WO2023116862A1 - Composé indole hydrogéné, son procédé de préparation et son utilisation médicale - Google Patents

Composé indole hydrogéné, son procédé de préparation et son utilisation médicale Download PDF

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WO2023116862A1
WO2023116862A1 PCT/CN2022/141271 CN2022141271W WO2023116862A1 WO 2023116862 A1 WO2023116862 A1 WO 2023116862A1 CN 2022141271 W CN2022141271 W CN 2022141271W WO 2023116862 A1 WO2023116862 A1 WO 2023116862A1
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cancer
alkyl
general formula
group
cycloalkyl
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PCT/CN2022/141271
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English (en)
Chinese (zh)
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李心
白东栋
董怀德
陈阳
贺峰
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江苏恒瑞医药股份有限公司
上海恒瑞医药有限公司
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Publication of WO2023116862A1 publication Critical patent/WO2023116862A1/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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • the disclosure belongs to the field of medicine, and relates to a hydrogenated indole compound, its preparation method and its application in medicine.
  • the disclosure relates to indoline compounds represented by general formula (I), their preparation methods and pharmaceutical compositions containing such compounds, and their use as CDK4 inhibitors in the treatment of CDK4 activity-related diseases or disorders .
  • CDKs Cyclin-dependent protein kinases
  • CDK family members can be divided into two categories: CDKs related to cell cycle (such as CDK 1/2/4/6) and CDKs related to cell transcription (such as CDK 7/9/12). CDK kinases need to combine with Cyclin to exert enzymatic activity.
  • CDK4/6 itself does not have enzymatic activity, and needs to be combined with cyclin D to be activated.
  • the cyclin D-CDK4/6-Rb signaling pathway is a key pathway for advancing the cell cycle from G1 phase to S phase.
  • Cyclin D is regulated by multiple mitotic signaling pathways, such as PI3K-AKT pathway, RAS-MEK pathway, and estrogen receptor pathway. Increased expression of cyclin D activates the kinase activity of CDK4/6 and phosphorylates the cell cycle negative regulator RB1, and non-phosphorylated RB1 has a transcriptional repressive effect on transcription factors E2F1/2/3.
  • Phosphorylated RB1 is detached from E2F1/2/3, thereby releasing the transcriptional activity of E2F1/2/3, promoting the transcription of genes required for the cell to enter the S phase, prompting the cell to complete the G1-S phase transition, and the cell to complete the replication through mitosis .
  • Other biological functions of CDK4 include regulation of aging, survival, genome stability, glycolysis, fat metabolism, and the mechanism is related to its kinase activity. CDK4 and its cyclin D expression are increased in a variety of tumors and are the ultimate targets of many oncogenic signals.
  • CDK4 and CDK6 have 70% amino acid homology, CDK4 is highly expressed in most tumor tissues, while CDK6 is weakly expressed, including mRNA and protein levels.
  • the expression level of CDK4 in luminol, HER2-positive and triple-negative breast cancer is higher than that in normal tissues, and the three types are also similar, while the expression of CDK6 in breast cancer is not only weak, but also lower than normal Tissue expression level, among which the lowest expression in luminol-type breast cancer.
  • Preclinical studies have shown that the occurrence and development of breast cancer mainly depends on CDK4. High expression of cyclin D1 is a pathogenic factor of breast cancer, but its downstream effector molecules have been unclear. Yu et al.
  • CDK4 gene knockout mice have no obvious hematopoietic system damage phenotype, but will suffer from body loss, decreased fertility in male mice, infertility in female mice, and insulin-deficient diabetes.
  • CDK6 knockout mice showed damage to the hematopoietic system, including shrinkage of the thymus and atrophy of the cortex; normal white pulp in the spleen, shrinkage of the red pulp, and a slow cycle arrest in the S phase when T lymphocytes were activated. Preclinical studies have shown that CDK6 is a key factor for the activation of hematopoietic stem cells.
  • CDK6 Inhibition of CDK6 affects the reconstruction of the bone marrow hematopoietic system, thereby causing a decrease in hematopoietic or immune cells. No significant hematopoietic system damage has been found to be caused by inhibition of CDK4.
  • Ring A is a heterocyclic group
  • G is CR g or N
  • Each R 1 is the same or different, and each independently selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -(alkylene) u - NRaRb , hydroxy , hydroxyalkyl , cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • each of the cycloalkyl or heterocyclic groups is independently selected from the group consisting of halogen, alkyl, One or more of alkoxy, haloalkyl, haloalkoxy, cyano, amino, hydroxyl and hydroxyalkyl are substituted;
  • R is selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclic group;
  • R 3 , R 4 , R 5 , R 6 , R 7 , R and R g are the same or different, and each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano , -(alkylene) v -NR c R d , -C(O)R x , -C(O)NR y R z , hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and hetero Aryl, the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, Substituted by one or more of amino, hydroxyl and hydroxyalkyl;
  • R 8 and R 9 are the same or different, and each independently selected from a hydrogen atom, halogen, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl and heterocyclic group, the alkyl, cycloalkyl and heterocyclic Each group is independently optionally selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -(alkylene) w -NR e R f , hydroxyl and hydroxyalkyl multiple replaced;
  • R 8 and R 9 form a cycloalkyl or heterocyclic group together with the carbon atoms connected to them, and each of the cycloalkyl or heterocyclic groups is independently optionally selected from halogen, alkyl, alkoxy, haloalkyl , Haloalkoxy, cyano, -(alkylene) y -NR m R n , hydroxyl and hydroxyalkyl are substituted by one or more;
  • R and R form a cycloalkyl group or a heterocyclic group together with the carbon atoms connected to them, and each of the cycloalkyl groups or heterocyclic groups is independently selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, One or more of haloalkoxy, cyano, -(alkylene) z -NR j R k , hydroxyl and hydroxyalkyl;
  • R a , R b , R c , R d , Re , R f , R m , R n , R j , R k , R y and R z are the same or different, and each independently selected from a hydrogen atom, an alkyl group , haloalkyl, hydroxyalkyl and cycloalkyl;
  • R x is selected from alkyl, haloalkyl, hydroxyalkyl and cycloalkyl;
  • n is an integer from 0 to 15;
  • u 0, 1, 2, 3 or 4;
  • v 0, 1, 2, 3 or 4;
  • w 0, 1, 2, 3 or 4;
  • y is 0, 1, 2, 3 or 4;
  • z 0, 1, 2, 3 or 4.
  • the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof wherein ring A is 3 to 8 membered heterocyclic group; preferably, ring A is 4 to 6 membered Heterocyclyl; Further preferably, Ring A is a 6-membered heterocyclyl; More preferably, Ring A is tetrahydropyranyl; Most preferably, Ring A is tetrahydropyran-4-yl (ie ).
  • each R 1 is the same or different, and each independently selected from hydrogen atom, halogen, C 1- 6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, cyano, -(C 1-6 alkylene) u -NR a R b , hydroxyl and C 1-6 hydroxyalkyl, R a , R b and u are as defined in the general formula (I); preferably, each R 1 is the same or different, and each independently is a hydrogen atom or a hydroxyl group; more preferably, R 1 For hydroxyl.
  • the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof wherein m is 0, 1, 2, 3, 4, 5, 6 or 7; preferably, m is 0, 1 or 2; more preferably m is 1.
  • the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof:
  • Q is selected from NRq , O and S;
  • Rq is selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclic group;
  • R 1a , R 1b , R 1c , R 1d , R 1e , R 1f , R 1g and R 1h are the same or different, and each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy group, cyano group, -(alkylene) u -NR a R b , hydroxyl, hydroxyalkyl, cycloalkyl and heterocyclyl;
  • p 0, 1 or 2;
  • q 0, 1 or 2;
  • R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R, R a , R b and u are as defined in the general formula (I).
  • the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof wherein R 2 is selected from hydrogen atom, C 1-6 alkyl and C 1- 6 haloalkyl; preferably, R 2 is a hydrogen atom.
  • the compound represented by general formula (II) or a pharmaceutically acceptable salt thereof wherein p is 0 or 1; preferably, p is 1.
  • the compound represented by general formula (II) or a pharmaceutically acceptable salt thereof wherein q is 0 or 1; preferably, q is 1.
  • the compound represented by general formula (II) or a pharmaceutically acceptable salt thereof wherein R 1c , R 1d , R 1e , R 1f , R 1g and R 1h are the same or different, and each independently selected from hydrogen atom, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, cyano, -(C 1-6 Alkylene) u -NR a R b , hydroxyl and C 1-6 hydroxyalkyl, R a , R b and u are as defined in general formula (II); preferably, R 1c , R 1d , R 1e , R 1f , R 1g and R 1h are the same or different, and each independently selected from a hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; more preferably, R 1c , R 1d , R 1e
  • the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof :
  • Q is selected from NRq , O and S;
  • Rq is selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclic group;
  • R 1a and R 1b are the same or different, and are each independently selected from a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -(alkylene) u -NR a R b , Hydroxy, hydroxyalkyl, cycloalkyl and heterocyclyl;
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R, R a , R b and u are as defined in the general formula (I).
  • the compound represented by general formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (III-1) or Its pharmaceutically acceptable salts:
  • Q is selected from NRq , O and S;
  • Rq is selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclic group;
  • R 1a is selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -(alkylene) u - NRaRb , hydroxy, hydroxyalkyl, cycloalkyl and heterocyclyl;
  • R 1b is selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -(alkylene) u - NRaRb , hydroxyl, hydroxyalkyl, cycloalkyl and hetero ring group;
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R, R a , R b and u are as defined in the general formula (I).
  • the carbon atoms together form a 3 to 8 membered cycloalkyl group or a 3 to 8 membered heterocyclic group, and each of the 3 to 8 membered cycloalkyl groups or the 3 to 8 membered heterocyclic group is independently optionally selected from halogen, C substituted by one or more of 1-6 alkyl and C 1-6 haloalkyl; preferably, R 8 and R 9 together form a 3 to 6 membered cycloalkyl or a 3 to 6 membered heterocyclic ring with the carbon atoms to which they are attached
  • the 3 to 6-membered cycloalkyl group or the 3 to 6-membered heterocyclic group are each independently optionally selected from one or more of halogen, C 1-6 alkyl and C 1-6 haloalkyl
  • the compound represented by general formula (II) or (III) or a pharmaceutically acceptable salt thereof wherein R 1a is selected from hydrogen atom, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, cyano, -(C 1-6 alkylene) u -NR a R b , hydroxyl and C 1-6 hydroxyalkane R a , R b and u are as defined in general formula (I); preferably, R 1a is selected from hydrogen atom, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 Haloalkyl, hydroxy and C 1-6 hydroxyalkyl; more preferably, R 1a is hydroxy.
  • the compound represented by general formula (II), (III) or (III-1) or a pharmaceutically acceptable salt thereof wherein R 1a is selected from halogen, C 1-6 alkane radical, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, cyano, -(C 1-6 alkylene) u -NR a R b , hydroxyl and C 1- 6 hydroxyalkyl, R a , R b and u are as defined in general formula (I); preferably, R 1a is selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 Haloalkyl, hydroxy and C 1-6 hydroxyalkyl; more preferably, R 1a is hydroxy.
  • the compound represented by general formula (II), (III) or (III-1) or a pharmaceutically acceptable salt thereof wherein R 1b is selected from hydrogen atom, halogen, C 1 -6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, cyano, -(C 1-6 alkylene) u -NR a R b , hydroxyl and C 1-6 hydroxyalkyl, R a , R b and u are as defined in general formula (I); preferably, R 1b is selected from hydrogen atom, halogen, C 1-6 alkyl, C 1-6 alkoxy group, C 1-6 haloalkyl, hydroxyl and C 1-6 hydroxyalkyl; more preferably, R 1b is a hydrogen atom.
  • the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof wherein Q is NR q or O, R q is a hydrogen atom or a C 1-6 alkyl group; G is CR g or N; R g is selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; R 1c , R 1d , R 1e , R 1f , R 1g and R 1h are the same or different, and each independently selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; R 1a is selected from hydrogen atom, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, hydroxyl and C 1-6 hydroxyalkyl, R 1b is selected from hydrogen atom, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, hydroxy and
  • the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof wherein Q is NR q or O, R q is a hydrogen atom or a C 1-6 alkyl group; G is CR g or N; R g is selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; R 1c , R 1d , R 1e , R 1f , R 1g and R 1h are the same or different, and each independently selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; R 1a is selected from hydrogen atom, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, hydroxyl and C 1-6 hydroxyalkyl, R 1b is selected from hydrogen atom, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, hydroxy and
  • R 1a is selected from halogen, C 1-6 alkane radical, C 1-6 alkoxy, C 1-6 haloalkyl, hydroxyl and C 1-6 hydroxyalkyl
  • R 1b is selected from hydrogen atom, halogen, C 1-6 alkyl, C 1-6 alkoxy , C 1-6 haloalkyl, hydroxyl and C 1-6 hydroxyalkyl;
  • R 8 and R 9 are the same or different, and are independently C 1-6 alkyl; or the carbon atom to which R 8 and R 9 are connected form cyclopentyl or cyclohexyl together, and said cyclopentyl or cyclohexyl is optionally substituted by one or more of halogen, C 1-6 alkyl and C 1-6 haloalkyl;
  • R is selected from From C 1-6 alkyl, C 1-6 hydroxy
  • R 1a is selected from halogen, C 1-6 alkane radical, C 1-6 alkoxy, C 1-6 haloalkyl, hydroxyl and C 1-6 hydroxyalkyl
  • R 1b is selected from hydrogen atom, halogen, C 1-6 alkyl, C 1-6 alkoxy , C 1-6 haloalkyl, hydroxyl and C 1-6 hydroxyalkyl;
  • R 8 and R 9 are the same or different, and are independently C 1-6 alkyl; or the carbon atom to which R 8 and R 9 are connected
  • R 7 is selected from hydrogen atom, halogen, C 1-6 alkyl, C 1-6 haloalkyl and C 1-6
  • Typical compounds of the present disclosure include, but are not limited to:
  • X is halogen; preferably, X is Cl;
  • R is selected from Cl, Br, I, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -(alkylene) v- NRcRd , hydroxyl , hydroxyalkyl, cycloalkyl, Heterocyclyl, aryl and heteroaryl, said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from halogen, alkyl, alkoxy, haloalkyl , Haloalkoxy, cyano, amino, hydroxyl and hydroxyalkyl are substituted by one or more;
  • R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , R, R c , R d and v are as defined in the general formula (I).
  • X is halogen; preferably, X is Cl;
  • R is selected from Cl, Br, I, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -(alkylene) v- NRcRd , hydroxyl , hydroxyalkyl, cycloalkyl, Heterocyclyl, aryl and heteroaryl, said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from halogen, alkyl, alkoxy, haloalkyl , Haloalkoxy, cyano, amino, hydroxyl and hydroxyalkyl are substituted by one or more;
  • R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , R, R c , R d and v are as defined in the general formula (III).
  • Typical compounds of the disclosure include, but are not limited to:
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:
  • X is halogen; preferably, X is Cl;
  • Rings A, G, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R and m are as defined in general formula (I).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:
  • X is halogen; preferably, X is Cl;
  • R 1a , R 1b , R 1c , R 1d , R 1e , R 1f , R 1g , R 1h , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R, p and q are as defined in the general formula (II).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising:
  • X is halogen; preferably, X is Cl;
  • R 1a , R 1b , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R are as defined in general formula (III).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III-1) or a pharmaceutically acceptable salt thereof, the method comprising:
  • X is halogen; preferably, X is Cl;
  • R 1a , R 1b , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R are as defined in the general formula (III-1).
  • Another aspect of the present disclosure relates to a pharmaceutical composition containing the compounds shown in general formula (I), (II), (III), (III-1) and Table A of the present disclosure or its A pharmaceutically acceptable salt, and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the present disclosure further relates to compounds shown in general formula (I), (II), (III), (III-1) and Table A or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them in the preparation of Use in medicines for inhibiting CDK; preferably, the CDK is CDK4.
  • the present disclosure further relates to compounds shown in general formula (I), (II), (III), (III-1) and Table A or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them in the preparation of Use in medicines for the treatment and/or prevention of diseases or disorders mediated by CDK4; preferably, the diseases or disorders are selected from tumors, myelofibrosis, myelodysplastic syndrome, pulmonary hypertension, hypertension, neurodegeneration diseases and mucositis; more preferably, said disease or condition is cancer.
  • the present disclosure further relates to compounds shown in general formula (I), (II), (III), (III-1) and Table A or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them in the preparation of Use in medicine for treating and/or preventing diseases or conditions; wherein said diseases or conditions are selected from breast cancer, endometrial cancer, ovarian cancer, vaginal cancer, fallopian tube cancer, cervical cancer, kidney cancer, bladder cancer, urinary Carcinoma of the road, urethra, prostate, testis, colorectum, sarcoma, bone, multiple myeloma, leukemia, myxoma, rhabdomyoma, leiomyoma, fibroma, lipoma, teratoma, laryngeal Carcinoma, nasopharyngeal cancer, oral cancer, lung cancer, lymphoma, mesothelioma, small intestine cancer, gastric cancer, esophageal cancer, pancreatic cancer, liver cancer
  • the present disclosure further relates to a method for inhibiting CDK, which comprises administering a therapeutically effective amount of a compound shown in general formula (I), (II), (III), (III-1) and Table A to a patient in need, or an alternative thereof A pharmaceutically acceptable salt, or a pharmaceutical composition comprising it; preferably, the CDK is CDK4.
  • the present disclosure further relates to a method of treating and/or preventing a disease or condition mediated by CDK4, which comprises administering a therapeutically effective amount of the general formula (I), (II), (III), (III-1) to a patient in need ) and a compound shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it; preferably, the disease or disease is selected from tumors, myelofibrosis, myelodysplastic syndrome, pulmonary hypertension, Hypertension, neurodegenerative disease and mucositis; more preferably, said disease or condition is cancer.
  • the present disclosure further relates to a method for treating and/or preventing a disease or a disease, which comprises administering a therapeutically effective amount of the compounds of general formula (I), (II), (III), (III-1) and Table A to a patient in need.
  • said disease or disease is selected from breast cancer, endometrial cancer, ovarian cancer, vaginal cancer, fallopian tube cancer, cervical cancer, kidney cancer , bladder cancer, urothelial cancer, urethral cancer, prostate cancer, testicular cancer, colorectal cancer, sarcoma, bone cancer, multiple myeloma, leukemia, myxoma, rhabdomyoma, leiomyoma, fibroma, lipoma, Teratoma, laryngeal cancer, nasopharyngeal cancer, oral cancer, lung cancer, lymphoma, mesothelioma, small intestine cancer, stomach cancer, esophagus cancer, pancreatic cancer, liver cancer, bile duct cancer, biliary tract cancer, gallbladder cancer, peritoneal cancer, thymus cancer , central nervous system tumors, retinoblastoma
  • the present disclosure further relates to a compound shown in general formula (I), (II), (III), (III-1) and Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it, which is used for as medicine.
  • the present disclosure further relates to a compound shown in general formula (I), (II), (III), (III-1) and Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it, which is used for As a drug for inhibiting CDK; preferably, said CDK is CDK4.
  • the present disclosure further relates to a compound shown in general formula (I), (II), (III), (III-1) and Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it, which is used for As a medicine for treating and/or preventing diseases or diseases; wherein said diseases or diseases are selected from breast cancer, endometrial cancer, ovarian cancer, vaginal cancer, fallopian tube cancer, cervical cancer, kidney cancer, bladder cancer, urothelial Carcinoma, urethral cancer, prostate cancer, testicular cancer, colorectal cancer, sarcoma, bone cancer, multiple myeloma, leukemia, myxoma, rhabdomyoma, leiomyoma, fibroma, lipoma, teratoma, laryngeal cancer, Nasopharyngeal cancer, oral cancer, lung cancer, lymphoma, mesothelioma, small intestine cancer, stomach cancer, esophagus cancer, pancreatic
  • the disease or disease mediated by CDK4 described in the present disclosure is preferably selected from tumor, myelofibrosis, myelodysplastic syndrome, pulmonary hypertension, hypertension, neurodegenerative disease and mucositis; more preferably, the The disease or condition is cancer.
  • the disease or condition mediated by CDK4 described in the present disclosure is preferably selected from breast cancer, endometrial cancer, ovarian cancer, vaginal cancer, fallopian tube cancer, cervical cancer, kidney cancer, bladder cancer, urothelial cancer, urethral cancer , prostate cancer, testicular cancer, colorectal cancer, sarcoma, bone cancer, multiple myeloma, leukemia, myxoma, rhabdomyoma, leiomyoma, fibroma, lipoma, teratoma, laryngeal cancer, nasopharyngeal cancer, Oral cancer, lung cancer, lymphoma, mesothelioma, small intestine cancer, stomach cancer, esophagus cancer, pancreatic cancer, liver cancer, bile duct cancer, biliary tract cancer, gallbladder cancer, peritoneal cancer, thymus cancer, central nervous system tumor, retinoblastoma, Glio
  • the lymphoma described in the present disclosure is selected from Hodgkin's disease and non-Hodgkin's lymphoma (e.g., mantle cell lymphoma, diffuse large B-cell lymphoma, follicle center lymphoma, marginal zone B-cell lymphoma) Lymphoma, lymphoplasmacytic lymphoma and peripheral T-cell lymphoma); said lung cancer is non-small cell lung cancer (NSCLC) (such as lung squamous cell carcinoma and lung adenocarcinoma, wherein lung adenocarcinoma is preferably bronchioloalveolar carcinoma) and Small cell lung cancer (SCLC); the kidney cancer is selected from renal cell carcinoma (RCC), clear cell and renal oncocytoma; the liver cancer is hepatocellular carcinoma (HCC); the neuroblastoma ( Also known as neuroblastoma) is medulloblastoma; the pancreatic cancer is pancreatic ductal adenocarcino
  • the compounds of the present disclosure or pharmaceutically acceptable salts thereof or pharmaceutical compositions comprising the same have higher selectivity for CDK4 than for CDK6.
  • the active compounds of the present disclosure are preferably presented in unit dosage form, or in such a form that the patient can self-administer as a single dose.
  • the unit dosage form of a compound or composition of the present disclosure may be presented as a tablet, capsule, cachet, bottle, powder, granule, lozenge, suppository, reconstitution powder or liquid preparation.
  • a suitable unit dosage may be from 0.1 to 1000 mg.
  • the pharmaceutical composition of the present disclosure may contain one or more auxiliary materials selected from the following components: fillers (diluents), binders, wetting agents, disintegrants or excipients wait.
  • auxiliary materials selected from the following components: fillers (diluents), binders, wetting agents, disintegrants or excipients wait.
  • the compositions may contain from 0.1 to 99% by weight of active compound.
  • the pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixir.
  • Oral compositions can be prepared according to any method known in the art for the preparation of pharmaceutical compositions, and such compositions can contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, coloring agents and preservatives, To provide pleasing and palatable medicinal preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets.
  • excipients may be inert excipients, granulating agents, disintegrants, binders and lubricants. These tablets may be uncoated or may be coated by known techniques to mask the taste of the drug or to delay disintegration and absorption in the gastrointestinal tract, thus providing sustained release over an extended period of time.
  • Oral formulations can also be provided in soft gelatin capsules, wherein the active ingredient is mixed with an inert solid diluent, or where the active ingredient is mixed with a water-soluble carrier or an oil vehicle.
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending, dispersing or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents and one or more sweetening agents.
  • Oily suspensions can be formulated by suspending the active ingredient in a vegetable or mineral oil.
  • the oily suspensions may contain a thickening agent.
  • Sweetening and flavoring agents as mentioned above may be added to provide a palatable preparation. These compositions can be preserved by adding antioxidants.
  • compositions of the present disclosure may also be in the form of oil-in-water emulsions.
  • the oily phase may be vegetable oil, mineral oil or mixtures thereof.
  • Suitable emulsifiers may be naturally occurring phospholipids, and the emulsions may also contain sweetening agents, flavoring agents, preservatives and antioxidants.
  • Such formulations may also contain a demulcent, a preservative, coloring agents and antioxidants.
  • compositions of the present disclosure may be in the form of sterile injectable aqueous solutions.
  • acceptable vehicles or solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • the sterile injectable preparation can be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oily phase, and the injection or microemulsion can be injected into the patient's bloodstream by local bulk injection.
  • solutions and microemulsions are preferably administered in a manner that maintains a constant circulating concentration of the disclosed compounds.
  • a continuous intravenous delivery device can be used.
  • An example of such a device is the Deltec CADD-PLUS.TM. Model 5400 IV pump.
  • compositions of the present disclosure may be in the form of sterile injectable aqueous or oily suspensions for intramuscular and subcutaneous administration.
  • This suspension may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension prepared in a parenterally acceptable non-toxic diluent or solvent.
  • sterile fixed oils are conveniently employed as a solvent or suspending medium. For this purpose, any blended and fixed oil may be used.
  • fatty acids are also used in the preparation of injectables.
  • the disclosed compounds may be administered in the form of suppositories for rectal administration.
  • These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and will therefore melt in the rectum to release the drug.
  • the dosage of the drug to be administered depends on many factors, including but not limited to the following factors: the activity of the specific compound used, the age of the patient, the weight of the patient, the state of health of the patient, the behavior of the patient , the patient's diet, administration time, administration method, excretion rate, drug combination, disease severity, etc.; in addition, the optimal treatment method such as the mode of treatment, the daily dosage of the compound or the pharmaceutically acceptable salt Kinds can be validated against traditional treatment regimens.
  • alkyl refers to a saturated linear or branched aliphatic hydrocarbon group having 1 to 20 (for example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (ie C 1-20 alkyl).
  • the alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (ie, a C 1-12 alkyl group), more preferably an alkyl group having 1 to 6 carbon atoms (ie, a C 1-6 alkyl group).
  • 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, 5-methyl
  • Alkyl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, substituents are preferably selected from D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, ring One or more of alkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • alkylene refers to a divalent alkyl group, wherein alkyl is as defined above, having from 1 to 20 (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 , 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (ie C 1-20 alkylene).
  • the alkylene group is preferably an alkylene group having 1 to 12 carbon atoms (ie, a C 1-12 alkylene group), more preferably an alkylene group having 1 to 6 carbon atoms (ie, a C 1-6 alkylene group).
  • Non-limiting examples include : -CH2- , -CH( CH3 )-, -C ( CH3 ) 2- , -CH2CH2-, -CH( CH2CH3 )-, -CH2CH (CH 3 )-, -CH 2 C(CH 3 ) 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, etc.
  • the alkylene group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents being preferably selected from D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, One or more of cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • alkenyl refers to an alkyl group containing at least one carbon-carbon double bond in the molecule, wherein the definition of the alkyl group is as above, and it has 2 to 12 (such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (ie C 2-12 alkenyl).
  • the alkenyl group is preferably an alkenyl group having 2 to 6 carbon atoms (ie, a C 2-6 alkenyl group).
  • Non-limiting examples include: vinyl, propenyl, isopropenyl, butenyl, and the like.
  • Alkenyl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents being preferably selected from D atoms, alkoxy, halogen, haloalkyl, haloalkoxy, ring One or more of alkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • alkynyl refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, wherein the definition of the alkyl group is as described above, and it has 2 to 12 (such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (ie C 2-12 alkynyl).
  • the alkynyl group is preferably an alkynyl group having 2 to 6 carbon atoms (ie, a C 2-6 alkynyl group).
  • Non-limiting examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.
  • Alkynyl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, the substituents being preferably selected from D atoms, alkoxy, halogen, haloalkyl, haloalkoxy, ring One or more of alkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • alkoxy refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples include: methoxy, ethoxy, propoxy, and butoxy, and the like. Alkoxy may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, substituents are preferably selected from D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, One or more of cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic full carbocycle (ie monocyclic cycloalkyl) or polycyclic ring system (ie polycyclic cycloalkyl) having 3 to 20 (eg 3, 4 , 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (ie 3 to 20 membered cycloalkyl).
  • the cycloalkyl group is preferably a cycloalkyl group having 3 to 12 ring atoms (i.e. a 3 to 12 membered cycloalkyl group), more preferably a cycloalkyl group having 3 to 8 ring atoms (i.e. a 3 to 8 membered cycloalkyl group). ), most preferably a cycloalkyl group having 3 to 6 ring atoms (ie a 3 to 6 membered cycloalkyl group).
  • Said monocyclic cycloalkyl non-limiting examples include: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl , cycloheptatrienyl and cyclooctyl, etc.
  • the polycyclic cycloalkyl includes: spirocycloalkyl, condensed cycloalkyl and bridged cycloalkyl.
  • spirocycloalkyl refers to a polycyclic ring system that shares one carbon atom (called a spiro atom) between the rings, which may contain one or more double bonds in the ring, or may contain one or more rings selected from nitrogen, Oxygen and sulfur heteroatoms (the nitrogen may be optionally oxidized, i.e. form nitrogen oxides; the sulfur may be optionally oxo, i.e.
  • the spirocycloalkyl is preferably a spirocycloalkyl having 6 to 14 ring atoms (i.e.
  • spirocycloalkyl a 6 to 14 membered spirocycloalkyl, more preferably a spirocycloalkyl having 7 to 10 ring atoms (i.e. 7 to 10 member spirocycloalkyl).
  • the spirocycloalkyl group includes single spirocycloalkyl and polyspirocycloalkyl (such as double spirocycloalkyl, etc.), preferably single spirocycloalkyl or double spirocycloalkyl, more preferably 3-membered/4-membered, 3-membered Yuan/5 yuan, 3 yuan/6 yuan, 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/3 yuan, 5 yuan/4 yuan, 5 yuan/5 yuan, 5 yuan/ 6
  • connection point can be at any position
  • fused cycloalkyl refers to a polycyclic ring system in which two adjacent carbon atoms are shared between the rings, which is a monocyclic cycloalkyl fused to one or more monocyclic cycloalkyls, or a monocyclic cycloalkyl to a heterocyclic
  • cyclic groups, aryl groups or heteroaryl groups are condensed, wherein the point of attachment is on the monocyclic cycloalkyl group, which can contain one or more double bonds in the ring, and have 5 to 20 (for example, 5 , 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (ie 5 to 20 membered fused cycloalkyl).
  • the condensed cycloalkyl group is preferably a condensed cycloalkyl group having 6 to 14 ring atoms (i.e. a 6 to 14 membered fused cycloalkyl group), more preferably a fused cycloalkyl group having 7 to 10 ring atoms (i.e. 7 to 10 fused cycloalkyl).
  • the fused cycloalkyl includes bicyclic fused cycloalkyl and polycyclic fused cycloalkyl (such as tricyclic fused cycloalkyl, tetracyclic fused cycloalkyl, etc.), preferably bicyclic fused cycloalkyl or tricyclic fused cycloalkyl , more preferably 3 yuan/4 yuan, 3 yuan/5 yuan, 3 yuan/6 yuan, 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/3 yuan, 5 yuan/4 yuan , 5 yuan/5 yuan, 5 yuan/6 yuan, 5 yuan/7 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 yuan/5 yuan, 6 y
  • connection point can be at any position
  • bridged cycloalkyl refers to an all-carbon polycyclic ring system that shares two carbon atoms not directly connected between the rings, may contain one or more double bonds in the ring, and has 5 to 20 (for example, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (ie, 5 to 20 membered bridged cycloalkyl).
  • the bridged cycloalkyl group is preferably a bridged cycloalkyl group having 6 to 14 carbon atoms (i.e. a 6 to 14 membered bridged cycloalkyl group), more preferably a bridged cycloalkyl group having 7 to 10 carbon atoms (i.e.
  • the bridged cycloalkyl includes bicyclic bridged cycloalkyl and polycyclic bridged cycloalkyl (such as tricyclic bridged cycloalkyl, tetracyclic bridged cycloalkyl, etc.), preferably bicyclic bridged cycloalkyl or tricyclic bridged cycloalkyl .
  • Non-limiting examples include:
  • Cycloalkyl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, substituents are preferably selected from D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkane One of oxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl or more.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic heterocycle (i.e. monocyclic heterocyclyl) or polycyclic heterocyclic ring system (i.e. polycyclic heterocyclyl) containing at least one (eg 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may optionally be oxidized, i.e. form nitrogen oxides; the sulfur may optionally be oxo, i.e.
  • the heterocyclic group is preferably a heterocyclic group having 3 to 12 ring atoms (i.e. a 3 to 12 membered heterocyclic group); further preferably a heterocyclic group having 3 to 8 ring atoms (i.e.
  • a 3 to 8 membered heterocyclic group ); more preferably a heterocyclic group with 3 to 6 ring atoms (ie, a 3 to 6 membered heterocyclic group), a heterocyclic group with 4 to 6 ring atoms (ie, a 4 to 6 membered heterocyclic group) or a heterocyclic group with 5
  • a heterocyclyl group having up to 7 ring atoms ie, a 5- to 7-membered heterocyclyl group
  • Non-limiting examples of the monocyclic heterocyclic group include: pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl , Thiomorpholinyl and Homopiperazinyl, etc.
  • the polycyclic heterocyclic groups include spiro heterocyclic groups, condensed heterocyclic groups and bridged heterocyclic groups.
  • spiroheterocyclyl refers to a polycyclic heterocyclic ring system that shares one atom (called a spiro atom) between the rings, which may contain one or more double bonds in the ring, and at least one (such as 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized, i.e. to form nitrogen oxides; the sulfur may be optionally oxo, i.e.
  • the condition is to contain at least one monocyclic heterocyclic group and the point of attachment is on the monocyclic heterocyclic group, which has 5 to 20 (such as 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (ie 5 to 20 membered spiroheterocyclyl).
  • the spiroheterocyclyl is preferably a spiroheterocyclyl having 6 to 14 ring atoms (i.e.
  • the spiroheterocyclyl includes single spiroheterocyclyl and polyspiroheterocyclyl (such as double spiroheterocyclyl, etc.), preferably single spiroheterocyclyl or double spiroheterocyclyl, more preferably 3-membered/4-membered, 3-membered Yuan/5 yuan, 3 yuan/6 yuan, 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/3 yuan, 5 yuan/4 yuan, 5 yuan/5 yuan, 5 yuan/ 6 yuan,
  • fused heterocyclyl refers to a polycyclic heterocyclic ring system which shares two adjacent atoms between the rings, which may contain one or more double bonds, and which contains at least one (for example, 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized, i.e. to form nitrogen oxides; the sulfur may be optionally oxo, i.e.
  • sulfoxides or sulfones but not Including -O-O-, -O-S- or -S-S-), which is a monocyclic heterocyclic group fused with one or more monocyclic heterocyclic groups, or a monocyclic heterocyclic group with a cycloalkyl, aryl or heteroaryl
  • the fused heterocyclic group is preferably a fused heterocyclic group having 6 to 14 ring atoms (ie, a 6 to 14 membered fused heterocyclic group), more preferably a condensed heterocyclic group having 7 to 10 ring atoms (ie, 7 to 10 membered fused heterocyclyl).
  • the fused heterocyclic group includes bicyclic and polycyclic fused heterocyclic groups (such as tricyclic fused heterocyclic groups, tetracyclic fused heterocyclic groups, etc.), preferably bicyclic fused heterocyclic groups or tricyclic fused heterocyclic groups, more preferably 3 Yuan/4 Yuan, 3 Yuan/5 Yuan, 3 Yuan/6 Yuan, 4 Yuan/4 Yuan, 4 Yuan/5 Yuan, 4 Yuan/6 Yuan, 5 Yuan/3 Yuan, 5 Yuan/4 Yuan, 5 Yuan/ 5 yuan, 5 yuan/6 yuan, 5 yuan/7 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 yuan/5 yuan, 6 yuan/6 yuan, 6 yuan/7 yuan, 7 yuan/5 yuan Or a 7-membered/6-membered bicyclic condensed heterocyclic group.
  • bridged heterocyclyl refers to a polycyclic heterocyclic ring system that shares two atoms that are not directly connected between the rings, and may contain one or more double bonds in the ring, and at least one (for example, 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized, i.e. to form nitrogen oxides; the sulfur may be optionally oxo, i.e.
  • the bridged heterocyclic group is preferably a bridged heterocyclic group having 6 to 14 ring atoms (i.e. a 6 to 14 membered bridged heterocyclic group), more preferably a bridged heterocyclic group having 7 to 10 ring atoms (i.e. 7 to 10 bridged heterocyclyl).
  • bicyclic bridged heterocyclic group and polycyclic bridged heterocyclic group such as tricyclic bridged heterocyclic group, tetracyclic bridged heterocyclic group, etc.
  • bicyclic bridged heterocyclic group or tricyclic bridged heterocyclic group base preferably bicyclic bridged heterocyclic group or tricyclic bridged heterocyclic group base.
  • Non-limiting examples include:
  • the heterocyclyl group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents are preferably selected from D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkane One of oxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl or more.
  • aryl refers to a monocyclic all-carbon aromatic ring (i.e., a monocyclic aryl) or a polycyclic aromatic ring system (i.e., a polycyclic aryl) having a conjugated ⁇ -electron system, which has 6 to 14 (e.g., 6 , 7, 8, 9, 10, 11, 12, 13 or 14) ring atoms (ie 6 to 14 membered aryl).
  • the aryl group is preferably an aryl group having 6 to 10 ring atoms (ie, a 6 to 10 membered aryl group).
  • the monocyclic aryl group such as phenyl.
  • Non-limiting examples of the polycyclic aryl group include: naphthyl, anthracenyl, phenanthrenyl and the like.
  • the polycyclic aryl also includes the condensing of phenyl with one or more of heterocyclic or cycloalkyl, or the fused of naphthyl with one or more of heterocyclic or cycloalkyl, wherein the connection point On phenyl or naphthyl, and in this case, the number of ring atoms continues to mean the number of ring atoms in a polycyclic aromatic ring system, non-limiting examples include:
  • Aryl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, substituents are preferably selected from D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy one or Multiple.
  • heteroaryl refers to a monocyclic heteroaryl ring (ie, monocyclic heteroaryl) or a polycyclic heteroaryl ring system (ie, polycyclic heteroaryl) having a conjugated ⁇ -electron system, which contains at least one (eg 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may optionally be oxidized, i.e. form nitrogen oxides; the sulfur may optionally be oxo, i.e.
  • the heteroaryl group is preferably a heteroaryl group having 5 to 10 ring atoms (i.e. a 5 to 10 membered heteroaryl group), more preferably a heteroaryl group having 5 or 6 ring atoms (i.e. a 5 or 6 membered heteroaryl group).
  • Non-limiting examples of the monocyclic heteroaryl include: furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl , pyrazolyl, triazolyl, tetrazolyl, furazanyl, pyrrolyl, N-alkylpyrrolyl, pyridyl, pyrimidinyl, pyridonyl, N-alkylpyridone (such as etc.), pyrazinyl, pyridazinyl, etc.
  • the polycyclic heteroaryl non-limiting examples include: indolyl, indazolyl, quinolinyl, isoquinolyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothiophene group, quinazoline group, benzothiazolyl group, carbazolyl group, etc.
  • the polycyclic heteroaryl also includes a monocyclic heteroaryl fused with one or more aryls, wherein the point of attachment is on the aromatic ring, and in this case the number of ring atoms continues to represent the polycyclic heteroaryl The number of ring atoms in the system.
  • the polycyclic heteroaryl also includes monocyclic heteroaryl fused with one or more of cycloalkyl or heterocyclic, wherein the point of attachment is on the monocyclic heteroaryl ring, and in this case, the ring
  • the number of atoms continues to indicate the number of ring atoms in the polycyclic heteroaryl ring system.
  • Non-limiting examples include:
  • Heteroaryl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, substituents are preferably selected from D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkane One or more of oxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • amino-protecting group refers to an easily detachable group introduced on an amino group in order to keep the amino group unchanged when other parts of the molecule are reacted.
  • Non-limiting examples include: (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), methoxycarbonyl (Fmoc), allyl Oxycarbonyl (Alloc), Trimethylsilylethoxycarbonyl (Teoc), Methoxycarbonyl, Ethoxycarbonyl, Phthalyl (Pht), p-Toluenesulfonyl (Tos), Trifluoroacetyl (Tfa), Trityl (Trt), 2,4-dimethoxybenzyl (DMB), acetyl, benzyl, allyl, p-methoxybenzyl, etc.
  • hydroxyl protecting group refers to an easy-to-remove group introduced on the hydroxyl group, which is used to block or protect the hydroxyl group and react on other functional groups of the compound.
  • Non-limiting examples include: trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS), tert-butyl Diphenylsilyl (TBDPS), methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), methyl Acyl, acetyl, benzoyl, p-nitrobenzoyl, etc.
  • cycloalkyloxy refers to cycloalkyl-O-, wherein cycloalkyl is as defined above.
  • heterocyclyloxy refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.
  • aryloxy refers to aryl-O-, wherein aryl is as defined above.
  • heteroaryloxy refers to heteroaryl-O-, wherein heteroaryl is as defined above.
  • alkylthio refers to alkyl-S-, wherein alkyl is as defined above.
  • haloalkyl refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogens, wherein alkoxy group is as defined above.
  • deuteroalkyl refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.
  • hydroxyalkyl refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • hydroxyl refers to -OH.
  • mercapto refers to -SH.
  • amino refers to -NH2 .
  • cyano refers to -CN.
  • nitro refers to -NO2 .
  • carboxylate refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O- or (cycloalkyl)C(O )O-, wherein alkyl and cycloalkyl are as defined above.
  • stereoisomer refers to isomers that are identical in structure but differ in the arrangement of the atoms in space. It includes cis and trans (or Z and E) isomers, (-)- and (+)-isomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)- and (L)-isomers, tautomers, atropisomers, conformers and mixtures thereof (e.g. racemates, mixtures of diastereomers) . Substituents in compounds of the present disclosure may be present with additional asymmetric atoms.
  • Optically active (-)- and (+)-isomers, (R)- and (S)-enantiomers, and (D)- and (L)-isomer Optically active (-)- and (+)-isomers, (R)- and (S)-enantiomers, and (D)- and (L)-isomer.
  • An isomer of a certain compound in the present disclosure can be prepared by asymmetric synthesis or chiral auxiliary agents, or, when the molecule contains a basic functional group (such as amino) or an acidic functional group (such as carboxyl), with appropriate optical Reactive acids or bases form diastereomeric salts, which are then resolved by conventional methods well known in the art to yield the pure isomers. Furthermore, separation of enantiomers and diastereomers is usually accomplished by chromatography.
  • the bond Indicates that no configuration is specified, that is, if chiral isomers exist in the chemical structure, the bond can be or or both and Two configurations. For all carbon-carbon double bonds, even if only one configuration is named, both Z and E forms are included.
  • tautomer or tautomeric form
  • tautomer refers to structural isomers that exist in equilibrium and are readily converted from one isomeric form to the other. It includes all possible tautomers, ie present as single isomers or as mixtures of said tautomers in any ratio. Non-limiting examples include: keto-enol, imine-enamine, lactam-lactam, and the like. An example of a lactam-lactam equilibrium is shown below:
  • isotopic derivatives refers to a compound in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass.
  • isotopes that may be incorporated into compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, etc., such as 2 H (deuterium, D), respectively, 3 H (tritium, T), 11 C, 13 C, 14 C, 15 N , 17 O, 18 O, 32 p, 33 p, 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl, 82 Br, 123 I, 124 I, 125 I, 129 I, and 131 I, etc., preferably deuterium.
  • deuterated drugs Compared with non-deuterated drugs, deuterated drugs have the advantages of reducing toxic and side effects, increasing drug stability, enhancing curative effect, and prolonging the biological half-life of drugs. All permutations of isotopic composition of the disclosed compounds, whether radioactive or not, are included within the scope of the present disclosure.
  • Each available hydrogen atom attached to a carbon atom may be independently replaced by a deuterium atom, wherein the replacement of deuterium may be partial or complete, and partial deuterium replacement means that at least one hydrogen is replaced by at least one deuterium.
  • this position is understood to mean that the abundance of deuterium is at least 1000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e. at least 15% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 1000 times greater than the natural abundance of deuterium (ie, at least 15% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 2000 times greater than the natural abundance of deuterium (ie, at least 30% deuterium incorporation).
  • the abundance of deuterium per designated deuterium atom is at least 3000 times greater than the natural abundance of deuterium (ie, at least 45% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 3340 times greater than the natural abundance of deuterium (ie, at least 50.1% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 3500 times greater than the natural abundance of deuterium (ie, at least 52.5% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 4000 times greater than the natural abundance of deuterium (ie, at least 60% deuterium incorporation).
  • the abundance of deuterium per designated deuterium atom is at least 4500 times greater than the natural abundance of deuterium (ie, at least 67.5% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 5000 times greater than the natural abundance of deuterium (ie, at least 75% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 5500 times greater than the natural abundance of deuterium (ie, at least 82.5% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 6000 times greater than the natural abundance of deuterium (ie, at least 90% deuterium incorporation).
  • the abundance of deuterium per designated deuterium atom is at least 6333.3 times greater than the natural abundance of deuterium (ie, at least 95% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 6466.7 times greater than the natural abundance of deuterium (ie, at least 97% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 6600 times greater than the natural abundance of deuterium (ie, at least 99% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 6633.3 times greater than the natural abundance of deuterium (i.e., at least 99.5% deuterium incorporation).
  • alkyl optionally (optionally) substituted by halogen or cyano includes the case where the alkyl is substituted by halogen or cyano and the case where the alkyl is not substituted by halogen or cyano.
  • Substituted or “substituted” means that one or more hydrogen atoms in a group, preferably 1 to 6, more preferably 1 to 3 hydrogen atoms are independently substituted by the corresponding number of substituents. Possible or impossible substitutions can be determined (by experiment or theory) by those skilled in the art without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated bond such as an alkene.
  • “Pharmaceutical composition” means a mixture containing one or more compounds described herein, or a pharmaceutically acceptable salt thereof, and other chemical components, such as pharmaceutically acceptable carriers and excipients.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and thus exert biological activity.
  • “Pharmaceutically acceptable salt” refers to a salt of a compound of the present disclosure, which may be selected from inorganic or organic salts. Such salts are safe and effective when used in mammals, and have proper biological activity. They can be prepared separately during the final isolation and purification of the compound, or by reacting the appropriate group with an appropriate base or acid.
  • Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids as well as organic acids.
  • the term "therapeutically effective amount” refers to an amount of the drug or agent sufficient to achieve, or at least partially achieve, the desired effect.
  • the determination of the therapeutically effective dose varies from person to person, depending on the age and general condition of the recipient, and also depends on the specific active substance. The appropriate therapeutically effective dose in individual cases can be determined by those skilled in the art according to routine tests.
  • the term "pharmaceutically acceptable” means those compounds, materials, compositions and/or dosage forms, which are suitable for use in contact with patient tissues without undue toxicity, irritation, allergic reaction or Other problems or complications that have a reasonable benefit/risk ratio and are valid for the intended use.
  • the preparation method of the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof of the present disclosure comprises:
  • X is halogen; preferably, X is Cl;
  • Rings A, G, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R and m are as defined in general formula (I).
  • the preparation method of the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof of the present disclosure comprises:
  • X is halogen; preferably, X is Cl;
  • R 1a , R 1b , R 1c , R 1d , R 1e , R 1f , R 1g , R 1h , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R, p and q are as defined in the general formula (II).
  • the preparation method of the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof of the present disclosure comprises:
  • X is halogen; preferably, X is Cl;
  • R 1a , R 1b , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R are as defined in general formula (III).
  • the preparation method of the compound represented by the general formula (III-1) or a pharmaceutically acceptable salt thereof of the present disclosure comprises:
  • X is halogen; preferably, X is Cl;
  • R 1a , R 1b , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R are as defined in the general formula (III-1).
  • the reagents that provide basic conditions in the above synthesis scheme include organic bases and inorganic bases.
  • the organic bases include but are not limited to triethylamine, pyridine, N,N-diisopropylethylamine, n-butyllithium, Lithium diisopropylamide, sodium acetate, potassium acetate, sodium tert-butoxide, potassium tert-butoxide or 1,8-diazabicycloundec-7-ene;
  • the inorganic bases include but are not limited to Sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide and potassium hydroxide; preferably N,N-diisopropylethylamine.
  • the reaction of the above steps is preferably carried out in a solvent, and the solvent used includes but is not limited to: pyridine, ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, methylene chloride, petroleum ether, Ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylacetamide, 1,2-dibromo Ethane and its mixtures.
  • the solvent used includes but is not limited to: pyridine, ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, methylene chloride, petroleum ether, Ethyl acetate, n-hex
  • NMR nuclear magnetic resonance
  • MS mass spectroscopy
  • MS uses Agilent 1200/1290 DAD-6110/6120 Quadrupole MS liquid mass spectrometer (manufacturer: Agilent, MS model: 6110/6120Quadrupole MS), waters ACQuity UPLC-QD/SQD (manufacturer: waters, MS model : waters ACQuity Qda Detector/waters SQ Detector), THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).
  • HPLC High-performance liquid chromatography
  • Chiral HPLC analysis was performed using an Agilent 1260 DAD high performance liquid chromatograph.
  • the CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).
  • the thin-layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate.
  • the specification of the silica gel plate used in thin-layer chromatography (TLC) is 0.15mm-0.2mm, and the specification of thin-layer chromatography separation and purification products is 0.4mm. ⁇ 0.5mm.
  • Silica gel column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
  • the known starting materials of the present disclosure can be adopted or synthesized according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (Accela ChemBio Inc), Darui chemical companies.
  • the reactions can all be carried out under an argon atmosphere or a nitrogen atmosphere.
  • Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a volume of about 1 L.
  • the hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.
  • the pressurized hydrogenation reaction uses Parr 3916EKX hydrogenation instrument and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenation instrument.
  • the hydrogenation reaction is usually vacuumized and filled with hydrogen, and the operation is repeated 3 times.
  • the solution refers to an aqueous solution.
  • reaction temperature is room temperature, which is 20°C to 30°C.
  • the monitoring of the reaction process in the embodiment adopts thin-layer chromatography (TLC), the developer used for reaction, the eluent system of the column chromatography that purifies compound adopts and the developer system of thin-layer chromatography comprise: A: Dichloromethane/methanol system, B: n-hexane/ethyl acetate system, C: petroleum ether/ethyl acetate system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of triethylamine and Alkaline or acidic reagents such as acetic acid for adjustment.
  • TLC thin-layer chromatography
  • reaction solution was concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography (Waters-2545, chromatographic column: YMC Triart-Exrs, Prep 30*150mm, 5 ⁇ m, C18; mobile phase: aqueous phase (10mmol/L ammonium bicarbonate) and Acetonitrile, gradient ratio: acetonitrile 40%-55%, flow rate: 30 mL/min) was purified to obtain the title compound 2 (10 mg, yield: 5.2%).
  • high performance liquid chromatography Waters-2545, chromatographic column: YMC Triart-Exrs, Prep 30*150mm, 5 ⁇ m, C18; mobile phase: aqueous phase (10mmol/L ammonium bicarbonate) and Acetonitrile, gradient ratio: acetonitrile 40%-55%, flow rate: 30 mL/min
  • reaction solution was concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography (Waters-2545, chromatographic column: YMC Triart-Exrs, Prep 30*150mm, 5 ⁇ m, C18; mobile phase: aqueous phase (10mmol/L ammonium bicarbonate) and Acetonitrile, gradient ratio: acetonitrile 30%-45%, flow rate: 30 mL/min) was purified to obtain the title compound 3 (43 mg, yield: 22.9%).
  • high performance liquid chromatography Waters-2545, chromatographic column: YMC Triart-Exrs, Prep 30*150mm, 5 ⁇ m, C18; mobile phase: aqueous phase (10mmol/L ammonium bicarbonate) and Acetonitrile, gradient ratio: acetonitrile 30%-45%, flow rate: 30 mL/min
  • reaction solution was concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography (Waters-2545, chromatographic column: YMC Triart-Exrs, Prep 30*150mm, 5 ⁇ m, C18; mobile phase: aqueous phase (10mmol/L ammonium bicarbonate) and Acetonitrile, gradient ratio: acetonitrile 30%-45%, flow rate: 30 mL/min) was purified to obtain the title compound 4 (28 mg, yield: 8.5%).
  • high performance liquid chromatography Waters-2545, chromatographic column: YMC Triart-Exrs, Prep 30*150mm, 5 ⁇ m, C18; mobile phase: aqueous phase (10mmol/L ammonium bicarbonate) and Acetonitrile, gradient ratio: acetonitrile 30%-45%, flow rate: 30 mL/min
  • reaction solution was concentrated under reduced pressure, and the residue was analyzed by high performance liquid chromatography Method (Waters-2545, chromatographic column: YMC Triart-Exrs, Prep 30*150mm, 5 ⁇ m, C18; mobile phase: aqueous phase (10mmol/L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-45%, Flow rate: 30 mL/min) to obtain a mixture of title compounds 7b and 7c (50 mg, yield: 4%) and 7d (70 mg, yield: 5.7%).
  • chromatographic column YMC Triart-Exrs, Prep 30*150mm, 5 ⁇ m, C18
  • mobile phase aqueous phase (10mmol/L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-45%, Flow rate: 30 mL/min
  • the third step raw material compound 1d was replaced by a mixture of compounds 7b and 7c to obtain the title compound 7-p1 (5 mg, yield: 10.3%) and 7-p2 (4 mg, yield: 8.3%).
  • HPLC analysis retention time 2.623 minutes, purity: 96% (chromatographic column: C18, 2.7 ⁇ m, 3.0*30mm; mobile phase: water (1 ⁇ trifluoroacetic acid), acetonitrile, gradient ratio: acetonitrile 10%-95%).
  • HPLC analysis retention time 2.670 minutes, purity: 95% (chromatographic column: C18, 2.7 ⁇ m, 3.0*30mm; mobile phase: water (1 ⁇ trifluoroacetic acid), acetonitrile, gradient ratio: acetonitrile 10%-95%).
  • the third step raw material compound 1d was replaced by a mixture of compounds 8e and 8f to obtain the title compound 8-p1 (10 mg, yield: 4.1%) and 8-p2 (30 mg, yield: 12.4%).
  • HPLC analysis retention time 1.55 minutes, purity: 96% (chromatographic column: ACQUITY C18, 1.7 ⁇ m, 2.1*50mm; mobile phase: water (10mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).
  • HPLC analysis retention time 1.59 minutes, purity: 95% (chromatographic column: ACQUITY C18, 1.7 ⁇ m, 2.1*50mm; mobile phase: water (10mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).
  • the second step raw material compound 1c was replaced by the compound cyclohexyl ketone (Shanghai Pide) to obtain the title compound 11 (10 mg, yield: 8.1%).
  • the third step raw material compound 1d was replaced by a mixture of compounds 8g and 8h to obtain the title compound 12-p1 (3 mg, yield: 2.9%) and 12-p2 (10 mg, yield: 9.6%).
  • HPLC analysis retention time 1.29 minutes, purity: 99% (chromatographic column: ACQUITY C18, 1.7 ⁇ m, 2.1*50mm; mobile phase: water (10mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).
  • HPLC analysis retention time 1.38 minutes, purity: 99% (chromatographic column: ACQUITY C18, 1.7 ⁇ m, 2.1*50mm; mobile phase: water (10mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).
  • test examples are not meant to limit the scope of the present disclosure.
  • Test example 1 the inhibitory effect of the disclosed compound on CDK4 enzyme
  • CDK4/CycD3 (Carna biosciences, 04-105)
  • CDK4 enzyme final concentration 1ng/ ⁇ L
  • small molecule compounds of different concentrations first concentration 1 ⁇ M, 3-fold serial dilution 11 concentrations
  • CDKs substrate-biotin Substrate-biotin
  • ATP solution final concentration 10 ⁇ M
  • CDKs antibody-cryptate Antibody-Cryptate
  • streptavidin-XL665 final concentration 37.5nM
  • the EnVision multi-mode detection platform was used to detect the fluorescence values at 665nm and 620nm excited at 337nm in HTRF mode. Data were processed using GraphPad software, see Table 1.
  • Test example 2 the inhibitory effect of the disclosed compound on CDK6 enzyme
  • CDK6/CycD3 (Carna biosciences, 04-107)
  • CDK6 enzyme final concentration 2.5ng/ ⁇ L was mixed with small molecule compounds of different concentrations (first concentration 1 ⁇ M, 3-fold serial dilution of 11 concentrations), incubated at room temperature for 30 minutes, and then CDKs substrate-biotin (Substrate-biotin) was added. ) (final concentration 0.3 ⁇ M) and ATP solution (final concentration 50 ⁇ M), mixed and incubated at room temperature for 180 minutes.
  • CDKs antibody-cryptate Antibody-Cryptate
  • streptavidin-XL665 final concentration 37.5nM
  • the EnVision multi-mode detection platform was used to detect the fluorescence values at 665nm and 620nm excited at 337nm in HTRF mode. Data were processed using GraphPad software, see Table 2.
  • MCF-7 cells are a CDK4-dependent human breast cancer cell line that is sensitive to CDK4-selective inhibitors.
  • CellTite-Glo reagent was used to measure the luminescence value.
  • the luminescence value is directly proportional to the amount of ATP, and ATP is positively correlated with the number of living cells. Therefore, the cell viability is reflected by detecting the ATP content in the cells.
  • the inhibitory effect of the compounds on the proliferation of MCF-7 cells was evaluated according to the IC 50 .
  • MCF-7 cells (ATCC, HTB-22) were digested with trypsin (Invitrogen, 25200-072), centrifuged and resuspended to prepare a single cell suspension, and cell culture medium (EMEM+10%FBS+0.01mg/mL insulin) was used Adjust the viable cell density to 8.4 ⁇ 10 3 cells/mL, mix well, and add 180 ⁇ L/well to a 96-well cell culture plate (Corning, 3903). Plates were incubated in an incubator (37°C, 5% CO 2 ) for 20-24 hours.
  • trypsin Invitrogen, 25200-072
  • cell culture medium EMEM+10%FBS+0.01mg/mL insulin
  • Compounds were dissolved in DMSO to prepare stock solutions with an initial concentration of 20 mM.
  • the initial concentration of the small molecule compound is 0.6mM, 3-fold dilution, 10 points of dilution, the 11th and 12th points are DMSO.
  • Take another 96-well plate add 95 ⁇ L of cell culture medium (EMEM+10% FBS+0.01 mg/mL insulin) to each well, then add 5 ⁇ L of different concentrations of samples to be tested in each well, mix well, and then add to the cell culture plate Add 20 ⁇ L/well of different concentrations of samples to be tested, and duplicate wells for each sample.
  • the plates were incubated in an incubator (37°C, 5% CO 2 ) for 6 days.
  • the disclosed compound has obvious growth inhibitory activity on MCF-7 cells.
  • Pfeiffer cells are a CDK6-dependent human diffuse large B-cell lymphoma cell line that is insensitive to CDK4-selective inhibitors.
  • CellTite-Glo reagent was used to measure the luminescence value. The luminescence value is directly proportional to the amount of ATP, and ATP is positively correlated with the number of living cells. Therefore, the cell viability is reflected by detecting the ATP content in the cells.
  • the inhibitory effect of compounds on the proliferation of Pfeiffer cells was evaluated according to IC 50 .
  • Compounds were dissolved in DMSO to prepare stock solutions with an initial concentration of 20 mM.
  • the initial concentration of the small molecule compound is 2 mM, diluted 3 times, diluted 10 points, and the 11th and 12th points are DMSO.
  • Take another 96-well plate add 95 ⁇ L of cell culture medium (RPMI-1640+10% FBS) to each well, then add 5 ⁇ L of different concentrations of samples to be tested in each well, mix well, and then add 20 ⁇ L/well to the cell culture plate Samples to be tested at different concentrations, and each sample was duplicated. The plates were incubated in an incubator (37°C, 5% CO 2 ) for 6 days.
  • MOLM-13 cells are a CDK6-dependent human acute myeloid leukemia cell line that is insensitive to CDK4-selective inhibitors.
  • CellTite-Glo reagent was used to measure the luminescence value. The luminescence value is directly proportional to the amount of ATP, and ATP is positively correlated with the number of living cells. Therefore, the cell viability is reflected by detecting the ATP content in the cells.
  • the inhibitory effect of the compounds on the proliferation of MOLM-13 cells was evaluated according to the IC 50 .
  • Compounds were dissolved in DMSO to prepare stock solutions with an initial concentration of 20 mM.
  • the initial concentration of the small molecule compound is 2 mM, diluted 3 times, diluted 10 points, and the 11th and 12th points are DMSO.
  • Take another 96-well plate add 95 ⁇ L of cell culture medium (RPMI-1640+20% FBS) to each well, then add 5 ⁇ L of different concentrations of samples to be tested in each well, mix well, and then add 20 ⁇ L/well to the cell culture plate Samples to be tested at different concentrations, and each sample was duplicated. The plates were incubated in an incubator (37°C, 5% CO 2 ) for 6 days.
  • Test Example 6 Determination of Rat Brain Permeability of the Disclosed Compound
  • the rat brain permeability of the disclosed compound is determined by the following experimental method:
  • RED device (Device Inserts) (Thermo Scientific, QL21291110)
  • Blood collection In the intragastric administration group, blood was collected from the orbit 2 hours after the administration (blood collection volume: 0.5ml), placed in an EDTA-K2 anticoagulant test tube, centrifuged at 10,000rpm for 1min (4°C), and the plasma was separated within 1h, which was recorded as plasma 1, - Store at 20°C for testing. The process from blood collection to centrifugation was operated under ice bath conditions.
  • Brain tissue collection After rats were anesthetized with 20% urethane, cardiac perfusion was performed (open the abdominal cavity, cut open 3-4 parts of the liver, quickly insert a needle into the left apex and perfuse 30ml of normal saline), collect brain tissue after perfusion, and record it as brain tissue 1 , and stored at -20 degrees.
  • the chromatographic peak area ratio of the total drug (brain homo chamber) and free drug (buffer chamber) to the internal standard was determined by the established LC/MS/MS method, and the free percentage ( fu brain hom %) was calculated.
  • Plasma free percentage C buffer / C plasma ⁇ 100%
  • the brain permeability index of the disclosed compounds is as follows:
  • the disclosed compound has a high free drug concentration in the brain, has a strong ability to penetrate the blood-brain barrier, and has high brain permeability.

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Abstract

L'invention concerne un composé indole hydrogéné, son procédé de préparation et son utilisation médicale. En particulier, l'invention concerne un composé indole hydrogéné représenté par la formule générale (I), son procédé de préparation, une composition pharmaceutique le contenant, et son utilisation en tant qu'inhibiteur de CDK4 dans le traitement de maladies ou d'états liés à l'activité de CDK4.
PCT/CN2022/141271 2021-12-24 2022-12-23 Composé indole hydrogéné, son procédé de préparation et son utilisation médicale WO2023116862A1 (fr)

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