (dba) 3 and Xantphos reagent;
  • X is a halogen; preferably chlorine
  • Rings A, L, R, R 1 , R 2 and x are as described for the general formula (I). .
  • the present invention also relates to a method of treating a disease preventing and/or treating a CDK4/6 mediated pathological feature comprising administering to a patient a therapeutically effective amount of a compound of the formula (I): a stereoisomer thereof Or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the present invention further relates to a compound represented by the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, which is prepared for the treatment and/or prevention by CDK kinase 4 and/or 6 Use in drugs that mediate cancer or tumor-related diseases.
  • the present invention further relates to a compound represented by the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the preparation of a medicament for treating cancer or a tumor, wherein the cancer or Tumor-associated diseases are selected from brain tumors, lung cancer, liver cancer, stomach cancer, oral cancer, head and neck cancer, intestinal or rectal cancer, colon cancer, kidney cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, squamous cell carcinoma, thyroid cancer.
  • the cancer or Tumor-associated diseases are selected from brain tumors, lung cancer, liver cancer, stomach cancer, oral cancer, head and neck cancer, intestinal or rectal cancer, colon cancer, kidney cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, squamous cell carcinoma, thyroid cancer.
  • bone cancer bone cancer, skin cancer, non-small cell lung cancer, carcinoma in situ, lymphoma, neurofibromatosis, neuroblastoma, mast cell tumor, multiple myeloma, melanoma, glioma, sarcoma or liposarcoma, glue Progesteroma, bladder cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, uterine cancer, cervical cancer, endometrial cancer, Prostate cancer, female genital tract cancer, testicular cancer, gastrointestinal stromal tumor or prostate tumor; preferably from bladder cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, uterine cancer, cervical cancer, endometrial cancer, Prostate cancer, female genital tract cancer, testicular cancer, gastrointestinal stromal tumor or prostate tumor.
  • the present invention further relates to a compound represented by the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the preparation of a method for treating a cancer or a tumor-related disease, which comprises administering a treatment to a patient
  • the breast cancer comprises: a late-stage or metastatic breast cancer that is negative for estrogen receptor-positive and/or human epidermal growth factor receptor 2 negative in postmenopausal women.
  • the present invention further relates to a compound represented by the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, a pharmaceutical composition comprising a therapeutically effective amount of any one of the formulas (I) a compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • alkyl refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group having from 1 to 8 carbon atoms, more preferably from 1 to 6 carbon atoms.
  • the alkyl group is most preferably an alkyl group of 1 to 3 carbon atoms.
  • 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, 1,3 - dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -methylhexyl, 3-methylhexyl, 4-methylhexyl,
  • lower alkyl groups having from 1 to 6 carbon atoms, non-limiting examples including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl Base, 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 Base, 2,3-dimethylbutyl and the like.
  • the alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups independently selected from the group consisting of an alkane Base, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, naphthenic An oxy group, a heterocycloalkoxy group, a cycloalkylthio group, a heterocycloalkylthio group, an oxo group, a carboxyl group or a carboxylate group, and a methyl group, an ethyl group, an isopropyl group, a t-butyl group or a halogenated alkyl group is preferred in the invention.
  • alkylene means that one hydrogen atom of the alkyl group is further substituted, for example, "methylene” refers to -CH 2 -, "ethylene” refers to -(CH 2 ) 2 -, "propylene” Refers to -(CH 2 ) 3 -, "butylene” means -(CH 2 ) 4 - and the like.
  • alkenyl refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or -butenyl and the like.
  • the alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio group.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 8 carbon atoms. One carbon atom, most preferably containing from 3 to 6 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene
  • Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl and cycloheptyl.
  • spirocycloalkyl refers to a polycyclic group that shares a carbon atom (referred to as a spiro atom) between 5 to 20 members of a single ring, which may contain one or more double bonds, but none of the rings have a fully conjugated ⁇ electronic system. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • the spirocycloalkyl group is classified into a monospirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a monospirocycloalkyl group and a bispirocycloalkyl group, depending on the number of common spiro atoms between the rings.
  • spirocycloalkyl groups include:
  • spirocycloalkyl groups in which a monospirocycloalkyl group shares a spiro atom with a heterocycloalkyl group, and non-limiting examples include:
  • fused cycloalkyl refers to 5 to 20 members, and each ring in the system shares an all-carbon polycyclic group of an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated ⁇ -electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • fused cycloalkyl groups include:
  • bridged cycloalkyl refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two carbon atoms which are not directly bonded, which may contain one or more double bonds, but none of the rings have complete Conjugate ⁇ -electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group, preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, and more preferably a bicyclic ring or a tricyclic ring.
  • bridged cycloalkyl groups include:
  • the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring to which the parent structure is attached is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthalene Base, benzocycloheptyl and the like.
  • the cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, an oxo group, a carboxyl group or a carboxylate group.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms wherein one or more ring atoms are selected from nitrogen, oxygen or S(O).
  • the hetero atom of m (where m is an integer of 0 to 2), but does not include the ring moiety of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. It preferably comprises from 3 to 12 ring atoms, wherein from 1 to 4 are heteroatoms; further preferably from 3 to 10 ring atoms; more preferably from 3 to 8 ring atoms; most preferably from 6 to 10 ring atoms.
  • Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidine.
  • Base piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., preferably piperidinyl and
  • Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.
  • spiroheterocyclyl refers to a polycyclic heterocyclic group in which one atom (called a spiro atom) is shared between 5 to 20 members of a single ring, wherein one or more ring atoms are selected from nitrogen, oxygen or S (O). ) m (where m is an integer 0 to 2) heteroatoms, and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system. It is preferably 6 to 14 members, more preferably 6 to 10 members.
  • the spiroheterocyclyl group is classified into a monospiroheterocyclic group, a dispiroheterocyclic group or a polyspirocyclic group according to the number of shared spiro atoms between the ring and the ring, and is preferably a monospiroheterocyclic group and a dispiroheterocyclic group.
  • spiroheterocyclyl groups include:
  • fused heterocyclyl refers to 5 to 20 members, and each ring in the system shares an adjacent pair of atomic polycyclic heterocyclic groups with other rings in the system, and one or more rings may contain one or more Double bond, but none of the rings have a fully conjugated ⁇ -electron system in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), and the remaining rings
  • the atom is carbon. It is preferably 6 to 14 members, more preferably 6 to 10 members.
  • fused heterocyclic groups include:
  • bridge heterocyclyl refers to a polycyclic heterocyclic group of 5 to 14 members, any two rings sharing two atoms which are not directly bonded, which may contain one or more double bonds, but none of the rings have a total ⁇ electron conjugated system in which one or more ring atoms selected from nitrogen, oxygen, or S (O) m (wherein m is an integer of 0 to 2) heteroatoms, the remaining ring atoms being carbon. It is preferably 6 to 14 members, more preferably 6 to 10 members.
  • bridge heterocyclic groups include:
  • the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heterocyclic group, non-limiting examples of which include:
  • the heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, an oxo group, a carboxyl group or a carboxylate group.
  • aryl refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic ring (ie, a ring that shares a pair of adjacent carbon atoms) having a conjugated ⁇ -electron system, preferably 6 to 10 members, such as benzene. Base and naphthyl. More preferred is phenyl.
  • the aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring to which the parent structure is attached is an aryl ring, non-limiting examples of which include:
  • the aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle An alkylthio group, a carboxyl group or a carboxylate group.
  • heteroaryl refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms are selected from the group consisting of oxygen, sulfur and nitrogen.
  • the heteroaryl group is preferably 5 to 10 members, more preferably 5 members or 6 members, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetra An oxazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl or the like, preferably a triazolyl, thienyl, imidazolyl, pyrazolyl or pyrimidinyl, thiazolyl; more preferably a triazolyl, pyrrolyl, Thienyl, thiazolyl and pyrimidinyl.
  • the heteroaryl ring may be fused to
  • the heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, a carboxyl group or a carboxylate group.
  • alkoxy refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above.
  • alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • the alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, a carboxyl group or a carboxylate group.
  • Haloalkyl means an alkyl group substituted by one or more halogens, wherein alkyl is as defined above.
  • Haloalkoxy means an alkoxy group substituted by one or more halogens, wherein alkoxy is as defined above.
  • Hydroalkyl means an alkyl group substituted by a hydroxy group, wherein alkyl is as defined above.
  • Hydrophilicity refers to an -OH group.
  • Halogen means fluoro, chloro, bromo or iodo.
  • Amino means -NH 2 .
  • Niro means -NO 2 .
  • Carboxy refers to -C(O)OH.
  • oxo refers to Such as oxopiperidinyl
  • THF tetrahydrofuran
  • EtOAc means ethyl acetate
  • MeOH refers to methanol
  • DMF N,N-dimethylformamide
  • DIPEA diisopropylethylamine
  • TFA trifluoroacetic acid
  • MeCN means ⁇ .
  • DMA N,N-dimethylacetamide
  • Et 2 O means diethyl ether
  • DCE 1,2 dichloroethane
  • DIPEA N,N-diisopropylethylamine
  • NBS N-bromosuccinimide
  • NIS N-iodosuccinimide
  • Cbz-Cl means benzyl chloroformate
  • Pd 2 (dba) 3 refers to tris(dibenzylideneacetone) dipalladium.
  • Dppf means 1,1'-bisdiphenylphosphinoferrocene.
  • HATU means 2-(7-oxobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate.
  • KHMDS means potassium hexamethyldisilazide
  • LiHMDS refers to lithium bistrimethylsilylamine.
  • MeLi means methyl lithium
  • n-BuLi means n-butyllithium
  • NaBH(OAc) 3 refers to sodium triacetoxyborohydride.
  • X is selected from A, B, or C
  • X is selected from A, B, and C
  • X is A, B, or C
  • X is A, B, and C
  • Stepoisomerization includes three types of geometric isomerism (cis-trans isomerization), optical isomerism, and conformational isomerism.
  • the hydrogen atom of the present invention may be substituted by its isotope ruthenium, and any of the hydrogen atoms in the examples of the present invention may also be substituted by a ruthenium atom.
  • heterocyclic group optionally substituted by an alkyl group means that an alkyl group may be, but not necessarily, present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group.
  • Substituted refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3, hydrogen atoms, independently of each other, substituted by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.
  • “Pharmaceutical composition” means a mixture comprising one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers. Body and excipients. The purpose of the pharmaceutical composition is to promote the administration of the organism, which facilitates the absorption of the active ingredient and thereby exerts biological activity.
  • “Pharmaceutically acceptable salt” refers to a salt of a compound of the invention which is safe and effective for use in a mammal and which possesses the desired biological activity.
  • the structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS).
  • NMR chemical shift ( ⁇ ) is given in parts per million (ppm).
  • NMR was measured using a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3 ).
  • the internal standard was four.
  • Methyl silane (TMS) Methyl silane
  • LC-MS was determined by LC-MS using an Agilent 1200 Infinity Series mass spectrometer.
  • the HPLC was measured using an Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C18 150 x 4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 x 4.6 mm column).
  • the thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.
  • the specification for TLC is 0.15mm ⁇ 0.20mm, and the specification for separation and purification of thin layer chromatography is 0.4mm ⁇ 0.5mm.
  • Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as a carrier.
  • 6-Chloro-2-methylnicotonic acid 0.7 g, 4.1 mmol
  • tert-butyl 1,4-diazo heptane-1-carboxylate 1.0 g, 4.9 mmol
  • TEA 1.2 g , 12.2 mmol
  • reaction solution was (30mL) was diluted with CH 2 Cl 2 after NaHCO 3 solution (30mL), saturated brine (30mL), dried over anhydrous sodium sulfate, and concentrated by column chromatography [eluent: CH 2 Cl 2 ⁇ CH 2 Cl 2 /MeOH (10:1)] product tert-butyl 4-(6-chloro-2-methyl nicotine)-1,4-diazo heptane-1-carboxylate (1.4 g , yield 96%).
  • Second step Preparation of 5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-amine
  • the third step tert-butyl 4-(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole-6-yl)) Preparation of pyrimidin-2-yl)amino)-2-methylnicotinyl)-1,4-diazo heptane-1-carboxylate
  • the second step (1-(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidine-2) Of tert-butyl ester of 2-amino)-2-methylpyridin-3-yl)-2-carbonylpiperidin-4-yl)carbamate
  • the third step (1-(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidine-2) Of tert-butyl (meth)amino-2-methylpyridin-3-yl)-2-carbonylpiperidin-4-yl)(methyl)carbamate
  • Second step Preparation of 5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-amine
  • the third step 1-(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2- Of amino)amino)-2-methylnicotinoylpiperidin-4-one
  • the fourth step (4-(cyclopropylamino)piperidin-1-yl)(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzene) And [d]imidazole-6-yl)pyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone
  • the third step preparation of benzyl 3-(6-chloro-2-methylnicobutyryl)-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate
  • Step 4 Benzyl 3-(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole-6-yl)pyrimidine) Preparation of 2-yl)amino)-2-methylnicotinyl)-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate
  • Step 5 (3,9-diazabicyclo[4.2.1]nonan-3-yl)(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-) Preparation of methyl-1H-benzo[d]imidazol-6-ylpyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone
  • Step 6 (6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl) Preparation of amino)-2-methylpyridin-3-yl)(9-methyl-3,9-diazabicyclo[4.2.1]nonan-3-yl)methanone
  • reaction solution was concentrated and purified by reverse-phase column chromatography to afford compound (6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole-6) -yl)pyrimidin-2-yl)amino)-2-methylpyridin-3-yl)(9-methyl-3,9-diazabicyclo[4.2.1]nonan-3-yl)- Ketone (56 mg, yield 50%).
  • Inhibition rate (%) 100 - (signal value - min) / (max - min) * 100.
  • the compounds of the examples of the present invention have a strong inhibitory activity against CDK kinase activity, and particularly have a good inhibitory activity and selectivity for CDK 4 and/or 6 kinase activity.
  • the compound's proliferative activity against colon cancer tumor cell colo205 was tested by the following method.
  • This method was used to determine the inhibitory effect of the compound of the present invention on the proliferative activity of colon cancer tumor cell colo205.
  • the method of the present study the inhibition of a test compound on the colo205 CellTiter-Glo cell proliferation, and to obtain the compound inhibited cell proliferation half maximal inhibitory concentration IC 50 activity.
  • the plate reader measures the chemiluminescence signal value of each plate.
  • the compound of the present invention was assayed for the proliferative activity of colon cancer tumor cell colo205, and the measured IC 50 values are shown in Table 2.
  • the compound of the present invention has a strong inhibitory effect on the proliferation activity of colon cancer tumor cell colo205.
  • Example Compound 3 10 g was weighed, dissolved in 1000 mL of purified water, and 2.5 mL of Tween 80 and 0.5 mL of antifoaming agent were added. Mix well to form a clear solution. 6.1 mg of Example Compound 3, 6.9 mg of Example Compound 34, 5.8 mg of Example Compound 63 were weighed and dissolved in the solution, shaken and sonicated for 15 minutes to give a colorless clear solution at a concentration of 0.5 mg/mL.
  • HEC hydroxyethyl cellulose
  • 0.2 mL of jugular vein blood was taken before administration and 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 24.0 h after administration.
  • plasma was separated by centrifugation at 6000 rpm for 6 min at 4 ° C, and stored at -80 ° C; 4 h after administration.
  • Example 34 Example 34 and Example 63 of the present invention achieved high exposure in rat plasma at a dose of 5 mg/kg orally.
  • the highest blood drug concentration and duration of action vary widely, but the AUC difference is small. Both can guarantee an effective concentration of action.
  • Colo205 tumor-bearing mice were used as test animals, and the pharmacokinetic behavior of Compound Example Compound 3, Compound 34 and Compound 63 was orally administered in mice (plasma and tumor tissue) at a dose of 50 mg/kg.
  • Example Compound 3 10 g was weighed, dissolved in 1000 mL of purified water, and 2.5 mL of Tween 80 and 0.5 mL of antifoaming agent were added. Mix well to form a clear solution. 36.6 mg of Example Compound 3, 22.6 mg of Example Compound 34, and 35.2 mg of Example Compound 63 were weighed and dissolved in the solution, shaken, and sonicated for 15 minutes to obtain a colorless clear solution at a concentration of 5.0 mg/mL.
  • HEC hydroxyethyl cellulose
  • mice were sacrificed by CO 2 , 0.2 ml of blood was collected from the heart, placed in an EDTA-2K test tube, and the plasma was separated by centrifugation at 6000 rpm for 6 min at 4 ° C, and stored at -80 ° C. After the tumor tissue was weighed, it was placed in 2 mL. Store in a centrifuge tube at -80 °C.
  • Example 3 As shown by the data in the table, the exposure of Example 3, Example 34 and Example 63 to mouse plasma and tumor reached a very high level at a dose of 50 mg/kg, Example 3 and Example 63 Exposure in the tumor is significantly higher than in the blood, and Tmax and MRT can be seen that the concentration in the tumor is a gradually increasing process, and the metabolic rate is slower, indicating that the compound will gradually accumulate in the tumor and has been Maintain a high concentration in the tumor to ensure a better anti-tumor effect.
  • the BALB/c nude mice were used as test animals, and the human colorectal cancer cell Colo205 xenograft tumor (CDX) model was used for in vivo pharmacodynamic experiments to evaluate the antitumor effect of the test compounds.
  • CDX human colorectal cancer cell Colo205 xenograft tumor
  • Vernier caliper 500-196, Mitutoyo, Japan
  • Fetal bovine serum (FBS) (10099-141, Gibco)
  • Streptomycin double antibody (SV30010, GE)
  • PBS Phosphate buffer
  • One Colo205 cell was taken out from the cell bank, and the cells were resuscitated with 1640 medium (1640+10% FBS+1%Glu +1% SP).
  • the resuscitated cells were placed in a cell culture flask (the cell type was marked on the bottle wall, The date, culture name, etc.) were placed in a CO 2 incubator (incubator temperature 37 ° C, CO 2 concentration 5%). After the cells were covered with 80-90% of the bottom of the culture flask, they were passaged, and after passage, the cells were further cultured in a CO 2 incubator. This process is repeated until the number of cells meets the in vivo efficacy requirements.
  • the cultured cells were collected, counted by a fully automatic cell counter, and the cells were resuspended in PBS according to the counting results to prepare a cell suspension (density 4 ⁇ 10 7 /ml). Place in an ice box for use.
  • mice Female, 6-8 weeks old, weigh approximately 18-22 grams. Mice were maintained in a special pathogen-free environment and in a single ventilated cage, 5 mice per cage. All cages, litter and water are sterilized prior to use. All animals are free to access a standard certified commercial laboratory diet. Nude mice were labeled with a disposable large mouse universal ear tag prior to inoculation and the skin of the inoculated site was disinfected with 75% medical alcohol. Each mouse was inoculated subcutaneously into the right flank and at a density of 4 x 10 6 cells per 0.1 ml for tumor growth. Dosing begins when the average tumor volume reaches 100-200 cubic millimeters.
  • the test compound was orally administered orally daily at a dose of 50 mg/kg.
  • the anti-tumor efficacy is determined by dividing the average tumor-increased volume of the compound-treated animals by the average tumor-increased volume of the untreated animals.
  • Tumor inhibition rate 1 - [(Vt - V0) administration group / (Vt - V0) solvent control group] * 100%. Animals were euthanized after the experiment.
  • Example 3 In the case where the tumor in the placebo group was increased to 1763 mm 3 , the tumor of the animal group administered in Example 34 was increased to 430 mm 3 , which showed an excellent effect of inhibiting tumor growth.
  • the administration of Example 3 and Example 63 was carried out. Tumor growth was slower in the animal group. The effect was more pronounced.
  • the cells used in this experiment are transfected with hERG, cDNA and CHO stably expressing hERG channels.
  • Cell line supplied by Sophion Bioscience, Denmark
  • the cells were cultured in a medium containing the following components: Ham's F12 medium, 10% (v/v) inactivated fetal bovine serum, 100 ⁇ g/ml hygromycin B, and 100 ⁇ g/ml Geneticin.
  • CHO hERG cells were grown in a Petri dish containing the above culture medium and cultured in an incubator containing 5% CO 2 at 37 °C. 24 to 48 hours before the electrophysiological experiment, CHO hERG cells were transferred to a circular glass plate placed in a petri dish and grown under the same culture medium and culture conditions as above, and the density of CHO hERG cells on each circular slide. The need to reach the vast majority of cells is an independent, single requirement.
  • This experiment used a manual patch clamp system (HEKA EPC-10 signal amplifier and digital conversion system, purchased from HEKA Electronics, Germany) for the recording of whole cell currents.
  • a circular slide with CHO hERG cells grown on it was placed in an electrophysiology recording trough under an inverted microscope.
  • the extracellular fluid was continuously perfused in the recording tank (about 1 ml per minute).
  • the experimental procedure uses conventional whole-cell patch clamp current recording techniques. Unless otherwise stated, the experiments were carried out at regular room temperature ( ⁇ 25 ° C). The cells were clamped at a voltage of -80 mV.
  • the cell clamp voltage was depolarized to +20 mV to activate the hERG potassium channel, and after 5 seconds it was clamped to -50 mV to eliminate inactivation and generate tail current.
  • the tail current peak is used as the value of the hERG current magnitude.
  • the drug to be tested can be superimposed and filled until the inhibition of the hERG current reaches a steady state.
  • the recent three consecutive current recording lines are recombined as a criterion for judging whether or not the state is stable. After reaching a steady state, rinse with extracellular fluid until the hERG current returns to the size before the drug is added.
  • Cisapride (cisapride, purchased from Sigma) was used in the experiment as a positive control to ensure that the cells used were of normal quality.
  • DMSO dimethyl methacrylate
  • concentrations 30, 10, 3, 1, 0.3 and 0.1, 3 (30, 10, 3, 1, 0.3 and 0.1 ⁇ M) for testing.
  • DMSO diluted to 10, 3, 1, 0.3, and 0.1 mM stocks in a gradient dilution, and then diluted 1000 times with extracellular fluid to a final ⁇ M test concentration, except for a final concentration of 0.3% for the 30 ⁇ M test concentration of DMSO.
  • the final concentration of DMSO in the other concentrations of the compound solution was 0.1%.
  • the positive control Cisapride West sapride was tested at a concentration of 0.1 ⁇ M. All compound solutions were sonicated and shaken for 5 to 10 minutes to ensure complete dissolution of the compound. .
  • test data was analyzed by HEKA Patchmaster (V2x73.2), Microsoft Excel and data analysis software provided by Graphpad Prism 5.0.
  • test data in the report needs to meet the following criteria:
  • 0.1 ⁇ M cisapride (C4740-10 mg, Sigma) blocked more than 50% of the hERG current as a positive control.
  • Example Compound 3 Compound 34 and Compound 63 had substantially no inhibitory effect on cardiac hERG potassium ion channels.
  • the present invention provides a series of highly active, highly selective CDK4/6 kinase inhibitors having novel structures with stronger enzymatic activity and cell viability, and better selectivity to kinases. It shows better pharmacokinetic properties in both rats and mice, and also shows better drug efficacy. Cardiac toxicity is significantly reduced. There is great potential to be developed as a drug for diseases of cell cycle proliferative disorders. Especially for HR+/Her-type breast cancer drugs.

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Abstract

L'invention concerne un composé de formule générale (I), son procédé de préparation, et une composition pharmaceutique le contenant, ainsi que l'utilisation de celui-ci en tant qu'inhibiteur de kinase de benzimidazole dans la préparation d'un médicament pour la prévention et/ou le traitement du cancer ou de maladies associées à une tumeur, notamment des maladies telles que le cancer de la vessie, le cancer de l'ovaire, le cancer du péritoine, le cancer du pancréas, le cancer du sein, le cancer de l'utérus, le cancer du col de l'utérus, le cancer de l'endomètre, le cancer de la prostate, le cancer du tractus reproducteur féminin, le cancer des testicules, les tumeurs stromales gastro-intestinales et les tumeurs de la prostate.
PCT/CN2017/100678 2016-09-07 2017-09-06 Composé de benzimidazole inhibiteur de kinase, son procédé de préparation et son application WO2018045956A1 (fr)

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CN113264920B (zh) * 2021-05-10 2022-09-02 中国药科大学 一种嘧啶苯并六元环母核的cdk6抑制剂及其制备方法和应用
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