WO2024007985A1 - Dérivé de pyrimidine, son procédé de préparation et son utilisation - Google Patents

Dérivé de pyrimidine, son procédé de préparation et son utilisation Download PDF

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Publication number
WO2024007985A1
WO2024007985A1 PCT/CN2023/104681 CN2023104681W WO2024007985A1 WO 2024007985 A1 WO2024007985 A1 WO 2024007985A1 CN 2023104681 W CN2023104681 W CN 2023104681W WO 2024007985 A1 WO2024007985 A1 WO 2024007985A1
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alkyl
compound
substituted
membered
hydrogen
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PCT/CN2023/104681
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English (en)
Chinese (zh)
Inventor
刘春池
杨国良
王琼
李莉
向永哲
陈洪
王颖
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成都苑东生物制药股份有限公司
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Priority to CN202380013860.6A priority Critical patent/CN118176189A/zh
Publication of WO2024007985A1 publication Critical patent/WO2024007985A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present application relates to the field of medicinal chemistry, specifically to a pyrimidine derivative as a cyclin-dependent kinase 7 (CDK7) inhibitor or a pharmaceutically acceptable salt thereof, its preparation method and use.
  • CDK7 cyclin-dependent kinase 7
  • Cyclin-dependent kinase 7 is a serine-threonine kinase that plays a key role in the transcription and regulation of genes in combination with cyclins.
  • Mammalian cyclin-activated kinase (CAK) composed of CDK7, Cyclin H and MAT1, can coordinate cell cycle progression by phosphorylating the T-loops of other CDK S (CDK1, 2, 4 and 6).
  • CDK7 as part of the multi-subunit general transcription factor TFIIH complex, participates in the regulation of the transcription process. It can phosphorylate Ser residues at positions 5 and 7 of the carboxyl-terminal (C-terminal) domain (CTD) of RNA polymerase II subunit, thereby promoting the initiation of transcription.
  • CDK7 is closely related to the occurrence and development of various tumors. For example, enhancers promote high expression of CDK7 in tumor tissues such as triple-negative breast cancer, high-grade serous ovarian cancer, and small cell lung cancer. Therefore, CDK7 is considered a potential drug target for the treatment of malignant tumors. It is of great significance to develop an efficient and specific CDK7 inhibitor for the treatment of malignant tumor-related diseases.
  • This application relates to a pyrimidine derivative as a CDK7 inhibitor, in particular to a pyrimidine derivative and its preparation method and application in medicine, especially to the pyrimidine derivative represented by the following formula I and its preparation Use in medicines for CDK7-mediated diseases, more specifically, use in the preparation of medicines suitable for tumors.
  • One aspect of the present application provides a compound with the structure shown in Formula I below, its stereoisomer or a pharmaceutically acceptable salt thereof:
  • Ring A is selected from a cyclic hydrocarbon group or a heterocyclic hydrocarbon group, wherein the cyclic hydrocarbon group or heterocyclic hydrocarbon group can be selected from a monocyclic ring, a bicyclic ring, a bridged ring or a spiro ring;
  • X 1 is selected from CH or N;
  • R 1 is selected from hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl,
  • R 2 is selected from halogen, cyano, oxo, hydroxyl, substituted or unsubstituted amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl or C 3 -C 8 cycloalkyloxy, wherein the C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl or C 3 -C 8 cycloalkyloxy is not Substituted or substituted by one or more substituents, which are halogen, cyano, hydroxyl, amino, C 1 -C 6 alkyl or C 1 -C 6 alkoxy;
  • R 3 and R 4 are independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxycarbonyl, C 3 -C 8 cycloalkyl, 3-8 One-membered heterocycloalkyl, aryl or heteroaryl, wherein the C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, 3-8 membered heterocycloalkyl , aryl or heteroaryl is unsubstituted or substituted by one or more substituents, which are halogen, cyano, hydroxyl, amino, C 1 -C 6 alkyl or C 1 -C 6 alkoxy base;
  • n is selected from 0, 1, 2, 3, 4 or 5.
  • the compound with the structure shown in formula I its stereoisomer or its pharmaceutically acceptable salt,
  • Ring A is selected from a 4-8-membered cyclic hydrocarbon group or a 4-10-membered heterocyclic hydrocarbon group, wherein the cyclic hydrocarbon group and heterocyclic hydrocarbon group can be selected from a monocyclic ring, a bicyclic ring, a bridged ring or a spirocyclic ring, and the heterocyclic hydrocarbon group contains at least 1 nitrogen atom as a heteroatom;
  • X 1 is selected from CH or N;
  • R 1 is selected from hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl,
  • R 2 is selected from halogen, cyano, oxo, hydroxyl, substituted or unsubstituted amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl or C 3 -C 8 cycloalkyloxy, wherein the C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl or C 3 -C 8 cycloalkyloxy is not Substituted or substituted by one or more substituents, which are halogen, cyano, hydroxyl, amino, C 1 -C 6 alkyl or C 1 -C 6 alkoxy;
  • R 3 and R 4 are independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxycarbonyl, C 3 -C 8 cycloalkyl, 3-8 heterocyclic ring Alkyl, 6-10-membered aryl or 5-10-membered heteroaryl, wherein the C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, 3-8 One-membered heterocycloalkyl, 6-10-membered aryl or 5-10-membered heteroaryl is unsubstituted or substituted by one or more substituents, the substituents are halogen, cyano, hydroxyl, amino, C 1 -C 6 alkyl or C 1 -C 6 alkoxy;
  • n is selected from 0, 1, 2, 3, 4 or 5.
  • Ring A is selected from 5-7 membered cycloalkyl or 5-7 membered heterocycloalkyl, the heterocycloalkyl containing 1-2 heteroatoms selected from N or O.
  • Ring A is cyclopentyl, cyclohexyl, cycloheptyl, tetrahydrofuryl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, oxeptanyl, or azepanyl .
  • X1 is CH or N, preferably CH.
  • R 1 is selected from hydrogen, halogen (e.g., fluorine, chlorine, bromine, iodine), C 1 -C 5 alkyl (e.g., C 1 -C 4 alkyl, C 1 -C 3 alkyl), C 3 -C 6 cycloalkyl (such as C 3 -C 5 cycloalkyl, C 3 -C 4 cycloalkyl), and
  • R 3 and R 4 are each independently selected from hydrogen, C 1 -C 5 alkyl (such as C 1 -C 4 alkyl, C 1 -C 3 alkyl), C 1 -C 5 alkylcarbonyl (such as C 1 - C 4 alkylcarbonyl, C 1 -C 3 alkylcarbonyl), C 1 -C 5 alkoxycarbonyl (such as C 1 -C 4 alkoxycarbonyl, C 1 -C 3 alkoxycarbonyl), 4- 7-membered heterocycloalkyl, 6-membered aryl or 5-7-membered heteroaryl, the 4-7-membered heterocycloalkyl, 6-membered aryl or 5-7-membered heteroaryl is unsubstituted or substituted by a Or multiple substituents, the substituents are hydroxyl, C 1 -C 5 alkyl (such as C 1 -C 4 alkyl, C 1 -C 3 alkyl) or C 1 -C
  • R 1 is selected from hydrogen, fluorine, chlorine, bromine, C 1 -C 4 alkyl (e.g., methyl, ethyl, propyl, or butyl), C 3 -C 5 cycloalkyl (e.g., cyclopropyl, cyclobutyl or cyclopentyl), or and
  • R 3 and R 4 are independently selected from hydrogen, C 1 -C 5 alkylcarbonyl (such as C 1 -C 4 alkylcarbonyl, C 1 -C 3 alkylcarbonyl), C 1 -C 5 alkoxycarbonyl ( For example, C 1 -C 4 alkoxycarbonyl, C 1 -C 3 alkoxycarbonyl), or 5-7 membered heteroaryl, the 5-7 membered heteroaryl is unsubstituted or substituted by one or more Substituted with a substituent, the substituent is C 1 -C 5 alkyl (such as C 1 -C 4 alkyl, C 1 -C 3 alkyl), and the heteroaryl group contains 1-2 selected from N, O Or a heteroatom of S; preferably, R 3 and R 4 are independently selected from hydrogen, C 1 -C 4 alkoxycarbonyl (such as C 1 -C 3 alkoxycarbonyl), or 5-6 membered heteroaryl , the 5-6 membere
  • R is selected from halogen, cyano, oxo, hydroxy, amino, or C 1 -C 5 alkyl (e.g., C 1 -C 4 alkyl, C 1 -C 3 alkyl), and m is 0, 1, 2 or 3; preferably, R 2 is selected from halogen, hydroxyl, amino or C 1 -C 3 alkyl, and m is 0, 1 or 2 (for example, m is 0).
  • this application provides a compound with the structure shown in Formula II, its stereoisomer or its pharmaceutically acceptable salt,
  • R 1 is selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, cyclopropyl,
  • R 2 is selected from fluorine, chlorine, cyano, oxo, hydroxyl, methyl, ethyl or isopropyl;
  • R 3 and R 4 are independently selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, n-propyl, cyclobutyl, cyclopentyl, cyclohexyl, Phenyl or 5-6 membered heteroaryl, the 5-6 membered heteroaryl may be further substituted by one or more C 1 -C 3 alkyl;
  • n is selected from 0, 1 or 2.
  • R 1 , R 2 , R 3 , R 4 and m are the same as the relevant definitions in the various embodiments for the compound of the structure shown in Formula I above. same.
  • R1 is selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, or (e.g. hydrogen, fluorine, chlorine, bromine, methyl, ethyl, cyclopropyl or );
  • R 2 is selected from methyl, ethyl or isopropyl (such as methyl);
  • R 3 and R 4 are independently selected from hydrogen, Or a 5-6 membered heteroaryl group, the 5-6 membered heteroaryl group may be further substituted by one or more (for example, 1-3, 1-2) C 1 -C 5 alkyl groups, the heteroaryl group may be The group contains 1-2 heteroatoms selected from N, O or S (for example, R 3 and R 4 are independently selected from hydrogen, Or a 5-membered heteroaryl group, the 5-membered heteroaryl group may be further substituted by 1-2 C 1 -C 3 alkyl groups, the heteroaryl
  • this application provides a compound with the structure shown in Formula III, its stereoisomer or its pharmaceutically acceptable salt,
  • R 2 is selected from fluorine, chlorine, cyano, oxo, hydroxyl, methyl, ethyl or isopropyl;
  • R 3 and R 4 are independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Phenyl or 5-6 membered heteroaryl, the 5-6 membered heteroaryl may be further substituted by one or more C 1 -C 3 alkyl;
  • n is selected from 0, 1 or 2.
  • R 1 , R 2 , R 3 , R 4 and m are the same as the relevant definitions in various embodiments for the compound of the structure shown in Formula I above. same.
  • R 2 is selected from methyl, ethyl or isopropyl (such as methyl);
  • R 3 and R 4 are each independently selected from hydrogen, Or a 5-6 membered heteroaryl group, the 5-6 membered heteroaryl group may be further substituted by one or more (for example, 1-3, 1-2) C 1 -C 5 alkyl groups, the heteroaryl group may be The group contains 1-2 heteroatoms selected from N, O or S (for example, R 3 and R 4 are independently selected from hydrogen, Or a 5-membered heteroaryl group, the 5-membered heteroaryl group may be further substituted by 1-2 C 1 -C 3 alkyl groups, the heteroaryl group contains 1-2 heteroatoms selected from N or O); m is selected from 0, 1 or 2 (eg 0).
  • the application provides a compound of the structure shown in Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein
  • Ring A is selected from 5-7 membered cycloalkyl or 5-7 membered heterocycloalkyl, wherein the heterocycloalkyl contains 1-2 heteroatoms selected from N or O; preferably, Ring A is a ring Hexyl, pyrrolidinyl, piperidyl or azepanyl (preferably piperidyl);
  • X 1 is CH or N, preferably CH;
  • R 1 is selected from hydrogen, fluorine, chlorine, bromine, C 1 -C 4 alkyl (such as methyl, ethyl, propyl or butyl), C 3 -C 5 cycloalkyl (such as cyclopropyl, cyclobutyl or cyclopentyl), or
  • R 3 and R 4 are independently selected from hydrogen, C 1 -C 5 alkylcarbonyl (such as C 1 -C 4 alkylcarbonyl, C 1 -C 3 alkylcarbonyl), C 1 -C 5 alkoxycarbonyl ( For example, C 1 -C 4 alkoxycarbonyl, C 1 -C 3 alkoxycarbonyl), or 5-7 membered heteroaryl, the 5-7 membered heteroaryl is unsubstituted or substituted by one or more (for example, 1-3, 1-2) substituents, the substituents are C 1 -C 5 alkyl (for example, C 1 -C 4 alkyl, C 1 -C 3 alkyl), and the hetero
  • the aryl group contains 1-2 heteroatoms selected from N, O or S;
  • R 2 is selected from halogen, hydroxyl, amino or C 1 -C 3 alkyl, and m is 0, 1 or 2 (eg m is 0).
  • the application provides a compound of the structure shown in Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein
  • Ring A is selected from 5-7 membered heterocycloalkyl, wherein the heterocycloalkyl contains 1-2 heteroatoms selected from N or O; preferably, Ring A is pyrrolidinyl, piperidinyl or nitrogen Heterocycloheptyl (preferably piperidyl);
  • X 1 is CH or N, preferably CH;
  • R 1 is selected from hydrogen, fluorine, chlorine, bromine, C 1 -C 4 alkyl (such as methyl, ethyl, propyl or butyl), C 3 -C 5 cycloalkyl (such as cyclopropyl, cyclobutyl base or cyclopentyl), or
  • R 3 and R 4 are each independently selected from hydrogen, C 1 -C 5 alkoxycarbonyl (such as C 1 -C 4 alkoxycarbonyl, C 1 -C 3 alkoxycarbonyl), or 5-7 membered heteroaryl base, the 5-7-membered heteroaryl group is unsubstituted or substituted by one or more (such as 1-3, 1-2) substituents, and the substituents are C 1 -C 5 alkyl ( For example, C 1 -C 4 alkyl, C 1 -C 3 alkyl), the heteroaryl group contains 1-2 heteroatoms selected from N, O or S;
  • the application provides a compound of the structure shown in Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein
  • Ring A is selected from 5-7 membered heterocycloalkyl, wherein the heterocycloalkyl contains 1-2 heteroatoms selected from N or O; preferably, Ring A is pyrrolidinyl, piperidinyl or nitrogen Heterocycloheptyl (preferably piperidyl);
  • X 1 is CH or N, preferably CH;
  • R 1 is selected from hydrogen, fluorine, chlorine, bromine, C 1 -C 4 alkyl (such as methyl, ethyl, propyl or butyl), or
  • R 3 and R 4 are each independently selected from hydrogen, C 1 -C 5 alkoxycarbonyl (such as C 1 -C 4 alkoxycarbonyl, C 1 -C 3 alkoxycarbonyl), or 5-7 membered heteroaryl base, the 5-7-membered heteroaryl group is unsubstituted or substituted by one or more (such as 1-3, 1-2) substituents, and the substituents are C 1 -C 5 alkyl ( For example, C 1 -C 4 alkyl, C 1 -C 3 alkyl), the heteroaryl group contains 1-2 heteroatoms selected from N, O or S;
  • the present application provides a compound with the structure shown in Formula I, its stereoisomer or a pharmaceutically acceptable salt thereof, and the compound is selected from:
  • Another aspect of the present application provides a method for preparing a compound of the structure shown in Formula I above, including:
  • LG represents a leaving group
  • PG represents a protecting group
  • R 1 , R 2 , X 1 , ring A, and m are as described above for the compound with the structure shown in formula I.
  • the leaving group selects a halogen atom, methanesulfonyloxy group or p-toluenesulfonyloxy group
  • the protecting group selects 2-(trimethylsilyl)ethoxymethyl or tert-butyl Oxycarbonyl;
  • the reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent can be selected from tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile and any combination thereof, preferably N,N -dimethylformamide.
  • the reaction is preferably carried out in the presence of a suitable base.
  • the base can be selected from the group consisting of triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine, potassium carbonate, cesium carbonate, and sodium carbonate, with diisopropylethylamine being preferred.
  • the reaction is preferably carried out at a suitable temperature, preferably 100-150°C.
  • the reaction is preferably carried out for a suitable time, for example 8-12 hours.
  • the reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent may be selected from tetrahydrofuran, 1,4-dioxane, toluene, acetonitrile, ethanol, water and any combination thereof, preferably a combination of 1,4-dioxane and water.
  • the reaction is preferably carried out in the presence of a suitable catalyst.
  • the catalyst can be selected from Pd(dppf)Cl 2 , Pd(OAc) 2 , Pd 2 (dba) 3 , Pd(PPh 3 ) 4 , preferably Pd(dppf)Cl 2 .
  • the reaction is preferably carried out in the presence of a suitable base.
  • the base can be selected from the group consisting of triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine, potassium carbonate, cesium carbonate, and sodium carbonate, with potassium carbonate being preferred.
  • the reaction is preferably carried out at a suitable temperature, preferably 80-120°C.
  • the reaction is preferably carried out for a suitable time, for example 8-12 hours.
  • the reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent may be selected from tetrahydrofuran, 1,4-dioxane, dichloromethane, and ethyl acetate, with dichloromethane being preferred.
  • the reaction is preferably carried out in the presence of a suitable acid.
  • the acid may be selected from hydrochloric acid, trifluoroacetic acid, preferably trifluoroacetic acid.
  • the reaction is preferably carried out at a suitable temperature, preferably 20-50°C.
  • the reaction is preferably carried out for a suitable time, for example 4-6 hours.
  • the present application also relates to a pharmaceutical composition, comprising the above-mentioned compound of formula I, its stereoisomer or its pharmaceutically acceptable salt, and pharmaceutically acceptable excipients.
  • the present application also relates to a pharmaceutical composition, comprising the above-mentioned compound of formula II, its stereoisomer or its pharmaceutically acceptable salt, and pharmaceutically acceptable excipients.
  • the present application also relates to a pharmaceutical composition, comprising the above-mentioned compound of formula III, its stereoisomer or its pharmaceutically acceptable salt, and pharmaceutically acceptable excipients.
  • the present application also relates to the use of the above-mentioned compound of formula I, its stereoisomer or its pharmaceutically acceptable salt, or the above-mentioned pharmaceutical composition in the preparation of medicaments for preventing or treating CDK7-mediated diseases or conditions.
  • the present application also relates to a compound of formula I, its stereoisomer or a pharmaceutically acceptable salt thereof, or the above pharmaceutical composition for preventing or treating CDK7-mediated diseases or disorders.
  • the present application also relates to a method for preventing or treating CDK7-mediated diseases or conditions, comprising administering the above-mentioned compound of formula I, its stereoisomer or a pharmaceutically acceptable salt thereof to a subject in need thereof, or The above pharmaceutical composition.
  • the subject may be a mammal, such as a human, a monkey, a cat, a dog, a pig, a sheep, a cow, a horse, a rabbit, a mouse, etc.
  • the CDK7-mediated diseases or conditions refer to those diseases or conditions in which a desired clinical benefit can be obtained by inhibiting CDK7.
  • the CDK7-mediated disease or disorder is selected from a tumor or cancer, such as breast cancer, pancreatic cancer, ovarian cancer, colorectal cancer, lung cancer, prostate cancer, lymphoma, malignant sarcoma, cervical cancer, Oral cancer, brain cancer, stomach cancer, liver cancer, skin cancer, bone cancer, kidney cancer, bladder cancer, fallopian tube tumors, peritoneal tumors, melanoma, glioma, glioblastoma, papillary malignant tumors, head and neck tumors, myeloma, or leukemia.
  • a tumor or cancer such as breast cancer, pancreatic cancer, ovarian cancer, colorectal cancer, lung cancer, prostate cancer, lymphoma, malignant sarcoma, cervical cancer, Oral cancer, brain cancer, stomach cancer, liver cancer, skin cancer, bone cancer, kidney cancer, bladder cancer
  • the present application also relates to the use of the above-mentioned compound of formula I, its stereoisomer or its pharmaceutically acceptable salt, or the above-mentioned pharmaceutical composition in the preparation of CDK7 inhibitors.
  • this application also relates to the above-mentioned compound of formula I used as a CDK7 inhibitor, its stereoisomer or its pharmaceutically acceptable salt, or the above-mentioned pharmaceutical composition.
  • the present application also relates to a method for inhibiting CDK7, comprising administering the above-mentioned compound of formula I, its stereoisomer or its pharmaceutically acceptable salt, or the above-mentioned pharmaceutical composition to a subject in need.
  • This application has discovered a new type of CDK7 inhibitor with a structure as shown in Formula I, which has good CDK7 inhibitory activity and can exhibit the desired anti-tumor effect.
  • hydrocarbyl refers to a group consisting only of two atoms, carbon atoms and hydrogen atoms, including saturated hydrocarbon groups (also known as alkyl groups) and unsaturated hydrocarbon groups, such as alkenes and alkynes.
  • cycloalkyl refers to a cyclic group consisting only of carbon atoms and hydrogen atoms, including saturated cycloalkyl (also known as cycloalkyl) and unsaturated cycloalkyl, such as Cyclic hydrocarbon groups containing carbon-carbon double bonds, etc.
  • heterocyclic hydrocarbon group refers to a group that, in addition to carbon atoms and hydrogen atoms, also contains nitrogen atoms, oxygen atoms, sulfur atoms and other heterocyclic atoms participating in ring formation, including saturated heterocyclic rings Hydrocarbon groups (also known as heterocycloalkyl groups) and unsaturated heterocyclic hydrocarbon groups, such as heterocyclic hydrocarbon groups containing carbon-carbon double bonds, etc.
  • alkyl refers to a saturated hydrocarbon group consisting only of carbon atoms and hydrogen atoms. The carbon-carbon and carbon-hydrogen atoms are connected by single bonds.
  • the alkyl group can be a straight chain or branched chain. Representative branched alkyl groups have one, two or three branches. Alkyl groups may be optionally substituted with one or more substituents as defined herein.
  • Alkyl groups include, but are not limited to, methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl and tert-butyl), pentyl (n-pentyl, isopentyl and neopentyl) and hexyl.
  • the alkyl group can also be part of other groups, and the other groups can be (C 1 to C 6 alkyl)-O-, etc.
  • cycloalkyl refers to a carbocyclic ring that is fully saturated and may exist as a monocyclic, bridged or spirocyclic ring.
  • a cycloalkyl group herein may be a C 3 -C 8 cycloalkyl group, such as a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring or an 8-membered ring.
  • Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • heterocycloalkyl refers to a saturated ring or a non-aromatic partially saturated ring having a single ring or multiple rings (fused, bridged, spiro) containing at least one heteroatom.
  • Ring; heteroatoms refer to nitrogen atoms, oxygen atoms, sulfur atoms, etc.
  • aromatic ring refers to an aromatic hydrocarbon group having multiple carbon atoms.
  • Aryl groups are usually monocyclic, bicyclic or tricyclic aryl groups having multiple carbon atoms.
  • aryl refers to an aromatic substituent that may be a single aromatic ring or multiple aromatic rings fused together.
  • aromatic heterocycle refers to an aromatic unsaturated ring containing at least one heteroatom, where the heteroatom refers to a nitrogen atom, an oxygen atom, a sulfur atom, etc.; usually refers to a ring containing multiple ring atoms.
  • Aromatic monocyclic or bicyclic hydrocarbons in which one or more ring atoms are substituted by heteroatoms selected from O, N, and S. Preferably one to three heteroatoms are included.
  • heterocyclic aryl groups include: pyridyl, indolyl, quinoxalinyl, quinolyl, isoquinolinyl, benzothienyl, benzofuranyl, benzothienyl, benzopyranyl , benzothiopyranyl, furyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thienyl, oxadiazolyl, benzene Imidazolyl, benzothiazolyl, benzoxazolyl, etc.
  • unsaturated means that the group or molecule contains carbon-carbon double bonds, carbon-nitrogen double bonds, etc.
  • alkoxy refers to -O-alkyl unless otherwise stated.
  • halogen refers to fluorine, chlorine, bromine or iodine unless otherwise stated.
  • cycloalkyloxy refers to cycloalkyl-O-.
  • substituted or unsubstituted amino encompasses unsubstituted amino or amino substituted with a group selected from: C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, or halogenated C 3 -C 8 cycloalkyl.
  • Cm - Cn is used to mean that there are mn carbon atoms in the moiety modified by this term (n is greater than m, and both are integers).
  • C 1 -C 6 represents 1-6 carbon atoms in the modified moiety, such as 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbons atom.
  • mn-membered (hetero)cycloalkyl refers to the total number of mn carbon atoms and heteroatoms participating in the ring formation in the moiety modified by this term.
  • the heteroatoms may be nitrogen. atoms, sulfur atoms, oxygen atoms, etc. (n is greater than m, and both are integers).
  • a 4-8-membered cyclic olefin means that the modified ring structure has 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms or 8 carbon atoms;
  • a 4-10-membered heterocyclic hydrocarbon group means The total number of carbon atoms and heteroatoms contained in the modified ring structure is 4, 5, 6, 7, 8, 9 Or 10.
  • the structure of the compound can be determined by mass spectrometry (MS) or nuclear magnetic resonance ( 1 H NMR).
  • the hydrogen nuclear magnetic resonance spectrum ( 1 H NMR) shift ( ⁇ ) is given in units of parts per million (ppm); the nuclear magnetic resonance ( 1 H NMR) was measured using a Bruker AVANCE-400 nuclear magnetic instrument, and the solvent was deuterated.
  • Methyl sulfoxide (DMSO-d 6 ) the internal standard is tetramethylsilane (TMS), and chemical shifts are given in units of 10 -6 (ppm).
  • Mass spectrometry was measured using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Therm, model: Finnigan LCQ advantage MAX).
  • the thin layer of silica gel uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel sheet.
  • nitrogen atmosphere in this application refers to, for example, connecting the reaction bottle to a 1 L nitrogen balloon.
  • hydrogen atmosphere in this application refers to, for example, connecting the reaction bottle to a 1 L hydrogen balloon.
  • the solution mentioned in the reaction in this application is an aqueous solution.
  • room temperature in this application refers to a temperature between 10°C and 25°C.
  • Step 1 (S)-3-(2-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-6
  • Step 1 (S)-3-(2-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-6
  • Step 1 (S)-3-(2-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-6
  • Step 1 (S)-3-(2-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-6
  • Step 2 (S)-3,5-dimethyl-N-(3-(2-(piperidin-3-amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H - Preparation of pyrrolo[2,3-b]pyridin-6-yl)isoxazole-4-amine (3)
  • Step 1 (S)-3-(2-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-6
  • (S)-3-(2-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-6 Preparation of -Methyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (5a)
  • Step 2 (S)-4-(6-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-(piperidin-3-yl)-5-(trifluoro Preparation of methyl)pyrimidin-2-amine (5)
  • Test Example 1 HCC70 cell proliferation inhibitory activity test
  • the CCK-8 method was used to test the cell activity and calculate the IC 50 .
  • ICEC-0942 purchased from Shanghai Tebo Chemical Technology Co., Ltd., batch number 2110809;
  • Test drug Each compound was prepared by the examples of this application.
  • Compound 10mM stock solution preparation Dissolve the compound powder in 100% DMSO and prepare a 10mM compound stock solution.
  • the seeded cells were cultured overnight in a CO2 constant temperature incubator at 37°C.
  • Test Example 2 MDA-MB-231 cell proliferation inhibitory activity test
  • ICEC-0942 purchased from Shanghai Tebo Chemical Technology Co., Ltd., batch number 2110809;
  • Test drug Each compound was prepared by the examples of this application.
  • Compound 10mM stock solution preparation Dissolve the compound powder in 100% DMSO and prepare a 10mM compound stock solution.
  • the seeded cells were cultured overnight in a CO2 constant temperature incubator at 37°C.
  • This test reflects the kinase activity by detecting the amount of ADP generated by the kinase reaction, and uses a three-step method to detect the inhibitory activity of the compound on CDK7 enzyme.
  • the first step is to incubate CDK7/CyclinH1/MNAT1, different concentrations of compounds, substrate (MBP), and ATP at room temperature for a fixed time.
  • ADPglo detection reagent is added to terminate the enzymatic reaction, and incubation at room temperature is continued for a fixed time.
  • the third step is to add Kinase Detection Reagent, incubate at room temperature for a fixed time and then read.
  • Use the BMG microplate reader Lumi module for continuous reading to evaluate the impact of the test compound on CDK7 enzyme activity, and use the inhibition rate to calculate the IC 50 value of the test compound on CDK7 enzyme.
  • ICEC-0942 purchased from Shanghai Tebo Chemical Technology Co., Ltd., batch number 2110809;
  • Test drug Each compound was prepared from the examples of this application.
  • Compound 10mM stock solution preparation Dissolve the compound powder in 100% DMSO and prepare a 10mM compound stock solution.
  • the CDK7 enzyme inhibitory activity of the compounds of the present application is shown in Table 1.
  • SD rats were used as test animals, and the LC-MS/MS method was used to measure the plasma drug concentrations in the plasma of the rats at different times after they were administered the compound of the present application by gavage. Study the pharmacokinetic behavior of the compound of the present application in rats and evaluate its pharmacokinetic characteristics.
  • ICEC-0942 purchased from Shanghai Tebo Chemical Technology Co., Ltd., batch number 2110809;
  • Test drug Each compound was prepared by the examples of this application.
  • SD rats Male, weight 180-220g, 3 rats in each group. After the animals are purchased, they are raised in the animal room with an adaptation period of at least 3 days. They will be used for experiments after passing the quarantine.
  • test drugs were administered to each group by gavage. Before administration and 15min, 30min, 1h, 2h, 4h, 6h, 8h, and 24h after administration, 200 ⁇ L of blood was collected through the orbit and placed in EDTA-K2 for anticoagulation. tube, centrifuge at 5000 rpm for 10 min, separate the plasma into a centrifuge tube, and freeze in a -80°C refrigerator.
  • Non-compartmental model fitting was performed on the pharmacokinetic behavior of the test compound, and the main pharmacokinetic parameters (T 1/2 , T max , C max , AUC last , etc.) were calculated using DAS3.31 software.
  • Test Example 5 In vivo drug efficacy test in HCC70 cell subcutaneous xenograft tumor model
  • Test drug compound 5;
  • mice Female, 6-8 weeks old, weighing about 18-22 grams, each mouse was subcutaneously inoculated with 0.1mL (1 ⁇ 10 7 cells + Matrigel) HCC70 cells on the right side.
  • the drugs will be administered in groups.
  • the administration terminated, the mice in each group were sacrificed, and the tumor blocks were dissected.
  • the tumor weight and tumor volume of each mouse were weighed and compared with the positive group (ICEC- 0942 and SY5609), the test compound group (compound 5) and the vehicle group.
  • the tumor inhibitory effect of the compound was evaluated by TGI (%), which can reflect the tumor growth inhibition rate.
  • TGI (%) [1-(Average tumor volume at the time of the compound - Average tumor volume at the beginning of the compound)/(Average tumor volume at the time of the vehicle group - Average tumor volume at the beginning of the vehicle group)] ⁇ 100%
  • the compound of the present application exhibits good in vivo efficacy in the breast cancer HCC70 cell subcutaneous xenograft tumor model, has a significant anti-tumor effect (TGI>60%), and the anti-tumor effect is better than the compounds under clinical development ICEC-0942 and SY5609, and the test animals tolerated the compounds well, and the body weight of the mice did not decrease after administration. Therefore, the compounds of the present application can exhibit good anti-tumor effects in vivo.

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Abstract

La présente invention concerne un composé représenté par la formule (I), un stéréoisomère de celui-ci ou un sel pharmaceutiquement acceptable associé, et une composition pharmaceutique le comprenant. Le composé, le stéréoisomère du composé ou le sel pharmaceutiquement acceptable associé dans la présente invention sont des inhibiteurs de CDK7 efficaces et spécifiques, et peuvent être utilisés pour traiter des maladies associées à une tumeur maligne.
PCT/CN2023/104681 2022-07-08 2023-06-30 Dérivé de pyrimidine, son procédé de préparation et son utilisation WO2024007985A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110036004A (zh) * 2016-07-13 2019-07-19 希洛斯医药品股份有限公司 细胞周期蛋白依赖性激酶7(cdk7)的抑制剂
WO2019143719A1 (fr) * 2018-01-16 2019-07-25 Syros Pharmaceuticals, Inc. Inhibiteurs de la kinase cycline-dépendante 7 (cdk7)
WO2022134641A1 (fr) * 2020-12-24 2022-06-30 湃隆生物科技有限公司（香港） Composé hétérocyclique aromatique, composition pharmaceutique et utilisation de celui-ci

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110036004A (zh) * 2016-07-13 2019-07-19 希洛斯医药品股份有限公司 细胞周期蛋白依赖性激酶7(cdk7)的抑制剂
WO2019143719A1 (fr) * 2018-01-16 2019-07-25 Syros Pharmaceuticals, Inc. Inhibiteurs de la kinase cycline-dépendante 7 (cdk7)
WO2022134641A1 (fr) * 2020-12-24 2022-06-30 湃隆生物科技有限公司（香港） Composé hétérocyclique aromatique, composition pharmaceutique et utilisation de celui-ci

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