WO2023116862A1 - Hydrogenated indole compound, and preparation method and medical use therefor - Google Patents

Hydrogenated indole compound, and preparation method and medical use therefor Download PDF

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Publication number
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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French (fr)
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/en

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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.

Abstract

Provided are a hydrogenated indole compound, and a preparation method and medical use therefor. In particular, provided are a hydrogenated indole compound represented by general formula (I), a preparation method therefor, a pharmaceutical composition containing same, and a use thereof as a CDK4 inhibitor in the treatment of diseases or conditions related to CDK4 activity.

Description

氢化吲哚类化合物、其制备方法及其在医药上的应用Indoline compound, its preparation method and its application in medicine 技术领域technical field
本公开属于医药领域，涉及一种氢化吲哚类化合物、其制备方法及其在医药上的应用。特别地，本公开涉及通式(I)所示的氢化吲哚类化合物、其制备方法及含有该类化合物的药物组合物，以及其作为CDK4抑制剂在治疗CDK4活性相关的疾病或病症的用途。The disclosure belongs to the field of medicine, and relates to a hydrogenated indole compound, its preparation method and its application in medicine. In particular, 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 .
背景技术Background technique
肿瘤细胞区别于正常细胞的一个重要特征是细胞周期调控异常，细胞复制失控是所有癌症的基本特征。周期蛋白依赖性蛋白激酶(CDK)是一组丝氨酸/苏氨酸蛋白激酶，是调控细胞周期和转录的重要因子。从功能上可以将CDK家族成员分为两大类：细胞周期相关的CDK(如CDK 1/2/4/6)以及与细胞转录相关的CDK(如CDK 7/9/12)。CDK激酶需要和细胞周期蛋白(Cyclin)结合才能发挥酶催化活性。An important feature that distinguishes tumor cells from normal cells is the abnormal regulation of the cell cycle, and uncontrolled cell replication is a basic feature of all cancers. Cyclin-dependent protein kinases (CDKs) are a group of serine/threonine protein kinases that are important factors in the regulation of cell cycle and transcription. Functionally, 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自身不具备酶活性，需要和细胞周期蛋白D结合，才能被激活酶活性。细胞周期蛋白D-CDK4/6-Rb信号通路是推进细胞周期由G1期进入S期的关键通路。细胞周期蛋白D受多条有丝***信号通路调控，如PI3K-AKT通路、RAS-MEK通路、***受体通路。细胞周期蛋白D表达增加后，激活CDK4/6的激酶活性，磷酸化细胞周期负调节因子RB1，非磷酸化的RB1对转录因子E2F1/2/3有转录抑制作用。而磷酸化的RB1从E2F1/2/3脱离，从而释放E2F1/2/3的转录活性，促进细胞转录进入S期所需的基因，促使细胞完成G1-S期转化，细胞再经过有丝***完成复制。CDK4的其他生物学功能包括调控衰老、存活、基因组稳定性、糖酵解、脂肪代谢，机制和它的激酶活性相关。CDK4及其细胞周期蛋白D在多种肿瘤中表达增加，是许多致癌信号的最终靶标。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.
虽然CDK4和CDK6有70％的氨基酸同源性，但是CDK4在大部分的肿瘤组织中表达高，而CDK6的表达较弱，包括mRNA和蛋白水平。尤其是CDK4在鲁米诺、HER2阳性和三阴性乳腺癌中表达水平较正常组织升高，三种类型之间也是相近的，而CDK6的表达在乳腺癌中不仅较弱，而且是低于正常组织表达水平的，其中以鲁米诺型乳腺癌中表达最低。临床前研究表明乳腺癌的发生发展主要依赖CDK4。细胞周期蛋白D1高表达是乳腺癌的致病因素，但是它的下游效应分子一直不清楚。Yu等(Cancer Cell(2006),9(1),23-32)在MMTV-ERBB2小鼠乳腺癌模型中发现，敲除CDK4完全不会诱发乳腺癌，野生型小鼠全部发生乳腺癌。当把野生小鼠的乳腺肿瘤取出在体外培养，用siRNA敲低CDK4后再接种回小鼠乳腺脂肪垫下，CDK4不表达的乳腺癌细胞不能重新长出肿瘤，而敲低CDK6不影 响肿瘤生长。Reddy等(Cancer Research(2005),65(22),10174-10178)也在MMTV-Neu和Ras小鼠乳腺癌模型中证实，缺失CDK4会降低和延迟小鼠乳腺癌的发生，因此细胞周期蛋白D1-CDK4是驱动乳腺癌发生的主要因素。CRISPR高通量敲除筛选也证实，人乳腺癌细胞系对缺失CDK4更敏感，血液细胞系对缺失CDK6更为敏感。Although 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. In particular, 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. (Cancer Cell (2006), 9(1), 23-32) found in the MMTV-ERBB2 mouse breast cancer model that knocking out CDK4 did not induce breast cancer at all, and all wild-type mice developed breast cancer. When the mammary gland tumors of wild mice were taken out and cultured in vitro, CDK4 was knocked down by siRNA and then inoculated back under the mammary fat pad of mice, breast cancer cells that did not express CDK4 could not regenerate tumors, while knocking down CDK6 did not affect tumor growth . Reddy et al. (Cancer Research (2005), 65 (22), 10174-10178) also confirmed in the MMTV-Neu and Ras mouse breast cancer models that the loss of CDK4 can reduce and delay the occurrence of mouse breast cancer, so the cyclin D1-CDK4 is the main factor driving breast cancer. CRISPR high-throughput knockout screens also confirmed that human breast cancer cell lines are more sensitive to loss of CDK4 and blood cell lines are more sensitive to loss of CDK6.
CDK4基因敲除小鼠没有明显的造血***损伤表型，会发生身体减少、雄性小鼠生育率下降、雌性小鼠***以及胰岛素缺乏的糖尿病。CDK6基因敲除小鼠则表现出造血***损伤，包括胸腺缩小，皮质萎缩；脾脏里的白髓正常，红髓缩小，以及产生T淋巴细胞被激活时进入S期较慢的周期阻滞现象。临床前研究表明CDK6是造血干细胞激活的关键因子，抑制CDK6影响骨髓造血***的重建，从而引起造血或免疫细胞减少，没有发现抑制CDK4会产生显著的造血***损伤。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. 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.
乳腺癌已经超越肺癌，成为全球第一大癌种。HR+，HER2-乳腺癌是最常见的亚型，大约占其中70％。FDA目前共批准3款治疗HR+，HER2-乳腺癌的CDK4/6药物。中性粒细胞减少是这3款药物最严重的副反应，白细胞减少会导致人体的抗感染能力降低，极易发生各种感染，容易引起死亡。因此，亟需解决CDK4/6抑制剂引起的中性粒细胞减少症。Breast cancer has surpassed lung cancer to become the largest cancer in the world. HR+, HER2- breast cancers are the most common subtype, accounting for about 70% of them. FDA currently approves 3 CDK4/6 drugs for the treatment of HR+, HER2- breast cancer. Neutropenia is the most serious side effect of these 3 drugs. Leukopenia will reduce the body's anti-infection ability, making it prone to various infections and death. Therefore, there is an urgent need to address neutropenia induced by CDK4/6 inhibitors.
公开的CDK4抑制剂专利申请包括WO2019207463A1、WO2020224568A1、WO2017092635A1、WO2018045957A1、WO2014183520A1等。Published CDK4 inhibitor patent applications include WO2019207463A1, WO2020224568A1, WO2017092635A1, WO2018045957A1, WO2014183520A1, etc.
发明内容Contents of the invention
本公开的目的在于提供一种通式(I)所示的化合物或其可药用的盐：The purpose of this disclosure is to provide a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022141271-appb-000001
Figure PCTCN2022141271-appb-000001
其中：in:
环A为杂环基；Ring A is a heterocyclic group;
G为CR g或N； G is CR g or N;
各个R 1相同或不同，且各自独立地选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、-(亚烷基) u-NR aR b、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基； 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;
或者连在同一碳原子上的两个R 1与其相连的碳原子一起形成环烷基或杂环基， 所述的环烷基或杂环基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、羟基和羟烷基中的一个或多个所取代； Or two R connected to the same carbon atom form a cycloalkyl or a heterocyclic group together with the carbon atom connected to it, and 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 2选自氢原子、烷基、卤代烷基、羟烷基、环烷基和杂环基； 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和R g相同或不同，且各自独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、-(亚烷基) v-NR cR d、-C(O)R x、-C(O)NR yR z、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基，所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、羟基和羟烷基中的一个或多个所取代； 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和R 9相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、羟烷基、环烷基和杂环基，所述的烷基、环烷基和杂环基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、-(亚烷基) w-NR eR f、羟基和羟烷基中的一个或多个所取代； 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;
或者R 8和R 9与其相连的碳原子一起形成环烷基或杂环基，所述的环烷基或杂环基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、-(亚烷基) y-NR mR n、羟基和羟烷基中的一个或多个所取代； Or 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;
或者R和R 9与其相连的碳原子一起形成环烷基或杂环基，所述的环烷基或杂环基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、-(亚烷基) z-NR jR k、羟基和羟烷基中的一个或多个所取代； Or 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、R e、R f、R m、R n、R j、R k、R y和R z相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、羟烷基和环烷基； 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选自烷基、卤代烷基、羟烷基和环烷基； R x is selected from alkyl, haloalkyl, hydroxyalkyl and cycloalkyl;
m为0至15的整数；m is an integer from 0 to 15;
u为0、1、2、3或4；u is 0, 1, 2, 3 or 4;
v为0、1、2、3或4；v is 0, 1, 2, 3 or 4;
w为0、1、2、3或4；w is 0, 1, 2, 3 or 4;
y为0、1、2、3或4；且y is 0, 1, 2, 3 or 4; and
z为0、1、2、3或4。z is 0, 1, 2, 3 or 4.
在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中环A为3至8元杂环基；优选地，环A为4至6元杂环基；进一步优选地，环A为6元杂环基；更优选地，环A为四氢吡喃基；最优选地，环A为四氢吡喃-4-基(即
Figure PCTCN2022141271-appb-000002
)。 In some embodiments of the present disclosure, 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
Figure PCTCN2022141271-appb-000002
).
在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中各个R 1相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、氰基、-(C 1-6亚烷基) u-NR aR b、羟基和C 1-6羟烷基， R a、R b和u如通式(I)中所定义；优选地，各个R 1相同或不同，且各自独立地为氢原子或羟基；更优选地，R 1为羟基。 In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein 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.
在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中m为0、1、2、3、4、5、6或7；优选地，m为0、1或2；更优选地m为1。In some embodiments of the present disclosure, 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.
在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其为通式(II)所示的化合物或其可药用的盐：In some embodiments of the present disclosure, 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:
Figure PCTCN2022141271-appb-000003
Figure PCTCN2022141271-appb-000003
其中：in:
Q选自NR q、O和S； Q is selected from NRq , O and S;
R q选自氢原子、烷基、卤代烷基、羟烷基、环烷基和杂环基； 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和R 1h相同或不同，且各自独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、-(亚烷基) u-NR aR b、羟基、羟烷基、环烷基和杂环基； 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为0、1或2；p is 0, 1 or 2;
q为0、1或2；且q is 0, 1 or 2; and
G、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R、R a、R b和u如通式(I)中所定义。 G, 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).
在本公开一些实施方案中，所述的通式(I)或(II)所示的化合物或其可药用的盐，其中R 2选自氢原子、C 1-6烷基和C 1-6卤代烷基；优选地，R 2为氢原子。 In some embodiments of the present disclosure, 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.
在本公开一些实施方案中，所述的通式(I)或(II)所示的化合物或其可药用的盐，其中G为N。In some embodiments of the present disclosure, the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein G is N.
在本公开一些实施方案中，所述的通式(I)或(II)所示的化合物或其可药用的盐，其中R g选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基。 In some embodiments of the present disclosure, the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein R g is selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl.
在本公开一些实施方案中，所述的通式(II)所示的化合物或其可药用的盐，其中p为0或1；优选地，p为1。In some embodiments of the present disclosure, the compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, wherein p is 0 or 1; preferably, p is 1.
在本公开一些实施方案中，所述的通式(II)所示的化合物或其可药用的盐，其中q为0或1；优选地，q为1。In some embodiments of the present disclosure, the compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, wherein q is 0 or 1; preferably, q is 1.
在本公开一些实施方案中，所述的通式(II)所示的化合物或其可药用的盐，其中R 1c、R 1d、R 1e、R 1f、R 1g和R 1h相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、氰基、-(C 1-6亚烷基) u-NR aR b、羟基和C 1-6羟烷基，R a、R b和u如通式(II)中所定义；优选地，R 1c、R 1d、R 1e、R 1f、 R 1g和R 1h相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基；更优选地，R 1c、R 1d、R 1e、R 1f、R 1g和R 1h均为氢原子。 In some embodiments of the present disclosure, 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 , R 1f , R 1g and R 1h are all hydrogen atoms.
在本公开一些实施方案中，所述的通式(I)或(II)所示的化合物或其可药用的盐，其为通式(III)所示的化合物或其可药用的盐：In some embodiments of the present disclosure, 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 :
Figure PCTCN2022141271-appb-000004
Figure PCTCN2022141271-appb-000004
其中：in:
Q选自NR q、O和S； Q is selected from NRq , O and S;
R q选自氢原子、烷基、卤代烷基、羟烷基、环烷基和杂环基； 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和R 1b相同或不同，且各自独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、-(亚烷基) u-NR aR b、羟基、羟烷基、环烷基和杂环基； 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和u如通式(I)中所定义。 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).
在本公开一些实施方案中，所述的通式(I)、(II)或(III)所示的化合物或其可药用的盐，其为通式(III-1)所示的化合物或其可药用的盐：In some embodiments of the present disclosure, 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:
Figure PCTCN2022141271-appb-000005
Figure PCTCN2022141271-appb-000005
其中：in:
Q选自NR q、O和S； Q is selected from NRq , O and S;
R q选自氢原子、烷基、卤代烷基、羟烷基、环烷基和杂环基； 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选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、-(亚烷基) u-NR aR b、羟基、羟烷基、环烷基和杂环基； 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选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、-(亚烷基) u-NR aR b、羟基、羟烷基、环烷基和杂环基； 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和u如通式(I)中所定义。 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).
在本公开一些实施方案中，所述的通式(I)、(II)、(III)或(III-1)所示的化合物或其可药用的盐，其中R 8和R 9相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基、C 1-6卤代烷基和C 1-6羟烷基；或者R 8和R 9与其相连的碳原子一起形成3至 8元环烷基或3至8元杂环基，所述的3至8元环烷基或3至8元杂环基各自独立地任选被选自卤素、C 1-6烷基和C 1-6卤代烷基中的一个或多个所取代；优选地，R 8和R 9相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基、C 1-6卤代烷基和C 1-6羟烷基；或者R 8和R 9与其相连的碳原子一起形成3至8元环烷基，所述的3至8元环烷基任选被选自卤素、C 1-6烷基和C 1-6卤代烷基中的一个或多个所取代。 In some embodiments of the present disclosure, the compound represented by general formula (I), (II), (III) or (III-1) or a pharmaceutically acceptable salt thereof, wherein R 8 and R 9 are the same or different, and each independently selected from hydrogen atom, halogen, C 1-6 alkyl, C 1-6 haloalkyl and C 1-6 hydroxyalkyl; or R 8 and R 9 together form 3 to 8-membered cycloalkyl or 3 to 8-membered heterocyclic group, each of the 3-8 membered cycloalkyl or 3-8 membered heterocyclic group is independently optionally selected from halogen, C 1-6 alkyl and C One or more of 1-6 haloalkyl groups are substituted; preferably, R8 and R9 are the same or different, and are each independently selected from hydrogen atom, halogen, C1-6 alkyl, C1-6 haloalkyl and C 1-6 hydroxyalkyl; or R 8 and R 9 form a 3 to 8-membered cycloalkyl group together with the carbon atoms they are connected to, and the 3 to 8-membered cycloalkyl group is optionally selected from halogen, C 1- One or more of 6 alkyl and C 1-6 haloalkyl.
在本公开一些实施方案中，所述的通式(I)、(II)、(III)或(III-1)所示的化合物或其可药用的盐，其中R 8和R 9相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基、C 1-6卤代烷基和C 1-6羟烷基，所述的C 1-6烷基任选被选自C 1-6烷氧基、C 1-6卤代烷氧基、氰基和-(C 1-6亚烷基) w-NR eR f中的一个或多个所取代；R e、R f和w如通式(I)中所定义；优选地，R 8和R 9相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基、C 1-6卤代烷基和C 1-6羟烷基；进一步优选地，R 8和R 9相同或不同，且各自独立地为C 1-6烷基；更优选地，R 8和R 9相同或不同，且各自独立地为甲基或乙基。 In some embodiments of the present disclosure, the compound represented by general formula (I), (II), (III) or (III-1) or a pharmaceutically acceptable salt thereof, wherein R 8 and R 9 are the same or different, and each independently selected from hydrogen atom, halogen, C 1-6 alkyl, C 1-6 haloalkyl and C 1-6 hydroxyalkyl, the C 1-6 alkyl is optionally selected from C One or more of 1-6 alkoxy, C 1-6 haloalkoxy, cyano and -(C 1-6 alkylene) w -NR e R f are substituted; R e , R f and w As defined in general formula (I); preferably, R 8 and R 9 are the same or different, and each independently selected from hydrogen atom, halogen, C 1-6 alkyl, C 1-6 haloalkyl and C 1- 6 hydroxyalkyl; further preferably, R8 and R9 are the same or different, and each independently is a C1-6 alkyl group; more preferably, R8 and R9 are the same or different, and each independently is a methyl group or ethyl.
在本公开一些实施方案中，所述的通式(I)、(II)、(III)或(III-1)所示的化合物或其可药用的盐，其中R 8和R 9与其相连的碳原子一起形成3至8元环烷基，所述的3至8元环烷基任选被选自卤素、C 1-6烷基和C 1-6卤代烷基中的一个或多个所取代；优选地，R 8和R 9与其相连的碳原子一起形成3至6元环烷基，所述的3至6元环烷基任选被选自卤素、C 1-6烷基和C 1-6卤代烷基中的一个或多个所取代；进一步优选地，R 8和R 9与其相连的碳原子一起形成环戊基或环己基，所述的环戊基或环己基各自独立地任选被选自卤素、C 1-6烷基和C 1-6卤代烷基中的一个或多个所取代；更优选地，R 8和R 9与其相连的碳原子一起形成环戊基，所述的环戊基任选被选自卤素、C 1-6烷基和C 1-6卤代烷基中的一个或多个所取代；最优选地，R 8和R 9与其相连的碳原子一起形成环戊基。 In some embodiments of the present disclosure, the compound represented by general formula (I), (II), (III) or (III-1) or a pharmaceutically acceptable salt thereof, wherein R 8 and R 9 are connected to it The carbon atoms together form a 3 to 8 membered cycloalkyl group, and the 3 to 8 membered cycloalkyl group is optionally selected from one or more of halogen, C 1-6 alkyl and C 1-6 haloalkyl Substitution; preferably, R 8 and R 9 together form a 3 to 6 membered cycloalkyl group with the carbon atoms they are connected to, and the 3 to 6 membered cycloalkyl group is optionally selected from halogen, C 1-6 alkyl and C One or more of 1-6 haloalkyl groups are substituted; further preferably, R 8 and R 9 form cyclopentyl or cyclohexyl together with the carbon atoms they are connected to, and each of the cyclopentyl or cyclohexyl is independently any is optionally substituted by one or more selected from halogen, C 1-6 alkyl and C 1-6 haloalkyl; more preferably, R 8 and R 9 together form a cyclopentyl group with the carbon atoms they are attached to, said The cyclopentyl of is optionally substituted by one or more selected from halogen, C 1-6 alkyl and C 1-6 haloalkyl; most preferably, R 8 and R 9 together form a ring with the carbon atoms to which they are attached Amyl.
在本公开一些实施方案中，所述的通式(I)、(II)、(III)或(III-1)所示的化合物或其可药用的盐，其中R 8和R 9与其相连的碳原子一起形成3至8元环烷基或3至8元杂环基，所述的3至8元环烷基或3至8元杂环基各自独立地任选被选自卤素、C 1-6烷基和C 1-6卤代烷基中的一个或多个所取代；优选地，R 8和R 9与其相连的碳原子一起形成3至6元环烷基或3至6元杂环基，所述的3至6元环烷基或3至6元杂环基各自独立地任选被选自卤素、C 1-6烷基和C 1-6卤代烷基中的一个或多个所取代；进一步优选地，R 8和R 9与其相连的碳原子一起形成四氢吡喃基、环戊基或环己基，所述的四氢吡喃基、环戊基或环己基各自独立地任选被选自卤素、C 1-6烷基和C 1-6卤代烷基中的一个或多个所取代；更优选地，R 8和R 9与其相连的碳原子一起形成四氢吡喃基，所述的四氢吡喃基任选被选自卤素、C 1-6烷基和C 1-6卤代烷基中的一个或多个所取代；最优选地，R 8和R 9与其相连的碳原子一起形成四氢吡喃基。 In some embodiments of the present disclosure, the compound represented by general formula (I), (II), (III) or (III-1) or a pharmaceutically acceptable salt thereof, wherein R 8 and R 9 are connected to it 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 Substitution; further preferably, R 8 and R 9 form tetrahydropyranyl, cyclopentyl or cyclohexyl together with the carbon atoms connected to them, and said tetrahydropyranyl, cyclopentyl or cyclohexyl are each independently any is optionally substituted by one or more selected from halogen, C 1-6 alkyl and C 1-6 haloalkyl; more preferably, R 8 and R 9 form tetrahydropyranyl together with the carbon atoms they are connected to, The tetrahydropyranyl group is optionally substituted by one or more selected from halogen, C 1-6 alkyl and C 1-6 haloalkyl; most preferably, R 8 and R 9 are connected to the carbon atoms together to form a tetrahydropyranyl group.
在本公开一些实施方案中，所述的通式(I)、(II)、(III)或(III-1)所示的化合物或 其可药用的盐，其中R 8和R 9与其相连的碳原子一起形成环己基，所述的环己基任选被选自卤素、C 1-6烷基和C 1-6卤代烷基中的一个或多个所取代；优选地，R 8和R 9与其相连的碳原子一起形成环己基。 In some embodiments of the present disclosure, the compound represented by general formula (I), (II), (III) or (III-1) or a pharmaceutically acceptable salt thereof, wherein R 8 and R 9 are connected to it The carbon atoms together form a cyclohexyl group, and the cyclohexyl group is optionally substituted by one or more of halogen, C 1-6 alkyl and C 1-6 haloalkyl; preferably, R 8 and R 9 Together with the carbon atoms it is attached to form a cyclohexyl group.
在本公开一些实施方案中，所述的通式(I)、(II)、(III)或(III-1)所示的化合物或其可药用的盐，其中R 8和R 9与其相连的碳原子一起形成四氢吡喃基、环戊基或环己基；优选地，R 8和R 9与其相连的碳原子一起形成环戊基或环己基。 In some embodiments of the present disclosure, the compound represented by general formula (I), (II), (III) or (III-1) or a pharmaceutically acceptable salt thereof, wherein R 8 and R 9 are connected to it The carbon atoms together form tetrahydropyranyl, cyclopentyl or cyclohexyl; preferably, R 8 and R 9 form cyclopentyl or cyclohexyl together with the carbon atoms they are connected to.
在本公开一些实施方案中，所述的通式(I)、(II)、(III)或(III-1)所示的化合物或其可药用的盐，其中R和R 9与其相连的碳原子一起形成3至8元杂环基，所述的3至8元杂环基各自独立地任选被选自卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、氰基、-(C 1-6亚烷基) z-NR jR k、羟基和C 1-6羟烷基中的一个或多个所取代，R j、R k和z如通式(I)中所定义；优选地，R和R 9与其相连的碳原子一起形成5至7元杂环基，所述的5至7元杂环基各自独立地任选被选自卤素、C 1-6烷基、C 1-6卤代烷基、氰基、氨基、羟基和C 1-6羟烷基中的一个或多个所取代。 In some embodiments of the present disclosure, the compound represented by general formula (I), (II), (III) or (III-1) or a pharmaceutically acceptable salt thereof, wherein R and R 9 are linked to The carbon atoms together form a 3 to 8-membered heterocyclic group, and each of the 3 to 8-membered heterocyclic groups is independently optionally selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 One or more of 6 haloalkyl, C 1-6 haloalkoxy, cyano, -(C 1-6 alkylene) z -NR j R k , hydroxyl and C 1-6 hydroxyalkyl, R j , R k and z are as defined in general formula (I); preferably, R and R 9 form a 5 to 7-membered heterocyclic group together with the carbon atoms to which they are attached, and each of the 5 to 7-membered heterocyclic groups are independently optionally substituted by one or more selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, cyano, amino, hydroxyl and C 1-6 hydroxyalkyl.
在本公开一些实施方案中，所述的通式(I)、(II)、(III)或(III-1)所示的化合物或其可药用的盐，其中R 7选自氢原子、卤素、C 1-6烷基、C 1-6卤代烷基、氰基、-C(O)R x、-C(O)NR yR z和C 1-6羟烷基，所述的C 1-6烷基任选被选自C 1-6烷氧基、C 1-6卤代烷氧基、氰基和氨基中的一个或多个所取代，R x、R y和R z如通式(I)中所定义；优选地，R 7选自氢原子、卤素、C 1-6烷基、C 1-6卤代烷基和C 1-6羟烷基；更优选地，R 7为C 1-6烷基或C 1-6羟烷基；更优选地，R 7选自甲基、异丁基和C 1-6羟烷基。 In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (III) or (III-1) or a pharmaceutically acceptable salt thereof, wherein R 7 is selected from a hydrogen atom, Halogen, C 1-6 alkyl, C 1-6 haloalkyl, cyano, -C(O)R x , -C(O)NR y R z and C 1-6 hydroxyalkyl, the C 1 -6 alkyl is optionally substituted by one or more selected from C 1-6 alkoxy, C 1-6 haloalkoxy, cyano and amino, R x , R y and R z are as in the general formula ( I) defined; preferably, R 7 is selected from hydrogen atom, halogen, C 1-6 alkyl, C 1-6 haloalkyl and C 1-6 hydroxyalkyl; more preferably, R 7 is C 1-6 6 alkyl or C 1-6 hydroxyalkyl; more preferably, R 7 is selected from methyl, isobutyl and C 1-6 hydroxyalkyl.
在本公开一些实施方案中，所述的通式(I)、(II)、(III)或(III-1)所示的化合物或其可药用的盐，其中R 7选自氢原子、卤素、C 1-6烷基、C 1-6卤代烷基、氰基、-C(O)R x、-C(O)NR yR z、C 1-6羟烷基和3至8元环烷基，所述的C 1-6烷基和3至8元环烷基任选被选自C 1-6烷氧基、C 1-6卤代烷氧基、氰基和氨基中的一个或多个所取代，R x、R y和R z如通式(I)中所定义；优选地，R 7选自氢原子、卤素、C 1-6烷基、C 1-6卤代烷基、C 1-6羟烷基和3至8元环烷基，所述的3至8元环烷基任选被一个或多个羟基取代；进一步优选地，R 7选自C 1-6烷基、C 1-6羟烷基和3至8元环烷基，所述的3至8元环烷基任选被一个或多个羟基取代；更优选地，R 7选自甲基、异丙基、仲丁基、环戊基和环己基，所述的异丙基、仲丁基、环戊基和环己基各自独立地任选被一个或多个羟基取代。 In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (III) or (III-1) or a pharmaceutically acceptable salt thereof, wherein R 7 is selected from a hydrogen atom, Halogen, C 1-6 alkyl, C 1-6 haloalkyl, cyano, -C(O)R x , -C(O)NR y R z , C 1-6 hydroxyalkyl and 3 to 8 membered ring Alkyl, the C 1-6 alkyl and 3 to 8-membered cycloalkyl are optionally selected from one or more of C 1-6 alkoxy, C 1-6 haloalkoxy, cyano and amino R x , R y and R z are as defined in general formula (I); preferably, R 7 is selected from hydrogen atom, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1 -6 hydroxyalkyl groups and 3 to 8 membered cycloalkyl groups, the 3 to 8 membered cycloalkyl groups are optionally substituted by one or more hydroxyl groups; more preferably, R 7 is selected from C 1-6 alkyl, C 1-6 hydroxyalkyl groups and 3 to 8 membered cycloalkyl groups, the 3 to 8 membered cycloalkyl groups are optionally substituted by one or more hydroxyl groups; more preferably, R is selected from methyl, isopropyl, sec-butyl, cyclopentyl and cyclohexyl, said isopropyl, sec-butyl, cyclopentyl and cyclohexyl are each independently optionally substituted by one or more hydroxyl groups.
在本公开一些实施方案中，所述的通式(I)、(II)、(III)或(III-1)所示的化合物或其可药用的盐，其中R 7选自C 1-6烷基、C 1-6羟烷基和3至8元环烷基，所述的3至8元环烷基任选被一个或多个羟基取代；优选地，R 7为C 1-6烷基或C 1-6羟烷基。 In some embodiments of the present disclosure, the compound represented by general formula (I), (II), (III) or (III-1) or a pharmaceutically acceptable salt thereof, wherein R 7 is selected from C 1- 6 alkyl, C 1-6 hydroxyalkyl and 3 to 8 membered cycloalkyl, said 3 to 8 membered cycloalkyl is optionally substituted by one or more hydroxyl groups; preferably, R 7 is C 1-6 Alkyl or C 1-6 hydroxyalkyl.
在本公开一些实施方案中，所述的通式(II)、(III)或(III-1)所示的化合物或其可药用的盐，其中R 1a为羟基；和/或R 1b为氢原子。 In some embodiments of the present disclosure, the compound represented by general formula (II), (III) or (III-1) or a pharmaceutically acceptable salt thereof, wherein R 1a is hydroxyl; and/or R 1b is A hydrogen atom.
在本公开一些实施方案中，所述的通式(II)或(III)所示的化合物或其可药用的盐，其中R 1a选自氢原子、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代 烷氧基、氰基、-(C 1-6亚烷基) u-NR aR b、羟基和C 1-6羟烷基，R a、R b和u如通式(I)中所定义；优选地，R 1a选自氢原子、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、羟基和C 1-6羟烷基；更优选地，R 1a为羟基。 In some embodiments of the present disclosure, 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.
在本公开一些实施方案中，所述的通式(II)、(III)或(III-1)所示的化合物或其可药用的盐，其中R 1a选自卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、氰基、-(C 1-6亚烷基) u-NR aR b、羟基和C 1-6羟烷基，R a、R b和u如通式(I)中所定义；优选地，R 1a选自卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、羟基和C 1-6羟烷基；更优选地，R 1a为羟基。 In some embodiments of the present disclosure, 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.
在本公开一些实施方案中，所述的通式(II)、(III)或(III-1)所示的化合物或其可药用的盐，其中R 1b选自氢原子、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、氰基、-(C 1-6亚烷基) u-NR aR b、羟基和C 1-6羟烷基，R a、R b和u如通式(I)中所定义；优选地，R 1b选自氢原子、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、羟基和C 1-6羟烷基；更优选地，R 1b为氢原子。 In some embodiments of the present disclosure, 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.
在本公开一些实施方案中，所述的通式(II)、(III)或(III-1)所示的化合物或其可药用的盐，其中Q为NR q或O，R q如通式(II)中所定义；优选地，Q为O。 In some embodiments of the present disclosure, the compound represented by general formula (II), (III) or (III-1) or a pharmaceutically acceptable salt thereof, wherein Q is NR q or O, and R q is as in general defined in formula (II); preferably, Q is O.
在本公开一些实施方案中，所述的通式(II)、(III)或(III-1)所示的化合物或其可药用的盐，其中R q为氢原子或C 1-6烷基。 In some embodiments of the present disclosure, the compound represented by the general formula (II), (III) or (III-1) or a pharmaceutically acceptable salt thereof, wherein R q is a hydrogen atom or a C 1-6 alkane base.
在本公开一些实施方案中，所述的通式(I)、(II)、(III)或(III-1)所示的化合物或其可药用的盐，其中R 3选自氢原子、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、氰基、-(C 1-6亚烷基) v-NR cR d、-C(O)R x、-C(O)NR yR z、羟基和C 1-6羟烷基，所述的C 1-6烷基任选被选自C 1-6烷氧基、C 1-6卤代烷氧基、氰基和氨基中的一个或多个所取代，R c、R d、R x、R y、R z和v如通式(I)中所定义；优选地，R 3选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基；更优选地，R 3为氢原子。 In some embodiments of the present disclosure, the compound represented by general formula (I), (II), (III) or (III-1) or a pharmaceutically acceptable salt thereof, wherein R 3 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) v -NR c R d , -C(O)R x , -C(O)NR y R z , hydroxyl and C 1-6 hydroxyalkyl, the C 1-6 alkyl is optionally selected from C 1-6 alkoxy One or more of C 1-6 haloalkoxy, cyano and amino are substituted, R c , R d , R x , R y , R z and v are as defined in general formula (I); preferably Preferably, R 3 is selected from a hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; more preferably, R 3 is a hydrogen atom.
在本公开一些实施方案中，所述的通式(I)、(II)、(III)或(III-1)所示的化合物或其可药用的盐，其中R 4选自氢原子、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、氰基、-(C 1-6亚烷基) v-NR cR d、-C(O)R x、-C(O)NR yR z、羟基和C 1-6羟烷基，所述的C 1-6烷基任选被选自C 1-6烷氧基、C 1-6卤代烷氧基、氰基和氨基中的一个或多个所取代，R c、R d、R x、R y、R z和v如通式(I)中所定义；优选地，R 4选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基；进一步优选地，R 4为卤素；更优选地，R 4为Cl。 In some embodiments of the present disclosure, the compound represented by general formula (I), (II), (III) or (III-1) or a pharmaceutically acceptable salt thereof, wherein R 4 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) v -NR c R d , -C(O)R x , -C(O)NR y R z , hydroxyl and C 1-6 hydroxyalkyl, the C 1-6 alkyl is optionally selected from C 1-6 alkoxy One or more of C 1-6 haloalkoxy, cyano and amino are substituted, R c , R d , R x , R y , R z and v are as defined in general formula (I); preferably Preferably, R 4 is selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; more preferably, R 4 is halogen; more preferably, R 4 is Cl.
在本公开一些实施方案中，所述的通式(I)、(II)、(III)或(III-1)所示的化合物或其可药用的盐，其中R 5为氢原子；和/或R为氢原子。 In some embodiments of the present disclosure, the compound represented by general formula (I), (II), (III) or (III-1) or a pharmaceutically acceptable salt thereof, wherein R 5 is a hydrogen atom; and /or R is a hydrogen atom.
在本公开一些实施方案中，所述的通式(I)、(II)、(III)或(III-1)所示的化合物或其可药用的盐，其中R 5选自氢原子、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、氰基、-(C 1-6亚烷基) v-NR cR d、-C(O)R x、-C(O)NR yR z、羟基和C 1-6羟烷基，所述的C 1-6烷基任选被选自C 1-6烷氧基、C 1-6卤代烷氧基、氰基和氨基中 的一个或多个所取代，R c、R d、R x、R y、R z和v如通式(I)中所定义；优选地，R 5选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基；更优选地，R 5为氢原子。 In some embodiments of the present disclosure, the compound represented by general formula (I), (II), (III) or (III-1) or a pharmaceutically acceptable salt thereof, wherein R 5 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) v -NR c R d , -C(O)R x , -C(O)NR y R z , hydroxyl and C 1-6 hydroxyalkyl, the C 1-6 alkyl is optionally selected from C 1-6 alkoxy One or more of C 1-6 haloalkoxy, cyano and amino are substituted, R c , R d , R x , R y , R z and v are as defined in general formula (I); preferably Preferably, R 5 is selected from a hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; more preferably, R 5 is a hydrogen atom.
在本公开一些实施方案中，所述的通式(I)、(II)、(III)或(III-1)所示的化合物或其可药用的盐，其中R选自氢原子、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、氰基、-(C 1-6亚烷基) v-NR cR d、-C(O)R x、-C(O)NR yR z、羟基和C 1-6羟烷基，所述的C 1-6烷基任选被选自C 1-6烷氧基、C 1-6卤代烷氧基、氰基和氨基中的一个或多个所取代，R c、R d、R x、R y、R z和v如通式(I)中所定义；优选地，R选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基；更优选地，R为氢原子。 In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (III) or (III-1) or a pharmaceutically acceptable salt thereof, wherein R 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) v -NR c R d , -C(O)R x , -C(O)NR y R z , hydroxyl and C 1-6 hydroxyalkyl, the C 1-6 alkyl is optionally selected from C 1-6 alkoxy , C 1-6 haloalkoxy, cyano and amino are substituted by one or more, R c , R d , R x , R y , R z and v are as defined in general formula (I); preferably , R is selected from a hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; more preferably, R is a hydrogen atom.
在本公开一些实施方案中，所述的通式(I)、(II)、(III)或(III-1)所示的化合物或其可药用的盐，其中R 6选自氢原子、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、氰基、-(C 1-6亚烷基) v-NR cR d、-C(O)R x、-C(O)NR yR z、羟基和C 1-6羟烷基，所述的C 1-6烷基任选被选自C 1-6烷氧基、C 1-6卤代烷氧基、氰基和氨基中的一个或多个所取代，R c、R d、R x、R y、R z和v如通式(I)中所定义；优选地，R 6选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基；进一步优选地，R 6为卤素；更优选地，R 6为F。 In some embodiments of the present disclosure, the compound represented by general formula (I), (II), (III) or (III-1) or a pharmaceutically acceptable salt thereof, wherein R 6 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) v -NR c R d , -C(O)R x , -C(O)NR y R z , hydroxyl and C 1-6 hydroxyalkyl, the C 1-6 alkyl is optionally selected from C 1-6 alkoxy One or more of C 1-6 haloalkoxy, cyano and amino are substituted, R c , R d , R x , R y , R z and v are as defined in general formula (I); preferably Preferably, R 6 is selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; more preferably, R 6 is halogen; more preferably, R 6 is F.
在本公开一些实施方案中，所述的通式(I)、(II)、(III)或(III-1)所示的化合物或其可药用的盐，其中R a和R b相同或不同，且各自独立地为氢原子或C 1-6烷基。 In some embodiments of the present disclosure, the compound represented by general formula (I), (II), (III) or (III-1) or a pharmaceutically acceptable salt thereof, wherein R a and R b are the same or different, and each independently is a hydrogen atom or a C 1-6 alkyl group.
在本公开一些实施方案中，所述的通式(I)、(II)、(III)或(III-1)所示的化合物或其可药用的盐，其中u为0、1或2。In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (III) or (III-1) or a pharmaceutically acceptable salt thereof, wherein u is 0, 1 or 2 .
在本公开一些实施方案中，所述的通式(I)、(II)、(III)或(III-1)所示的化合物或其可药用的盐，其中R c和R d相同或不同，且各自独立地为氢原子或C 1-6烷基。 In some embodiments of the present disclosure, the compound represented by general formula (I), (II), (III) or (III-1) or a pharmaceutically acceptable salt thereof, wherein R c and R d are the same or different, and each independently is a hydrogen atom or a C 1-6 alkyl group.
在本公开一些实施方案中，所述的通式(I)、(II)、(III)或(III-1)所示的化合物或其可药用的盐，其中v为0、1或2。In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (III) or (III-1) or a pharmaceutically acceptable salt thereof, wherein v is 0, 1 or 2 .
在本公开一些实施方案中，所述的通式(I)、(II)、(III)或(III-1)所示的化合物或其可药用的盐，其中R x选自C 1-6烷基、C 1-6卤代烷基和C 1-6羟烷基；优选地，R x为C 1-6烷基。 In some embodiments of the present disclosure, the compound represented by general formula (I), (II), (III) or (III-1) or a pharmaceutically acceptable salt thereof, wherein R x is selected from C 1- 6 alkyl, C 1-6 haloalkyl and C 1-6 hydroxyalkyl; preferably, R x is C 1-6 alkyl.
在本公开一些实施方案中，所述的通式(I)、(II)、(III)或(III-1)所示的化合物或其可药用的盐，其中R y和R z相同或不同，且各自独立地为氢原子或C 1-6烷基。 In some embodiments of the present disclosure, the compound represented by general formula (I), (II), (III) or (III-1) or a pharmaceutically acceptable salt thereof, wherein R y and R z are the same or different, and each independently is a hydrogen atom or a C 1-6 alkyl group.
在本公开一些实施方案中，所述的通式(I)、(II)、(III)或(III-1)所示的化合物或其可药用的盐，其中R e和R f相同或不同，且各自独立地为氢原子或C 1-6烷基。 In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (III) or (III-1) or a pharmaceutically acceptable salt thereof, wherein R e and R f are the same or different, and each independently is a hydrogen atom or a C 1-6 alkyl group.
在本公开一些实施方案中，所述的通式(I)、(II)、(III)或(III-1)所示的化合物或其可药用的盐，其中w为0、1或2。In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (III) or (III-1) or a pharmaceutically acceptable salt thereof, wherein w is 0, 1 or 2 .
在本公开一些实施方案中，所述的通式(I)、(II)、(III)或(III-1)所示的化合物或其可药用的盐，其中R m和R n相同或不同，且各自独立地为氢原子或C 1-6烷基。 In some embodiments of the present disclosure, the compound represented by general formula (I), (II), (III) or (III-1) or a pharmaceutically acceptable salt thereof, wherein R m and R n are the same or different, and each independently is a hydrogen atom or a C 1-6 alkyl group.
在本公开一些实施方案中，所述的通式(I)、(II)、(III)或(III-1)所示的化合物或其可药用的盐，其中y为0、1或2。In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (III) or (III-1) or a pharmaceutically acceptable salt thereof, wherein y is 0, 1 or 2 .
在本公开一些实施方案中，所述的通式(I)、(II)、(III)或(III-1)所示的化合物或其可药用的盐，其中R j和R k相同或不同，且各自独立地为氢原子或C 1-6烷基。 In some embodiments of the present disclosure, the compound represented by general formula (I), (II), (III) or (III-1) or a pharmaceutically acceptable salt thereof, wherein R j and R k are the same or different, and each independently is a hydrogen atom or a C 1-6 alkyl group.
在本公开一些实施方案中，所述的通式(I)、(II)、(III)或(III-1)所示的化合物或其可药用的盐，其中z为0、1或2。In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (III) or (III-1) or a pharmaceutically acceptable salt thereof, wherein z is 0, 1 or 2 .
在本公开一些实施方案中，所述的通式(II)所示的化合物或其可药用的盐，其中Q为NR q或O，R q为氢原子或C 1-6烷基；G为CR g或N；R g选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基；R 1c、R 1d、R 1e、R 1f、R 1g和R 1h相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基；R 1a选自氢原子、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、羟基和C 1-6羟烷基，R 1b选自氢原子、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、羟基和C 1-6羟烷基；p为0或1；q为0或1；R 2选自氢原子、C 1-6烷基和C 1-6卤代烷基；R 8和R 9相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基、C 1-6卤代烷基和C 1-6羟烷基；或者R 8和R 9与其相连的碳原子一起形成3至8元环烷基，所述的3至8元环烷基任选被选自卤素、C 1-6烷基和C 1-6卤代烷基中的一个或多个所取代；R 7选自氢原子、卤素、C 1-6烷基、C 1-6卤代烷基、C 1-6羟烷基和3至8元环烷基，所述的3至8元环烷基任选被一个或多个羟基取代；R 3选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基；R 4选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基；R 5选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基；R选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基；且R 6选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基。 In some embodiments of the present disclosure, 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 C 1-6 hydroxyalkyl; p is 0 or 1; q is 0 or 1; R is selected from hydrogen atom, C 1-6 alkyl and C 1-6 haloalkyl; R 8 and R 9 are the same or different, and each independently selected from a hydrogen atom, halogen, C 1-6 alkyl, C 1-6 haloalkyl and C 1-6 hydroxyalkyl; or R 8 and R 9 form a 3 to 8-membered ring together with the carbon atoms to which they are attached Alkyl, the 3 to 8-membered cycloalkyl is optionally substituted by one or more selected from halogen, C 1-6 alkyl and C 1-6 haloalkyl; R 7 is selected from hydrogen atom, halogen , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl and 3 to 8 membered cycloalkyl, said 3 to 8 membered cycloalkyl is optionally substituted by one or more hydroxyl groups ; R 3 is selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; R 4 is selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; R 5 is selected from R is selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; R is selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; and R is selected from hydrogen atom, Halogen, C 1-6 alkyl and C 1-6 haloalkyl.
在本公开一些实施方案中，所述的通式(II)所示的化合物或其可药用的盐，其中Q为NR q或O，R q为氢原子或C 1-6烷基；G为CR g或N；R g选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基；R 1c、R 1d、R 1e、R 1f、R 1g和R 1h相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基；R 1a选自氢原子、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、羟基和C 1-6羟烷基，R 1b选自氢原子、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、羟基和C 1-6羟烷基；p为0或1；q为0或1；R 2选自氢原子、C 1-6烷基和C 1-6卤代烷基；R 8和R 9相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基、C 1-6卤代烷基和C 1-6羟烷基；或者R 8和R 9与其相连的碳原子一起形成3至8元环烷基，所述的3至8元环烷基任选被选自卤素、C 1-6烷基和C 1-6卤代烷基中的一个或多个所取代；R 7选自氢原子、卤素、C 1-6烷基、C 1-6卤代烷基和C 1-6羟烷基；R 3选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基；R 4选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基；R 5选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基；R选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基；且R 6选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基。 In some embodiments of the present disclosure, 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 C 1-6 hydroxyalkyl; p is 0 or 1; q is 0 or 1; R is selected from hydrogen atom, C 1-6 alkyl and C 1-6 haloalkyl; R 8 and R 9 are the same or different, and each independently selected from a hydrogen atom, halogen, C 1-6 alkyl, C 1-6 haloalkyl and C 1-6 hydroxyalkyl; or R 8 and R 9 form a 3 to 8-membered ring together with the carbon atoms to which they are attached Alkyl, the 3 to 8-membered cycloalkyl is optionally substituted by one or more selected from halogen, C 1-6 alkyl and C 1-6 haloalkyl; R 7 is selected from hydrogen atom, halogen , C 1-6 alkyl, C 1-6 haloalkyl and C 1-6 hydroxyalkyl; R 3 is selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; R 4 is selected from Hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; R 5 is selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; R is selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; and R 6 is selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl.
在本公开一些实施方案中，所述的通式(III)或(III-1)所示的化合物或其可药用的盐，其中Q为O；R 1a选自卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、羟基和C 1-6羟烷基，R 1b选自氢原子、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、羟基 和C 1-6羟烷基；R 8和R 9相同或不同，且各自独立地为C 1-6烷基；或者R 8和R 9与其相连的碳原子一起形成环戊基或环己基，所述的环戊基或环己基任选被选自卤素、C 1-6烷基和C 1-6卤代烷基中的一个或多个所取代；R 7选自C 1-6烷基、C 1-6羟烷基和3至8元环烷基，所述的3至8元环烷基任选被一个或多个羟基取代；R 3选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基；R 4选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基；R 5选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基；R选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基；且R 6选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基。 In some embodiments of the present disclosure, the compound represented by the general formula (III) or (III-1) or a pharmaceutically acceptable salt thereof, wherein Q is O; 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 hydroxyalkyl and 3 to 8 membered cycloalkyl, said 3 to 8 membered cycloalkyl is optionally substituted by one or more hydroxyl groups; R is selected from hydrogen atom , halogen, C 1-6 alkyl and C 1-6 haloalkyl; R 4 is selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; R 5 is selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl ; R is selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; and R is selected from hydrogen atom, halogen, C 1-6 alkane and C 1-6 haloalkyl.
在本公开一些实施方案中，所述的通式(III)或(III-1)所示的化合物或其可药用的盐，其中Q为O；R 1a选自卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、羟基和C 1-6羟烷基，R 1b选自氢原子、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、羟基和C 1-6羟烷基；R 8和R 9相同或不同，且各自独立地为C 1-6烷基；或者R 8和R 9与其相连的碳原子一起形成环戊基，所述的环戊基任选被选自卤素、C 1-6烷基和C 1-6卤代烷基中的一个或多个所取代；R 7选自氢原子、卤素、C 1-6烷基、C 1-6卤代烷基和C 1-6羟烷基；R 3选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基；R 4选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基；R 5选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基；R选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基；且R 6选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基。 In some embodiments of the present disclosure, the compound represented by the general formula (III) or (III-1) or a pharmaceutically acceptable salt thereof, wherein Q is O; 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 together, described cyclopentyl is optionally substituted by one or more selected from halogen, C 1-6 alkyl and C 1-6 haloalkyl; R 7 is selected from hydrogen atom, halogen, C 1-6 alkyl, C 1-6 haloalkyl and C 1-6 hydroxyalkyl; R 3 is selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; R 4 is selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; R 5 is selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; R is selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; and R 6 is selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl.
在本公开一些实施方案中，所述的通式(III)或(III-1)所示的化合物或其可药用的盐，其中Q为O；R 1a为羟基，R 1b为氢原子；R 8和R 9相同或不同，且各自独立地为C 1-6烷基；或者R 8和R 9与其相连的碳原子一起形成四氢吡喃基、环戊基或环己基；R 7选自C 1-6烷基、C 1-6羟烷基和3至8元环烷基，所述的3至8元环烷基任选被一个或多个羟基取代；R 3为氢原子；R 4为卤素；R 5为氢原子；R为氢原子；且R 6为卤素。 In some embodiments of the present disclosure, the compound represented by the general formula (III) or (III-1) or a pharmaceutically acceptable salt thereof, wherein Q is O; R 1a is a hydroxyl group, and R 1b is a hydrogen atom; R 8 and R 9 are the same or different, and each is independently a C 1-6 alkyl group; or R 8 and R 9 form tetrahydropyranyl, cyclopentyl or cyclohexyl together with the carbon atoms connected to them; R 7 is selected from From C 1-6 alkyl, C 1-6 hydroxyalkyl and 3 to 8 membered cycloalkyl, said 3 to 8 membered cycloalkyl is optionally substituted by one or more hydroxyl groups; R 3 is a hydrogen atom; R4 is halogen; R5 is a hydrogen atom; R is a hydrogen atom; and R6 is halogen.
在本公开一些实施方案中，所述的通式(III)或(III-1)所示的化合物或其可药用的盐，其中Q为O；R 1a为羟基，R 1b为氢原子；R 8和R 9相同或不同，且各自独立地为C 1-6烷基；或者R 8和R 9与其相连的碳原子一起形成环戊基或环己基；R 7选自甲基、异丙基、仲丁基、环戊基和环己基，所述的异丙基、仲丁基、环戊基和环己基任选被一个或多个羟基取代；R 3为氢原子；R 4为卤素；R 5为氢原子；R为氢原子；且R 6为卤素。 In some embodiments of the present disclosure, the compound represented by the general formula (III) or (III-1) or a pharmaceutically acceptable salt thereof, wherein Q is O; R 1a is a hydroxyl group, and R 1b is a hydrogen atom; R 8 and R 9 are the same or different, and each is independently a C 1-6 alkyl group; or R 8 and R 9 form a cyclopentyl or cyclohexyl group together with the carbon atoms connected to them; R 7 is selected from methyl, isopropyl Base, sec-butyl, cyclopentyl and cyclohexyl, said isopropyl, sec-butyl, cyclopentyl and cyclohexyl are optionally substituted by one or more hydroxyl groups; R 3 is a hydrogen atom; R 4 is a halogen ; R 5 is a hydrogen atom; R is a hydrogen atom; and R 6 is a halogen.
在本公开一些实施方案中，所述的通式(III)或(III-1)所示的化合物或其可药用的盐，其中Q为O；R 1a为羟基，R 1b为氢原子；R 8和R 9相同或不同，且各自独立地为C 1-6烷基；或者R 8和R 9与其相连的碳原子一起形成环戊基；R 7为C 1-6烷基或C 1-6羟烷基；R 3为氢原子；R 4为卤素；R 5为氢原子；R为氢原子；且R 6为卤素。 In some embodiments of the present disclosure, the compound represented by the general formula (III) or (III-1) or a pharmaceutically acceptable salt thereof, wherein Q is O; R 1a is a hydroxyl group, and R 1b is a hydrogen atom; R 8 and R 9 are the same or different, and each is independently a C 1-6 alkyl group; or R 8 and R 9 form a cyclopentyl group together with the carbon atoms connected to them; R 7 is a C 1-6 alkyl group or C 1 R is a hydrogen atom; R is a halogen; R is a hydrogen atom ; R is a hydrogen atom; and R is a halogen.
表A本公开的典型化合物包括但不限于：Table A Typical compounds of the present disclosure include, but are not limited to:
Figure PCTCN2022141271-appb-000006
Figure PCTCN2022141271-appb-000006
Figure PCTCN2022141271-appb-000007
Figure PCTCN2022141271-appb-000007
Figure PCTCN2022141271-appb-000008
Figure PCTCN2022141271-appb-000008
Figure PCTCN2022141271-appb-000009
Figure PCTCN2022141271-appb-000009
Figure PCTCN2022141271-appb-000010
Figure PCTCN2022141271-appb-000010
本公开的另一方面涉及通式(IA)所示的化合物或其盐：Another aspect of the present disclosure relates to compounds represented by general formula (IA) or salts thereof:
Figure PCTCN2022141271-appb-000011
Figure PCTCN2022141271-appb-000011
其中：in:
X为卤素；优选地，X为Cl；X is halogen; preferably, X is Cl;
R 4选自Cl、Br、I、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、-(亚烷基) v-NR cR d、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基，所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、羟基和羟烷基中的一个或多个所取代； 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;
G、R 3、R 5、R 6、R 7、R 8、R 9、R、R c、R d和v如通式(I)中所定义。 G, 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).
本公开的另一方面涉及通式(IIIA)所示的化合物或其盐：Another aspect of the present disclosure relates to compounds represented by general formula (IIIA) or salts thereof:
Figure PCTCN2022141271-appb-000012
Figure PCTCN2022141271-appb-000012
其中：in:
X为卤素；优选地，X为Cl；X is halogen; preferably, X is Cl;
R 4选自Cl、Br、I、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、-(亚烷基) v-NR cR d、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基，所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、羟基和羟烷基中的一个或多个所取代； 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和v如通式(III)中所定义。 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).
表B本公开的典型化合物包括但不限于：Table B Typical compounds of the disclosure include, but are not limited to:
Figure PCTCN2022141271-appb-000013
Figure PCTCN2022141271-appb-000013
Figure PCTCN2022141271-appb-000014
Figure PCTCN2022141271-appb-000014
Figure PCTCN2022141271-appb-000015
Figure PCTCN2022141271-appb-000015
Figure PCTCN2022141271-appb-000016
Figure PCTCN2022141271-appb-000016
本公开的另一方面涉及一种制备通式(I)所示的化合物或其可药用的盐的方法，该方法包括：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:
Figure PCTCN2022141271-appb-000017
Figure PCTCN2022141271-appb-000017
通式(IA)所示的化合物或其盐与通式(IB)所示的化合物或其盐(优选为盐酸盐)发生偶联反应，得到通式(I)所示的化合物或其可药用的盐，The compound shown in general formula (IA) or its salt and the compound shown in general formula (IB) or its salt (preferably hydrochloride) generation coupling reaction, obtain the compound shown in general formula (I) or its salt medicinal salt,
其中：in:
X为卤素；优选地，X为Cl；X is halogen; preferably, X is Cl;
环A、G、R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R和m如通式(I)中所定义。 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).
本公开的另一方面涉及一种制备通式(II)所示的化合物或其可药用的盐的方法，该方法包括：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:
Figure PCTCN2022141271-appb-000018
Figure PCTCN2022141271-appb-000018
通式(IA)所示的化合物或其盐与通式(IIB)所示的化合物或其盐(优选为盐酸盐)发生偶联反应，得到通式(II)所示的化合物或其可药用的盐，The compound shown in general formula (IA) or its salt and the compound shown in general formula (IIB) or its salt (preferably hydrochloride) generation coupling reaction, obtain the compound shown in general formula (II) or its salt medicinal salt,
其中：in:
X为卤素；优选地，X为Cl；X is halogen; preferably, X is Cl;
G、Q、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和q如通式(II)中所定义。 G, Q, 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).
本公开的另一方面涉及一种制备通式(III)所示的化合物或其可药用的盐的方法，该方法包括：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:
Figure PCTCN2022141271-appb-000019
Figure PCTCN2022141271-appb-000019
通式(IIIA)所示的化合物或其盐与通式(IIIB)所示的化合物或其盐(优选为盐酸盐)发生偶联反应，得到通式(III)所示的化合物或其可药用的盐，The compound shown in general formula (IIIA) or its salt and the compound shown in general formula (IIIB) or its salt (preferably hydrochloride) generation coupling reaction, obtain the compound shown in general formula (III) or its salt medicinal salt,
其中：in:
X为卤素；优选地，X为Cl；X is halogen; preferably, X is Cl;
Q、R 1a、R 1b、R 3、R 4、R 5、R 6、R 7、R 8、R 9和R如通式(III)中所定义。 Q, 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).
本公开的另一方面涉及一种制备通式(III-1)所示的化合物或其可药用的盐的方法，该方法包括：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:
Figure PCTCN2022141271-appb-000020
Figure PCTCN2022141271-appb-000020
通式(IIIA)所示的化合物或其盐与通式(III-1B)所示的化合物或其盐(优选为盐 酸盐)发生偶联反应，得到通式(III-1)所示的化合物或其可药用的盐，The compound shown in general formula (IIIA) or its salt and the compound shown in general formula (III-1B) or its salt (preferably hydrochloride) generation coupling reaction, obtain the compound shown in general formula (III-1) compound or a pharmaceutically acceptable salt thereof,
其中：in:
X为卤素；优选地，X为Cl；X is halogen; preferably, X is Cl;
Q、R 1a、R 1b、R 3、R 4、R 5、R 6、R 7、R 8、R 9和R如通式(III-1)中所定义。 Q, 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).
本公开的另一方面涉及一种药物组合物，所述药物组合物含有本公开通式(I)、(II)、(III)、(III-1)和表A中所示的化合物或其可药用的盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。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.
本公开进一步涉及通式(I)、(II)、(III)、(III-1)和表A中所示的化合物或其可药用的盐、或包括其的药物组合物在制备用于抑制CDK的药物中的用途；优选地，其中所述的CDK为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 inhibiting CDK; preferably, the CDK is CDK4.
本公开进一步涉及通式(I)、(II)、(III)、(III-1)和表A中所示的化合物或其可药用的盐、或包括其的药物组合物在制备用于治疗和/或预防由CDK4介导的疾病或病症的药物中的用途；优选地，所述的疾病或病症选自肿瘤、骨髓纤维化、骨髓增生异常综合征、肺动脉高压、高血压、神经退行性疾病和黏膜炎；更优选地，所述的疾病或病症为癌症。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.
本公开进一步涉及通式(I)、(II)、(III)、(III-1)和表A中所示的化合物或其可药用的盐、或包括其的药物组合物在制备用于治疗和/或预防疾病或病症的药物中的用途；其中所述的疾病或病症选自乳腺癌、子宫内膜癌、卵巢癌、***癌、输卵管癌、***、肾癌、膀胱癌、尿路上皮癌、尿道癌、***癌、睾丸癌、结直肠癌、肉瘤、骨癌、多发性骨髓瘤、白血病、粘液瘤、横纹肌瘤、平滑肌瘤、纤维瘤、脂肪瘤、畸胎瘤、喉癌、鼻咽癌、口腔癌、肺癌、淋巴瘤、间皮瘤、小肠癌、胃癌、食道癌、胰腺癌、肝癌、胆管癌、胆道癌、胆囊癌、腹膜癌、胸腺癌、中枢神经***肿瘤、视网膜母细胞瘤、多形性成胶质细胞瘤、神经纤维瘤、神经胶质瘤、成神经细胞瘤、黑色素瘤、皮肤癌、基底细胞癌、鳞状细胞癌、甲状腺癌、头颈癌、脑癌、唾液腺癌和胃肠道间质瘤；优选地，所述的疾病或病症为乳腺癌。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, bile duct cancer, biliary tract cancer, gallbladder cancer, peritoneal cancer, thymus cancer, central nervous system tumor , retinoblastoma, glioblastoma multiforme, neurofibroma, glioma, neuroblastoma, melanoma, skin cancer, basal cell carcinoma, squamous cell carcinoma, thyroid cancer, head and neck cancer, Brain cancer, salivary gland cancer and gastrointestinal stromal tumor; preferably, the disease or condition is breast cancer.
本公开进一步涉及一种抑制CDK的方法，其包括给予所需患者治疗有效量的通式(I)、(II)、(III)、(III-1)和表A所示的化合物或其可药用的盐、或包括其的药物组合物；优选地，其中所述的CDK为CDK4。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.
本公开进一步涉及一种治疗和/或预防由CDK4介导的疾病或病症的方法，其包括给予所需患者治疗有效量的通式(I)、(II)、(III)、(III-1)和表A所示的化合物或其可药用的盐、或包括其的药物组合物；优选地，所述的疾病或病症选自肿瘤、骨髓纤维化、骨髓增生异常综合征、肺动脉高压、高血压、神经退行性疾病和黏膜炎；更优选地，所述的疾病或病症为癌症。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.
本公开进一步涉及一种治疗和/或预防疾病或病症的方法，其包括给予所需患者治疗有效量的通式(I)、(II)、(III)、(III-1)和表A所示的化合物或其可药用的盐、 或包括其的药物组合物；其中所述的疾病或病症选自乳腺癌、子宫内膜癌、卵巢癌、***癌、输卵管癌、***、肾癌、膀胱癌、尿路上皮癌、尿道癌、***癌、睾丸癌、结直肠癌、肉瘤、骨癌、多发性骨髓瘤、白血病、粘液瘤、横纹肌瘤、平滑肌瘤、纤维瘤、脂肪瘤、畸胎瘤、喉癌、鼻咽癌、口腔癌、肺癌、淋巴瘤、间皮瘤、小肠癌、胃癌、食道癌、胰腺癌、肝癌、胆管癌、胆道癌、胆囊癌、腹膜癌、胸腺癌、中枢神经***肿瘤、视网膜母细胞瘤、多形性成胶质细胞瘤、神经纤维瘤、神经胶质瘤、成神经细胞瘤、黑色素瘤、皮肤癌、基底细胞癌、鳞状细胞癌、甲状腺癌、头颈癌、脑癌、唾液腺癌和胃肠道间质瘤；优选地，所述的疾病或病症为乳腺癌。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. The compound or its pharmaceutically acceptable salt, or the pharmaceutical composition comprising it; Wherein 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, glioblastoma multiforme, neurofibroma, glioma, neuroblastoma, melanoma, skin cancer, basal cell carcinoma, squamous cell carcinoma, thyroid cancer, head and neck cancer, brain cancer, salivary gland cancer and gastrointestinal stromal tumor; preferably, the disease or condition is breast cancer.
本公开进一步涉及一种通式(I)、(II)、(III)、(III-1)和表A所示的化合物或其可药用的盐、或包括其的药物组合物，其用作药物。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.
本公开进一步涉及一种通式(I)、(II)、(III)、(III-1)和表A所示的化合物或其可药用的盐、或包括其的药物组合物，其用作抑制CDK的药物；优选地，其中所述的CDK为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 drug for inhibiting CDK; preferably, said CDK is CDK4.
本公开进一步涉及一种通式(I)、(II)、(III)、(III-1)和表A所示的化合物或其可药用的盐、或包括其的药物组合物，其用作治疗和/或预防疾病或病症的药物；其中所述的疾病或病症选自乳腺癌、子宫内膜癌、卵巢癌、***癌、输卵管癌、***、肾癌、膀胱癌、尿路上皮癌、尿道癌、***癌、睾丸癌、结直肠癌、肉瘤、骨癌、多发性骨髓瘤、白血病、粘液瘤、横纹肌瘤、平滑肌瘤、纤维瘤、脂肪瘤、畸胎瘤、喉癌、鼻咽癌、口腔癌、肺癌、淋巴瘤、间皮瘤、小肠癌、胃癌、食道癌、胰腺癌、肝癌、胆管癌、胆道癌、胆囊癌、腹膜癌、胸腺癌、中枢神经***肿瘤、视网膜母细胞瘤、多形性成胶质细胞瘤、神经纤维瘤、神经胶质瘤、成神经细胞瘤、黑色素瘤、皮肤癌、基底细胞癌、鳞状细胞癌、甲状腺癌、头颈癌、脑癌、唾液腺癌和胃肠道间质瘤；优选地，所述的疾病或病症为乳腺癌。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 cancer, liver cancer, bile duct cancer, biliary tract cancer, gallbladder cancer, peritoneal cancer, thymus cancer, central nervous system tumor, retina Blastoma, glioblastoma multiforme, neurofibroma, glioma, neuroblastoma, melanoma, skin cancer, basal cell carcinoma, squamous cell carcinoma, thyroid cancer, head and neck cancer, brain cancer , salivary gland cancer and gastrointestinal stromal tumor; preferably, the disease or disease is breast cancer.
本公开中所述的由CDK4介导的疾病或病症优选选自肿瘤、骨髓纤维化、骨髓增生异常综合征、肺动脉高压、高血压、神经退行性疾病和黏膜炎；更优选地，所述的疾病或病症为癌症。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.
本公开中所述的由CDK4介导的疾病或病症优选选自乳腺癌、子宫内膜癌、卵巢癌、***癌、输卵管癌、***、肾癌、膀胱癌、尿路上皮癌、尿道癌、***癌、睾丸癌、结直肠癌、肉瘤、骨癌、多发性骨髓瘤、白血病、粘液瘤、横纹肌瘤、平滑肌瘤、纤维瘤、脂肪瘤、畸胎瘤、喉癌、鼻咽癌、口腔癌、肺癌、淋巴瘤、间皮瘤、小肠癌、胃癌、食道癌、胰腺癌、肝癌、胆管癌、胆道癌、胆囊癌、腹膜癌、胸腺癌、中枢神经***肿瘤、视网膜母细胞瘤、多形性成胶质细胞瘤、神经纤维瘤、神经胶质瘤、成神经细胞瘤、黑色素瘤、皮肤癌、基底细胞癌、鳞状细胞癌、甲状腺癌、头颈癌、脑癌、唾液腺癌和胃肠道间质瘤；更优选地，所述的疾病或病症为乳腺癌。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, Glioblastoma multiforme, neurofibroma, glioma, neuroblastoma, melanoma, skin cancer, basal cell carcinoma, squamous cell carcinoma, thyroid cancer, head and neck cancer, brain cancer, salivary gland cancer, and Gastrointestinal stromal tumor; more preferably, the disease or condition is breast cancer.
优选地，本公开中所述的淋巴瘤选自霍奇金氏疾病和非霍奇金淋巴瘤(例如套细胞淋巴瘤、弥漫性大B细胞淋巴瘤、滤泡中心淋巴瘤、边缘区B细胞淋巴瘤、淋巴浆细胞淋巴瘤和外周T细胞淋巴瘤)；所述的肺癌为非小细胞肺癌(NSCLC)(例如肺鳞癌和肺腺癌，其中肺腺癌优选为细支气管肺泡癌)和小细胞肺癌(SCLC)；所述的肾癌选自肾细胞癌(RCC)、透明细胞和肾嗜酸细胞瘤；所述的肝癌为肝细胞癌(HCC)；所述的成神经细胞瘤(又称神经母细胞瘤)为成神经管细胞瘤；所述的胰腺癌为胰腺导管腺癌；所述的肉瘤为软骨肉瘤；所述的结直肠癌为结肠癌和直肠癌；所述的白血病选自慢性淋巴细胞性白血病(CLL)、急性成淋巴细胞性白血病(ALL)、T-细胞急性成淋巴细胞性白血病(T-ALL)、慢性髓细胞性白血病(CML)和急性骨髓性白血病(AML)。Preferably, 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 adenocarcinoma; the sarcoma is chondrosarcoma; the colorectal cancer is colon cancer and rectal cancer; selected from chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), T-cell acute lymphoblastic leukemia (T-ALL), chronic myelogenous leukemia (CML) and acute myelogenous leukemia ( AML).
本公开所述的化合物或其可药用的盐或包括其的药物组合物，对CDK4的选择性高于CDK6。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.
作为一般性指导，本公开活性化合物优选是以单位剂量的方式，或者是以患者可以以单剂自我给药的方式。本公开化合物或组合物的单位剂量的表达方式可以是片剂、胶囊、扁囊剂、瓶装药水、药粉、颗粒剂、锭剂、栓剂、再生药粉或液体制剂。合适的单位剂量可以是0.1～1000mg。As a general guide, 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.
本公开的药物组合物除活性化合物外，可含有一种或多种辅料，所述辅料选自以下成分：填充剂(稀释剂)、粘合剂、润湿剂、崩解剂或赋形剂等。根据给药方法的不同，组合物可含有0.1至99重量％的活性化合物。In addition to the active compound, 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. Depending on the method of administration, the compositions may contain from 0.1 to 99% by weight of active compound.
含活性成分的药物组合物可以是适用于口服的形式，例如片剂、糖锭剂、锭剂、水或油混悬液、可分散粉末或颗粒、乳液、硬或软胶囊，或糖浆剂或酏剂。可按照本领域任何已知制备药用组合物的方法制备口服组合物，此类组合物可含有一种或多种选自以下的成分：甜味剂、矫味剂、着色剂和防腐剂，以提供悦目和可口的药用制剂。片剂含有活性成分和用于混合的适宜制备片剂的无毒的可药用的赋形剂。这些赋形剂可以是惰性赋形剂、造粒剂、崩解剂、粘合剂和润滑剂。这些片剂可以不包衣或可通过掩盖药物的味道或在胃肠道中延迟崩解和吸收，因而在较长时间内提供缓释作用的已知技术将其包衣。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. These 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.
也可用其中活性成分与惰性固体稀释剂或其中活性成分与水溶性载体或油溶媒混合的软明胶胶囊提供口服制剂。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.
水混悬液含有活性物质和用于混合的适宜制备水混悬液的赋形剂。此类赋形剂是悬浮剂、分散剂或湿润剂。水混悬液也可以含有一种或多种防腐剂、一种或多种着色剂、一种或多种矫味剂和一种或多种甜味剂。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.
油混悬液可通过使活性成分悬浮于植物油或矿物油配制而成。油悬浮液可含有增稠剂。可加入上述的甜味剂和矫味剂，以提供可口的制剂。可通过加入抗氧化剂保存这些组合物。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.
本公开的药物组合物也可以是水包油乳剂的形式。油相可以是植物油、矿物油或其混合物。适宜的乳化剂可以是天然产生的磷脂，乳剂也可以含有甜味剂、矫味剂、防腐剂和抗氧剂。此类制剂也可含有缓和剂、防腐剂、着色剂和抗氧剂。The pharmaceutical 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.
本公开的药物组合物可以是无菌注射水溶液形式。可以使用的可接受的溶媒或溶剂有水、林格氏液和等渗氯化钠溶液。无菌注射制剂可以是其中活性成分溶于油相的无菌注射水包油微乳，可通过局部大量注射将注射液或微乳注入患者的血流中。或者，最好按可保持本公开化合物恒定循环浓度的方式给予溶液和微乳。为保持这种恒定浓度，可使用连续静脉内递药装置。这种装置的实例是Deltec CADD-PLUS.TM.5400型静脉注射泵。The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous solutions. Among the 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. Alternatively, solutions and microemulsions are preferably administered in a manner that maintains a constant circulating concentration of the disclosed compounds. To maintain this constant concentration, a continuous intravenous delivery device can be used. An example of such a device is the Deltec CADD-PLUS.TM. Model 5400 IV pump.
本公开的药物组合物可以是用于肌内和皮下给药的无菌注射水或油混悬液的形式。可按已知技术，用适宜的分散剂或湿润剂和悬浮剂配制该混悬液。无菌注射制剂也可以是在肠胃外可接受的无毒稀释剂或溶剂中制备的无菌注射溶液或混悬液。此外，可方便地用无菌固定油作为溶剂或悬浮介质。为此目的，可使用任何调和固定油。此外，脂肪酸也可以制备注射剂。The pharmaceutical 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. In addition, sterile fixed oils are conveniently employed as a solvent or suspending medium. For this purpose, any blended and fixed oil may be used. In addition, fatty acids are also used in the preparation of injectables.
可按用于直肠给药的栓剂形式给予本公开化合物。可通过将药物与在普通温度下为固体但在直肠中为液体，因而在直肠中会溶化而释放药物的适宜的无刺激性赋形剂混合来制备这些药物组合物。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.
如本领域技术人员所熟知的，药物的给药剂量依赖于多种因素，包括但并非限定于以下因素：所用具体化合物的活性、患者的年龄、患者的体重、患者的健康状况、患者的行为、患者的饮食、给药时间、给药方式、***的速率、药物的组合、疾病的严重性等；另外，最佳的治疗方式如治疗的模式、化合物的日用量或可药用的盐的种类可以根据传统的治疗方案来验证。As is well known to those skilled in the art, 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.
术语说明Glossary
除非有相反陈述，在说明书和权利要求书中使用的术语具有下述含义。Unless stated to the contrary, the terms used in the specification and claims have the following meanings.
术语“烷基”指饱和的直链或带有支链的脂肪族烃基，其具有1至20个(例如1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)碳原子(即C 1-20烷基)。所述烷基优选具有1至12个碳原子的烷基(即C 1-12烷基)，更优选具有1至6个碳原子的烷基(即C 1-6烷基)。非限制性的实例包括：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5- 二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各种支链异构体等。烷基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自D原子、卤素、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。 The term "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-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-di Methylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl , 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4 -Ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3 -Ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof. 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.
术语“亚烷基”指二价烷基，其中烷基如上所定义，其具有1至20个(例如1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)碳原子(即C 1-20亚烷基)。所述亚烷基优选具有1至12个碳原子的亚烷基(即C 1-12亚烷基)，更优选具有1至6个碳原子的亚烷基(即C 1-6亚烷基)。非限制性的实例包括：-CH 2-、-CH(CH 3)-、-C(CH 3) 2-、-CH 2CH 2-、-CH(CH 2CH 3)-、-CH 2CH(CH 3)-、-CH 2C(CH 3) 2-、-CH 2CH 2CH 2-、-CH 2CH 2CH 2CH 2-等。亚烷基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自D原子、卤素、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。 The term "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.
术语“烯基”指分子中含有至少一个碳碳双键的烷基，其中烷基的定义如上所述，其具有2至12个(例如2、3、4、5、6、7、8、9、10、11或12个)碳原子(即C 2-12烯基)。所述烯基优选具有2至6个碳原子的烯基(即C 2-6烯基)。非限制性的实例包括：乙烯基、丙烯基、异丙烯基、丁烯基等。烯基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自D原子、烷氧基、卤素、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。 The term "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.
术语“炔基”指分子中含有至少一个碳碳三键的烷基，其中烷基的定义如上所述，其具有2至12个(例如2、3、4、5、6、7、8、9、10、11或12个)碳原子(即C 2-12炔基)。所述炔基优选具有2至6个碳原子的炔基(即C 2-6炔基)。非限制性的实例包括：乙炔基、丙炔基、丁炔基、戊炔基、己炔基等。炔基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自D原子、烷氧基、卤素、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。 The term "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.
术语“烷氧基”指-O-(烷基)，其中烷基的定义如上所述。非限制性的实例包括：甲氧基、乙氧基、丙氧基和丁氧基等。烷氧基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自D原子、卤素、 烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。The term "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.
术语“环烷基”指饱和或部分不饱和的单环全碳环(即单环环烷基)或多环***(即多环环烷基)，其具有3至20个(例如3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即3至20元环烷基)。所述环烷基优选具有3至12个环原子的环烷基(即3至12元环烷基)，更优选具有3至8个环原子的环烷基(即3至8元环烷基)，最优选具有3至6个环原子的环烷基(即3至6元环烷基)。The term "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).
所述的单环环烷基，非限制性的实例包括：环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基和环辛基等。Said monocyclic cycloalkyl, non-limiting examples include: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl , cycloheptatrienyl and cyclooctyl, etc.
所述的多环环烷基包括：螺环烷基、稠环烷基和桥环烷基。The polycyclic cycloalkyl includes: spirocycloalkyl, condensed cycloalkyl and bridged cycloalkyl.
术语“螺环烷基”指环之间共用一个碳原子(称螺原子)的多环***，其环内可以含有一个或多个双键，或其环内可以含有一个或多个选自氮、氧和硫的杂原子(所述的氮可任选被氧化，即形成氮氧化物；所述的硫可任选被氧代，即形成亚砜或砜，但不包括-O-O-、-O-S-或-S-S-)，条件是至少含有一个全碳环且连接点在该全碳环上，其具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即5至20元螺环烷基)。所述螺环烷基优选具有6至14个环原子的螺环烷基(即6至14元螺环烷基)，更优选具有7至10个环原子的螺环烷基(即7至10元螺环烷基)。所述螺环烷基包括单螺环烷基和多螺环烷基(如双螺环烷基等)，优选单螺环烷基或双螺环烷基，更优选3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/3元、5元/4元、5元/5元、5元/6元、5元/7元、6元/3元、6元/4元、6元/5元、6元/6元、6元/7元、7元/5元或7元/6元单螺环烷基。非限制性的实例包括：The term "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. form sulfoxides or sulfones, but excluding -O-O-, -O-S -or-S-S-), provided that it contains at least one full carbon ring and the point of attachment is on the full carbon ring, it 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 spirocycloalkyl). The spirocycloalkyl is preferably a spirocycloalkyl having 6 to 14 ring atoms (i.e. 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 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 7 yuan/6 yuan Single spirocycloalkyl. Non-limiting examples include:
Figure PCTCN2022141271-appb-000021
其连接点可在任意位置；
Figure PCTCN2022141271-appb-000021
Its connection point can be at any position;
Figure PCTCN2022141271-appb-000022
等。
Figure PCTCN2022141271-appb-000022
wait.
术语“稠环烷基”指环之间共享毗邻的两个碳原子的多环***，其为单环环烷基与一个或多个单环环烷基稠合，或者单环环烷基与杂环基、芳基或杂芳基中的一个或多个稠合，其中连接点在单环环烷基上，其环内可以含有一个或多个双键，且具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、 18、19或20个)环原子(即5至20元稠环烷基)。所述稠环烷基优选具有6至14个环原子的稠环烷基(即6至14元稠环烷基)，更优选具有7至10个环原子的稠环烷基(即7至10元稠环烷基)。所述稠环烷基包括双环稠环烷基和多环稠环烷基(如三环稠环烷基、四环稠环烷基等)，优选双环稠环烷基或三环稠环烷基，更优选3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/3元、5元/4元、5元/5元、5元/6元、5元/7元、6元/3元、6元/4元、6元/5元、6元/6元、6元/7元、7元/5元或7元/6元双环稠环烷基。非限制性的实例包括：The term "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 One or more of 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 yuan/6 yuan, 6 yuan/7 yuan, 7 yuan Member/5-member or 7-member/6-membered bicyclic fused cycloalkyl group. Non-limiting examples include:
Figure PCTCN2022141271-appb-000023
Figure PCTCN2022141271-appb-000023
，其连接点可在任意位置；, its connection point can be at any position;
Figure PCTCN2022141271-appb-000024
Figure PCTCN2022141271-appb-000024
Figure PCTCN2022141271-appb-000025
等。
Figure PCTCN2022141271-appb-000025
wait.
术语“桥环烷基”指环之间共用两个不直接连接的碳原子的全碳多环***，其环内可以含有一个或多个双键，且具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)碳原子(即5至20元桥环烷基)。所述桥环烷基优选具有6至14个碳原子的桥环烷基(即6至14元桥环烷基)，更优选具有7至10个碳原子的桥环烷基(即7至10元桥环烷基)。所述桥环烷基包括双环桥环烷基和多环桥环烷基(如三环桥环烷基、四环桥环烷基等)，优选双环桥环烷基或三环桥环烷基。非限制性的实例包括：The term "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. 7 to 10 bridged cycloalkyl). 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:
Figure PCTCN2022141271-appb-000026
其连接点可在任意位置。
Figure PCTCN2022141271-appb-000026
Its connection point can be anywhere.
环烷基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自D原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氧代基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。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.
术语“杂环基”指饱和或部分不饱和的单环杂环(即单环杂环基)或多环杂环***(即多环杂环基)，其环内至少含有一个(例如1、2、3或4个)选自氮、氧和硫的杂原子(所述的氮可任选被氧化，即形成氮氧化物；所述的硫可任选被氧代，即形成亚砜或砜，但不包括-O-O-、-O-S-或-S-S-)，且具有3至20个(例如3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环 原子(即3至20元杂环基)。所述杂环基优选具有3至12个环原子的杂环基(即3至12元杂环基)；进一步优选具有3至8个环原子的杂环基(即3至8元杂环基)；更优选具有3至6个环原子的杂环基(即3至6元杂环基)、具有4至6个环原子的杂环基(即4至6元杂环基)或具有5至7个环原子的杂环基(即5至7元杂环基)；最优选具有5或6个环原子的杂环基(即5或6元杂环基)。The term "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. form sulfoxides or sulfone, but not including -O-O-, -O-S- or -S-S-), with 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 heterocyclyl). 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); most preferably a heterocyclyl group having 5 or 6 ring atoms (ie, a 5- or 6-membered heterocyclyl group).
所述的单环杂环基，非限制性的实例包括：吡咯烷基、四氢吡喃基、1,2,3,6-四氢吡啶基、哌啶基、哌嗪基、吗啉基、硫代吗啉基和高哌嗪基等。Non-limiting examples of the monocyclic heterocyclic group include: pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl , Thiomorpholinyl and Homopiperazinyl, etc.
所述的多环杂环基包括螺杂环基、稠杂环基和桥杂环基。The polycyclic heterocyclic groups include spiro heterocyclic groups, condensed heterocyclic groups and bridged heterocyclic groups.
术语“螺杂环基”指环之间共用一个原子(称螺原子)的多环杂环***，其环内可以含有一个或多个双键，且其环内至少含有一个(例如1、2、3或4个)选自氮、氧和硫的杂原子(所述的氮可任选被氧化，即形成氮氧化物；所述的硫可任选被氧代，即形成亚砜或砜，但不包括-O-O-、-O-S-或-S-S-)，条件是至少含有一个单环杂环基且连接点在该单环杂环基上，其具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即5至20元螺杂环基)。所述螺杂环基优选具有6至14个环原子的螺杂环基(即6至14元螺杂环基)，更优选具有7至10个环原子的螺杂环基(即7至10元螺杂环基)。所述螺杂环基包括单螺杂环基和多螺杂环基(如双螺杂环基等)，优选单螺杂环基或双螺杂环基，更优选3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/3元、5元/4元、5元/5元、5元/6元、5元/7元、6元/3元、6元/4元、6元/5元、6元/6元、6元/7元、7元/5元或7元/6元单螺杂环基。非限制性的实例包括：The term "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. to form sulfoxides or sulfones, But not including -O-O-, -O-S- or -S-S-), 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. 6 to 14 membered spiroheterocyclyl), more preferably a spiroheterocyclyl having 7 to 10 ring atoms (i.e. 7 to 10 membered spiroheterocyclyl). 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, 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 7 yuan/6 yuan Monospiroheterocyclyl. Non-limiting examples include:
Figure PCTCN2022141271-appb-000027
等。
Figure PCTCN2022141271-appb-000027
wait.
术语“稠杂环基”指环之间共享毗邻的两个原子的多环杂环***，其环内可以含有一个或多个双键，且其环内至少含有一个(例如1、2、3或4个)选自氮、氧和硫的杂原子(所述的氮可任选被氧化，即形成氮氧化物；所述的硫可任选被氧代，即形成亚砜或砜，但不包括-O-O-、-O-S-或-S-S-)，其为单环杂环基与一个或多个单环杂环基稠合，或者单环杂环基与环烷基、芳基或杂芳基中的一个或多个稠合，其中连接点在单环杂环基上，且具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即5至20元稠杂环基)。所述稠杂环基优选具有6至14个环原子的稠杂环基(即6至14元稠杂环基)，更优选具有7至10个环原子的稠杂环基(即7至10元稠杂环基)。所述稠杂环基包括双环和多环稠杂环基(如三环稠杂环基、四环稠杂环基等)，优选双环稠杂环基或三环稠杂环基，更优选3元/4元、3元/5元、3元/6元、4元/4 元、4元/5元、4元/6元、5元/3元、5元/4元、5元/5元、5元/6元、5元/7元、6元/3元、6元/4元、6元/5元、6元/6元、6元/7元、7元/5元或7元/6元双环稠杂环基。非限制性的实例包括：The term "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. to form 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 One or more of the fused groups, wherein the point of attachment is on the monocyclic heterocyclic group, and there are 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 fused heterocyclyl). 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. Non-limiting examples include:
Figure PCTCN2022141271-appb-000028
等。
Figure PCTCN2022141271-appb-000028
wait.
术语“桥杂环基”指环之间共用两个不直接连接的原子的多环杂环***，其环内可以含有一个或多个双键，并且其环内至少含有一个(例如1、2、3或4个)选自氮、氧和硫的杂原子(所述的氮可任选被氧化，即形成氮氧化物；所述的硫可任选被氧代，即形成亚砜或砜，但不包括-O-O-、-O-S-或-S-S-)，其具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即5至20元桥杂环基)。所述桥杂环基优选具有6至14个环原子的桥杂环基(即6至14元桥杂环基)，更优选具有7至10个环原子的桥杂环基(即7至10元桥杂环基)。根据组成环的数目可以分为双环桥杂环基和多环桥杂环基(如三环桥杂环基、四环桥杂环基等)，优选双环桥杂环基或三环桥杂环基。非限制性的实例包括：The term "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. to form sulfoxides or sulfones, but not including -O-O-, -O-S- or -S-S-), which have 5 to 20 (eg 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (ie 5 to 20 membered bridged heterocyclyl). 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). According to the number of rings, it can be divided into bicyclic bridged heterocyclic group and polycyclic bridged heterocyclic group (such as tricyclic bridged heterocyclic group, tetracyclic bridged heterocyclic group, etc.), preferably bicyclic bridged heterocyclic group or tricyclic bridged heterocyclic group base. Non-limiting examples include:
Figure PCTCN2022141271-appb-000029
等。
Figure PCTCN2022141271-appb-000029
wait.
杂环基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自D原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氧代基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。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.
术语“芳基”指具有共轭的π电子体系的单环全碳芳环(即单环芳基)或多环芳环***(即多环芳基)，其具有6至14个(例如6、7、8、9、10、11、12、 13或14个)环原子(即6至14元芳基)。所述芳基优选具有6至10个环原子的芳基(即6至10元芳基)。所述的单环芳基，例如苯基。所述的多环芳基，非限制性的实例包括：萘基、蒽基、菲基等。所述多环芳基还包括苯基与杂环基或环烷基中的一个或多个稠合，或萘基与杂环基或环烷基中的一个或多个稠合，其中连接点在苯基或萘基上，并且在这种情况下，环原子个数继续表示多环芳环***中的环原子个数，非限制性的实例包括：The term "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 π-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:
Figure PCTCN2022141271-appb-000030
等。
Figure PCTCN2022141271-appb-000030
wait.
芳基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自D原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氧代基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。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.
术语“杂芳基”指具有共轭的π电子体系的单环杂芳环(即单环杂芳基)或多环杂芳环***(即多环杂芳基)，其环内至少含有一个(例如1、2、3或4个)选自氮、氧和硫的杂原子(所述的氮可任选被氧化，即形成氮氧化物；所述的硫可任选被氧代，即形成亚砜或砜，但不包括-O-O-、-O-S-或-S-S-)，其具有5至14个(例如5、6、7、8、9、10、11、12、13或14个)环原子(即5至14元杂芳基)。所述杂芳基优选具有5至10个环原子的杂芳基(即5至10元杂芳基)，更优选具有5或6个环原子的杂芳基(即5或6元杂芳基)。The term "heteroaryl" refers to a monocyclic heteroaryl ring (ie, monocyclic heteroaryl) or a polycyclic heteroaryl ring system (ie, polycyclic heteroaryl) having a conjugated π-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. forming sulfoxides or sulfones, but excluding -O-O-, -O-S- or -S-S-), which have 5 to 14 (eg 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ) ring atoms (ie 5 to 14 membered heteroaryl). 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). ).
所述的单环杂芳基，非限制性的实例包括：呋喃基、噻吩基、噻唑基、异噻唑基、噁唑基、异噁唑基、噁二唑基、噻二唑基、咪唑基、吡唑基、***基、四唑基、呋咱基、吡咯基、N-烷基吡咯基、吡啶基、嘧啶基、吡啶酮基、N-烷基吡啶酮(如
Figure PCTCN2022141271-appb-000031
等)、吡嗪基、哒嗪基等。 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
Figure PCTCN2022141271-appb-000031
etc.), pyrazinyl, pyridazinyl, etc.
所述的多环杂芳基，非限制性的实例包括：吲哚基、吲唑基、喹啉基、异喹啉基、喹喔啉基、酞嗪基、苯并咪唑基、苯并噻吩基、喹唑啉基、苯并噻唑基、咔唑基等。所述多环杂芳基还包括单环杂芳基与一个或多个芳基稠合，其中连接点在芳香环上，并且在这种情况下，环原子个数继续表示多环杂芳环***中的环原子个数。所述多环杂芳基还包括单环杂芳基与环烷基或杂环基中的一个或多个稠合，其中连接点在单环杂芳环上，并且在这种情况下，环原子个数继续表示多环杂芳环***中的环原子个数。非限制性的实例包括：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:
Figure PCTCN2022141271-appb-000032
Figure PCTCN2022141271-appb-000032
Figure PCTCN2022141271-appb-000033
Figure PCTCN2022141271-appb-000033
Figure PCTCN2022141271-appb-000034
等。
Figure PCTCN2022141271-appb-000034
wait.
杂芳基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自D原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。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.
术语“氨基保护基”是指为了使分子其它部位进行反应时氨基保持不变，在氨基上引入的易于脱去的基团。非限制性的实例包括：(三甲基硅)乙氧基甲基、四氢吡喃基、叔丁氧羰基(Boc)、苄氧羰基(Cbz)、笏甲氧羰基(Fmoc)、烯丙氧羰基(Alloc)、三甲基硅乙氧羰基(Teoc)、甲氧羰基、乙氧羰基、邻苯二甲酰基(Pht)、对甲苯磺酰基(Tos)、三氟乙酰基(Tfa)、三苯甲基(Trt)、2,4-二甲氧基苄基(DMB)、乙酰基、苄基、烯丙基、对甲氧苄基等。The term "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.
术语“羟基保护基”是指在羟基上引入的易于脱去的基团，用于阻断或保护羟基而在化合物的其它官能团上进行反应。非限制性的实例包括：三甲基硅基(TMS)、三乙基硅基(TES)、三异丙基硅基(TIPS)、叔丁基二甲基硅基(TBS)、叔丁基二苯基硅基(TBDPS)、甲基、叔丁基、烯丙基、苄基、甲氧基甲基(MOM)、乙氧基乙基、2-四氢吡喃基(THP)、甲酰基、乙酰基、苯甲酰基、对硝基苯甲酰基等。The term "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.
术语“环烷基氧基”指环烷基-O-，其中环烷基如上所定义。The term "cycloalkyloxy" refers to cycloalkyl-O-, wherein cycloalkyl is as defined above.
术语“杂环基氧基”指杂环基-O-，其中杂环基如上所定义。The term "heterocyclyloxy" refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.
术语“芳基氧基”指芳基-O-，其中芳基如上所定义。The term "aryloxy" refers to aryl-O-, wherein aryl is as defined above.
术语“杂芳基氧基”指杂芳基-O-，其中杂芳基如上所定义。The term "heteroaryloxy" refers to heteroaryl-O-, wherein heteroaryl is as defined above.
术语“烷硫基”指烷基-S-，其中烷基如上所定义。The term "alkylthio" refers to alkyl-S-, wherein alkyl is as defined above.
术语“卤代烷基”指烷基被一个或多个卤素取代，其中烷基如上所定义。The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
术语“卤代烷氧基”指烷氧基被一个或多个卤素取代，其中烷氧基如上所定义。The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy group is as defined above.
术语“氘代烷基”指烷基被一个或多个氘原子取代，其中烷基如上所定义。The term "deuteroalkyl" refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.
术语“羟烷基”指烷基被一个或多个羟基取代，其中烷基如上所定义。The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.
术语“甲叉基”指＝CH 2。 The term "methylene" refers to = CH2 .
术语“卤素”指氟、氯、溴或碘。The term "halogen" refers to fluorine, chlorine, bromine or iodine.
术语“羟基”指-OH。The term "hydroxyl" refers to -OH.
术语“巯基”指-SH。The term "mercapto" refers to -SH.
术语“氨基”指-NH 2。 The term "amino" refers to -NH2 .
术语“氰基”指-CN。The term "cyano" refers to -CN.
术语“硝基”指-NO 2。 The term "nitro" refers to -NO2 .
术语“氧代”或“氧代基”指“＝O”。The term "oxo" or "oxo" refers to "=O".
术语“羰基”指C＝O。The term "carbonyl" refers to C=O.
术语“羧基”指-C(O)OH。The term "carboxy" refers to -C(O)OH.
术语“羧酸酯基”指-C(O)O(烷基)、-C(O)O(环烷基)、(烷基)C(O)O-或(环烷基)C(O)O-，其中烷基和环烷基如上所定义。The term "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.
本公开化合物可以存在特定的立体异构体形式。术语“立体异构体”是指结构相同但原子在空间中的排列不同的异构体。其包括顺式和反式(或Z和E)异构体、(-)-和(+)-异构体、(R)-和(S)-对映异构体、非对映异构体、(D)-和(L)-异构体、互变异构体、阻转异构体、构象异构体及其混合物(如外消旋体、非对映异构体的混合物)。本公开化合物中的取代基可以存在另外的不对称原子。所有这些立体异构体以及它们的混合物，均包括在本公开的范围内。可以通过手性合成、手性试剂或者其他常规技术制备光学活性的(-)-和(+)-异构体、(R)-和(S)-对映异构体以及(D)-和(L)-异构体。本公开某化合物的一种异构体，可以通过不对称合成或者手性助剂来制备，或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，得到纯的异构体。此外，对映异构体和非对映异构体的分离通常是通过色谱法完成。Compounds of the present disclosure may exist in particular stereoisomeric forms. The term "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. All such stereoisomers, as well as mixtures thereof, are included within the scope of the present disclosure. 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.
本公开所述化合物的化学结构中，键
Figure PCTCN2022141271-appb-000035
表示未指定构型，即如果化学结构中存在手性异构体，键
Figure PCTCN2022141271-appb-000036
可以为
Figure PCTCN2022141271-appb-000037
或
Figure PCTCN2022141271-appb-000038
或者同时包含
Figure PCTCN2022141271-appb-000039
和
Figure PCTCN2022141271-appb-000040
两种构型。对于所有的碳-碳双键，即使仅命名了一个构型，Z型和E型均包括在内。 In the chemical structures of the compounds described in this disclosure, the bond
Figure PCTCN2022141271-appb-000035
Indicates that no configuration is specified, that is, if chiral isomers exist in the chemical structure, the bond
Figure PCTCN2022141271-appb-000036
can be
Figure PCTCN2022141271-appb-000037
or
Figure PCTCN2022141271-appb-000038
or both
Figure PCTCN2022141271-appb-000039
and
Figure PCTCN2022141271-appb-000040
Two configurations. For all carbon-carbon double bonds, even if only one configuration is named, both Z and E forms are included.
本公开的化合物可以以不同的互变异构体形式存在，并且所有这样的形式包含在本公开的范围内。术语“互变异构体”或“互变异构体形式”是指平衡存在并且容易从一种异构形式转化为另一种异构形式的结构异构体。其包括所有可能的互变异构体，即以单一异构体的形式或以所述互变异构体的任意比例的混合物的形式存在。非限制性的实例包括：酮-烯醇、亚胺-烯胺、内酰胺-内酰亚胺等。内酰胺-内酰亚胺的平衡实例如下所示：The compounds of the present disclosure may exist in different tautomeric forms and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" 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:
Figure PCTCN2022141271-appb-000041
Figure PCTCN2022141271-appb-000041
如当提及吡唑基时，应理解为包括如下两种结构中的任何一种或两种互变异构体的混合物：For example, when referring to pyrazolyl, it should be understood to include any one of the following two structures or a mixture of two tautomers:
Figure PCTCN2022141271-appb-000042
Figure PCTCN2022141271-appb-000042
所有的互变异构形式在本公开的范围内，且化合物的命名不排除任何互变异构体。All tautomeric forms are within the scope of the present disclosure, and the naming of compounds does not exclude any tautomers.
本公开的化合物包括其化合物的所有合适的同位素衍生物。术语“同位素衍生物”是指至少一个原子被具有相同原子序数但原子质量不同的原子替代的化合物。可引入到本公开化合物中的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、氯、溴和碘等的稳定和放射性的同位素，例如分别为 2H(氘，D)、 3H(氚，T)、 11C、 13C、 14C、 15N、 17O、 18O、 32p、 33p、 33S、 34S、 35S、 36S、 18F、 36Cl、 82Br、 123I、 124I、 125I、 129I和 131I等，优选氘。 Compounds of the present disclosure include all suitable isotopic derivatives of their compounds. The term "isotopic derivative" 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. Examples of 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.
相比于未氘代药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本公开的化合物的所有同位素组成的变换，无论放射性与否，都包括在本公开的范围之内。与碳原子连接的各个可用的氢原子可独立地被氘原子替换，其中氘的替换可以是部分或完全的，部分氘的替换是指至少一个氢被至少一个氘替换。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.
本公开的化合物，当其一个位置被特别地指定为“氘”或“D”时，该位置应理解为氘的丰度比氘的天然丰度(其为0.015％)大至少1000倍(即至少15％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少1000倍(即至少15％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少2000倍(即至少30％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少3000倍(即至少45％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少3340倍(即至少50.1％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少3500倍(即至少52.5％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少4000倍(即至少60％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少4500倍(即至少67.5％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少5000倍(即至少75％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少5500倍(即至少82.5％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少6000倍(即至少90％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少6333.3倍(即至少95％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少6466.7倍(即至少97％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少6600倍(即至少99％的氘掺入)。在一些实施方 案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少6633.3倍(即至少99.5％的氘掺入)。In a compound of the present disclosure, when a position is specifically designated as "deuterium" or "D", 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). In some embodiments, 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). In some embodiments, 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). In some embodiments, 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).
“任选地”或“任选”是指随后所描述的事件或环境可以但不必然发生，其包括该事件或环境发生或不发生两种情形。例如“任选地(任选)被卤素或者氰基取代的烷基”包括烷基被卤素或者氰基取代的情形和烷基不被卤素和氰基取代的情形。"Optionally" or "optionally" means that the subsequently described event or circumstance may but not necessarily occur, and it includes two situations in which the event or circumstance occurs or does not occur. For example, "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.
“取代”或“取代的”指基团中的一个或多个氢原子，优选1～6个，更优选1～3个氢原子彼此独立地被相应数目的取代基取代。本领域技术人员能够在不付出过多努力的情况下(通过实验或理论)确定可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和键的碳原子(如烯)结合时可能是不稳定的。"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.
“药物组合物”表示含有一种或多种本文所述化合物或其可药用的盐与其他化学组分的混合物，以及其他组分例如药学上可接受的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。"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.
“可药用的盐”是指本公开化合物的盐，可选自无机盐或有机盐。这类盐用于哺乳动物体内时具有安全性和有效性，且具有应有的生物活性。可以在化合物的最终分离和纯化过程中，或通过使合适的基团与合适的碱或酸反应来单独制备。通常用于形成药学上可接受的盐的碱包括无机碱，例如氢氧化钠和氢氧化钾，以及有机碱，例如氨。通常用于形成药学上可接受的盐的酸包括无机酸以及有机酸。"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.
针对药物或药理学活性剂而言，术语“治疗有效量”是指足以达到或至少部分达到预期效果的药物或药剂的用量。治疗有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的治疗有效量可以由本领域技术人员根据常规试验确定。With respect to a drug or pharmacologically active agent, 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.
本文所用的术语“药学上可接受的”是指这些化合物、材料、组合物和/或剂型，在合理的医学判断范围内，适用于与患者组织接触而没有过度毒性、刺激性、过敏反应或其他问题或并发症，具有合理的获益/风险比，并且对预期的用途是有效。As used herein, 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.
本文所使用的，单数形式的“一个”、“一种”和“该”包括复数引用，反之亦然，除非上下文另外明确指出。As used herein, the singular forms "a", "an" and "the" include plural references and vice versa unless the context clearly dictates otherwise.
当将术语“约”应用于诸如pH、浓度、温度等的参数时，表明该参数可以变化±10％，并且有时更优选地在±5％之内。如本领域技术人员将理解的，当参数不是关键时，通常仅出于说明目的给出数字，而不是限制。When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it means that the parameter may vary by ±10%, and sometimes more preferably within ±5%. As will be understood by those skilled in the art, when a parameter is not critical, the numbers are generally given for illustrative purposes only, and not for limitation.
本公开化合物的合成方法Synthetic Methods of the Disclosed Compounds
为了完成本公开的目的，本公开采用如下技术方案：In order to accomplish the purpose of this disclosure, this disclosure adopts the following technical solutions:
方案一Option One
本公开通式(I)所示的化合物或其可药用的盐的制备方法，该方法包括：The preparation method of the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof of the present disclosure, the method comprises:
Figure PCTCN2022141271-appb-000043
Figure PCTCN2022141271-appb-000043
通式(IA)所示的化合物或其盐与通式(IB)所示的化合物或其盐(优选为盐酸盐)在碱性条件下发生偶联反应，得到通式(I)所示的化合物或其可药用的盐，The compound represented by general formula (IA) or its salt and the compound represented by general formula (IB) or its salt (preferably hydrochloride) take place coupling reaction under alkaline condition, obtain the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof,
其中：in:
X为卤素；优选地，X为Cl；X is halogen; preferably, X is Cl;
环A、G、R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R和m如通式(I)中所定义。 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).
方案二Option II
本公开通式(II)所示的化合物或其可药用的盐的制备方法，该方法包括：The preparation method of the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof of the present disclosure, the method comprises:
Figure PCTCN2022141271-appb-000044
Figure PCTCN2022141271-appb-000044
通式(IA)所示的化合物或其盐与通式(IIB)所示的化合物或其盐(优选为盐酸盐)在碱性条件下发生偶联反应，得到通式(II)所示的化合物或其可药用的盐，The compound represented by general formula (IA) or its salt and the compound represented by general formula (IIB) or its salt (preferably hydrochloride) take place coupling reaction under basic condition, obtain the compound represented by general formula (II) or a pharmaceutically acceptable salt thereof,
其中：in:
X为卤素；优选地，X为Cl；X is halogen; preferably, X is Cl;
G、Q、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和q如通式(II)中所定义。 G, Q, 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).
方案三third solution
本公开通式(III)所示的化合物或其可药用的盐的制备方法，该方法包括：The preparation method of the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof of the present disclosure, the method comprises:
Figure PCTCN2022141271-appb-000045
Figure PCTCN2022141271-appb-000045
通式(IIIA)所示的化合物或其盐与通式(IIIB)所示的化合物或其盐(优选为盐酸 盐)在碱性条件下发生偶联反应，得到通式(III)所示的化合物或其可药用的盐，The compound represented by the general formula (IIIA) or its salt and the compound represented by the general formula (IIIB) or its salt (preferably hydrochloride) undergo a coupling reaction under alkaline conditions to obtain the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof,
其中：in:
X为卤素；优选地，X为Cl；X is halogen; preferably, X is Cl;
Q、R 1a、R 1b、R 3、R 4、R 5、R 6、R 7、R 8、R 9和R如通式(III)中所定义。 Q, 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).
方案四Option four
本公开通式(III-1)所示的化合物或其可药用的盐的制备方法，该方法包括：The preparation method of the compound represented by the general formula (III-1) or a pharmaceutically acceptable salt thereof of the present disclosure, the method comprises:
Figure PCTCN2022141271-appb-000046
Figure PCTCN2022141271-appb-000046
通式(IIIA)所示的化合物或其盐与通式(III-1B)所示的化合物或其盐(优选为盐酸盐)在碱性条件下发生偶联反应，得到通式(III-1)所示的化合物或其可药用的盐，The compound shown in general formula (IIIA) or its salt and the compound shown in general formula (III-1B) or its salt (preferably hydrochloride) take place coupling reaction under alkaline condition, obtain general formula (III- 1) the indicated compound or its pharmaceutically acceptable salt,
其中：in:
X为卤素；优选地，X为Cl；X is halogen; preferably, X is Cl;
Q、R 1a、R 1b、R 3、R 4、R 5、R 6、R 7、R 8、R 9和R如通式(III-1)中所定义。 Q, 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).
以上合成方案中提供碱性条件的试剂包括有机碱和无机碱类，所述的有机碱类包括但不限于三乙胺、吡啶、N,N-二异丙基乙胺、正丁基锂、二异丙基氨基锂、醋酸钠、醋酸钾、叔丁醇钠、叔丁醇钾或1,8-二氮杂二环十一碳-7-烯；所述的无机碱类包括但不限于氢化钠、磷酸钾、碳酸钠、碳酸钾、碳酸铯、氢氧化钠、氢氧化锂和氢氧化钾；优选为N,N-二异丙基乙胺。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.
上述步骤的反应优选在溶剂中进行，所用的溶剂包括但不限于：吡啶、乙二醇二甲醚、醋酸、甲醇、乙醇、乙腈、正丁醇、甲苯、四氢呋喃、二氯甲烷、石油醚、乙酸乙酯、正己烷、二甲基亚砜、1,4-二氧六环、水、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、1,2-二溴乙烷及其混合物。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.
具体实施方式Detailed ways
以下结合实施例用于进一步描述本公开，但这些实施例并非限制着本公开的范围。The following examples are used to further describe the present disclosure, but these examples do not limit the scope of the present disclosure.
实施例Example
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10 -6(ppm)的单位给出。NMR的测定是用Bruker AVANCE NEO 500M，测定溶剂为氘代二甲基亚砜(DMSO-d 6)、氘代氯仿(CDCl 3)、氘代甲醇(CD 3OD)，内标为四甲基硅烷(TMS)。 Compound structures were determined by nuclear magnetic resonance (NMR) or/and mass spectroscopy (MS). NMR shifts (δ) are given in units of 10 -6 (ppm). The determination of NMR is carried out with Bruker AVANCE NEO 500M, the determination solvent is deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard is tetramethyl Silane (TMS).
MS的测定用Agilent 1200/1290 DAD-6110/6120 Quadrupole MS液质联用仪(生产商：Agilent，MS型号：6110/6120Quadrupole MS)，waters ACQuity UPLC-QD/SQD(生产商：waters，MS型号：waters ACQuity Qda Detector/waters SQ Detector)，THERMO Ultimate 3000-Q Exactive(生产商：THERMO，MS型号：THERMO Q Exactive)。The determination of 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).
高效液相色谱法(HPLC)分析使用Agilent HPLC 1200DAD、Agilent HPLC 1200VWD和Waters HPLC e2695-2489液相色谱仪。High-performance liquid chromatography (HPLC) was analyzed using Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 liquid chromatograph.
手性HPLC分析测定使用Agilent 1260 DAD高效液相色谱仪。Chiral HPLC analysis was performed using an Agilent 1260 DAD high performance liquid chromatograph.
高效液相制备使用Waters 2545-2767、Waters 2767-SQ Detecor2、Shimadzu LC-20AP和Gilson GX-281制备型色谱仪。Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs were used for HPLC preparation.
手性制备使用Gilson GX-281和Shimadzu LC-20AP制备型色谱仪。Chiral preparations were performed using Gilson GX-281 and Shimadzu LC-20AP preparative chromatographs.
CombiFlash快速制备仪使用Combiflash Rf200(TELEDYNE ISCO)。The CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。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.
硅胶柱色谱法一般使用烟台黄海硅胶200～300目硅胶为载体。Silica gel column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
激酶平均抑制率及IC 50值的测定用NovoStar酶标仪(德国BMG公司)。 Kinase average inhibition rate and IC 50 value were measured with NovoStar microplate reader (BMG Company, Germany).
本公开的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自ABCR GmbH&Co.KG，Acros Organics，Aldrich Chemical Company，韶远化学科技(Accela ChemBio Inc)、达瑞化学品等公司。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.
实施例中无特殊说明，反应均能够在氩气氛或氮气氛下进行。Unless otherwise specified in the examples, the reactions can all be carried out under an argon atmosphere or a nitrogen atmosphere.
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。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.
氢气氛是指反应瓶连接一个约1L容积的氢气气球。The hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.
加压氢化反应使用Parr 3916EKX型氢化仪和清蓝QL-500型氢气发生器或HC2-SS型氢化仪。The pressurized hydrogenation reaction uses Parr 3916EKX hydrogenation instrument and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenation instrument.
氢化反应通常抽真空，充入氢气，反复操作3次。The hydrogenation reaction is usually vacuumized and filled with hydrogen, and the operation is repeated 3 times.
微波反应使用CEM Discover-S 908860型微波反应器。For the microwave reaction, a CEM Discover-S 908860 microwave reactor was used.
实施例中无特殊说明，溶液是指水溶液。Unless otherwise specified in the examples, the solution refers to an aqueous solution.
实施例中无特殊说明，反应的温度为室温，为20℃～30℃。Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20°C to 30°C.
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂，纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系包括：A：二氯甲烷/甲醇体系，B：正己烷/乙酸乙酯体系，C：石油醚/乙酸乙酯体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。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.
实施例1Example 1
(3S,4R)-4-((5-氯-4-(3-乙基-7-氟-2,3-二甲基-3H-吲哚-5-基)嘧啶-2-基)氨基)四氢(3S,4R)-4-((5-chloro-4-(3-ethyl-7-fluoro-2,3-dimethyl-3H-indol-5-yl)pyrimidin-2-yl)amino ) Tetrahydro
-2H-吡喃-3-醇1(非对映异构体混合物)-2H-pyran-3-ol 1 (mixture of diastereoisomers)
Figure PCTCN2022141271-appb-000047
Figure PCTCN2022141271-appb-000047
第一步first step
(4-溴-2-氟苯基)肼盐酸盐1b(4-Bromo-2-fluorophenyl)hydrazine hydrochloride 1b
冰浴下，将化合物4-溴-2-氟苯胺1a(20g，105.25mmol，上海毕得)溶于浓盐酸(100mL)，加入亚硝酸钠(7.6g，110.15mmol)的水溶液(10mL)，搅拌30分钟，将反应液滴加到二水合氯化亚锡(72g，319.08mmol)的浓盐酸(100mL)溶液中，自然恢复室温搅拌反应16小时，过滤，滤饼用甲基叔丁基醚洗涤，固体干燥后即得粗品标题化合物1b(22g)，产品不经纯化直接用于下步反应。Under ice bath, the compound 4-bromo-2-fluoroaniline 1a (20g, 105.25mmol, Shanghai Pide) was dissolved in concentrated hydrochloric acid (100mL), and an aqueous solution (10mL) of sodium nitrite (7.6g, 110.15mmol) was added, Stir for 30 minutes, add the reaction solution dropwise into a solution of stannous chloride dihydrate (72g, 319.08mmol) in concentrated hydrochloric acid (100mL), return to room temperature and react for 16 hours with stirring, filter, and filter cake with methyl tert-butyl ether After washing and drying the solid, the crude title compound 1b (22 g) was obtained, and the product was directly used in the next reaction without purification.
MS m/z(ESI):204.9[M+1]。MS m/z (ESI): 204.9 [M+1].
第二步second step
(±)-5-溴-3-乙基-7-氟-2,3-二甲基-3H-吲哚1d(±)-5-Bromo-3-ethyl-7-fluoro-2,3-dimethyl-3H-indole 1d
将化合物1b(0.2g，828.19μmol)，(±)-3-甲基戊烷-2-酮1c(107.83mg，1.07mmol，上海毕得)溶于乙酸(5mL)，回流反应5小时，反应液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系C纯化得到标题化合物1d(100mg，产率：44.7％)。MS m/z(ESI):270.2[M+1]。Compound 1b (0.2g, 828.19μmol), (±)-3-methylpentan-2-one 1c (107.83mg, 1.07mmol, Shanghai Bide) was dissolved in acetic acid (5mL), refluxed for 5 hours, and the reaction The liquid was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system C to obtain the title compound 1d (100 mg, yield: 44.7%). MS m/z (ESI): 270.2 [M+1].
第三步third step
(±)-3-乙基-7-氟-2,3-二甲基-5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊-2-基)-3H-吲哚1e(±)-3-Ethyl-7-fluoro-2,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -yl)-3H-indole 1e
将化合物1d(0.21g，777.37μmol)，联硼酸频那醇酯(296.10mg，1.16mmol，上海韶远)溶于1,4-二氧六环(10mL)，加入乙酸钾(190.73mg，1.94mmol)，[1,1’- 双(二苯基膦)二茂铁]二氯化钯(II)二氯甲烷络合物(126.86mg，155.47μmol，上海泰坦)，氮气置换，100℃反应3小时，反应液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系B纯化得到标题化合物1e(190mg，产率：77％)。Compound 1d (0.21g, 777.37μmol), pinacol diboronate (296.10mg, 1.16mmol, Shaoyuan, Shanghai) was dissolved in 1,4-dioxane (10mL), and potassium acetate (190.73mg, 1.94 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (126.86mg, 155.47μmol, Shanghai Titan), nitrogen replacement, 100 ℃ reaction After 3 hours, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 1e (190 mg, yield: 77%).
MS m/z(ESI):318.2[M+1]。MS m/z (ESI): 318.2 [M+1].
第四步the fourth step
(±)-5-(2,5-二氯嘧啶-4-基)-3-乙基-7-氟-2,3-二甲基-3H-吲哚1g(±)-5-(2,5-dichloropyrimidin-4-yl)-3-ethyl-7-fluoro-2,3-dimethyl-3H-indole 1g
将化合物1e(190mg，598.9μmol)，2,4,5-三氯嘧啶1f(120.8mg，658.8μmol，上海韶远)，四(三苯基膦)钯(138.4mg，119.7μmol，上海泰坦)，碳酸钾(165.3mg，1.19mmol)溶于6mL 1,4-二氧六环和水(V:V＝5:1)的混合溶液中。氮气氛围下，95℃反应8小时，反应液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系B纯化得到标题化合物1g(150mg，产率：74％)。Compound 1e (190mg, 598.9μmol), 2,4,5-trichloropyrimidine 1f (120.8mg, 658.8μmol, Shanghai Shaoyuan), tetrakis (triphenylphosphine) palladium (138.4mg, 119.7μmol, Shanghai Titan) , Potassium carbonate (165.3mg, 1.19mmol) was dissolved in a mixed solution of 6mL 1,4-dioxane and water (V:V=5:1). Under nitrogen atmosphere, reacted at 95°C for 8 hours, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 1g (150 mg, yield: 74%).
MS m/z(ESI):338.2[M+1]。MS m/z (ESI): 338.2 [M+1].
第五步the fifth step
(3S,4R)-4-((5-氯-4-(3-乙基-7-氟-2,3-二甲基-3H-吲哚-5-基)嘧啶-2-基)氨基)四氢-2H-吡喃-3-醇1(非对映异构体混合物)(3S,4R)-4-((5-chloro-4-(3-ethyl-7-fluoro-2,3-dimethyl-3H-indol-5-yl)pyrimidin-2-yl)amino ) Tetrahydro-2H-pyran-3-ol 1 (mixture of diastereoisomers)
将化合物1g(150mg，455μmol)，(3S,4R)-4-氨基-3-羟基四氢吡喃盐酸盐(104.91mg，683.01μmol，南京药石)溶于溶剂二甲亚砜(2mL)中，加入N,N-二异丙基乙胺(235.39mg，1.82mmol)，100℃反应1.5小时，反应液减压浓缩，残余物用高效液相色谱法(Waters-2545，色谱柱：YMC Triart-Exrs,Prep 30*150mm,5μm,C18；流动相：水相(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈35％-50％，流速：30mL/min)纯化得到标题化合物1(10mg，非对映异构体混合物，产率：5.2％)。Compound 1g (150 mg, 455 μmol), (3S,4R)-4-amino-3-hydroxytetrahydropyran hydrochloride (104.91 mg, 683.01 μmol, Nanjing Yaoshi) was dissolved in the solvent dimethyl sulfoxide (2 mL) , add N,N-diisopropylethylamine (235.39mg, 1.82mmol), react at 100°C for 1.5 hours, the reaction solution is concentrated under reduced pressure, and the residue is subjected to high performance liquid chromatography (Waters-2545, chromatographic column: YMC Triart -Exrs, Prep 30*150mm, 5μm, C18; mobile phase: aqueous phase (10mmol/L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35%-50%, flow rate: 30mL/min) purification to obtain the title compound 1 (10 mg, mixture of diastereomers, yield: 5.2%).
MS m/z(ESI):419.2[M+1]。MS m/z (ESI): 419.2 [M+1].
1H NMR(500MHz,CD 3OD):δ8.35(s,1H),7.69-7.65(m,1H),7.60(dd,1H),4.01-3.95(m,2H),3.92(dd,1H),3.61(td,1H),3.50(td,1H),3.23(dd,1H),2.35(s,3H),2.17-2.05(m,2H),1.97(dd,1H),1.68-1.61(m,1H),1.41(s,3H),0.45(t,3H). 1 H NMR(500MHz,CD 3 OD):δ8.35(s,1H),7.69-7.65(m,1H),7.60(dd,1H),4.01-3.95(m,2H),3.92(dd,1H ),3.61(td,1H),3.50(td,1H),3.23(dd,1H),2.35(s,3H),2.17-2.05(m,2H),1.97(dd,1H),1.68-1.61( m,1H),1.41(s,3H),0.45(t,3H).
实施例2Example 2
(3S,4R)-4-((5-氯-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)嘧啶-2-基)氨基)四氢-2H-吡喃-3-醇2(3S,4R)-4-((5-Chloro-4-(7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indol]-5'-yl)pyrimidine-2 -yl)amino)tetrahydro-2H-pyran-3-ol 2
Figure PCTCN2022141271-appb-000048
Figure PCTCN2022141271-appb-000048
Figure PCTCN2022141271-appb-000049
Figure PCTCN2022141271-appb-000049
第一步first step
5'-溴-7'-氟-2'-甲基螺环[环戊烷-1,3'-吲哚]2b5'-Bromo-7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indole] 2b
将化合物1b(1g，4.1410mmol)，环戊基乙酮2a(487.71mg，4.34mmol，上海毕得)溶于乙酸(5mL)，回流反应5小时。反应液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系C纯化得到标题化合物2b(500mg，产率：42.7％)。Compound 1b (1g, 4.1410mmol), cyclopentyl ethyl ketone 2a (487.71mg, 4.34mmol, Shanghai Pide) were dissolved in acetic acid (5mL), and refluxed for 5 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system C to obtain the title compound 2b (500 mg, yield: 42.7%).
MS m/z(ESI):282.2[M+1]。MS m/z (ESI): 282.2 [M+1].
第二步second step
7'-氟-2'-甲基-5'-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊-2-基)螺[环戊烷-1,3'-吲哚]2c7'-fluoro-2'-methyl-5'-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)spiro[cyclopentane- 1,3'-indole]2c
将化合物2b(0.5g，1.77mmol)，联硼酸频那醇酯(450mg，1.77mmol)溶于1,4-二氧六环(10mL)，加入乙酸钾(43.5mg，4.43mmol)，[1,1’-双(二苯基膦)二茂铁]二氯化钯(II)二氯甲烷络合物(289mg，354μmol)，氮气置换，100℃反应3小时，反应液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系B纯化得到标题化合物2c(500mg，产率：85.7％)。Compound 2b (0.5g, 1.77mmol), pinacol diboronate (450mg, 1.77mmol) was dissolved in 1,4-dioxane (10mL), potassium acetate (43.5mg, 4.43mmol) was added, [1 , 1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (289mg, 354μmol), replaced with nitrogen, reacted at 100°C for 3 hours, the reaction solution was concentrated under reduced pressure, and the residue The material was purified by silica gel column chromatography with eluent system B to obtain the title compound 2c (500 mg, yield: 85.7%).
MS m/z(ESI):330.2[M+1]。MS m/z (ESI): 330.2 [M+1].
第三步third step
5'-(2,5-二氯嘧啶-4-基)-7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]2d5'-(2,5-Dichloropyrimidin-4-yl)-7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indole]2d
将化合物2c(197mg，598.9μmol)，2,4,5-三氯嘧啶1f(120.8mg，658.8μmol)，四(三苯基膦)钯(138.4mg，119.7μmol，adamas)，碳酸钾(165.3mg，1.19mmol)溶于6mL 1,4-二氧六环和水(V:V＝5:1)的混合溶液中。氮气氛围下，95℃反应8小时，反应液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系B纯化得到标题化合物2d(150mg，产率：71.5％)。Compound 2c (197 mg, 598.9 μmol), 2,4,5-trichloropyrimidine 1f (120.8 mg, 658.8 μmol), tetrakis(triphenylphosphine) palladium (138.4 mg, 119.7 μmol, adamas), potassium carbonate (165.3 mg, 1.19mmol) was dissolved in 6mL of a mixed solution of 1,4-dioxane and water (V:V=5:1). Under nitrogen atmosphere, reacted at 95°C for 8 hours, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 2d (150 mg, yield: 71.5%).
MS m/z(ESI):350.2[M+1]。MS m/z (ESI): 350.2 [M+1].
第四步the fourth step
(3S,4R)-4-((5-氯-4-(7'-氟-2'-甲基螺[环戊烷-1,3'-吲哚]-5'-基)嘧啶-2-基)氨基)四氢-2H-吡喃-3-醇2(3S,4R)-4-((5-Chloro-4-(7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indol]-5'-yl)pyrimidine-2 -yl)amino)tetrahydro-2H-pyran-3-ol 2
将化合物2d(140mg，399μmol)，(3S,4R)-4-氨基-3-羟基四氢吡喃盐酸盐(105mg，683μmol)溶于二甲亚砜(2mL)中，加入N,N-二异丙基乙胺(235.39mg，1.82 mmol)，100℃反应1.5小时。反应液减压浓缩，残余物用高效液相色谱法(Waters-2545，色谱柱：YMC Triart-Exrs,Prep 30*150mm,5μm,C18；流动相：水相(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈40％-55％，流速：30mL/min)纯化得到标题化合物2(10mg，产率：5.2％)。Compound 2d (140 mg, 399 μmol), (3S,4R)-4-amino-3-hydroxytetrahydropyran hydrochloride (105 mg, 683 μmol) was dissolved in dimethyl sulfoxide (2 mL), and N,N- Diisopropylethylamine (235.39 mg, 1.82 mmol) was reacted at 100°C for 1.5 hours. The 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 μm, 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%).
MS m/z(ESI):431.2[M+1]。MS m/z (ESI): 431.2 [M+1].
1H NMR(500MHz,CD 3OD):δ8.35(s,1H),7.74(d,1H),7.60(dd,1H),4.01-3.95(m,2H),3.95-3.90(m,1H),3.62(td,1H),3.50(td,1H),3.22(dd,1H),2.41(s,3H),2.24-09(m,8H),1.92-1.83(m,2H)。 1 H NMR (500MHz, CD 3 OD): δ8.35(s,1H),7.74(d,1H),7.60(dd,1H),4.01-3.95(m,2H),3.95-3.90(m,1H ), 3.62(td,1H), 3.50(td,1H), 3.22(dd,1H), 2.41(s,3H), 2.24-09(m,8H), 1.92-1.83(m,2H).
实施例3Example 3
(3S,4R)-4-((5-氯-4-(7-氟-2,3,3-三甲基-3H-吲哚-5-基)嘧啶-2-基)氨基)四氢-2H-吡喃-3-醇3(3S,4R)-4-((5-chloro-4-(7-fluoro-2,3,3-trimethyl-3H-indol-5-yl)pyrimidin-2-yl)amino)tetrahydro -2H-pyran-3-ol 3
Figure PCTCN2022141271-appb-000050
Figure PCTCN2022141271-appb-000050
第一步first step
5-溴-7-氟-2,3,3-三甲基-3H-吲哚3b5-Bromo-7-fluoro-2,3,3-trimethyl-3H-indole 3b
将化合物1b(1.5g，6.2mmol)，3-甲基-2-丁酮3a(600mg，6.9mmol，上海毕得)溶于乙酸(5mL)，回流反应16小时。反应液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系C纯化得到标题化合物3b(880mg，产率：55.3％)。Compound 1b (1.5g, 6.2mmol), 3-methyl-2-butanone 3a (600mg, 6.9mmol, Shanghai Pide) was dissolved in acetic acid (5mL), and refluxed for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system C to obtain the title compound 3b (880 mg, yield: 55.3%).
MS m/z(ESI):256.2[M+1]。MS m/z (ESI): 256.2 [M+1].
第二步second step
7-氟-2,3,3-三甲基-5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊-2-基)-3H-吲哚3c7-Fluoro-2,3,3-trimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-3H-ind indole 3c
将化合物3b(880mg，3.43mmol)，联硼酸频那醇酯(900mg，3.54mmol)溶于 1,4-二氧六环(25mL)，加入乙酸钾(400mg，4.07mmol)，[1,1’-双(二苯基膦)二茂铁]二氯化钯(II)二氯甲烷络合物(250mg，341μmol)，氮气置换，100℃反应3小时，反应液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系B纯化得到标题化合物3c(910mg，产率：87.3％)。Compound 3b (880mg, 3.43mmol), pinacol diboronate (900mg, 3.54mmol) were dissolved in 1,4-dioxane (25mL), potassium acetate (400mg, 4.07mmol) was added, [1,1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (250 mg, 341 μmol), nitrogen replacement, 100 ° C reaction for 3 hours, the reaction solution was concentrated under reduced pressure, and the residue was used Purification by silica gel column chromatography with eluent system B gave the title compound 3c (910 mg, yield: 87.3%).
MS m/z(ESI):304.2[M+1]。MS m/z (ESI): 304.2 [M+1].
第三步third step
5-(2,5-二氯嘧啶-4-基)-7-氟-2,3,3-三甲基-3H-吲哚3d5-(2,5-Dichloropyrimidin-4-yl)-7-fluoro-2,3,3-trimethyl-3H-indole 3d
将化合物3c(350mg，1.15mmol)，化合物1f(180mg，981μmol)，四(三苯基膦)钯(114mg，98.6μmol)，碳酸钠(210mg，1.98mmol)溶于6mL 1,4-二氧六环和水(V:V＝5:1)的混合溶液中。氮气氛围下，95℃反应8小时，反应液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系B纯化得到标题化合物3d(240mg，产率：75.4％)。Compound 3c (350 mg, 1.15 mmol), compound 1f (180 mg, 981 μmol), tetrakis(triphenylphosphine) palladium (114 mg, 98.6 μmol), sodium carbonate (210 mg, 1.98 mmol) were dissolved in 6 mL of 1,4-dioxo Hexacyclic and water (V:V=5:1) mixed solution. Under nitrogen atmosphere, reacted at 95°C for 8 hours, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 3d (240 mg, yield: 75.4%).
MS m/z(ESI):324.2[M+1]。MS m/z (ESI): 324.2 [M+1].
第四步the fourth step
(3S,4R)-4-((5-氯-4-(7-氟-2,3,3-三甲基-3H-吲哚-5-基)嘧啶-2-基)氨基)四氢-2H-吡喃-3-醇3(3S,4R)-4-((5-chloro-4-(7-fluoro-2,3,3-trimethyl-3H-indol-5-yl)pyrimidin-2-yl)amino)tetrahydro -2H-pyran-3-ol 3
将化合物3d(150mg，462μmol)，(3S,4R)-4-氨基-3-羟基四氢吡喃盐酸盐(70mg，597μmol)溶于二甲亚砜(2mL)中，加入N,N-二异丙基乙胺(120mg，0.92mmol)，110℃反应2小时。反应液减压浓缩，残余物用高效液相色谱法(Waters-2545，色谱柱：YMC Triart-Exrs,Prep 30*150mm,5μm,C18；流动相：水相(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈30％-45％，流速：30mL/min)纯化得到标题化合物3(43mg，产率：22.9％)。Compound 3d (150 mg, 462 μmol), (3S,4R)-4-amino-3-hydroxytetrahydropyran hydrochloride (70 mg, 597 μmol) was dissolved in dimethyl sulfoxide (2 mL), and N,N- Diisopropylethylamine (120mg, 0.92mmol) was reacted at 110°C for 2 hours. The 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 μm, 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%).
MS m/z(ESI):405.2[M+1]。MS m/z (ESI): 405.2 [M+1].
1H NMR(500MHz,CD 3OD):δ8.35(s,1H),7.72(s,1H),7.63-7.58(d,1H),3.99-3.90(m,3H),3.63-3.59(m,1H),3.52-3.47(m,1H),3.25-3.21(m,1H),2.39(s,3H),2.15-2.11(m,1H),1.68-1.60(m,1H),1.42(s,6H)。 1 H NMR (500MHz, CD 3 OD): δ8.35(s,1H),7.72(s,1H),7.63-7.58(d,1H),3.99-3.90(m,3H),3.63-3.59(m ,1H),3.52-3.47(m,1H),3.25-3.21(m,1H),2.39(s,3H),2.15-2.11(m,1H),1.68-1.60(m,1H),1.42(s ,6H).
实施例4Example 4
(3S,4R)-4-((5-氯-4-(7-氟-2-(2-羟基丙-2-基)-3,3-二甲基-3H-吲哚-5-基)嘧啶-2-基)氨基)四氢-2H-吡喃-3-醇4(3S,4R)-4-((5-chloro-4-(7-fluoro-2-(2-hydroxypropan-2-yl)-3,3-dimethyl-3H-indol-5-yl )pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol 4
Figure PCTCN2022141271-appb-000051
Figure PCTCN2022141271-appb-000051
Figure PCTCN2022141271-appb-000052
Figure PCTCN2022141271-appb-000052
第一步first step
2-(5-溴-7-氟-3,3-二甲基-3H-吲哚-2-基)丙-2-醇4b2-(5-Bromo-7-fluoro-3,3-dimethyl-3H-indol-2-yl)propan-2-ol 4b
将化合物1b(2g，8.28mmol)，2,4-二甲基-3-戊酮4a(946mg，8.28mol，上海泰坦)溶于乙酸(20mL)，回流反应5小时。反应液减压浓缩，残余物用高效液相色谱法(Waters-2545，色谱柱：YMC Triart-Exrs,Prep 30*150mm,5μm,C18；流动相：水相(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈30％-45％，流速：30mL/min)纯化得到标题化合物4b(250mg，产率：10％)。Compound 1b (2g, 8.28mmol), 2,4-dimethyl-3-pentanone 4a (946mg, 8.28mol, Shanghai Titan) was dissolved in acetic acid (20mL), and refluxed for 5 hours. The 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 μm, 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 4b (250 mg, yield: 10%).
MS m/z(ESI):300.1[M+1]。MS m/z (ESI): 300.1 [M+1].
第二步second step
2-(7-氟-3,3-二甲基-5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊-2-基)-3H-吲哚-2-基)丙-2-醇4c2-(7-fluoro-3,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-3H- Indol-2-yl)propan-2-ol 4c
将化合物4b(180mg，599μmol)，联硼酸频那醇酯(228mg，899μmol)溶于1,4-二氧六环(10mL)，加入乙酸钾(176mg，1.79mmol)，[1,1’-双(二苯基膦)二茂铁]二氯化钯(II)二氯甲烷络合物(43mg，60μmol)，氮气置换，100℃反应3小时，反应液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系B纯化得到标题化合物4c(176mg，产率：85.7％)。Compound 4b (180mg, 599μmol), pinacol borate (228mg, 899μmol) was dissolved in 1,4-dioxane (10mL), potassium acetate (176mg, 1.79mmol) was added, [1,1'- Bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (43mg, 60μmol), replaced with nitrogen, reacted at 100°C for 3 hours, concentrated the reaction solution under reduced pressure, and the residue was purified by silica gel column Purification by chromatography with eluent system B afforded the title compound 4c (176 mg, yield: 85.7%).
MS m/z(ESI):348.2[M+1]。MS m/z (ESI): 348.2 [M+1].
第三步third step
2-(5-(2,5-二氯嘧啶-4-基)-7-氟-3,3-二甲基-3H-吲哚-2-基)丙-2-醇4d2-(5-(2,5-Dichloropyrimidin-4-yl)-7-fluoro-3,3-dimethyl-3H-indol-2-yl)propan-2-ol 4d
将化合物4c(240mg，691μmol)，化合物1f(126.7mg，691μmol)，四(三苯基膦)钯(79.8mg，69.1μmol)，乙酸钾(135.6mg，1.38mmol)溶于6mL 1,4-二氧六环和水(V:V＝5:1)的混合溶液中。氮气氛围下，95℃反应8小时，反应液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系B纯化得到标题化合物4d(216mg，产率：85％)。Compound 4c (240 mg, 691 μmol), compound 1f (126.7 mg, 691 μmol), tetrakis(triphenylphosphine) palladium (79.8 mg, 69.1 μmol), potassium acetate (135.6 mg, 1.38 mmol) were dissolved in 6 mL of 1,4- In the mixed solution of dioxane and water (V:V=5:1). Under nitrogen atmosphere, reacted at 95°C for 8 hours, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 4d (216 mg, yield: 85%).
MS m/z(ESI):368.2[M+1]。MS m/z (ESI): 368.2 [M+1].
第四步the fourth step
(3S,4R)-4-((5-氯-4-(7-氟-2-(2-羟基丙-2-基)-3,3-二甲基-3H-吲哚-5-基)嘧啶-2-基)氨基)四氢-2H-吡喃-3-醇4(3S,4R)-4-((5-chloro-4-(7-fluoro-2-(2-hydroxypropan-2-yl)-3,3-dimethyl-3H-indol-5-yl )pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol 4
将化合物4d(270mg，733μmol)，(3S,4R)-4-氨基-3-羟基四氢吡喃盐酸盐(168.9mg，1.1mmol)溶于二甲亚砜(5mL)中，加入N,N-二异丙基乙胺(478mg，3.6mmol)，110℃反应2小时。反应液减压浓缩，残余物用高效液相色谱法(Waters-2545，色谱柱：YMC Triart-Exrs,Prep 30*150mm,5μm,C18；流动相：水相(10mmol/L碳酸氢 铵)和乙腈，梯度配比：乙腈30％-45％，流速：30mL/min)纯化得到标题化合物4(28mg，产率：8.5％)。Compound 4d (270 mg, 733 μmol), (3S,4R)-4-amino-3-hydroxytetrahydropyran hydrochloride (168.9 mg, 1.1 mmol) was dissolved in dimethyl sulfoxide (5 mL), and N, N-Diisopropylethylamine (478mg, 3.6mmol) was reacted at 110°C for 2 hours. The 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 μm, 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%).
MS m/z(ESI):449.2[M+1]。MS m/z (ESI): 449.2 [M+1].
1H NMR(500MHz,CDCl 3):δ8.34(s,1H),7.54(dd,1H),7.51(d,1H),5.28(d,1H),4.68(s,1H),4.08(dd,1H),4.01(m,1H),3.87(m,1H),3.69-3.60(m,1H),3.49(td,1H),3.21(dd,1H),3.04(s,1H),2.11-2.01(m,1H),1.79-1.70(m,1H),1.69(s,6H),1.61(d,6H)。 1 H NMR (500MHz, CDCl 3 ): δ8.34(s,1H),7.54(dd,1H),7.51(d,1H),5.28(d,1H),4.68(s,1H),4.08(dd ,1H),4.01(m,1H),3.87(m,1H),3.69-3.60(m,1H),3.49(td,1H),3.21(dd,1H),3.04(s,1H),2.11- 2.01 (m, 1H), 1.79-1.70 (m, 1H), 1.69 (s, 6H), 1.61 (d, 6H).
实施例5Example 5
(3S,4R)-4-((5-氯-4-(7-氟-2-(2-羟基丁烷-2-基)-3,3-二甲基-3H-吲哚-5-基)嘧啶-2-基)氨基)四氢-2H-吡喃-3-醇5(非对映异构体混合物)(3S,4R)-4-((5-chloro-4-(7-fluoro-2-(2-hydroxybutane-2-yl)-3,3-dimethyl-3H-indole-5- base) pyrimidin-2-yl) amino) tetrahydro-2H-pyran-3-ol 5 (mixture of diastereoisomers)
Figure PCTCN2022141271-appb-000053
Figure PCTCN2022141271-appb-000053
第一步first step
2,4-二甲基己烷-3-醇5b(非对映异构体混合物)2,4-Dimethylhexan-3-ol 5b (mixture of diastereomers)
将(±)-2-甲基丁醛5a(5g，58.05mmol，上海泰坦)溶于四氢呋喃(100mL)，-78℃滴加1M异丙基溴化镁的四氢呋喃溶液(100mL)，保持温度反应1小时后自然恢复室温反应14小时，反应液中加入饱和氯化铵淬灭，用甲基叔丁基醚萃取(50mL×3)，合并有机相，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤除去干燥剂，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系B纯化得到标题化合物5b(4g，非对映异构体混合物，产率：52.9％)。Dissolve (±)-2-methylbutyraldehyde 5a (5g, 58.05mmol, Shanghai Titan) in tetrahydrofuran (100mL), add 1M tetrahydrofuran solution (100mL) of isopropylmagnesium bromide dropwise at -78°C, and keep the temperature for reaction After 1 hour, naturally return to room temperature and react for 14 hours. Add saturated ammonium chloride to the reaction solution to quench, extract with methyl tert-butyl ether (50mL×3), combine the organic phases, wash with saturated sodium chloride solution, anhydrous sulfuric acid Sodium-dried, filtered to remove the desiccant, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 5b (4 g, diastereoisomer mixture, yield: 52.9%).
第二步second step
(±)-2,4-二甲基己烷-3-酮5c(±)-2,4-Dimethylhexan-3-one 5c
将化合物5b(4g，30.71mmol)溶于二氯甲烷(50mL)，加入氯铬酸吡啶盐(13.24g，61.42mmol，上海毕得)，硅胶(13g，61.4mmol)，搅拌反应14小时，反应液过滤，滤液减压浓缩得到粗品标题化合物5c(1.8g)，产物不经纯化直接用于下步反应。Dissolve compound 5b (4g, 30.71mmol) in dichloromethane (50mL), add pyridinium chlorochromate (13.24g, 61.42mmol, Shanghai Bide), silica gel (13g, 61.4mmol), and stir for 14 hours. liquid, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 5c (1.8 g), which was directly used in the next reaction without purification.
第三步third step
(±)-2-(5-溴-7-氟-3,3-二甲基-3H-吲哚-2-基)丁-2-醇5d(±)-2-(5-Bromo-7-fluoro-3,3-dimethyl-3H-indol-2-yl)butan-2-ol 5d
(±)-5-溴-2-(仲丁基)-7-氟-3,3-二甲基-3H-吲哚5e(±)-5-Bromo-2-(sec-butyl)-7-fluoro-3,3-dimethyl-3H-indole 5e
将化合物1b(1g，4.14mmol)，粗品化合物5c(850mg，6.62mol)溶于乙酸(20mL)，回流反应5小时后，加入水(5mL)，继续回流反应2小时，反应液减压浓缩，残余物用高效液相色谱法(Waters-2545，色谱柱：YMC Triart-Exrs,Prep 30*150mm,5μm,C18；流动相：水相(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈30％-45％，流速：30mL/min)纯化得到标题化合物5d(94mg，产率：7.2％)和5e(100mg，产率：8.1％)Compound 1b (1g, 4.14mmol), crude compound 5c (850mg, 6.62mol) were dissolved in acetic acid (20mL), and after 5 hours of reflux reaction, water (5mL) was added, and the reflux reaction was continued for 2 hours, and the reaction solution was concentrated under reduced pressure. The residue was subjected to high performance liquid chromatography (Waters-2545, chromatographic column: YMC Triart-Exrs, Prep 30*150mm, 5 μm, C18; mobile phase: aqueous phase (10mmol/L ammonium bicarbonate) and acetonitrile, gradient ratio: Acetonitrile 30%-45%, flow rate: 30mL/min) was purified to obtain the title compound 5d (94mg, yield: 7.2%) and 5e (100mg, yield: 8.1%)
化合物5d:MS m/z(ESI):314.2[M+1]。Compound 5d: MS m/z (ESI): 314.2 [M+1].
化合物5e:MS m/z(ESI):298.2[M+1]。Compound 5e: MS m/z (ESI): 298.2 [M+1].
第四步the fourth step
(3S,4R)-4-((5-氯-4-(7-氟-2-(2-羟基丁烷-2-基)-3,3-二甲基-3H-吲哚-5-基)嘧啶-2-基)(3S,4R)-4-((5-chloro-4-(7-fluoro-2-(2-hydroxybutane-2-yl)-3,3-dimethyl-3H-indole-5- base) pyrimidin-2-yl)
氨基)四氢-2H-吡喃-3-醇5(非对映异构体混合物)Amino)tetrahydro-2H-pyran-3-ol 5 (mixture of diastereoisomers)
采用实施例1中的合成路线第三步至第五步，将第三步原料化合物1d替换为化合物5d得到标题化合物5(1mg，非对映异构体混合物，产率：2％)。Using the third step to the fifth step of the synthetic route in Example 1, the third step starting material compound 1d was replaced by compound 5d to obtain the title compound 5 (1 mg, diastereomer mixture, yield: 2%).
MS m/z(ESI):463.1[M+1]。MS m/z (ESI): 463.1 [M+1].
1H NMR(500MHz,CD 3OD):δ8.35(s,1H),7.64(d,1H),7.56(dd,1H),4.01-3.90(m,3H),3.61(td,1H),3.50(td,1H),3.23(dd,1H),2.23-2.17(m,1H),2.17-2.11(m,1H),1.83(dq,2H),1.66(s,3H),1.62(s,3H),1.58(s,3H),0.97(t,3H)。 1 H NMR (500MHz, CD 3 OD): δ8.35(s,1H),7.64(d,1H),7.56(dd,1H),4.01-3.90(m,3H),3.61(td,1H), 3.50(td,1H),3.23(dd,1H),2.23-2.17(m,1H),2.17-2.11(m,1H),1.83(dq,2H),1.66(s,3H),1.62(s, 3H), 1.58(s, 3H), 0.97(t, 3H).
实施例6Example 6
(3S,4R)-4-((4-(2-(仲丁基)-7-氟-3,3-二甲基-3H-吲哚-5-基)-5-氯嘧啶-2-基)氨基)四氢-2H-吡喃-3-醇6(非对映异构体混合物)(3S,4R)-4-((4-(2-(sec-butyl)-7-fluoro-3,3-dimethyl-3H-indol-5-yl)-5-chloropyrimidine-2- base)amino)tetrahydro-2H-pyran-3-ol 6 (mixture of diastereoisomers)
Figure PCTCN2022141271-appb-000054
Figure PCTCN2022141271-appb-000054
采用实施例1中的合成路线第三步至第五步，将第三步原料化合物1d替换为化合物5e得到标题化合物6(10mg，非对映异构体混合物，产率：21.3％)。Using the third step to the fifth step of the synthetic route in Example 1, the third step starting material compound 1d was replaced by compound 5e to obtain the title compound 6 (10 mg, diastereomer mixture, yield: 21.3%).
MS m/z(ESI):447.1[M+1]。MS m/z (ESI): 447.1 [M+1].
1H NMR(500MHz,CD 3OD):δ8.35(s,1H),7.70(d,1H),7.62-7.57(m,1H),3.99-3.90(m,3H),3.61(dt,1H),3.50(td,1H),3.25-3.20(m,1H),2.88(q,1H),2.17-2.11(m,1H),1.97-1.91(m,1H),1.75-1.71(m,1H),1.64(dd,1H),1.44(d,6H),1.33(d,3H),0.99(t,3H)。 1 H NMR(500MHz,CD 3 OD):δ8.35(s,1H),7.70(d,1H),7.62-7.57(m,1H),3.99-3.90(m,3H),3.61(dt,1H ),3.50(td,1H),3.25-3.20(m,1H),2.88(q,1H),2.17-2.11(m,1H),1.97-1.91(m,1H),1.75-1.71(m,1H ), 1.64(dd,1H), 1.44(d,6H), 1.33(d,3H), 0.99(t,3H).
实施例7Example 7
(3S,4R)-4-((5-氯-4-(7-氟-2-(1-羟基环戊基)-3,3-二甲基-3H-吲哚-5-基)嘧啶-2-基)氨基)四氢-2H-吡喃-3-醇7-p1(3S,4R)-4-((5-chloro-4-(7-fluoro-2-(1-hydroxycyclopentyl)-3,3-dimethyl-3H-indol-5-yl)pyrimidine -2-yl)amino)tetrahydro-2H-pyran-3-ol 7-p1
(3S,4R)-4-((5-氯-4-(7'-氟-2'-(2-羟基丙-2-基)螺[环戊烷-1,3'-吲哚]-5'-基)嘧啶-2-基)氨基)四氢-2H-吡喃-3-醇7-p2(3S,4R)-4-((5-Chloro-4-(7'-fluoro-2'-(2-hydroxypropan-2-yl)spiro[cyclopentane-1,3'-indole]- 5'-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol 7-p2
Figure PCTCN2022141271-appb-000055
Figure PCTCN2022141271-appb-000055
第一步first step
1-(5-溴-7-氟-3,3-二甲基-3H-吲哚-2-基)环戊-1-醇7b1-(5-Bromo-7-fluoro-3,3-dimethyl-3H-indol-2-yl)cyclopent-1-ol 7b
2-(5'-溴-7'-氟螺[环戊烷-1,3'-吲哚]-2'-基)丙-2-醇7c2-(5'-Bromo-7'-fluorospiro[cyclopentane-1,3'-indol]-2'-yl)propan-2-ol 7c
5'-溴-7'-氟-2'-异丙基螺[环戊烷-1,3'-吲哚]7d5'-Bromo-7'-fluoro-2'-isopropylspiro[cyclopentane-1,3'-indole]7d
将化合物1b(1g，4.14mmol)，1-环戊基-2-甲基丙-1-酮7a(527.8mg，3.76mol，采用公知的方法“Journal of the American Chemical Society,2004,vol.126,#33,p10240-10241”制备而得)溶于乙酸(10mL)，回流反应5小时后，加入水(5mL)，继续回流反应2小时，反应液减压浓缩，残余物用高效液相色谱法(Waters-2545，色谱柱：YMC Triart-Exrs,Prep 30*150mm,5μm,C18；流动相：水相(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈30％-45％，流速：30mL/min)纯化得到标题化合物7b和7c的混合物(50mg，产率：4％)和7d(70mg，产率：5.7％)。Compound 1b (1g, 4.14mmol), 1-cyclopentyl-2-methylpropan-1-one 7a (527.8mg, 3.76mol, using the known method "Journal of the American Chemical Society, 2004, vol.126 , #33, prepared from p10240-10241") was dissolved in acetic acid (10mL), and after reflux reaction for 5 hours, water (5mL) was added, and the reflux reaction was continued for 2 hours. The 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, 5μm, 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%).
化合物7b和化合物7c:MS m/z(ESI):326.2[M+1]。Compound 7b and Compound 7c: MS m/z (ESI): 326.2 [M+1].
化合物7d:MS m/z(ESI):310.2[M+1]。Compound 7d: MS m/z (ESI): 310.2 [M+1].
第二步second step
(3S,4R)-4-((5-氯-4-(7-氟-2-(1-羟基环戊基)-3,3-二甲基-3H-吲哚-5-基)嘧啶-2-基)氨基)四氢-2H-吡喃-3-醇7-p1(3S,4R)-4-((5-chloro-4-(7-fluoro-2-(1-hydroxycyclopentyl)-3,3-dimethyl-3H-indol-5-yl)pyrimidine -2-yl)amino)tetrahydro-2H-pyran-3-ol 7-p1
(3S,4R)-4-((5-氯-4-(7'-氟-2'-(2-羟基丙-2-基)螺[环戊烷-1,3'-吲哚]-5'-基)嘧啶-2-基)氨基)四氢-2H-吡喃-3-醇7-p2(3S,4R)-4-((5-Chloro-4-(7'-fluoro-2'-(2-hydroxypropan-2-yl)spiro[cyclopentane-1,3'-indole]- 5'-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol 7-p2
采用实施例1中的合成路线第三步至第五步，将第三步原料化合物1d替换为化合物7b和7c的混合物得到标题化合物7-p1(5mg，产率：10.3％)和7-p2(4mg，产率：8.3％)。Using the third step to the fifth step of the synthetic route in Example 1, 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%).
MS m/z(ESI):475.2[M+1]。MS m/z (ESI): 475.2 [M+1].
单一构型化合物7-p1:Single configuration compound 7-p1:
MS m/z(ESI):475.2[M+1]。MS m/z (ESI): 475.2 [M+1].
HPLC分析：保留时间2.623分钟，纯度：96％(色谱柱:
Figure PCTCN2022141271-appb-000056
C18,2.7μm，3.0*30mm；流动相：水(1‰三氟醋酸)，乙腈，梯度配比：乙腈10％-95％)。 HPLC analysis: retention time 2.623 minutes, purity: 96% (chromatographic column:
Figure PCTCN2022141271-appb-000056
C18, 2.7μm, 3.0*30mm; mobile phase: water (1‰ trifluoroacetic acid), acetonitrile, gradient ratio: acetonitrile 10%-95%).
1H NMR(500MHz,CDCl 3):δ8.33(s,1H),7.69(ddt,1H),7.58(d,1H),5.28(d,1H),4.72-4.68(m,1H),4.08(dd,1H),4.01(dd,1H),3.92-3.82(m,1H),3.65(tt,1H),3.49(td,1H),3.20(dd,1H),2.70(p,2H),2.35(s,1H),2.21-1.99(m,6H),1.87-1.74(m,2H),1.73(s,6H)。 1 H NMR (500MHz, CDCl 3 ): δ8.33(s,1H),7.69(ddt,1H),7.58(d,1H),5.28(d,1H),4.72-4.68(m,1H),4.08 (dd,1H),4.01(dd,1H),3.92-3.82(m,1H),3.65(tt,1H),3.49(td,1H),3.20(dd,1H),2.70(p,2H), 2.35 (s, 1H), 2.21-1.99 (m, 6H), 1.87-1.74 (m, 2H), 1.73 (s, 6H).
单一构型化合物7-p2:Single configuration compound 7-p2:
MS m/z(ESI):475.2[M+1]。MS m/z (ESI): 475.2 [M+1].
HPLC分析：保留时间2.670分钟，纯度：95％(色谱柱:
Figure PCTCN2022141271-appb-000057
C18,2.7μm，3.0*30mm；流动相：水(1‰三氟醋酸)，乙腈，梯度配比：乙腈10％-95％)。 HPLC analysis: retention time 2.670 minutes, purity: 95% (chromatographic column:
Figure PCTCN2022141271-appb-000057
C18, 2.7μm, 3.0*30mm; mobile phase: water (1‰ trifluoroacetic acid), acetonitrile, gradient ratio: acetonitrile 10%-95%).
1H NMR(500MHz,CDCl 3):δ8.34(s,1H),7.73-7.42(m,2H),5.27(d,1H),4.68(s,1H),4.08(dd,1H),4.01(dt,1H),3.87(dddd,1H),3.70-3.61(m,1H),3.49(td,1H),3.21(dd,1H),2.34(qd,2H),2.13-1.85(m,7H),1.80-1.68(m,2H),1.61(d,6H)。 1 H NMR (500MHz, CDCl 3 ): δ8.34(s,1H),7.73-7.42(m,2H),5.27(d,1H),4.68(s,1H),4.08(dd,1H),4.01 (dt,1H),3.87(dddd,1H),3.70-3.61(m,1H),3.49(td,1H),3.21(dd,1H),2.34(qd,2H),2.13-1.85(m,7H ), 1.80-1.68(m,2H), 1.61(d,6H).
实施例8Example 8
(3S,4R)-4-((5-氯-4-(7'-氟-2'-异丙基螺[环己烷-1,3'-吲哚]-5'-基)嘧啶-2-基)氨基)四氢-2H-吡喃-3-醇8-p1(3S,4R)-4-((5-Chloro-4-(7'-fluoro-2'-isopropylspiro[cyclohexane-1,3'-indol]-5'-yl)pyrimidine- 2-yl)amino)tetrahydro-2H-pyran-3-ol 8-p1
(3S,4R)-4-((5-氯-4-(2-环己基-7-氟-3,3-二甲基-3H-吲哚-5-基)嘧啶-2-基)氨基)四氢-2H-吡喃-3-醇8-p2(3S,4R)-4-((5-chloro-4-(2-cyclohexyl-7-fluoro-3,3-dimethyl-3H-indol-5-yl)pyrimidin-2-yl)amino ) Tetrahydro-2H-pyran-3-ol 8-p2
Figure PCTCN2022141271-appb-000058
Figure PCTCN2022141271-appb-000058
Figure PCTCN2022141271-appb-000059
Figure PCTCN2022141271-appb-000059
第一步first step
(±)-1-环己基-2-甲基丙-1-醇8c(±)-1-Cyclohexyl-2-methylpropan-1-ol 8c
将异丁醛8b(8.2g，113.72mmol，10.4mL，上海泰坦)溶于无水四氢呋喃中(80mL)，冰浴下滴加入1.3M环己基氯化镁的四氢呋喃溶液8a(105mL)，保持温度反应1小时，反应液中加水(105mL)淬灭，加入四氢呋喃150mL稀释，用1M稀盐酸调至酸性，用乙酸乙酯萃取(100mL×3)，合并有机相，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤除去干燥剂，滤液减压浓缩即得到粗品标题化合物8c(18g)，产物不经纯化，直接用于下步反应。Dissolve isobutyraldehyde 8b (8.2g, 113.72mmol, 10.4mL, Shanghai Titan) in anhydrous tetrahydrofuran (80mL), add 1.3M tetrahydrofuran solution 8a (105mL) of cyclohexylmagnesium chloride dropwise under ice-cooling, and keep the temperature for reaction 1 After 1 hour, add water (105mL) to the reaction solution to quench, add 150mL of tetrahydrofuran to dilute, adjust to acidity with 1M dilute hydrochloric acid, extract with ethyl acetate (100mL×3), combine the organic phases, wash with saturated sodium chloride solution, anhydrous Dry over sodium sulfate, remove the desiccant by filtration, and concentrate the filtrate under reduced pressure to obtain the crude title compound 8c (18 g). The product is directly used in the next reaction without purification.
第二步second step
1-环己基-2-甲基丙-1-酮8d1-cyclohexyl-2-methylpropan-1-one 8d
将粗产品8c(18g，115.2mmol)溶于150mL二氯甲烷，加入20g硅藻土和氯铬酸吡啶盐(PCC)(36.77g，170.5mmol，上海毕得)，搅拌2小时，过滤，滤饼用***(200mL×2)洗涤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系B纯化得到标题化合物8d(8g，产率：45.1％)。Dissolve the crude product 8c (18g, 115.2mmol) in 150mL of dichloromethane, add 20g of diatomaceous earth and pyridinium chlorochromate (PCC) (36.77g, 170.5mmol, Shanghai Bide), stir for 2 hours, filter, filter The cake was washed with ether (200 mL×2), the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 8d (8 g, yield: 45.1%).
第三步third step
5'-溴-7'-氟-2'-异丙基螺[环己烷-1,3'-吲哚]8e5'-Bromo-7'-fluoro-2'-isopropylspiro[cyclohexane-1,3'-indole] 8e
5-溴-2-环己基-7-氟-3,3-二甲基-3H-吲哚8f5-Bromo-2-cyclohexyl-7-fluoro-3,3-dimethyl-3H-indole 8f
2-(5'-溴-7'-氟螺[环己烷-1,3'-吲哚]-2'-基)丙-2-醇8g2-(5'-Bromo-7'-fluorospiro[cyclohexane-1,3'-indol]-2'-yl)propan-2-ol 8g
1-(5-溴-7-氟-3,3-二甲基-3H-吲哚-2-基)环己-1-醇8h1-(5-Bromo-7-fluoro-3,3-dimethyl-3H-indol-2-yl)cyclohex-1-ol 8h
将化合物1b(1g，4.14mmol)，化合物8d(958mg，6.2mol溶于乙酸(10mL)，回流反应5小时后，加入水(5mL)，继续回流反应48小时，反应液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系B纯化得到标题化合物8e和8f的混合物(300mg，产率：22.3％)和8g和8h的混合物(100mg，产率：7.4％)。Compound 1b (1g, 4.14mmol), compound 8d (958mg, 6.2mol) were dissolved in acetic acid (10mL), after reflux reaction for 5 hours, water (5mL) was added, and reflux reaction was continued for 48 hours, the reaction solution was concentrated under reduced pressure, and the residue Purification by silica gel column chromatography with eluent system B afforded a mixture of title compounds 8e and 8f (300 mg, yield: 22.3%) and a mixture of 8g and 8h (100 mg, yield: 7.4%).
化合物8e和化合物8f:MS m/z(ESI):324.2[M+1]。Compound 8e and Compound 8f: MS m/z (ESI): 324.2 [M+1].
化合物8g和化合物8h:MS m/z(ESI):340.2[M+1]。Compound 8g and Compound 8h: MS m/z (ESI): 340.2 [M+1].
第四步the fourth step
(3S,4R)-4-((5-氯-4-(7'-氟-2'-异丙基螺[环己烷-1,3'-吲哚]-5'-基)嘧啶-2-基)氨基)四氢-2H-吡喃-3-醇8-p1(3S,4R)-4-((5-Chloro-4-(7'-fluoro-2'-isopropylspiro[cyclohexane-1,3'-indol]-5'-yl)pyrimidine- 2-yl)amino)tetrahydro-2H-pyran-3-ol 8-p1
(3S,4R)-4-((5-氯-4-(2-环己基-7-氟-3,3-二甲基-3H-吲哚-5-基)嘧啶-2-基)氨基)四氢-2H-吡喃-3-醇8-p2(3S,4R)-4-((5-chloro-4-(2-cyclohexyl-7-fluoro-3,3-dimethyl-3H-indol-5-yl)pyrimidin-2-yl)amino ) Tetrahydro-2H-pyran-3-ol 8-p2
采用实施例1中的合成路线第三步至第五步，将第三步原料化合物1d替换为化合物8e和8f的混合物得到标题化合物8-p1(10mg，产率：4.1％)和8-p2(30mg，产率：12.4％)。Using the third step to the fifth step of the synthetic route in Example 1, 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%).
单一构型化合物8-p1:Single configuration compound 8-p1:
MS m/z(ESI):473.2[M+1]。MS m/z (ESI): 473.2 [M+1].
HPLC分析：保留时间1.55分钟，纯度：96％(色谱柱:ACQUITY
Figure PCTCN2022141271-appb-000060
C18,1.7μm,2.1*50mm；流动相：水(10mM碳酸氢铵)，乙腈，梯度配比：乙腈10％-95％)。 1H NMR(500MHz,CD 3OD):δ8.36(s,1H),8.15(s,1H),7.70(d,1H),3.99(dt,2H),3.95-3.89(m,1H),3.63(td,1H),3.49(t,1H),3.25-3.11(m,2H),2.19-2.12(m,1H),2.12-2.00(m,5H),1.97(d,1H),1.88(d,2H),1.68-1.55(m,2H),1.34(d,6H),1.28-1.32(m,1H)。 HPLC analysis: retention time 1.55 minutes, purity: 96% (chromatographic column: ACQUITY
Figure PCTCN2022141271-appb-000060
C18, 1.7μm, 2.1*50mm; mobile phase: water (10mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%). 1 H NMR(500MHz,CD 3 OD):δ8.36(s,1H),8.15(s,1H),7.70(d,1H),3.99(dt,2H),3.95-3.89(m,1H), 3.63(td,1H),3.49(t,1H),3.25-3.11(m,2H),2.19-2.12(m,1H),2.12-2.00(m,5H),1.97(d,1H),1.88( d,2H), 1.68-1.55(m,2H), 1.34(d,6H), 1.28-1.32(m,1H).
单一构型化合物8-p2:Single configuration compound 8-p2:
MS m/z(ESI):473.2[M+1]。MS m/z (ESI): 473.2 [M+1].
HPLC分析：保留时间1.59分钟，纯度：95％(色谱柱:ACQUITY
Figure PCTCN2022141271-appb-000061
C18,1.7μm,2.1*50mm；流动相：水(10mM碳酸氢铵)，乙腈，梯度配比：乙腈10％-95％)。 1H NMR(500MHz,CD 3OD):δ8.35(d,1H),7.69(s,1H),7.59(d,1H),3.97(dd,2H),3.92(d,1H),3.61(q,1H),3.50(t,1H),3.23(t,1H),2.79(t,1H),2.17-2.09(m,1H),1.92(s,1H),1.88(d,3H),1.81(d,1H),1.74(q,2H),1.64(q,1H),1.48(d,2H),1.43(s,6H),1.36-1.31(m,1H)。 HPLC analysis: retention time 1.59 minutes, purity: 95% (chromatographic column: ACQUITY
Figure PCTCN2022141271-appb-000061
C18, 1.7μm, 2.1*50mm; mobile phase: water (10mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%). 1 H NMR (500MHz, CD 3 OD): δ8.35(d,1H),7.69(s,1H),7.59(d,1H),3.97(dd,2H),3.92(d,1H),3.61( q,1H),3.50(t,1H),3.23(t,1H),2.79(t,1H),2.17-2.09(m,1H),1.92(s,1H),1.88(d,3H),1.81 (d,1H), 1.74(q,2H), 1.64(q,1H), 1.48(d,2H), 1.43(s,6H), 1.36-1.31(m,1H).
实施例9Example 9
(3S,4R)-4-((5-氯-4-(7'-氟-2'-异丙基螺[环戊烷-1,3'-吲哚]-5'-基)嘧啶-2-基)氨基)四氢-2H-吡喃-3-醇9(3S,4R)-4-((5-Chloro-4-(7'-fluoro-2'-isopropylspiro[cyclopentane-1,3'-indol]-5'-yl)pyrimidine- 2-yl)amino)tetrahydro-2H-pyran-3-ol 9
Figure PCTCN2022141271-appb-000062
Figure PCTCN2022141271-appb-000062
采用实施例1中的合成路线第三步至第五步，将第三步原料化合物1d替换为化合物7d得到标题化合物9(15mg，产率：18.7％)。Using the third step to the fifth step of the synthetic route in Example 1, the third step raw material compound 1d was replaced by compound 7d to obtain the title compound 9 (15 mg, yield: 18.7%).
MS m/z(ESI):459.1[M+1]。MS m/z (ESI): 459.1 [M+1].
1H NMR(500MHz,CDCl 3):δ8.33(d,1H),7.63(dd,1H),7.58(dt,1H),5.28(d,1H),4.69(d,1H),4.08(dt,1H),4.01(d,1H),3.88(dq,1H),3.65(s,1H),3.49(tt,1H),3.21(td,1H),2.99(dd,1H),2.66(dt,1H),2.60(td,1H),2.44(p,1H),2.25(q,1H),2.09-2.02(m,1H),1.88-1.79(m,1H),1.78-1.66(m,2H),1.54-1.45(m,1H),1.31-1.28(m,6H),1.13-1.06(m,1H)。 1 H NMR (500MHz, CDCl 3 ): δ8.33(d,1H),7.63(dd,1H),7.58(dt,1H),5.28(d,1H),4.69(d,1H),4.08(dt ,1H),4.01(d,1H),3.88(dq,1H),3.65(s,1H),3.49(tt,1H),3.21(td,1H),2.99(dd,1H),2.66(dt, 1H),2.60(td,1H),2.44(p,1H),2.25(q,1H),2.09-2.02(m,1H),1.88-1.79(m,1H),1.78-1.66(m,2H) ,1.54-1.45(m,1H),1.31-1.28(m,6H),1.13-1.06(m,1H).
实施例10Example 10
(3S,4R)-4-((5-氯-4-(7-氟-2-异丙基-3,3-二甲基-3H-吲哚-5-基)嘧啶-2-基)氨基)四氢-2H-吡喃-3-醇10(3S,4R)-4-((5-chloro-4-(7-fluoro-2-isopropyl-3,3-dimethyl-3H-indol-5-yl)pyrimidin-2-yl) Amino)tetrahydro-2H-pyran-3-ol 10
Figure PCTCN2022141271-appb-000063
Figure PCTCN2022141271-appb-000063
第一步first step
2-(5-溴-7-氟-3,3-二甲基-3H-吲哚-2-基)丙烷-2-醇4b2-(5-Bromo-7-fluoro-3,3-dimethyl-3H-indol-2-yl)propan-2-ol 4b
5-溴-7-氟-2-异丙基-3,3-二甲基-3H-吲哚10a5-Bromo-7-fluoro-2-isopropyl-3,3-dimethyl-3H-indole 10a
将化合物1b(1g，4.14mmol)，2,4-二甲基-3-戊酮4a(472.8mg，4.14mol)溶于乙酸(10mL)，回流反应5小时后，加入水(5mL)，继续回流反应2小时，反应液减压浓缩，残余物用高效液相色谱法(Waters-2545，色谱柱：YMC Triart-Exrs,Prep30*150mm,5μm,C18；流动相：水相(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈30％-45％，流速：30mL/min)纯化得到标题化合物4b(460mg，产率：37％)和10a(100mg，产率：8％)。Compound 1b (1g, 4.14mmol), 2,4-dimethyl-3-pentanone 4a (472.8mg, 4.14mol) was dissolved in acetic acid (10mL), after reflux for 5 hours, water (5mL) was added, and Reflux reaction for 2 hours, the reaction solution was concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography (Waters-2545, chromatographic column: YMC Triart-Exrs, Prep30*150mm, 5 μm, C18; mobile phase: aqueous phase (10mmol/L carbonic acid ammonium hydrogen) and acetonitrile, gradient ratio: acetonitrile 30%-45%, flow rate: 30mL/min) to obtain the title compound 4b (460mg, yield: 37%) and 10a (100mg, yield: 8%).
化合物4b:MS m/z(ESI):300.2[M+1]。Compound 4b: MS m/z (ESI): 300.2 [M+1].
化合物10a:MS m/z(ESI):284.2[M+1]。Compound 10a: MS m/z (ESI): 284.2 [M+1].
第二步second step
(3S,4R)-4-((5-氯-4-(7-氟-2-异丙基-3,3-二甲基-3H-吲哚-5-基)嘧啶-2-基)氨基)四氢-2H-吡喃-3-醇10(3S,4R)-4-((5-chloro-4-(7-fluoro-2-isopropyl-3,3-dimethyl-3H-indol-5-yl)pyrimidin-2-yl) Amino)tetrahydro-2H-pyran-3-ol 10
采用实施例1中的合成路线第三步至第五步，将第三步原料化合物1d替换为化合物10a得到标题化合物10(6mg，产率：10.9％)。Using the third step to the fifth step of the synthetic route in Example 1, the third step starting material compound 1d was replaced by compound 10a to obtain the title compound 10 (6 mg, yield: 10.9%).
MS m/z(ESI):433.2[M+1]。MS m/z (ESI): 433.2 [M+1].
1H NMR(500MHz,CDCl 3):δ8.33(s,1H),7.55(d,2H),5.27(d,1H),4.71(s,1H),4.08(dd,1H),4.01(dd,1H),3.87(tt,1H),3.65(dt,1H),3.49(t,1H),3.21(t,1H),2.98(p,1H),2.07(dd,2H),1.41(s,6H),1.38(d,6H)。 1 H NMR (500MHz, CDCl 3 ): δ8.33(s,1H),7.55(d,2H),5.27(d,1H),4.71(s,1H),4.08(dd,1H),4.01(dd ,1H),3.87(tt,1H),3.65(dt,1H),3.49(t,1H),3.21(t,1H),2.98(p,1H),2.07(dd,2H),1.41(s, 6H), 1.38(d, 6H).
实施例11Example 11
(3S,4R)-4-((5-氯-4-(7'-氟-2'-甲基螺[环己烷-1,3'-吲哚]-5'-基)嘧啶-2-基)氨基)四氢-2H-吡喃-3-醇11(3S,4R)-4-((5-Chloro-4-(7'-fluoro-2'-methylspiro[cyclohexane-1,3'-indol]-5'-yl)pyrimidine-2 -yl)amino)tetrahydro-2H-pyran-3-ol 11
Figure PCTCN2022141271-appb-000064
Figure PCTCN2022141271-appb-000064
采用实施例1中的合成路线第一步至第五步，将第二步原料化合物1c替换为化合物环己基甲酮(上海毕得)得到标题化合物11(10mg，产率：8.1％)。Using the first step to the fifth step of the synthetic route in Example 1, 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%).
MS m/z(ESI):445.2[M+1]。MS m/z (ESI): 445.2 [M+1].
1H NMR(500MHz,CD 3OD):δ8.36(s,1H),8.14(s,1H),7.72-7.60(m,1H),4.03-3.96(m,2H),3.93(ddd,1H),3.63(td,1H),3.49(td,1H),3.21(dd,1H),2.40(s,3H),2.15(ddd,1H),2.07-2.02(m,1H),2.01-1.94(m,4H),1.93-1.83(m,2H),1.70-1.56(m,2H),1.34(d,2H)。 1 H NMR(500MHz,CD 3 OD):δ8.36(s,1H),8.14(s,1H),7.72-7.60(m,1H),4.03-3.96(m,2H),3.93(ddd,1H ),3.63(td,1H),3.49(td,1H),3.21(dd,1H),2.40(s,3H),2.15(ddd,1H),2.07-2.02(m,1H),2.01-1.94( m, 4H), 1.93-1.83 (m, 2H), 1.70-1.56 (m, 2H), 1.34 (d, 2H).
实施例12Example 12
(3S,4R)-4-((5-氯-4-(7'-氟-2'-(2-羟基丙-2-基)螺[环己烷-1,3'-吲哚]-5'-基)嘧啶-2-基)氨基)四氢-2H-吡喃-3-醇12-p1(3S,4R)-4-((5-Chloro-4-(7'-fluoro-2'-(2-hydroxypropan-2-yl)spiro[cyclohexane-1,3'-indole]- 5'-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol 12-p1
(3S,4R)-4-((5-氯-4-(7-氟-2-(1-羟基环己基)-3,3-二甲基-3H-吲哚-5-基)嘧啶-2-基)氨基)四氢-2H-吡喃-3-醇12-p2(3S,4R)-4-((5-chloro-4-(7-fluoro-2-(1-hydroxycyclohexyl)-3,3-dimethyl-3H-indol-5-yl)pyrimidine- 2-yl)amino)tetrahydro-2H-pyran-3-ol 12-p2
Figure PCTCN2022141271-appb-000065
Figure PCTCN2022141271-appb-000065
采用实施例1中的合成路线第三步至第五步，将第三步原料化合物1d替换为化合物8g和8h的混合物得到标题化合物12-p1(3mg，产率：2.9％)和12-p2(10mg，产率：9.6％)。Using the third step to the fifth step of the synthetic route in Example 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%).
单一构型化合物12-p1:Single configuration compound 12-p1:
MS m/z(ESI):489.2[M+1]。MS m/z (ESI): 489.2 [M+1].
HPLC分析：保留时间1.29分钟，纯度：99％(色谱柱:ACQUITY
Figure PCTCN2022141271-appb-000066
C18,1.7μm,2.1*50mm；流动相：水(10mM碳酸氢铵)，乙腈，梯度配比：乙腈10％-95％)。 1H NMR(500MHz,CD3OD):δ8.36(s,1H),8.15(s,1H),7.67(d,1H),4.03-3.90(m,3H),3.63(td,1H),3.49(t,1H),3.21(t,1H),3.04(td,2H),2.24-2.12(m,2H),2.05(d,1H),1.98(d,3H),1.83(d,2H),1.67(d,1H),1.64(s,6H),1.59-1.55(m,1H)。 HPLC analysis: retention time 1.29 minutes, purity: 99% (chromatographic column: ACQUITY
Figure PCTCN2022141271-appb-000066
C18, 1.7μm, 2.1*50mm; mobile phase: water (10mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%). 1 H NMR (500MHz, CD3OD): δ8.36(s, 1H), 8.15(s, 1H), 7.67(d, 1H), 4.03-3.90(m, 3H), 3.63(td, 1H), 3.49( t,1H),3.21(t,1H),3.04(td,2H),2.24-2.12(m,2H),2.05(d,1H),1.98(d,3H),1.83(d,2H),1.67 (d,1H), 1.64(s,6H), 1.59-1.55(m,1H).
单一构型化合物12-p2:Single configuration compound 12-p2:
MS m/z(ESI):489.2[M+1]。MS m/z (ESI): 489.2 [M+1].
HPLC分析：保留时间1.38分钟，纯度：99％(色谱柱:ACQUITY
Figure PCTCN2022141271-appb-000067
C18,1.7μm,2.1*50mm；流动相：水(10mM碳酸氢铵)，乙腈，梯度配比：乙腈10％-95％)。 1H NMR(500MHz,CD 3OD):δ8.34(s,1H),7.63(s,1H),7.56(d,1H),3.98(dt,2H),3.92(d,1H),3.61(td,1H),3.50(t,1H),3.23(t,1H),2.17-2.10(m,1H),2.04(td,2H),1.92(d,2H),1.79(dt,4H),1.66(s,2H),1.63(s,6H),1.62-1.61(m,1H)。 HPLC analysis: retention time 1.38 minutes, purity: 99% (chromatographic column: ACQUITY
Figure PCTCN2022141271-appb-000067
C18, 1.7μm, 2.1*50mm; mobile phase: water (10mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%). 1 H NMR (500MHz, CD 3 OD): δ8.34(s, 1H), 7.63(s, 1H), 7.56(d, 1H), 3.98(dt, 2H), 3.92(d, 1H), 3.61( td,1H),3.50(t,1H),3.23(t,1H),2.17-2.10(m,1H),2.04(td,2H),1.92(d,2H),1.79(dt,4H),1.66 (s,2H), 1.63(s,6H), 1.62-1.61(m,1H).
实施例13Example 13
(3S,4R)-4-((5-氯-4-(3,3-二乙基-7-氟-2-甲基-3H-吲哚-5-基)嘧啶-2-基)氨基)四氢-2H-吡喃-3-醇13(3S,4R)-4-((5-chloro-4-(3,3-diethyl-7-fluoro-2-methyl-3H-indol-5-yl)pyrimidin-2-yl)amino ) Tetrahydro-2H-pyran-3-ol 13
Figure PCTCN2022141271-appb-000068
Figure PCTCN2022141271-appb-000068
采用实施例1中的合成路线第二步至第五步，将第二步原料化合物1c替换为3-乙基戊烷-2-酮得到标题化合物13(20mg，产率：3.2％)。Using the second step to the fifth step of the synthetic route in Example 1, the second step raw material compound 1c was replaced by 3-ethylpentan-2-one to obtain the title compound 13 (20 mg, yield: 3.2%).
MS m/z(ESI):433.2[M+1]。MS m/z (ESI): 433.2 [M+1].
1H NMR(500MHz,CD 3OD):δ8.35(s,1H),7.65-7.58(m,2H),3.98(dt,2H),3.94-3.89(m,1H),3.61(td,1H),3.50(t,1H),3.22(t,1H),2.32(s,3H),2.09(dtd,4H),1.97(dq,2H),0.43(t,6H)。 1 H NMR(500MHz,CD 3 OD):δ8.35(s,1H),7.65-7.58(m,2H),3.98(dt,2H),3.94-3.89(m,1H),3.61(td,1H ), 3.50(t,1H), 3.22(t,1H), 2.32(s,3H), 2.09(dtd,4H), 1.97(dq,2H), 0.43(t,6H).
实施例14Example 14
(3S,4R)-4-((5-氯-4-(7-氟-2-甲基-2',3',5',6'-四氢螺[吲哚-3,4'-吡喃]-5-基)嘧啶-2-基)氨基)四氢-2H-吡喃-3-醇14(3S,4R)-4-((5-Chloro-4-(7-fluoro-2-methyl-2',3',5',6'-tetrahydrospiro[indole-3,4'- Pyran]-5-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol 14
Figure PCTCN2022141271-appb-000069
Figure PCTCN2022141271-appb-000069
采用实施例1中的合成路线第二步至第五步，将第二步原料化合物1c替换为1-(四氢-2H-吡喃-4-基)乙酮得到标题化合物14(15mg，产率：8.2％)。Using the second step to the fifth step of the synthetic route in Example 1, the second step raw material compound 1c was replaced by 1-(tetrahydro-2H-pyran-4-yl)ethanone to obtain the title compound 14 (15mg, yield rate: 8.2%).
MS m/z(ESI):447.2[M+1]。MS m/z (ESI): 447.2 [M+1].
1H NMR(500MHz,CDCl 3):δ8.36(s,1H),8.13(s,1H),7.66(d,1H),5.29(d,1H),4.16-4.08(m,4H),4.02(dd,1H),3.89(dt,1H),3.66(s,1H),3.54-3.46(m,1H),3.21(t,1H),2.43(s,3H),2.26(dt,2H),2.08(d,1H),1.76(td,1H),1.39-1.29(m,4H)。 1 H NMR (500MHz, CDCl 3 ): δ8.36(s,1H),8.13(s,1H),7.66(d,1H),5.29(d,1H),4.16-4.08(m,4H),4.02 (dd,1H),3.89(dt,1H),3.66(s,1H),3.54-3.46(m,1H),3.21(t,1H),2.43(s,3H),2.26(dt,2H), 2.08 (d, 1H), 1.76 (td, 1H), 1.39-1.29 (m, 4H).
生物学评价biological evaluation
以下结合测试例进一步描述解释本公开，但这些测试例并非意味着限制本公开的范围。The following further describes and explains the present disclosure in combination with test examples, but these test examples are not meant to limit the scope of the present disclosure.
测试例1、本公开化合物对CDK4酶的抑制效应Test example 1, the inhibitory effect of the disclosed compound on CDK4 enzyme
以下方法用来测定本公开化合物对CDK4酶的抑制效应。实验方法简述如下：The following method was used to determine the inhibitory effect of the disclosed compounds on the CDK4 enzyme. The experimental method is briefly described as follows:
一、实验材料及仪器1. Experimental materials and instruments
1.CDK4/CycD3(Carna biosciences，04-105)1. CDK4/CycD3 (Carna biosciences, 04-105)
2.HTRF CDKs激酶(CDK1/4/6/7/12)试剂盒(Cisbio，63ADK000CB11PEG)2. HTRF CDKs Kinase (CDK1/4/6/7/12) Kit (Cisbio, 63ADK000CB11PEG)
3.ATP(Sigma，A7699-1G)3. ATP (Sigma, A7699-1G)
4.DTT(Sigma，43815-1G)4. DTT (Sigma, 43815-1G)
5.氯化镁溶液(Sigma，68475-100ML-F)5. Magnesium chloride solution (Sigma, 68475-100ML-F)
6. 384孔板(Corning，4513)6. 384-well plate (Corning, 4513)
7.U型底96孔板(Corning，3795)7. U-bottom 96-well plate (Corning, 3795)
8.EnVision多模式检测平台(PerkinElmer，EnVision)8. EnVision multi-mode detection platform (PerkinElmer, EnVision)
二、实验步骤2. Experimental steps
CDK4酶(终浓度为1ng/μL)，与不同浓度(首浓度1μM，3倍梯度稀释11个浓度)的小分子化合物混合，室温孵育30分钟，再加入CDKs底物-生物素(Substrate-biotin)(终浓度0.3μM)和ATP溶液(终浓度10μM)，混合，室温孵育90分钟。然后加入用检测缓冲液(Detection buffer)稀释的CDKs抗体-穴状化合物(Antibody-Cryptate)和用检测缓冲液稀释的链霉亲和素(Streptavidin)-XL665(终浓度37.5nM)，混匀，室温孵育1小时后，用EnVision多模式检测平台检测HTRF模式下信号。CDK4 enzyme (final concentration 1ng/μL), mixed with small molecule compounds of different concentrations (first concentration 1μM, 3-fold serial dilution 11 concentrations), incubated at room temperature for 30 minutes, and then added CDKs substrate-biotin (Substrate-biotin) ) (final concentration 0.3 μM) and ATP solution (final concentration 10 μM), mixed and incubated at room temperature for 90 minutes. Then add CDKs antibody-cryptate (Antibody-Cryptate) diluted with detection buffer and streptavidin-XL665 (final concentration 37.5nM) diluted with detection buffer, mix well, After incubation at room temperature for 1 hour, the EnVision multi-mode detection platform was used to detect the signal in HTRF mode.
三、实验数据3. Experimental data
用EnVision多模式检测平台检测HTRF模式下337nm激发，在665nm和 620nm的荧光值。数据使用GraphPad软件处理，见表1。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.
表1本公开化合物对CDK4酶活性抑制的IC 50 Table 1 The IC 50 of the compounds of the present disclosure on the inhibition of CDK4 enzyme activity
化合物compound IC 50(nM) IC 50 (nM)
11 0.90.9
22 4.14.1
33 4.04.0
44 9.69.6
7-p27-p2 11.511.5
99 2.82.8
1111 6.66.6
1313 1.71.7
结论：本公开化合物对CDK4酶活性具有明显的抑制作用。Conclusion: The disclosed compound has obvious inhibitory effect on CDK4 enzyme activity.
测试例2、本公开化合物对CDK6酶的抑制效应Test example 2, the inhibitory effect of the disclosed compound on CDK6 enzyme
以下方法用来测定本公开化合物对CDK6酶的抑制效应。实验方法简述如下：The following method was used to determine the inhibitory effect of the disclosed compounds on the CDK6 enzyme. The experimental method is briefly described as follows:
一、实验材料及仪器1. Experimental materials and instruments
1.CDK6/CycD3(Carna biosciences，04-107)1. CDK6/CycD3 (Carna biosciences, 04-107)
2.HTRF CDKs激酶(CDK1/4/6/7/12)试剂盒(Cisbio，63ADK000CB11PEG)2. HTRF CDKs Kinase (CDK1/4/6/7/12) Kit (Cisbio, 63ADK000CB11PEG)
3.ATP(Sigma，A7699-1G)3. ATP (Sigma, A7699-1G)
4.DTT(Sigma，43815-1G)4. DTT (Sigma, 43815-1G)
5.氯化镁溶液(Sigma，68475-100ML-F)5. Magnesium chloride solution (Sigma, 68475-100ML-F)
6. 384孔板(Corning，4513)6. 384-well plate (Corning, 4513)
7.U型底96孔板(Corning，3795)7. U-bottom 96-well plate (Corning, 3795)
8.EnVision多模式检测平台(PerkinElmer，EnVision)8. EnVision multi-mode detection platform (PerkinElmer, EnVision)
二、实验步骤2. Experimental steps
CDK6酶(终浓度为2.5ng/μL)与不同浓度(首浓度1μM，3倍梯度稀释11个浓度)的小分子化合物混合，室温孵育30分钟，再加入CDKs底物-生物素(Substrate-biotin)(终浓度0.3μM)和ATP溶液(终浓度50μM)，混合，室温孵育180分钟。然后加入用检测缓冲液(Detection buffer)稀释的CDKs抗体-穴状化合物(Antibody-Cryptate)和用检测缓冲液稀释的链霉亲和素(Streptavidin)-XL665(终浓度37.5nM)，混匀，室温孵育1小时后，用EnVision多模式检测平台检测HTRF模式下信号。CDK6 enzyme (final concentration 2.5ng/μL) was mixed with small molecule compounds of different concentrations (first concentration 1μM, 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 μM) and ATP solution (final concentration 50 μM), mixed and incubated at room temperature for 180 minutes. Then add CDKs antibody-cryptate (Antibody-Cryptate) diluted with detection buffer and streptavidin-XL665 (final concentration 37.5nM) diluted with detection buffer, mix well, After incubation at room temperature for 1 hour, the EnVision multi-mode detection platform was used to detect the signal in HTRF mode.
三、实验数据3. Experimental data
用EnVision多模式检测平台检测HTRF模式下337nm激发，在665nm和620nm的荧光值。数据使用GraphPad软件处理，见表2。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.
表2本公开化合物对CDK6酶活性抑制的IC 50 Table 2 The IC 50 of the compounds of the present disclosure on the inhibition of CDK6 enzyme activity
化合物compound IC 50(nM) IC 50 (nM)
11 7.37.3
22 32.032.0
33 26.426.4
44 128.0128.0
66 329.8329.8
7-p17-p1 700.4700.4
8-p18-p1 1038.01038.0
12-p112-p1 594.5594.5
12-p212-p2 329.1329.1
1414 427.6427.6
测试例3、MCF-7细胞增殖实验Test example 3, MCF-7 cell proliferation experiment
一、测试目的1. Purpose of test
本实验的目的是为了测试化合物分子对MCF-7细胞增殖活性的抑制作用，根据IC 50大小评价分子的体外活性。MCF-7细胞为CDK4依赖的人乳腺癌细胞系，对CDK4选择性抑制剂敏感。本实验采用CellTite-Glo试剂，测量发光值，发光值与ATP量成正比，而ATP又和活细胞数正相关，因此通过检测细胞内ATP含量来反映细胞活力。根据IC 50大小评价化合物对MCF-7细胞增殖的抑制效果。 The purpose of this experiment is to test the inhibitory effect of the compound molecule on the proliferation activity of MCF-7 cells, and evaluate the in vitro activity of the molecule according to the IC 50 size. MCF-7 cells are a CDK4-dependent human breast cancer cell line that is sensitive to CDK4-selective inhibitors. In this experiment, 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 .
二、实验方法2. Experimental method
胰酶(Invitrogen,25200-072)消化MCF-7细胞(ATCC，HTB-22)，离心后重悬，制备单细胞悬液，用细胞培养液(EMEM+10％FBS+0.01mg/mL胰岛素)调整活细胞密度至8.4×10 3细胞/mL，混匀，以180μL/孔加入96孔细胞培养板(Corning,3903)。将培养板在培养箱培养20-24小时(37℃，5％CO 2)。 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 μL/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.
用DMSO溶解化合物，配制成初始浓度为20mM的存储液。小分子化合物的起始浓度为0.6mM，3倍稀释，稀释10个点，第11、12个点为DMSO。另取一块96孔板，每孔加入95μL的细胞培养液(EMEM+10％FBS+0.01mg/mL胰岛素)，然后每孔加入5μL不同浓度的待测样品，混匀，接着向细胞培养板中加入20μL/孔的不同浓度的待测样品，每个样品两复孔。将培养板在培养箱孵育6天(37℃，5％CO 2)。取出96孔细胞培养板，向每孔加入90μL CellTiter-Glo试剂(Promega,G7573)，室温避光孵育10min，于酶标仪(PHERAstar，BMG labtech)中取化学发光信号值。 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 μL of cell culture medium (EMEM+10% FBS+0.01 mg/mL insulin) to each well, then add 5 μL of different concentrations of samples to be tested in each well, mix well, and then add to the cell culture plate Add 20 μL/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. Take out the 96-well cell culture plate, add 90 μL CellTiter-Glo reagent (Promega, G7573) to each well, incubate at room temperature in the dark for 10 min, and take the chemiluminescent signal value in a microplate reader (PHERAstar, BMG labtech).
三、实验数据3. Experimental data
用Microsoft Excel，Graphpad Prism 5对数据进行处理分析。得出化合物的IC 50值，结果参见下表3。 Data were processed and analyzed with Microsoft Excel and Graphpad Prism 5. The IC50 values of the compounds were obtained and the results are shown in Table 3 below.
表3本公开化合物对MCF-7细胞的增殖抑制的IC 50 Table 3 IC 50 of the compounds of the present disclosure on the proliferation inhibition of MCF-7 cells
化合物compound IC 50(nM) IC 50 (nM)
11 9.59.5
22 10.510.5
33 7.87.8
44 5.25.2
99 4.04.0
1313 6.36.3
结论：本公开化合物对MCF-7细胞具有明显的增殖抑制活性。Conclusion: The disclosed compound has obvious growth inhibitory activity on MCF-7 cells.
测试例4、Pfeiffer细胞增殖实验Test example 4, Pfeiffer cell proliferation experiment
一、测试目的1. Purpose of test
本实验的目的是为了测试化合物分子对Pfeiffer细胞增殖活性的抑制作用，根据IC 50大小评价分子的体外活性。Pfeiffer细胞为CDK6依赖的人弥漫性大B细胞淋巴瘤细胞系，对CDK4选择性抑制剂不敏感。本实验采用CellTite-Glo试剂，测量发光值，发光值与ATP量成正比，而ATP又和活细胞数正相关，因此通过检测细胞内ATP含量来反映细胞活力。根据IC 50大小评价化合物对Pfeiffer细胞增殖的抑制效果。 The purpose of this experiment is to test the inhibitory effect of the compound molecule on the proliferation activity of Pfeiffer cells, and evaluate the in vitro activity of the molecule according to the IC 50 size. Pfeiffer cells are a CDK6-dependent human diffuse large B-cell lymphoma cell line that is insensitive to CDK4-selective inhibitors. In this experiment, 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 .
二、实验方法2. Experimental method
收集Pfeiffer细胞(ATCC,CRL-2632)培养悬液，离心后重悬，制备单细胞悬液，用细胞培养液(RPMI-1640+10％FBS)调整活细胞密度至4.4×10 4细胞/mL，混匀，以180μL/孔加入96孔细胞培养板(Corning,3903)。将培养板在培养箱培养20-24小时(37℃，5％CO 2)。 Collect the Pfeiffer cell (ATCC, CRL-2632) culture suspension, centrifuge and resuspend to prepare a single cell suspension, and adjust the viable cell density to 4.4×10 4 cells/mL with cell culture medium (RPMI-1640+10% FBS) , mix well, and add 180 μL/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.
用DMSO溶解化合物，配制成初始浓度为20mM的存储液。小分子化合物的起始浓度为2mM，3倍稀释，稀释10个点，第11、12个点为DMSO。另取一块96孔板，每孔加入95μL的细胞培养液(RPMI-1640+10％FBS)，然后每孔加入5μL不同浓度的待测样品，混匀，接着向细胞培养板中加入20μL/孔的不同浓度的待测样品，每个样品两复孔。将培养板在培养箱孵育6天(37℃，5％CO 2)。取出96孔细胞培养板，向每孔加入90μL CellTiter-Glo试剂(Promega,G7573)，室温避光孵育10min，于酶标仪(PHERAstar，BMG labtech)中取化学发光信号值。 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 μL of cell culture medium (RPMI-1640+10% FBS) to each well, then add 5 μL of different concentrations of samples to be tested in each well, mix well, and then add 20 μL/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. Take out the 96-well cell culture plate, add 90 μL CellTiter-Glo reagent (Promega, G7573) to each well, incubate at room temperature in the dark for 10 min, and take the chemiluminescent signal value in a microplate reader (PHERAstar, BMG labtech).
三、实验数据3. Experimental data
用Microsoft Excel，Graphpad Prism 5对数据进行处理分析。得出化合物的IC 50值，结果参见下表4。 Data were processed and analyzed with Microsoft Excel and Graphpad Prism 5. The IC50 values of the compounds were obtained and the results are shown in Table 4 below.
表4本公开化合物对Pfeiffer细胞的增殖抑制的IC 50 Table 4 IC50 of the compounds of the present disclosure on the inhibition of Pfeiffer cell proliferation
化合物compound IC 50(nM) IC 50 (nM)
22 404404
33 572.5572.5
66 2296.02296.0
结论：结合表3和表4，本公开化合物对CDK4依赖的细胞相对于对CDK6依赖的细胞具有更强的增殖抑制活性，具有细胞选择性。Conclusion: Combining Table 3 and Table 4, the disclosed compound has stronger proliferation inhibitory activity on CDK4-dependent cells than CDK6-dependent cells, and has cell selectivity.
测试例5、MOLM-13细胞增殖实验Test example 5, MOLM-13 cell proliferation experiment
一、测试目的1. Purpose of test
本实验的目的是为了测试化合物分子对MOLM-13细胞增殖活性的抑制作用，根据IC 50大小评价分子的体外活性。MOLM-13细胞为CDK6依赖的人急性髓细胞样白血病细胞系，对CDK4选择性抑制剂不敏感。本实验采用CellTite-Glo试剂，测量发光值，发光值与ATP量成正比，而ATP又和活细胞数正相关，因此通过检测细胞内ATP含量来反映细胞活力。根据IC 50大小评价化合物对MOLM-13细胞增殖的抑制效果。 The purpose of this experiment is to test the inhibitory effect of the compound molecule on the proliferation activity of MOLM-13 cells, and evaluate the in vitro activity of the molecule according to the IC 50 size. MOLM-13 cells are a CDK6-dependent human acute myeloid leukemia cell line that is insensitive to CDK4-selective inhibitors. In this experiment, 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 .
二、实验方法2. Experimental method
收集MOLM-13细胞(科佰,CBP60678)培养悬液，离心后重悬，制备单细胞悬液，用细胞培养液(RPMI-1640+20％FBS)调整活细胞密度至3.4×10 4细胞/mL，混匀，以180μL/孔加入96孔细胞培养板(Corning,3903)。将培养板在培养箱培养20-24小时(37℃，5％CO 2)。 Collect the culture suspension of MOLM-13 cells (Kebai, CBP60678), centrifuge and resuspend to prepare a single cell suspension, and use cell culture medium (RPMI-1640+20% FBS) to adjust the viable cell density to 3.4× 104 cells/ mL, mix well, and add 180 μL/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.
用DMSO溶解化合物，配制成初始浓度为20mM的存储液。小分子化合物的起始浓度为2mM，3倍稀释，稀释10个点，第11、12个点为DMSO。另取一块96孔板，每孔加入95μL的细胞培养液(RPMI-1640+20％FBS)，然后每孔加入5μL不同浓度的待测样品，混匀，接着向细胞培养板中加入20μL/孔的不同浓度的待测样品，每个样品两复孔。将培养板在培养箱孵育6天(37℃，5％CO 2)。取出96孔细胞培养板，向每孔加入90μL CellTiter-Glo试剂(Promega,G7573)，室温避光孵育10min，于酶标仪(PHERAstar，BMG labtech)中取化学发光信号值。 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 μL of cell culture medium (RPMI-1640+20% FBS) to each well, then add 5 μL of different concentrations of samples to be tested in each well, mix well, and then add 20 μL/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. Take out the 96-well cell culture plate, add 90 μL CellTiter-Glo reagent (Promega, G7573) to each well, incubate at room temperature in the dark for 10 min, and take the chemiluminescent signal value in a microplate reader (PHERAstar, BMG labtech).
三、实验数据3. Experimental data
用Microsoft Excel，Graphpad Prism 5对数据进行处理分析。得出化合物的IC 50值，结果参见下表5。 Data were processed and analyzed with Microsoft Excel and Graphpad Prism 5. The IC50 values of the compounds were obtained and the results are shown in Table 5 below.
表5本公开化合物对MOLM-13细胞的增殖抑制的IC 50 Table 5 IC50 of the compounds of the present disclosure on the inhibition of MOLM-13 cell proliferation
化合物compound IC 50(nM) IC 50 (nM)
22 11281128
33 903903
44 18791879
结论：结合表3和表5，本公开化合物对CDK4依赖的细胞相对于对CDK6依赖的细胞具有更强的增殖抑制活性，具有细胞选择性。Conclusion: Combining Table 3 and Table 5, the compounds of the present disclosure have stronger proliferation inhibitory activity on CDK4-dependent cells than CDK6-dependent cells, and have cell selectivity.
测试例6、本公开化合物大鼠脑通透性的测定Test Example 6, Determination of Rat Brain Permeability of the Disclosed Compound
本公开化合物大鼠脑通透性采用如下实验方法测定：The rat brain permeability of the disclosed compound is determined by the following experimental method:
一.实验材料与仪器1. Experimental materials and instruments
1.RED装置(Device Inserts)(Thermo Scientific,QL21291110)1. RED device (Device Inserts) (Thermo Scientific, QL21291110)
2.API 4000 Q-trap三重四极杆串联质谱仪(Applied Biosystems)2. API 4000 Q-trap triple quadrupole tandem mass spectrometer (Applied Biosystems)
3.LC-30A超高压液相色谱***(岛津)3. LC-30A ultra-high pressure liquid chromatography system (Shimadzu)
4.pH7.4 PBS(100mM,4℃冰箱保存)4. pH7.4 PBS (100mM, stored in refrigerator at 4°C)
5.SD大鼠，由维通利华实验动物有限公司提供，动物生产许可证号SCXK(沪)2019-00015. SD rats, provided by Weitong Lihua Experimental Animal Co., Ltd., animal production license number SCXK (Shanghai) 2019-0001
二.实验动物操作2. Experimental animal operation
SD大鼠4只，雌雄各半。禁食一夜后灌胃给药。给药剂量20mg/kg。There were 4 SD rats, half male and half male. Administration was administered by intragastric administration after an overnight fast. The dosage is 20mg/kg.
取血：灌胃给药组于给药后2h眼眶采血(采血量0.5ml)，置EDTA-K2抗凝试管中，10000rpm离心1min(4℃)，1h内分离血浆，记为血浆1，-20℃保存待测。采血至离心过程在冰浴条件下操作。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.
取脑组织：大鼠20％乌拉坦麻醉后，进行心脏灌流(打开腹腔，肝脏剪开3-4处，左心尖迅速进针灌注生理盐水30ml)，灌流后采集脑组织，记为脑组织1，并于-20度保存。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.
另取3只动物取空白血浆和脑组织2，处理方法同给药组。Another 3 animals were taken to take blank plasma and brain tissue 2, and the treatment method was the same as that of the administration group.
三.血浆蛋白结合平衡透析过程3. Plasma protein binding equilibrium dialysis process
3.1样品制备3.1 Sample preparation
用DMSO溶解药物化合物至30mM，得到储备液I；移取适量储备液I，用甲醇稀释得到200μM稀释储备液II；移取10μl储备液II于1.5mL Eppendorf管中，加入990μL空白血浆，混匀得到2μM血浆样品2(DMSO含量≤0.2％)，用于该浓度血浆蛋白结合率的测定。移取上述配好的50μL血浆样品，加入50μL pH 7.4磷酸缓冲盐溶液，再加入250μL含内标的乙腈溶液，记为T 0，置于-4℃冰箱保存待测。 Dissolve the drug compound in DMSO to 30mM to obtain stock solution I; pipette an appropriate amount of stock solution I and dilute with methanol to obtain 200μM diluted stock solution II; pipette 10μl stock solution II into a 1.5mL Eppendorf tube, add 990μL blank plasma, and mix well A 2 μM plasma sample 2 (DMSO content≤0.2%) was obtained for the determination of the plasma protein binding rate at this concentration. Pipette 50 μL of the prepared plasma sample, add 50 μL of pH 7.4 phosphate buffered saline solution, and then add 250 μL of acetonitrile solution containing internal standard, record it as T 0 , and store it in a -4°C refrigerator for testing.
3.2实验过程3.2 Experimental process
取RED装置将平衡透析管插至于96孔的底板中。取上述配制好的含待测物血浆样品2(300mL)，置于红色标记的孔中(plasma chamber)。取500μL pH 7.4磷酸缓冲盐溶液，置于并排红色标记的另一孔中(buffer chamber)。按上述步骤处理方法，每个化合物每一个浓度为2个样本。完毕用封条(sealing tape)覆盖96孔板，并将整块底板放至热混仪中，以400rpm转速，于37℃平衡4h。孵化结束后，从热混仪中取出96孔底板装置，完成平衡透析。取50μL平衡后的血浆样品或透析液样品，加入50μL相对应的未平衡的不含药的空白磷酸盐缓冲液或不含药的空白血浆，加入内标(乙腈配制)250μL，涡旋混合5min，离心15min(4000rpm)，取上清液90uL，加入90uL水稀释，取5uL进行LC/MS/MS分析。T 0样品不经孵化，直接采用上述建立的LC/MS/MS法分别测定总药物(plasma chamber)及游离药物 (buffer chamber)与内标物色谱峰面积比，计算游离百分率(f u plasma％)。 Take the RED device and insert the balance dialysis tubing into the 96-well bottom plate. Take the prepared plasma sample 2 (300 mL) containing the analyte and place it in the well marked in red (plasma chamber). Take 500 μL of pH 7.4 phosphate-buffered saline solution and place it in another well marked in red (buffer chamber). According to the above-mentioned steps, each concentration of each compound is 2 samples. After that, the 96-well plate was covered with a sealing tape, and the entire bottom plate was placed in a thermomixer at 400 rpm to equilibrate at 37° C. for 4 hours. After the incubation, the 96-well bottom plate device was removed from the thermomixer to complete the equilibrium dialysis. Take 50 μL of balanced plasma sample or dialysate sample, add 50 μL of corresponding unbalanced drug-free blank phosphate buffer solution or drug-free blank plasma, add 250 μL of internal standard (prepared in acetonitrile), and vortex for 5 minutes , centrifuged for 15min (4000rpm), take 90uL of supernatant, add 90uL of water to dilute, take 5uL for LC/MS/MS analysis. The T0 sample was not incubated, and the LC/MS/MS method established above was directly used to determine the chromatographic peak area ratio of the total drug (plasma chamber) and free drug (buffer chamber) to the internal standard, and calculate the free percentage (fu plasma % ).
四.脑组织蛋白结合平衡透析过程4. Brain tissue protein binding equilibrium dialysis process
脑组织蛋白结合平衡透析过程：空白脑组织2按照稀释因子＝11的比例用pH7.4PBS将脑组织制成空白脑匀浆，加入化合物配制成2μM脑匀浆，其余与血浆蛋白结合的操作相同，采用建立的LC/MS/MS法分别测定总药物(brain homo chamber)及游离药物(buffer chamber)与内标物色谱峰面积比，计算游离百分率(f u  brain hom％)。 Brain tissue protein binding equilibrium dialysis process: Blank brain tissue 2 was made into blank brain homogenate with pH 7.4 PBS according to the ratio of dilution factor = 11, and the compound was added to prepare 2 μM brain homogenate, and the rest of the operation was the same as that of plasma protein binding 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.
五.脑通透试验数据计算方法5. Calculation method of brain permeabilization test data
5.1采用建立的LC/MS/MS法分别测定大鼠给药后2h的血浆1和脑组织1中的药物浓度，此为总浓度(C total,p和C total,b)； 5.1 Use the established LC/MS/MS method to measure the drug concentration in plasma 1 and brain tissue 1 of rats 2 hours after administration, which is the total concentration (C total,p and C total,b );
5.2采用RED Device Inserts装置，用平衡透析法分别测定化合物在大鼠血浆和脑组织中的蛋白结合率，从而计算出游离百分率(f u plasma％,f u brain％)； 5.2 Using the RED Device Inserts device, measure the protein binding rate of the compound in rat plasma and brain tissue by equilibrium dialysis, and then calculate the free percentage (fu plasma %, fu brain %);
血浆游离百分率(f u plasma％)＝C buffer/C plasma×100％； Plasma free percentage (fu plasma %) = C buffer / C plasma × 100%;
脑匀浆游离百分率(f u brain hom％)＝C buffer/C brain hom×100％； Brain homogenate free percentage (f u brain hom %) = C buffer / C brain hom × 100%;
脑组织游离百分率(f u brain％)＝f u brain hom/(Df-(Df-1)×f u brain hom)×100％；此处Df＝11 Brain tissue free percentage (f u brain %)=f u brain hom /(Df-(Df-1)×f u brain hom )×100%; where Df=11
5.3采用以下公式计算血脑通透指数Kp-unbound。5.3 Use the following formula to calculate the blood brain permeability index Kp-unbound.
Figure PCTCN2022141271-appb-000070
Figure PCTCN2022141271-appb-000070
六.试验结果与讨论6. Test results and discussion
表6本公开化合物的脑通透指数如下：Table 6 The brain permeability index of the disclosed compounds is as follows:
Figure PCTCN2022141271-appb-000071
Figure PCTCN2022141271-appb-000071
结论：本公开化合物在脑中的游离药物浓度高，透过血脑屏障能力强，具有较高的脑通透性。Conclusion: 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.

Claims (21)

  1. 一种通式(I)所示的化合物或其可药用的盐：A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof:
    Figure PCTCN2022141271-appb-100001
    Figure PCTCN2022141271-appb-100001
    其中：in:
    环A为杂环基；Ring A is a heterocyclic group;
    G为CR g或N； G is CR g or N;
    各个R 1相同或不同，且各自独立地选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、-(亚烷基) u-NR aR b、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基； 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;
    或者连在同一碳原子上的两个R 1与其相连的碳原子一起形成环烷基或杂环基，所述的环烷基或杂环基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、羟基和羟烷基中的一个或多个所取代； Or two R connected to the same carbon atom form a cycloalkyl or heterocyclic group together with the carbon atom connected to it, and 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 2选自氢原子、烷基、卤代烷基、羟烷基、环烷基和杂环基； 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和R g相同或不同，且各自独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、-(亚烷基) v-NR cR d、-C(O)R x、-C(O)NR yR z、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基，所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、羟基和羟烷基中的一个或多个所取代； 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和R 9相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、羟烷基、环烷基和杂环基，所述的烷基、环烷基和杂环基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、-(亚烷基) w-NR eR f、羟基和羟烷基中的一个或多个所取代； 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;
    或者R 8和R 9与其相连的碳原子一起形成环烷基或杂环基，所述的环烷基或杂环基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、-(亚烷基) y-NR mR n、羟基和羟烷基中的一个或多个所取代； Or 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;
    或者R和R 9与其相连的碳原子一起形成环烷基或杂环基，所述的环烷基或杂环基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、-(亚烷基) z-NR jR k、羟基和羟烷基中的一个或多个所取代； Or 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、R e、R f、R m、R n、R j、R k、R y和R z相同或不同，且各自独 立地选自氢原子、烷基、卤代烷基、羟烷基和环烷基； 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选自烷基、卤代烷基、羟烷基和环烷基； R x is selected from alkyl, haloalkyl, hydroxyalkyl and cycloalkyl;
    m为0至15的整数；m is an integer from 0 to 15;
    u为0、1、2、3或4；u is 0, 1, 2, 3 or 4;
    v为0、1、2、3或4；v is 0, 1, 2, 3 or 4;
    w为0、1、2、3或4；w is 0, 1, 2, 3 or 4;
    y为0、1、2、3或4；且y is 0, 1, 2, 3 or 4; and
    z为0、1、2、3或4。z is 0, 1, 2, 3 or 4.
  2. 根据权利要求1所述的通式(I)所示的化合物或其可药用的盐，其中环A为3至8元杂环基。The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein ring A is a 3- to 8-membered heterocyclic group.
  3. 根据权利要求1或2所述的通式(I)所示的化合物或其可药用的盐，其为通式(II)所示的化合物或其可药用的盐，The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, which is a compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof,
    Figure PCTCN2022141271-appb-100002
    Figure PCTCN2022141271-appb-100002
    其中：in:
    Q选自NR q、O和S； Q is selected from NRq , O and S;
    R q选自氢原子、烷基、卤代烷基、羟烷基、环烷基和杂环基； 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和R 1h相同或不同，且各自独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、-(亚烷基) u-NR aR b、羟基、羟烷基、环烷基和杂环基； 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为0、1或2；p is 0, 1 or 2;
    q为0、1或2；且q is 0, 1 or 2; and
    G、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R、R a、R b和u如权利要求1中所定义。 G, 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 claim 1 .
  4. 根据权利要求1至3中任一项所述的通式(I)所示的化合物或其可药用的盐，其中R 2为氢原子。 The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R 2 is a hydrogen atom.
  5. 根据权利要求1至4中任一项所述的通式(I)所示的化合物或其可药用的盐，其为通式(III)所示的化合物或其可药用的盐，The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, which is a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof,
    Figure PCTCN2022141271-appb-100003
    Figure PCTCN2022141271-appb-100003
    其中：in:
    Q选自NR q、O和S； Q is selected from NRq , O and S;
    R q选自氢原子、烷基、卤代烷基、羟烷基、环烷基和杂环基； 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和R 1b相同或不同，且各自独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、-(亚烷基) u-NR aR b、羟基、羟烷基、环烷基和杂环基；且 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; and
    R 3、R 4、R 5、R 6、R 7、R 8、R 9、R、R a、R b和u如权利要求1中所定义。 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 claim 1 .
  6. 根据权利要求1至5中任一项所述的通式(I)所示的化合物或其可药用的盐，其中R 8和R 9相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基、C 1-6卤代烷基和C 1-6羟烷基； The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein R 8 and R 9 are the same or different, and are each independently selected from a hydrogen atom, a halogen , C 1-6 alkyl, C 1-6 haloalkyl and C 1-6 hydroxyalkyl;
    或者R 8和R 9与其相连的碳原子一起形成3至8元环烷基或3至8元杂环基，所述的3至8元环烷基或3至8元杂环基各自独立地任选被选自卤素、C 1-6烷基和C 1-6卤代烷基中的一个或多个所取代。 Or R 8 and R 9 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 substituted by one or more selected from halogen, C 1-6 alkyl and C 1-6 haloalkyl.
  7. 根据权利要求1至6中任一项所述的通式(I)所示的化合物或其可药用的盐，其中R 7选自C 1-6烷基、C 1-6羟烷基和3至8元环烷基，所述的3至8元环烷基任选被一个或多个羟基取代；优选地，R 7为C 1-6烷基或C 1-6羟烷基。 According to the compound represented by general formula (I) or its pharmaceutically acceptable salt according to any one of claims 1 to 6, wherein R is selected from C 1-6 alkyl, C 1-6 hydroxyalkyl and 3 to 8-membered cycloalkyl, said 3 to 8-membered cycloalkyl is optionally substituted by one or more hydroxyl groups; preferably, R 7 is C 1-6 alkyl or C 1-6 hydroxyalkyl.
  8. 根据权利要求3至7中任一项所述的通式(I)所示的化合物或其可药用的盐，其中R 1a为羟基；和/或R 1b为氢原子。 The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 3 to 7, wherein R 1a is a hydroxyl group; and/or R 1b is a hydrogen atom.
  9. 根据权利要求3至8中任一项所述的通式(I)所示的化合物或其可药用的盐，其中Q为O。The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 3 to 8, wherein Q is O.
  10. 根据权利要求1至9中任一项所述的通式(I)所示的化合物或其可药用的盐，其中R 3为氢原子。 The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein R 3 is a hydrogen atom.
  11. 根据权利要求1至10中任一项所述的通式(I)所示的化合物或其可药用的盐，其中R 4为卤素。 The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein R 4 is halogen.
  12. 根据权利要求1至11中任一项所述的通式(I)所示的化合物或其可药用的盐，其中R 5为氢原子；和/或R为氢原子。 The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein R 5 is a hydrogen atom; and/or R is a hydrogen atom.
  13. 根据权利要求1至12中任一项所述的通式(I)所示的化合物或其可药用的盐，其中R 6为卤素。 The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, wherein R 6 is halogen.
  14. 根据权利要求1至13中任一项所述的通式(I)所示的化合物或其可药用的盐，其选自以下化合物：The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, which is selected from the following compounds:
    Figure PCTCN2022141271-appb-100004
    Figure PCTCN2022141271-appb-100004
    Figure PCTCN2022141271-appb-100005
    Figure PCTCN2022141271-appb-100005
  15. 一种通式(IA)所示的化合物或其盐：A compound or salt thereof shown in general formula (IA):
    Figure PCTCN2022141271-appb-100006
    Figure PCTCN2022141271-appb-100006
    其中：in:
    X为卤素；优选地，X为Cl；X is halogen; preferably, X is Cl;
    R 4选自Cl、Br、I、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、-(亚烷基) v-NR cR d、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基，所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、羟基和羟烷基中的一个或多个所取代； 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;
    G、R 3、R 5、R 6、R 7、R 8、R 9、R、R c、R d和v如权利要求1中所定义。 G, R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , R, R c , R d and v are as defined in claim 1 .
  16. 根据权利要求15所述的式(IA)所示的化合物或其盐，其选自以下化合物：The compound or salt thereof represented by the formula (IA) according to claim 15, which is selected from the following compounds:
    Figure PCTCN2022141271-appb-100007
    Figure PCTCN2022141271-appb-100007
    Figure PCTCN2022141271-appb-100008
    Figure PCTCN2022141271-appb-100008
  17. 一种制备根据权利要求1所述的通式(I)所示的化合物或其可药用的盐的方法，该方法包括：A method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, the method comprising:
    Figure PCTCN2022141271-appb-100009
    Figure PCTCN2022141271-appb-100009
    通式(IA)所示的化合物或其盐与通式(IB)所示的化合物或其盐发生偶联反应，得到通式(I)所示的化合物或其可药用的盐，Compounds represented by general formula (IA) or salts thereof are coupled with compounds represented by general formula (IB) or salts thereof to obtain compounds represented by general formula (I) or pharmaceutically acceptable salts thereof,
    其中：in:
    X为卤素；优选地，X为Cl；X is halogen; preferably, X is Cl;
    环A、G、R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R和m如权利要求1中所定义。 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 claim 1 .
  18. 一种药物组合物，所述药物组合物含有根据权利要求1至14中任一项所述的通式(I)所示的化合物或其可药用的盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。A pharmaceutical composition, which contains a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, and one or more pharmaceutically acceptable carrier, diluent or excipient.
  19. 根据权利要求1至14中任一项所述的通式(I)所示的化合物或其可药用的盐或根据权利要求18所述的药物组合物在制备用于抑制CDK的药物中的用途；优选地，其中所述的CDK为CDK4。According to the compound represented by the general formula (I) or its pharmaceutically acceptable salt according to any one of claims 1 to 14 or the pharmaceutical composition according to claim 18 in the preparation of medicines for inhibiting CDK Use; preferably, wherein said CDK is CDK4.
  20. 根据权利要求1至14中任一项所述的通式(I)所示的化合物或其可药用的盐或根据权利要求18所述的药物组合物在制备用于治疗和/或预防由CDK4介导的疾病或病症的药物中的用途；优选地，所述的疾病或病症选自肿瘤、骨髓纤维化、骨髓增生异常综合征、肺动脉高压、高血压、神经退行性疾病和黏膜炎；更优选 地，所述的疾病或病症为癌症。According to the compound represented by the general formula (I) or its pharmaceutically acceptable salt according to any one of claims 1 to 14 or the pharmaceutical composition according to claim 18 in the preparation for the treatment and/or prevention of Use in medicine for CDK4-mediated diseases or disorders; preferably, the diseases or disorders are selected from tumors, myelofibrosis, myelodysplastic syndrome, pulmonary hypertension, hypertension, neurodegenerative diseases and mucositis; More preferably, the disease or condition is cancer.
  21. 根据权利要求1至14中任一项所述的通式(I)所示的化合物或其可药用的盐或根据权利要求18所述的药物组合物在制备用于治疗和/或预防疾病或病症的药物中的用途，其中所述的疾病或病症选自乳腺癌、子宫内膜癌、卵巢癌、***癌、输卵管癌、***、肾癌、膀胱癌、尿路上皮癌、尿道癌、***癌、睾丸癌、结直肠癌、肉瘤、骨癌、多发性骨髓瘤、白血病、粘液瘤、横纹肌瘤、平滑肌瘤、纤维瘤、脂肪瘤、畸胎瘤、喉癌、鼻咽癌、口腔癌、肺癌、淋巴瘤、间皮瘤、小肠癌、胃癌、食道癌、胰腺癌、肝癌、胆管癌、胆道癌、胆囊癌、腹膜癌、胸腺癌、中枢神经***肿瘤、视网膜母细胞瘤、多形性成胶质细胞瘤、神经纤维瘤、神经胶质瘤、成神经细胞瘤、黑色素瘤、皮肤癌、基底细胞癌、鳞状细胞癌、甲状腺癌、头颈癌、脑癌、唾液腺癌和胃肠道间质瘤；优选地，所述的疾病或病症为乳腺癌。According to the compound represented by the general formula (I) according to any one of claims 1 to 14 or the pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 18 in the preparation for the treatment and/or prevention of 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 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, Glioblastoma multiforme, neurofibroma, glioma, neuroblastoma, melanoma, skin cancer, basal cell carcinoma, squamous cell carcinoma, thyroid cancer, head and neck cancer, brain cancer, salivary gland cancer, and Gastrointestinal stromal tumor; preferably, the disease or condition is breast cancer.
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