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WO2018045957A1 - Inhibiteur de cdk4/6, son procédé de préparation et son application - Google Patents

Inhibiteur de cdk4/6, son procédé de préparation et son application Download PDF

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Publication number
WO2018045957A1
WO2018045957A1 PCT/CN2017/100679 CN2017100679W WO2018045957A1 WO 2018045957 A1 WO2018045957 A1 WO 2018045957A1 CN 2017100679 W CN2017100679 W CN 2017100679W WO 2018045957 A1 WO2018045957 A1 WO 2018045957A1
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group
alkyl
cancer
compound
formula
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PCT/CN2017/100679
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English (en)
Chinese (zh)
Inventor
刘世强
周远峰
吴雪松
包如迪
Original Assignee
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 CN201780049731.7A priority Critical patent/CN109952295B/zh
Publication of WO2018045957A1 publication Critical patent/WO2018045957A1/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 CDK4/6 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.
  • some pharmaceutical companies including Novartis (LEE011) and Lilly (LY2835219), have compounds in clinical research and have performed well.
  • Novartis LEO011
  • Lilly LY2835219
  • studies have shown that 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.
  • the inventors discovered a CDK4/6 inhibitor having the structure of formula (I) and its preparation method and application during the research.
  • the compound of the formula (I) developed by the invention has strong inhibitory effect on CDK4/6 kinase activity and can be widely used for preparing and preventing or treating cancer or tumor related diseases, especially bladder cancer and eggs.
  • Drugs for diseases such as nest 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, are expected Developed as a new generation of CDK4/6 inhibitor drugs.
  • a first aspect of the invention provides a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
  • X 1 , X 2 , X 3 are each independently selected from O, S, N, NR 6 or CR 7 ;
  • X 4 is selected from N or CR 7 ;
  • Y is selected from the group consisting of a bond, O, S(O) n , C(O), C(O)NH, NR 6 or (CR 7 R 8 ) m ;
  • R 1 and R 2 are each independently selected from the group consisting of hydrogen, hydrazine, C 1-8 alkyl, halo-substituted C 1-8 alkyl, C 1-8 alkoxy C 1-8 alkyl, C 3-8 cycloalkyl.
  • R 1 and R 2 together with the nitrogen atom to which they are attached form a 5-12 membered heterocyclic group or a 5-10 membered heteroaryl group, optionally further selected from one or more selected from the group consisting of halogen, hydroxy, oxo, carbonyl.
  • R 3 , R 4 , R 5 , R 7 and R 8 are each independently selected from the group consisting of hydrogen, hydrazine, halogen, hydroxy, fluorenyl, cyano, nitro, azide, C 1-8 alkyl, halogen substituted C 1 -8 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclic oxy, 3-8 membered heterocyclic thio, -C 0-8 -S(O) r R 9 , -C 0-8 -OR 10 , -C 0-8 -C(O)OR 10 , -C 0-8 -C(O)OR 10 , -C 0-8 -C(O)R 11 , -C 0-8 -OC(O)R 11 , -C 0-8 -NR 12 R 13 , -C 0-8 -C(O)NR 12 R 13 , -N(R 12 )
  • R 3 and R 1 , R 4 and R 2 together with the group to which they are directly attached form a 5-8 membered heterocyclic group or a 5-10 membered heteroaryl group, optionally further selected from one or more selected from the group consisting of halogen and hydroxy.
  • R 9 is selected from the group consisting of hydrogen, hydrazine, C 1-8 alkyl, C 2-8 alkenyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, halo-substituted C 1-8 alkyl, phenyl , p-methylphenyl, amino, mono C 1-8 alkylamino, di C 1-8 alkylamino or C 1-8 alkanoylamino;
  • R 10 is selected from the group consisting of hydrogen, hydrazine, C 1-8 alkyl, C 3-8 cycloalkyl, C 5-10 aryl, halogen substituted C 1-8 alkyl or hydroxy substituted C 1-8 alkyl;
  • R 11 is selected from the group consisting of hydrogen, hydrazine, C 1-8 alkyl, C 1-8 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, halogen substituted C 1-8 alkyl, halogen Substituting a C 1-8 alkoxy group, a 3-8 membered heterocyclic group, a hydroxy substituted C 1-8 alkyl group or a hydroxy substituted C 1-8 alkoxy group;
  • R 6 , R 12 and R 13 are each independently selected from the group consisting of hydrogen, hydrazine, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy C 1-8 alkyl, C 3-8 cycloalkane.
  • n 0, 1 or 2;
  • the compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, R 5 is selected from the group consisting of hydrogen, hydrazine, halogen, hydroxy, thiol, cyano, nitro, azide , methyl, isopropyl, trifluoromethyl, methoxy, isopropoxy, cyclopropyl, cyclopropoxy, 3-oxetanyl, methylsulfonyl, isopropylsulfonyl, methoxy Carbonyl, ethoxycarbonyl, isopropoxycarbonyl, acetyl, acetoxy, amino, dimethylamino, aminoacyl or acetylamino.
  • R 5 is selected from the group consisting of hydrogen, hydrazine, halogen, hydroxy, cyano, trifluoromethyl, isopropyl Sulfonyl or amino group.
  • R 5 is selected from hydrogen or fluorine compound of the formula (the I), a stereoisomer thereof or a pharmaceutically acceptable.
  • the compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the group consisting of a compound of the formula (II), a compound of (IIa) or a compound of the formula (IIb):
  • R 1 and R 2 are each independently selected from the group consisting of hydrogen, deuterium, C 1-8 alkyl, hydroxy substituted C 1-8 alkyl or 3-8 membered heterocyclic;
  • R 1 and R 2 together with the nitrogen atom to which they are attached form a 5-12 membered heterocyclyl, optionally further selected from one or more selected from the group consisting of hydrogen, deuterium, amino, oxo, C 1-8 alkyl, Substituted by a substituent of C 1-8 haloalkyl, 3-8 membered heterocyclyl, -C 0-8 -C(O)OR 10 and -C 0-8 -NR 12 R 13 wherein said C 1
  • the -8 alkyl group is optionally further substituted with one or more substituents selected from the group consisting of halogen, cyano, amino, hydroxy, C 1-8 alkoxy and 3-8 membered heterocyclic; wherein 3-
  • the 8-membered heterocyclic group is optionally further substituted with one or more substituents selected from the group consisting of hydrogen, cyano, oxo, halogen, C 1-8 alkyl and -C 0-8 -NR 12 R 13
  • R 10 is a C 1-8 alkyl group
  • R 12 and R 13 are each independently selected from hydrogen, C 1-8 alkyl, C 2-8 alkenyl or halo C 1-8 alkyl.
  • the compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the group consisting of a compound of the formula (III), a compound of (IIIa-1) or a formula (IIIa-2) ) Compound:
  • Ring A is selected from C 3-8 cycloalkyl and 3-8 membered heterocyclic; preferably 6-membered heterocyclic;
  • R 3 is selected from the group consisting of hydrogen, deuterium, halogen, oxo, C 1-8 alkyl or -C 0-8 -C(O)R 11 wherein said C 1-8 alkyl and -C 0-8 -C(O)R 11 is optionally further substituted with one or more substituents selected from a C 1-8 alkyl group or a Boc substituted 3-8 membered heterocyclic group;
  • R 11 is selected from hydrogen, hydrazine, C 1-8 alkyl or 3-8 membered heterocyclic group, wherein said C 1-8 alkyl group and 3-8 membered heterocyclic group are optionally further selected by one or more Substituted from a hydroxyl group, a C 1-8 alkyl group or a substituent of -C 0-8 -NR 12 R 13 ;
  • n 1, 2, 3 or 4.
  • the compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the group consisting of a compound of the formula (IIIb-1), a compound of the formula (IIIb-2) or a formula (IIIb) -3) Compound:
  • R 6 and R 7 are each independently selected from hydrogen, hydrazine, C 1-8 alkyl, C 3-8 cycloalkyl or -C 0-8 -NR 12 R 13 ; wherein C 1-8 alkyl is preferably methyl And isopropyl; C 3-8 cycloalkyl is preferably cyclopentyl;
  • R 12 and R 13 are each independently selected from hydrogen, hydrazine, C 1-8 alkyl, or R 12 and R 13 together form a 3-8 membered heterocyclic group; wherein C 1-8 alkyl is preferably methyl or B. And isopropyl; R 12 and R 13 together form a 3-8 membered heterocyclic group, preferably azetidine, pyrrolidinyl and piperidinyl.
  • the compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, R 6 is selected from the group consisting of C 1-8 alkyl, C 3-8 cycloalkyl, 3- 8-membered heterocyclic group, amino group, mono C 1-8 alkylamino group or di C 1-8 alkylamino group.
  • the compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, R 6 is selected from the group consisting of isopropyl, cyclopropyl, cyclopentyl, cyclohexyl, and dimethyl. Alkylamino, diethylamino, methylisopropylamino, azetidinyl, azacyclopentyl or azacyclohexyl.
  • the compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof which is selected from the group consisting of the compounds of the formulae (IV), (IV-A) and (IV-B) :
  • M, M 1 , M 2 are NR 6 , O or CR 7 R 8 ;
  • Ring B is a monocyclic heterocyclic group, a fused ring heterocyclic group, a spirocyclic heterocyclic group or a bridged heterocyclic group;
  • M, M 1 , M 2 are N or CR 7 R 8 ;
  • R a and R b are each independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxy, decyl, cyano, oxo, nitro, azide, C 1-8 alkyl, halo-substituted C 1-8 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, 3-8 membered heterocyclic oxy group, 3-8 membered heterocyclic thio group, -C 0-8 -S(O) r R 9 , -C 0-8 -OR 10 , -C 0-8 -C(O)OR 10 , -C 0-8 -C(O)OR 10 , -C 0-8 -C(O)R 11 , -C 0-8 -OC(O)R 11 , -C 0- 8 -NR 12 R 13 , -C 0-8 -C(O)NR 12 R 13 , -N(R 12 )-C
  • x, y, z, u are integers of 1, 2, 3 or 4;
  • a preferred embodiment is a compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of the compounds of the formulae (V), (V-A) and (V-B):
  • a pharmaceutically acceptable salt thereof which is selected from the group consisting of the compounds of the formula (VI), (VI-A) and (VI-B). :
  • R v and R w are each independently selected from the group consisting of hydrogen, hydrazine, C 1-8 alkyl, halo-substituted C 1-8 alkyl, C 1-8 alkoxy C 1-8 alkyl, C 3-8 cycloalkyl C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, C 5-10 aryl, 5-10 Heteroaryl or C 1-8 alkanoyl,
  • R v and R w together with the nitrogen atom to which they are attached form a 5-8 membered heterocyclic group or a 5-10 membered heteroaryl group, optionally further selected from one or more selected from the group consisting of halogen, hydroxy, oxo, carbonyl.
  • R v and R w are each independently preferably methyl, ethyl and isopropyl; R v and R w together form a 3-8 membered heterocyclic group, preferably azetidine, pyrrolidinyl and piperidinyl;
  • a second aspect provides a process for the preparation of a compound of the above formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, comprising the steps of: a compound of formula (A) or an acid salt thereof and a compound of formula (B)
  • the condensation reaction in the presence of an acid binding agent produces a compound of formula (I) having the following reaction formula:
  • X 1 , X 2 , X 3 , X 4 , Y, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , m, r are as defined by the compound of formula (I);
  • X is halogen, preferably chlorine or bromine;
  • the preparation method is characterized in that the compound of the formula (A) is further selected from the group consisting of:
  • the compound of formula (B) is further selected from the group consisting of:
  • the acid binding agent is selected from the group consisting of an organic base, an inorganic base or a mixture thereof, preferably from ammonia water, methylamine, ethylamine, ethanolamine, ethylenediamine, trimethylamine, triethylamine, Propylamine, isopropylamine, 1,3-propanediamine, triethanolamine, diisopropylethylamine, pyridine, piperidine, morpholine or a mixture thereof;
  • the inorganic base is preferably selected from potassium carbonate, sodium hydrogencarbonate or potassium hydrogencarbonate , sodium carbonate, barium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium acetate or a mixture thereof;
  • the acid binding agent is selected from the group consisting of cesium carbonate.
  • a third aspect of the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of a compound of the above formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the present invention provides a compound of the above formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of a cancer or tumor mediated by CDK kinase.
  • a compound of the above formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof for use in the treatment and/or prevention of a cancer or tumor mediated by CDK kinase.
  • the application of drugs for related diseases are examples of drugs for related diseases.
  • the aforementioned compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and the aforementioned pharmaceutical composition are prepared for the treatment and/or prevention of mediated by CDK kinase 4 and/or 6 Use in drugs for cancer or tumor-related diseases.
  • the cancer or tumor-related disease is selected from the group consisting of brain tumor, lung cancer, liver cancer, stomach cancer, oral cancer, head and neck cancer, intestinal cancer or rectal cancer, colon cancer, kidney cancer, esophageal adenocarcinoma, esophageal squamous Cell carcinoma, squamous cell carcinoma, thyroid 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, glioblastoma, bladder cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, uterine cancer, cervical cancer, endometrial cancer, prostate cancer, female genital cancer , testicular cancer, gastrointestinal stromal tumor or prostate tumor; preferably from bladder cancer, ovarian cancer, peritoneal cancer,
  • the breast cancer comprises: a locally advanced or metastatic breast cancer that is negative for estrogen receptor positive and/or negative for human epidermal growth factor receptor 2 in postmenopausal women.
  • the present invention also relates to a method of treating a disease preventing and/or treating a disease having a pathological characteristic of a CDK kinase 4 and/or 6 mediated metabolic pathway comprising administering to a patient a therapeutically effective dose of the formula (I) A compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
  • These diseases include cancer or tumor-related diseases, 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 Epithelial cell carcinoma, thyroid 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, glioblastoma, bladder cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, uterine cancer, cervical cancer, endometrial cancer, prostate cancer, female genital cancer, testicular cancer, stomach Intestinal stromal tumor or prostate tumor; preferably from bladder cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer,
  • Another aspect of the invention relates to a method of treating cancer comprising administering to a patient a therapeutically effective amount of a compound of the formula (I) of the invention or a tautomer, a mesogen thereof, a foreign body A form of a rot, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • the method exhibits outstanding efficacy and less side effects, wherein the cancer can be selected from the group consisting of brain tumor, lung cancer, liver cancer, stomach cancer, oral cancer, head and neck cancer, intestinal cancer or rectal cancer, colon cancer, kidney cancer, esophageal gland.
  • Cancer esophageal squamous cell carcinoma, scale Epithelial cell carcinoma, thyroid 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, glioblastoma, bladder cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, uterine cancer, cervical cancer, endometrial cancer, prostate cancer, female genital 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 cancer, testicular cancer, A gastrointestinal stromal tumor or a prostate tumor, more preferably breast cancer.
  • C 1-8 alkyl means a straight-chain alkyl group having 1 to 8 carbon atoms and a branched alkyl group, and the alkyl group means a saturated aliphatic hydrocarbon group, preferably an alkyl group of 1 to 6 carbon atoms, more An alkyl group of 1 to 3 carbon atoms; for example, 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-dimethyl Butyl, 1,3-d
  • Cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent
  • C 3-8 cycloalkyl refers to a cycloalkyl group comprising from 3 to 8 carbon atoms, preferably from 3 to 6 a carbon atom; more preferably 4 to 6 carbon atoms; for example:
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptene Alkenyl, cyclooctyl and the like.
  • Polycyclic cycloalkyl groups include spiro, fused, and bridged cycloalkyl groups.
  • “Spirocycloalkyl” refers to a polycyclic group that shares a carbon atom (called a spiro atom) between the monocyclic rings. These may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system.
  • the spirocycloalkyl group is divided into a monospirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group according to the number of shared spiro atoms between the ring and the ring.
  • Non-limiting examples of spirocycloalkyl groups include:
  • fused cycloalkyl refers to an all-carbon polycyclic group in which each ring of the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more double bonds, but None of the rings have a fully conjugated ⁇ -electron system. Depending on the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyl groups, and non-limiting examples of fused cycloalkyl groups include:
  • Bridge cycloalkyl refers to an all-carbon polycyclic group in which two rings share two carbon atoms that are not directly bonded, which may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system . Depending on the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups. Non-limiting examples of 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, tetrahydrogen Naphthyl, 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 halogen, hydroxy, thiol, cyano, nitro, azide.
  • Heterocyclyl means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent wherein one or more of the ring atoms are selected from nitrogen, oxygen or S(O) r (where r is an integer 0, 1, 2 a hetero atom, but excluding the ring portion of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
  • the "5-10 membered heterocyclic group” means a ring group containing 5 to 10 ring atoms
  • the "3-8 membered heterocyclic group” means a ring group containing 3 to 8 ring atoms, preferably a 5-6 membered heterocyclic group. .
  • Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, diazepanyl, diaza Cyclooctyl and azetidinyl and the like, these heterocyclic groups are optionally substituted by a group such as an alkyl group, an oxo group, a halogen, a halogenated alkyl group, a Boc group, an amino group or the like.
  • 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 a single ring, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) r (where r is an integer) The heteroatoms of 0, 1, 2), and the remaining ring atoms are carbon. These may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system.
  • the spirocycloalkyl group is classified into a monospiroheterocyclic group, a dispiroheterocyclic group or a polyspiroheterocyclic group depending on the number of shared spiro atoms between the ring and the ring.
  • Non-limiting examples of spirocycloalkyl groups include:
  • fused heterocyclyl refers to a polycyclic heterocyclic group in which each ring of the system shares an adjacent pair of atoms with other rings in the system, and one or more rings may contain one or more double bonds, but none
  • the ring has a fully conjugated pi-electron system in which one or more ring atoms are selected from the group consisting of nitrogen, oxygen or S(O) r (wherein r is an integer of 0, 1, 2) heteroatoms, the remaining ring atoms being carbon.
  • r is an integer of 0, 1, 2
  • it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocycloalkyl groups, and non-limiting examples of fused heterocyclic groups include:
  • Bridge heterocyclyl refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly bonded, and these may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system, One or more of the ring atoms are selected from the group consisting of nitrogen, oxygen or S(O) r (wherein r is an integer of 0, 1, 2) heteroatoms, and the remaining ring atoms are carbon. Depending on the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups.
  • Non-limiting examples of bridged cycloalkyl 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 comprising:
  • 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 the group consisting of halogen, hydroxy, thiol, oxo, cyano, nitro , azido group, C 1-8 alkyl group, C 2-8 alkenyl group, C 2-8 alkynyl group, C 3-8 cycloalkyl group, 3-8 membered heterocyclic group, 3-8 membered heterocyclic ring Alkoxy, 3-8 membered heterocyclylthio, C 5-10 aryl, C 5-10 aryloxy, C 5-10 arylthio, 5-10 membered heteroaryl, 5-10 Nonheteroaryloxy, 5-10 membered heteroarylthio, -C 0-8 -S(O) r R 9 , -C 0-8 -OR 10 , -C 0-8 -C(O) OR 10 , -C 0
  • Aryl means an all-carbon monocyclic or fused polycyclic (ie, a ring that shares a pair of adjacent carbon atoms) groups having a polycyclic ring of a conjugated ⁇ -electron system (ie, having a ring adjacent to a carbon atom) a group
  • C 5-10 aryl means an all-carbon aryl group having 5 to 10 carbons
  • 5-10 membered aryl group means an all-carbon aryl group having 5 to 10 carbons, preferably 5-8 A aryl group, more preferably a 5-6 membered aryl group; for example, a phenyl group and a naphthyl group.
  • 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 comprising:
  • the aryl group can be substituted or unsubstituted.
  • the substituent is preferably one or more groups independently selected from halogen, hydroxy, mercapto, cyano, nitro, azido group, C 1 -8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclyloxy, 3-8 a heterocyclic heterothio group, a C 5-10 aryl group, a C 5-10 aryloxy group, a C 5-10 arylthio group, a 5-10 membered heteroaryl group, a 5-10 membered heteroaryloxy group, 5-10 membered heteroarylthio, -C 0-8 -S(O) r R 9 , -C 0-8 -OR 10 , -C 0-8 -C(O)OR 10 , -C 0- 8 -C(O)R 11
  • Heteroaryl refers to a heteroaromatic system containing from 1 to 4 heteroatoms including nitrogen, oxygen and a hetero atom of S(O)r (wherein r is an integer of 0, 1, 2), 5-
  • a 7-membered heteroaryl group means a heteroaromatic system containing 5 to 7 ring atoms
  • a 5-10 membered heteroaryl group means a heteroaromatic system having 5 to 10 ring atoms, preferably a 5-6 membered heteroaryl group; for example Furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like.
  • the heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring wherein the ring to which the parent structure is attached is a heteroaryl ring, non-limiting examples comprising:
  • 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 halogen, hydroxy, thiol, cyano, nitro, azide.
  • Alkenyl means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, and a C 2-8 alkenyl group means a straight or branched olefin containing from 2 to 8 carbons base.
  • alkenyl means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond
  • a C 2-8 alkenyl group means a straight or branched olefin containing from 2 to 8 carbons base.
  • vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, and the like are examples of the alkenyl group.
  • Alkenyl group may be substituted or unsubstituted.
  • the substituent is preferably one or more groups independently selected from halogen, hydroxy, mercapto, cyano, nitro, azido group, C 1 -8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclyloxy, 3-8 a heterocyclic heterothio group, a C 5-10 aryl group, a C 5-10 aryloxy group, a C 5-10 arylthio group, a 5-10 membered heteroaryl group, a 5-10 membered heteroaryloxy group, 5-10 membered heteroarylthio, -C 0-8 -S(O) r R 9 , -C 0-8 -OR 10 , -C 0-8 -C(O)OR 10 , -C 0- 8 -C(O)R 11
  • Alkynyl refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond
  • C2-8 alkynyl refers to a straight or branched alkynyl group containing from 2 to 8 carbons.
  • ethynyl 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, and the like.
  • Alkynyl group may be substituted or unsubstituted.
  • the substituent is preferably one or more groups independently selected from halogen, hydroxy, mercapto, cyano, nitro, azido group, C 1 -8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclyloxy, 3-8 a heterocyclic heterothio group, a C 5-10 aryl group, a C 5-10 aryloxy group, a C 5-10 arylthio group, a 5-10 membered heteroaryl group, a 5-10 membered heteroaryloxy group, 5-10 membered heteroarylthio, -C 0-8 -S(O) r R 9 , -C 0-8 -OR 10 , -C 0-8 -C(O)OR 10 , -C 0- 8 -C(O)R 11
  • Alkoxy means -O-(alkyl) wherein alkyl is as defined above.
  • C 1-8 alkoxy means an alkyloxy group having 1-8 carbons, preferably an alkyloxy group of 1 to 6 carbons, more preferably an alkyloxy group of 1 to 3 carbons, without limitation Examples include methoxy, ethoxy, propoxy, butoxy and the like.
  • the alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent, preferably one or more of the following groups, independently selected from the group consisting of halogen, hydroxy, thiol, cyano, nitro, azide , C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclyloxy 3-8 membered heterocyclylthio, C 5-10 aryl, C 5-10 aryloxy, C 5-10 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryl Alkoxy group, 5-10 membered heteroarylthio group, -C 0-8 -S(O) r R 9 , -C 0-8 -OR 10 , -C 0-8 -C(O)OR 10 , -C 0-8 -C(O)R 11 ,
  • Cycloalkoxy refers to -O-(unsubstituted cycloalkyl) wherein cycloalkyl is as defined above.
  • C 3-8 cycloalkoxy refers to a cycloalkyloxy group containing from 3 to 8 carbons, and non-limiting examples include cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like. .
  • the cycloalkoxy 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 halogen, hydroxy, thiol, cyano, nitro, azide.
  • Halo-substituted C 1-8 alkyl means a hydrogen on the alkyl group optionally substituted with 1-8 carbon alkyl groups substituted by fluorine, chlorine, bromine or iodine atoms, such as difluoromethyl, dichloromethyl , dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, and the like.
  • the hydrogen on the "halo-substituted C 1-8 alkoxy" alkyl group is optionally a 1-8 carbon alkoxy group substituted with a fluorine, chlorine, bromine or iodine atom.
  • a fluorine chlorine, bromine or iodine atom.
  • Halogen means fluoro, chloro, bromo or iodo.
  • X may be any one or several of 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 means that one or more hydrogen atoms in the group are each independently substituted with 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 bond such as an olefin.
  • “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. 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.
  • 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.
  • reaction system was adjusted to pH 8-10 with sodium hydroxide, extracted with methyl tert-ether (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and then cooled to 0 ° C, then 4 M HCl / MeOH (20 mL) The solution was stirred for 30 min and concentrated to give the compound (4-bromo-2-fluorophenyl)indole (4.8 g, yield 75%).
  • the second step preparation of 5-bromo-7-fluoro-3-isopropyl-2-methyl-1H-indole
  • the third step 7-fluoro-3-isopropyl-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H- ⁇ preparation
  • the third step 6-bromo-4-fluoro-1-toluenesulfonyl-1H-oxime
  • 6-Bromo-4-fluoro-1H-indole (2.5 g, 12 mmol) was dissolved in DMF (30 mL), cooled to 0 ° C, NaH (0.7 g, 18 mmol, 60% w/w). After h, TosCl (3.6 g, 19 mmol) was added, and the reaction was stirred for 2 h and slowly warmed to room temperature. Diluted with EtOAc (100 mL), EtOAc (EtOAc) (EtOAc) The compound 6-bromo-4-fluoro-1-toluenesulfonyl-1H-indole (3.5 g, yield 81%) was obtained.
  • the fourth step 6-bromo-4-fluoro-2-methyl-1-toluenesulfonyl-1H-oxime
  • 6-Bromo-4-fluoro-1-toluenesulfonyl-1H-indole (3.5 g, 9.5 mmol) was dissolved in THF (30 mL), cooled to -70 ° C, and LDA solution (7.1 mL, 14.2) mmol, 2M in THF / n- Heptane / ethylbenzene), was stirred at this temperature for 15min after addition of CH 3 I (2.7g, 19mmol) , stirred for 2h and the reaction was slowly warmed to room temperature.
  • 6-Bromo-4-fluoro-2-methyl-1-toluenesulfonyl-1H-indole (3.0 g, 7.9 mmol) was dissolved in MeOH (60 mL). After 6 h, it was cooled to room temperature, neutralized to neutral with 2N HCl solution, and concentrated to remove most of the organic solvent. The organic phase was washed with water (100 mL) and brine (100 mL) and dried over anhydrous sodium sulfate. :1)] The compound 6-bromo-4-fluoro-2-methyl-1H-indole (1.7 g, yield 95%) was obtained. MS m/z (ESI): 230 [M+H] + .
  • 6-Bromo-4-fluoro-2-methyl-1H-indole (1.9 g, 7.5 mmol) was dissolved in DMF (20 mL), cooled to 0 ° C, NaH (0.45 g, 11 mmol, 60% w /w), after stirring for 0.5 h, added 2-bromopropane (1.8 g, 15 mmol), warmed slowly to room temperature and stirred overnight. Diluted with EtOAc (50 mL), EtOAc (EtOAc) (EtOAc) The compound 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-indole (0.7 g, yield 35%) was obtained. MS m/z (ESI): 272 [M+H] +
  • Step 7 (4-Fluoro-1-isopropyl-2-methyl-1H-indol-6-yl)boronic acid
  • 6-Bromo-4-fluoro-1-isopropyl-2-methyl-1H-indole 0.1 g, 0.4 mmol
  • triisopropyl borate 0.4 g, 2.2 mmol
  • THF 10 mL
  • n-BuLi solution 1.2 mL, 1.8 M, 1.6 M in Hexane
  • 2N hydrochloric acid solution 4 mL
  • Step 8 6-(2-Chloro-5-fluoropyrimidin-4-yl)-4-fluoro-1-isopropyl-2-methyl-1H-indole
  • 6-Bromo-1-toluenesulfonyl-1H-indole (1.4 g, 3.8 mmol) was dissolved in THF (15 mL), cooled to -70 ° C, and then the mixture was applied to the solvent of LDA (3 mL, 6 mmol, 2M in THF / After stirring at the same temperature for 15 min, N-methoxy-N-methylisobutylamide (1.01 g, 7.7 mmol) was added, and the mixture was slowly warmed to room temperature and stirred overnight. 1N HCl solution (6 mL) was added and the mixture was evaporated. EtOAc EtOAc m. Crude product 1-(6-bromo-1-toluenesulfonyl-1H-indol-2-yl)-2-methylpropan-1-one (1.4 g, yield 87%).
  • the fourth step 1-(1-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole- 2-yl)-2-methylpropan-1-one
  • the fifth step 1-(6-(2-chloro-5-fluoropyrimidin-4-yl)-1-isopropyl-1H-indol-2-yl)-2-methylpropan-1-one preparation
  • Second step Preparation of 1-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole
  • 6-Bromo-1-isopropyl-1H-indazole (100 mg, 0.418 mmol), pinacol borate (159 mg, 0.626 mmol), Pd(dppf)Cl 2 (61 mg, 0.0834 mmol), potassium acetate ( 123 mg, 0.0834 mmol) was stirred in dioxane (10 mL) at 100 ° C under nitrogen for 5 h, cooled and concentrated to give product (100 mg, yield 83.6%).
  • the third step preparation of 6-(2-chloro-5-fluoropyrimidin-4-yl)-1-isopropyl-1H-carbazole
  • Step 2 - Step 4 1-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-carbazole Preparation
  • 1,1-Dimethylhydrazine hydrochloride (2.0 g, 20.4 mmol), diisopropylethylamine (8.0 g, 61.2 mmol) was dissolved in anhydrous dichloromethane (50 mL). Acetyl chloride (1.9 g, 24.5 mmol) was added. The reaction was stirred for 1 hour in an ice-bath. After the reaction was completed, the reaction mixture was evaporated to dryness, and the residue was evaporated to ethyl acetate (30mL) and stirred for 10 min, filtered, and the filtrate was concentrated to give the product N',N'-dimethylacetyl hydrazide. (2.0 g, 96%), the product was used directly in the next step without further purification.
  • the second step preparation of 2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline
  • the third step preparation of 4-(2-chloro-5-fluoropyrimidin-4-yl)-2,6-difluorobenzoquinone
  • N',N'-Dimethylacetylhydrazine (390 mg, 3.84 mmol) was dissolved in anhydrous toluene (15 mL) and phosphorus oxychloride (2 mL) was added.
  • the reaction solution was stirred at 110 ° C for 2 hours, after which a solution of 4-(2-chloro-5-fluoropyrimidin-4-yl)-2,6-difluoroaniline (500 mg, 1.92 mmol) in toluene (5 mL) was added. In the solution, the reaction solution was further stirred at 110 ° C for 4 hours.
  • Second step Preparation of 2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline
  • the third step preparation of 4-(2-chloro-5-fluoropyrimidin-4-yl)-2,6-difluoroaniline
  • the fourth step 6-(2-chloro-5-fluoropyrimidin-4-yl)-4-fluoro-2-methyl-1-(pyrrolidin-1-yl)-1H-benzo[d]imidazole preparation
  • N-(Pyrrolidin-1-yl)acetamide (300 mg, 2.3 mmol) was dissolved in anhydrous toluene (15 mL), and phosphorus oxychloride (2 mL) was added. The reaction solution was stirred at 110 ° C for 2 hours, after which a solution of 4-(2-chloro-5-fluoropyrimidin-4-yl)-2,6-difluoroaniline (300 mg, 1.15 mmol) in toluene (5 mL) was added. In the solution, the reaction solution was further stirred at 110 ° C for 4 hours.
  • the pH of the aqueous phase was adjusted to 8-10, extracted with DCM (150 mL*5), dried over anhydrous sodium sulfate, and then concentrated, and then eluted with column chromatography [eluent: CH 2 Cl 2 - CH 2 Cl 2 / MeOH (10:1) The compound 5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-amine (2.9 g, yield 66%) was obtained.
  • 6-Amino-o-picolinic acid (450 mg, 3.2 mmol) was slowly dissolved in thionyl chloride (5 mL), and stirred at room temperature for 8 hr. The reaction mixture was concentrated to dryness. This solution was slowly added to a solution of tert-butylpiperazine-l-carboxylate (910 mg, 4.9 mmol), triethylamine (1.4 mL, 9.6 mmol) in dichloromethane, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was washed with saturated sodium bicarbonate (3 ⁇ 10 mL), and then evaporated. (150 mg, 15%).
  • Example 2-16 The preparation of the compound of Example 2-16 was carried out by referring to the preparation method of Example 1, and the chemical structure and molecular weight were as follows:
  • Example 21-35 The preparation of the compound of Example 21-35 was carried out by referring to the preparation method of Example 17, and the chemical structure and molecular weight were as follows:
  • Example 38 The preparation of the compound of Example 38 and 40-53 was carried out by referring to the preparation method of Example 36, and the chemical structure and molecular weight were as follows:
  • Second step (6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl) Preparation of amino)pyridin-2-yl)(piperazin-1-yl)methanone
  • reaction solution was directly dried to dryness, and the residue was purified by purified silica gel column, and purified by preparative HPLC to give compound (6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H) -Benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)pyridin-2-yl)(piperazin-1-yl)methanone (10 mg, 55%).
  • reaction solution was directly dried to dryness, and the residue was purified by purified silica gel column, and purified by preparative HPLC to give the product 5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d] Imidazol-6-yl)-N-(6-(piperazin-1-ylmethyl)pyridin-2-yl)pyrimidin-2-amine (9.0 mg, 15%).
  • the preparation of the compound of Example 76-102 was carried out according to the preparation method of Example 17, and the preparation of the compound of Example 103 was carried out by referring to the preparation method of Example 1, and the preparation of the compound of Example 104-158 was carried out by referring to the preparation method of Example 17, and was carried out.
  • the preparation of the compound of Example 159-168 was carried out by referring to the preparation method of Example 1, and the chemical structure and molecular weight were as follows:
  • Inhibition rate (%) 100 - (signal value - min) / (max - min) * 100.
  • the data analysis and fitting calculation IC 50 were performed using Graphpad 5.0 software.
  • the data obtained is as follows:
  • 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 significant inhibitory effect on the proliferation activity of colon cancer tumor cell colo205.

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Abstract

La présente invention concerne un inhibiteur de CDK4/6 présentant la structure de la formule (I), un procédé pour sa préparation et une application de celui-ci. La série de composés de formule (I) qui sont développées dans la présente invention présente de forts effets inhibiteurs sur les activités de CDK4/6 kinase. Lesdits composés peuvent être largement utilisés dans la préparation d'un médicament pour la prévention et/ou le traitement du cancer ou des maladies associées à une tumeur, en particulier des maladies telles que le cancer de la vessie, le cancer de l'ovaire, le cancer péritonéal, 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. La présente invention est bien positionnée pour être développée en une nouvelle génération de médicaments inhibiteurs de CDK4/6.
PCT/CN2017/100679 2016-09-07 2017-09-06 Inhibiteur de cdk4/6, son procédé de préparation et son application WO2018045957A1 (fr)

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